（2025.V3）NCCN临床实践指南：造血细胞移植

指南外科· 器官移植 · 2025

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation

*Alison W. Loren, MD, MSCSE/Chair$\underset{\cdot}{\xi}$ Abramson Cancer Center at the University of Pennsylvania

*Marco Mielcarek, MD, PhD/Vice-Chair $\ddagger$ Fred Hutchinson Cancer Center

Mathew Angelos, MD, PhD $\ddagger$ University of Colorado Cancer Center

Javier Bolános-Meade, MD $\xi$ $ \xi$ Johns Hopkins Kimmel Cancer Center

Jonathan Brammer, MD $\ddagger$The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute

Meredith Cowden, MA¥

Antonio Di Stasi,MD P$\_$ O'Neal Comprehensive Cancer Center at UAB

Areej El-Jawahri, MD t $\xi$ Mass General Cancer Center

Hany Elmariah, MD, MS $\xi$ $ \ $ Moffitt Cancer Center

Krishna Gundabolu,MBBS,MS $\ddagger$ Fred & Pamela Buffet Cancer Center

Jonathan Gutman, MD $t$ University of Colorado Cancer Center

Vincent Ho, MD $\varnothing$ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $

Rasmus T. Hoeg, MD $\xi$ $\xi$ UC Davis Comprehensive Cancer Center

Mitchell Horwitz, MD Duke Cancer Institute

Omer Jamy, MD †ONeal Comprehensive Cancer Center at UAB

Adetola Kassim, MD, MS ÷ξ Vanderbilt-Ingram Cancer Center

Mohamed Karhan Dabaja, MD≠

Lauren Lee, MD $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$ $\xi$

Aaron Logan,MD,PhD,MPhil $\ddagger$ UCSF Helen Diller Family Comprehensive Cancer Center

Christina Luszczak, PharmD, BCOP ∑Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

John M. Magenau, MD $\ddagger$ University of Michigan Roger Cancer Center

Thomas G. Martin, MD $\ddagger$ UCSF Helen Diller Family Comprehensive Cancer Center

Varun Mittal, MD

Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Jonathan Moreira,MD $\ddagger$ Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Lori Muffy,MD $\_$

Rytoraro Nakamura, MD C City of Hope National Medical Center

Marian Nawas,MD $\ddagger$ <The UChicago Medicine Comprehensive Cancer Center

Yago Nieto, MD, PhD $\ddagger$ The University of Texas MD Anderson Cancer Center

Cameron Ninos, PharmD≠∑ University of Wisconsin Carbone Cancer Center

Caspian Oliai, MD †UCLA Jonsson Comprehensive Cancer Center

Genovefa Papanicolaou, MD $\Phi$ Memorial Sloan Kettering Cancer Center

Joseph Pidal, MD, PhD †Moffitt Cancer Center

Brion Randolph,MD $\xi$

St.Jude Children's Research Hospital/The University of Tennessee Health Science Center

Grant Schofield, MD,MSc T Roswell Park Comprehensive Cancer Center

Mark A. Schroeder, MD $\ddagger$ Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Jeffrey Tessier, MD ξUT Southwestern Simmons Comprehensive Cancer Center

Jeffrey Topal, MD Σ θ P.Jexlerr Tazachanis MD θ

Dimitrios Tzachanis MD, PhD $\ddagger$

Asya Nina varshavsky-Yanovsky, MD PhD ⚞ Fox Chase Cancer Center

NCCN Frankie Jones Katie Stehman,MMS,PA-C

|三Critical care medicine/ Pulmonary medicine ＵHematology �s Hematology|p Internal medicine ／ Medical oncology ［ Patient advocacy| |---|---| |○ Hematopoietic cell|∑ Pharmacology * Discussion Section| |transplantation|Writing Committee|

NCCN Guidelines Version 3.2025

Hematopoietic Cell Transplantation

Version 3.2025, 09/24/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may

NCCN Guidelines Index Table of Contents Discussion

Find an NCCN Member Institution:

https://www.nccn.org/home/memberinstitutions.

NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered appropriate.

See NCCN Categories of Preference.

NCCN Panel Members

Summary of the Guidelines Updates

Introduction (INTRO)

Indications for Transplantation (HCT-1)

Pre-Transplant Recipient Evaluation (HCT-2)

Hematopoietic Cell Mobilization (HCT-4)

Hematopoietic Cell Mobilization Regimens (HCT-4A)

Conditioning for Hematopoietic Cell Transplant (HCT-5)

Principles of Conditioning for Hematopoietic Cell Transplant (HCT-A)Diagnosis/Workup of Graft-Versus-Host Disease (GVHD-1)

Management of Acute GVHD (GVHD-2)

Management of Chronic GVHD (GVHD-4)

Acute GVHD: Staging and Grading (GVHD-A)

Chronic GVHD: Diagnosis (GVHD-B)

Chronic GVHD: Grading (GVHD-C)

GVHD Steroid Response Definitions/Criteria (GVHD-D)

Suggested Systemic Agents for Steroid-Refractory GVHD (GVHD-E)GVHD Supportive Care (GVHD-F)

Abbreviations (ABBR-1)

NCCN Guidelines Version 3.2025

Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Updates in Version 3.2025 of the NCCN Guidelines for Hematopoietic Cell Transplantation from Version 2.2025 include:

Continued

MS-1

• The Discussion section has been updated.

Updates in Version 2.2025 of the NCCN Guidelines for Hematopoietic Cell Transplantation from Version 1.2025 include:MS-1

• The Discussion section has been updated to reflect the changes in the algorithm.

NCCN Guidelines Version 3.2025

Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Updates in Version 1.2025 of the NCCN Guidelines for Hematopoietic Cell Transplantation from Version 2.2024 include:

Continued

HCT-4A

• Hematopoietic Cell Mobilization Regimens Autologous Donors

◊ Cyclophosphamide dosing language modified for the following regimens: Filgrastim + cyclophosphamide ± plerixafor and sargramostim +cyclophosphamide ± plerixafor

– Cyclophosphamide 1500–3000 mg/m2 IV for one dose

Footnote r added: An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

Footnote removed: An FDA-approved biosimilar is an appropriate substitute for pegfilgrastim.

HCT-5

• Post-Transplant Follow-Up

List of post-transplant complications has been revised.

◊ Bullets modified:

– Graft-versus-host disease (GVHD) (for allogeneic transplant), infections and

– Monitoring for disease relapse is recommended for all patients who have undergone HCT.

◊ Bullets added:

– Infections (See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections)

– Multi-organ dysfunction

▪ Footnote w added: Potential post-transplant organ toxicities are too numerous to list but can include cardiac, pulmonary, renal, and/or liver

complications. Hepatic VOD/SOS is one potentially life-threatening complication. Defibrotide is FDA approved for the treatment of hepatic VOD/SOS in patients with renal or pulmonary dysfunction following HCT based on non-randomized trials. See defibrotide prescribing information for further details.

◊ Footnote removed and added to algorithm bullet: NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

HCT-A 1 of 10

• Principles of Conditioning for Hematopoietic Cell Transplant

Non-myeloablative (NMA) conditioning regimen, examples removed to simplify list of examples provided:

◊ Fludarabine + cyclophosphamide ± antithymocyte globulin (ATG)

◊ Fludarabine + cytarabine + idarubicin

◊ Cladribine + cytarabine

HCT-A 3 of 10

• MA Regimens: Allogeneic Transplant

Fludarabine + treosulfan added as a category 2A recommendation with the following regimen/dosing:

◊ Treosulfan-based

– Fludarabine 30 mg/m2/day for 5 days

– Treosulfan 10 g/m2/day for 3 days

HCT-A 7 of 10

• Suggested Doses/Modifications by Weight

Treosulfan added to table:

◊ Treosulfan: Dose adults and children on BSA based on total body weight

NCCN Guidelines Version 3.2025

Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Updates in Version 1.2025 of the NCCN Guidelines for Hematopoietic Cell Transplantation from Version 2.2024 include:HCT-A 8 of 10

• References have been updated.

GVHD-4

• Management of Chronic GVHD First-Line Therapy

◊ Treatment option added: Sirolimus + prednisone

– Footnote s added with reference: Carpenter PA, et al. Haematologica 2018;103:1915-1924.

◊ ± changed to + for the following treatment options: Inhaled steroid + azithromycin + montelukast for lung involvement (eg, FAM [fluticasone,

azithromycin, and montelukast])

GVHD-E 1 of 3

• Suggested Systemic Agents for Steroid-Refractory GVHD

Acute and chronic GVHD headers modified:

◊ FDA-approved category 1 agents

◊ Other FDA-approved agents (listed in order by FDA approval date)

Acute GVHD: Alternative agents (listed in alphabetical order)

◊ Agent added: Urinary-derived human chorionic gonadotropin/epidermal growth factor (uhCG/EGF)

Footnote b added An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

Footnote removed: An FDA-approved biosimilar is an appropriate substitute.

GVHD-E 2 of 3

• References have been updated.

GVHD-F 1 of 2

• GVHD Supportive Care

Chronic GVHD

◊ Bullet 1, sub-bullet 3 modified: Consider dexamethasone or CNI mouth rinses (swish and spit).

NCCN Guidelines Version 3.2025

Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

INTRO

INTRODUCTION

The NCCN Guidelines for Hematopoietic Cell

Transplantation (HCT) pertain to the care of adult patients undergoing HCT for malignant diseases.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

INDICATIONS FOR TRANSPLANTATION

Indications for HCT vary by disease.Indications for HCT can be found in the following NCCN Guidelines:

●NCCN Guidelines for Acute Lymphoblastic Leukemia

●NCCN Guidelines for Acute Myeloid Leukemia

●NCCN Guidelines for B-Cell Lymphomas

●NCCN Guidelines for Central Nervous System Cancers

●NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

·NCCN Guidelines for Chronic Myeloid Leukemia

●NCCN Guidelines for Gestational Trophoblastic Neoplasia

●NCCN Guidelines for Hodgkin Lymphoma

●NCCN Guidelines for Multiple Myeloma

●NCCN Guidelines for Myelodysplastic Syndromes

·NCCN Guidelines for Myeloproliferative Neoplasms(MPN)

●NCCN Guidelines for Primary Cutaneous Lymphomas

●NCCN Guidelines for Systemic Light Chain Amyloidosis

●NCCN Guidelines for Systemic Mastocytosis(SM)

●NCCN Guidelines for T-Cell Lymphomas

●NCCN Guidelines for Testicular Cancer

●NCCN Guidelines for Waldenström Macroglobulinemia/Lymphoplasmacytlic Lymphoma

Pre-Transplant Recipient Evaluation (HCT-2)and Hematopoietic Cell Mobilization (HCT-4)

Note: All recommendations are category 2A unless otherwise indicated.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

PRE-TRANSLANT RECIPIENT EVALUATIONa,b

•Clinical Assessment:

▶ Confirm histologic diagnosis

History & physical exam, including evaluation of performance status (Eastern Cooperative Oncology Group [ECOG] or Karnofsky Performance Scale [KPS]) and body mass index

Assess disease status$^{c}$ (including cytogenetic/molecular testing for risk stratification and assessment of minimal residual disease, if applicable)

Bone marrow aspiration& biopsy'd to confirm remission status(as indicated by underlying disease: pathology, flow cytometry,cytogenetics, molecular studies) and rule out other diseases

●Pulmonary function tests(PFTs) including spirometry, lung volumes, and diffusing capacity of the lungs for carbon monoxide(DLCO)e,f

Electrocardiogram (with QTc interval assessment)

Measure left ventricular ejection fraction(LVEF)9 with echocardiogram(if valvular assessment required) or multigated acquisition scan

Psychosocial evaluation

HCT Comorbidity Index(HCT-CI) ${ }^{i}$ score (for allogeneic HCT)

●Imaging:

Disease-specific restaging studies (NCCN Guidelines for Treatment by Cancer Type)

Chest x-ray (if no other chest imaging done)

●Laboratory Tests:

Complete blood count with differential

ABO/Rh typing

Chemistry profile (including blood glucose, creatinine/estimated glomerular filtration rate,'electrolytes, and liver function tests [LFTs] [transaminases and bilirubin])^{k,l}

Prothrombin time/partial thromboplastin time Urinalysis

Infectious disease testing for cytomegalovirus(CMV),herpes simplex virus(HSV), varicella zoster virus(VZV),hepatitis B virus(HBV), hepatitis C virus(HCV), human immunodeficiency virus(HIV), and syphilis

Human leukocyte antigen(HLA) typing per FACT-JACIE International Standardsb

Toxoplasma serology(for allogeneic HCT)

Donor and recipient short tandem repeat (STR)genotyping to inform post-transplant chimerism analysis(for allogeneic HCT)

a The pre-transplant recipient evaluation generates data to estimate risks of post-transplant complications including non-relapse mortality (NRM). It also generates information that may inform other transplant-related decisions.

b For pre-transplant donor evaluation and HLA typing, refer to: Foundation for the Accreditation of Cellular Therapy and Joint Accreditation Committee- ISCT and EBMT.FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration(8th edition); 2021.

cDisease risk index may be used to predict overall survival based on only disease-related risk factors: http://www.cibmtr.org/ReferenceCenter/Statistical/Tools/Pages/DRI.aspx.

d For acute leukemia, bone marrow biopsy is ideally performed within 4 weeks of starting a conditioning regimen.

e DLCO should be corrected for hemoglobin concentration using the Dinakara method.In patients with significantly reduced DLCO, caution should be exercised when using busulfan or carstmine-based regimens. Coffey DG, et al. Bone Marrow Transplant 2013;48:1253-1256.

f Consider pulmonary consultation and/or arterial blood gas analysis if DLCO<60%.

9 Consider cardiac consultation in patients with compromised LVEF.

hAss medication adherence, high-risk behavior, mood disorders, and caregiver availability to ensure patient adherence to treatment. If needs are identified, ensure referral to psycho-oncology, social work, mental health provider, or addiction psychiatry as appropriate.

The HCT-CI predicts the risk of NRM after transplant more accurately than age and performance status; however, it does not predict the risk of relapse. Detailed explanation of the HCT-CI has been published (Srorr ML. Blood 2013;121:2854-2863). See HCT-CI score calculator: http://hctci.org.

Calcineurin inhibitors (CNIs) are associated with increased risk of renal failure after HCT.

k Cirrhosis (in particular with portal hypertension) is generally considered a contraindication for allogeneic HCT.

l Veno-occlusive disease/sinusoidal obstruction syndrome(VOD/SOS) risk calculator may be used to predict risk of VOD/SOS: http://www.cibmtr.org/ReferenceCenter/Statistical/Tools/Pages/VOD.aspx.

NCCN Guidelines Version 3.2025

Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

PRE-TRANSPLANT RECIPIENT EVALUATIONa,b

ADDITIONAL EVALUATION AS CLINICALLY INDICATED

HCT-3

a The pre-transplant recipient evaluation generates data to estimate risks of post-transplant complications including NRM. It also generates information that may inform other transplant-related decisions.

b For pre-transplant donor evaluation and HLA typing, refer to: Foundation for the Accreditation of Cellular Therapy and Joint Accreditation Committee- ISCT and EBMT.

Note: All recommendations are category 2A unless otherwise indicated.

FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration (8th edition); 2021.

As clinically indicated:

• Additional Clinical Assessment

Lumbar puncture for cerebrospinal fluid analysis

Discuss fertility preservation

Pregnancy test for individuals of childbearing potential

Physical therapy evaluation (strength, flexibility, function)Nutritional evaluation

Consider geriatric assessment for select patients (category 2B)

(See NCCN Guidelines for Older Adult Oncology)

Dental evaluation (for allogeneic HCT)

• Additional Imaging

CT (chest and/or sinuses)

• Additional Laboratory Tests

Epstein-Barr virus testing or other infectious disease testing(if high risk) (eg, tuberculosis, strongyloides, human T-cell

lymphotropic virus types I and II [for allogeneic HCT])

HLA antibody assessment if using HLA-mismatched donor 24-hour urine creatinine clearance (for borderline renal

dysfunction or low muscle mass)

Urine toxicology screen if history of substance use disorder Thyroid-stimulating hormone level

Iron profile (including ferritin level)

Blood lipid panel

Vitamin D level

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

![HEMATOPOIETIC CELL MOBILIZATION MBTREATMENTn,o\nGranulocyte colony-stimulating factor (G-CSF)+ plerixafor or Granulocyte colony-stimulating or clerish for granulocyte-macrophage colony-stimulating or Granulocyte-macrophage colony-stimulating or Granul30 colony-stimulating or Granul30 cells/kg (preferred)^P\nHEMATOPOIETIC CELL MOBILIZATION MBTREATMENTn,o0\nGranulocyte colony-stimulating or Granul30 cells-stimulating or Granul30234 cells/kg (preferred)^P\nStem cell collection with minimum target yield of 2-5x10°CD34 cells/kg (preferred)^P\nCD34 count (preferred)^CD34 cells/kg (preferred)^P\nIf insufficient collection, consider: Increasing G-CSF dose or changing dose schedule or Addition of plerixafor to G-CSF or for G-CSF + mix of plerixafor + Target yield of 2-5x10°CD34 cells/kg (preferred)^P\nChemo-mobilization± Bremmat. FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product, Processing, and Administration (8th edition); 2021. OAlternative chemo-mobilization depends on individual patient, and disease-related factors. Lower yields may be adequate, but>2 x 10° CD34 cells/kg is strongly preferred, with a target of 4-5 x 10° CD34 cells/kg. Stem cell yields <2 x 10° CD34 cells/kg may result in delayed engraftment, while larger cell doses have been associated with a more rapid time to platelet and neutrophil recovery. For bone marrow harvesto g\n CD34 = BHene marrow harvesto g\nConditioning HCT (HCT-5)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure32556b9c31a74f8eb854174ac1a96c4d_0_4.png) m For donor evaluation and follow-up recommendations, refer to: Foundation for the Accreditation of Cellular Therapy and Joint Accreditation Committee- ISCT and EBmatopioetic Cell Mobilization Regimens(HCT-4A).

o Alternative chemo-mobilization regimens with disease-specific activity are also appropriate.

P Adequate stem cell collection depends on individual patient- and disease-related factors. Lower yields may be adequate, but $2 \times 10^{6}$ CD34 cells/kg is strongly preferred, with a target of 4-5 x $10^{6}$ CD34 cells/kg. Stem cell yields <2 x $10^{6}$ CD34 cells/kg may result in delayed engraftment, while larger cell doses have been associated with a more rapid time to platelet and neutrophil recovery.

qFor bone marrow harvest recommendations, refer to the National Marrow Donor Program/Be the Match(https://bethematch.org).

Note:All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025

Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

HEMATOPOIETIC CELL MOBILIZATION REGIMENSr

HCT-4A

Autologous Donors

Filgrastims ± Plerixafor

• Filgrastim: 10 mcg/kg weight SC for 4–5 days

Continued daily until collection goal is met

• Plerixafor: 0.24 mg/kg actual body weight SC (max 40 mg/day) on the day before apheresist

Filgrastims + Cyclophosphamide ± Plerixafor

• Cyclophosphamide: 1500–3000 mg/m2 IV

• Filgrastim: 10 mcg/kg SC

Daily starting 24 hours after cyclophosphamide and continuing until collection goal is met.

Begin apheresis at least 4–5 days after cyclophosphamide administration.u

• Plerixafor: 0.24 mg/kg actual body weight SC (max 40 mg/day) on the day before apheresist

Sargramostim + Cyclophosphamide ± Plerixafor

• Cyclophosphamide: 1500–3000 mg/m2 IV

• Sargramostim: 250 mcg/m2/day SC

IV over 24 hours or SC once daily

Daily starting 24 hours after cyclophosphamide and continuing until collection goal is met.

Begin apheresis at least 4–5 days after cyclophosphamide administration.u

• Plerixafor: 0.24 mg/kg actual body weight SC (max 40 mg/day) on the day before apheresist

Pegfilgrastim + Plerixafor

• Pegfilgrastim: 6 mg SC on day 1

• Upfront plerixafor 0.24 mg/kg actual body weight SC (max 40 mg/day) on day 3 followed by apheresis on day 4

Filgrastims + Motixafortide

• Filgrastim: 10 mcg/kg SC daily x 4 days prior to first dose of motixafortide

• Motixafortide: 1.25 mg/kg actual body weight SC 10–14 hours prior to initiation of apheresis

r An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.s Tbo-filgrastim or an FDA-approved biosimilar is an appropriate substitute for filgrastim.t Plerixafor is generally administered 11 hours prior to stem cell collection. u Consider checking circulating CD34+ cells and initiating apheresis based on institutional guidelines.

Note: All recommendations are category 2A unless otherwise indicated.

Allogeneic Donors Filgrastims

• 10 mcg/kg donor weight SC (or split twice daily)

• Daily for 4–5 days

• Collect on day 4 or 5

NCCN

National Comprehensive Cancer Network

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

CONDITIONING FOR HCT

POST-TRANSLANT FOLLOW-UP

![Conditioning for allogeneic transplant based on disease\nInfusion of hematopoietic cells\nConditioning for autologous transplant based on disease\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figurec735b4d5768642389b89f0974be7cba3_0_7.png) • Monitoring for post-transplant complications such as:

Graft-versus-host disease (GVHD) (for allogeneic transplant)

Infections (See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections)

Multi-organ dysfunction ${}^{\wedge}$

Monitoring for disease relapse is recommended for all patients who have undergone HCT.

●Intensive supportive care is required for all post-transplant recipients until engraftment occurs.

•Allogeneic transplant: If GVHD is suspected, see Diagnosis/ Workup of GVHD(GVHD-1)

NCCN Guidelines Version 3.2025

Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

Definitions of Conditioning Regimen Intensity1

• Myeloablative (MA) conditioning regimen: One that will cause irreversible (or close to irreversible) pancytopenia. Hematopoietic cell support is required to rescue marrow function and prevent aplasia-related death. Examples include:

Total body irradiation (TBI) ≥5 Gy single dose or ≥8 Gy fractionated

Busulfan >8 mg/kg orally (>6.4 mg/kg IV) or busulfan plasma exposure unit equivalenta

• Non-myeloablative (NMA) conditioning regimen: One that will produce minimal cytopenia, and there is no absolute need for hematopoietic cell support. Examples include:

TBI ≤2 Gy ± purine analog

Total lymphoid irradiation + antithymocyte globulin (ATG)

• Reduced-intensity conditioning (RIC) regimen: One that does not fulfill criteria for MA or NMA.

• Indications for HCT vary by disease. Refer to applicable NCCN Guidelines for Treatment by Cancer Type.

a Busulfan plasma exposure unit should be reported as area under the curve (AUC) in mg x h/L. For example, AUC 5000 µM x min is equivalent to 20.5 mg x h/L (McCune JS, et al. Biol Blood Marrow Transplant 2019;25:1890-1897).

HCT-A 1 OF 10

Note: All recommendations are category 2A unless otherwise indicated.

Continued References on HCT-A (8 of 10)

NCCN

National Comprehensive Cancer Network

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSLANT

Allogeneic Conditioning Regimen Selection

●The choice among an MA, NMA, or RIC regimen is a nuanced decision that should be made by the transplant time of patient evaluation or upon review of pre-transplant organ testing,frailty/geriatric assessment, or other evaluation.

●Conditioning regimen intensity depends on:

Patient age (chronologic and physiologic)

Performance status

HCT-Cl and other pertinent comorbiditiesb

▶ Disease type

Remission status (including measurable residual disease)

History of prior HCT

●MA regimens may be preferred for the following disease types,if the patient is young and fitb,2:

●Acute lymphoblastic leukemia(TBI-based regimens preferred)

Acute myeloid leukemia

> Chronic myeloid leukemia

Myelodysplastic syndromes

●RIC/NMA regimens may be preferred for:

Lymphoma (non-Hodgkin lymphoma [NHL] or Hodgkin lymphoma [HL])

> Chronic lymphocytic leukemia

Plasma cell disorders (eg), multiple myeloma, plasma cell leukemia)

Patients who have received a prior autologous HCT

Patients who are older or unfitb

Special Situations

●For patients with significant pulmonary dysfunction, caution is recommended if using high-dose (HD) busulfan, cararmustine, and HD TBI.

●Increased risk of SOS has been associated with the use of:

HD busulfan and HD TBI in patients with significant liver dysfunction.

Dual alkylator-based regimens with pre-transplant inotuzumab or gemtuzumab.

●The combination of sirolimus ${}^{3,4}$ and tacrolimus may be associated with higher risk of SOS and thrombotic microangiopathy, especially if used with MA regimens. ${}^{5-10}$

●Increased risk of GVHD has been associated with patients treated with immune checkpoint inhibitors(pre- or post-HCT) and magamulizumab.

Consider a minimum 8- to 12-week window between these treatments and the start of transplant conditioning if clinically feasible. 7-10

●Thiotepa can be excreted through the skin and requires special skin care. Refer to the package insert.

b The HCT-CI predicts the risk of NRM after transplant more accurately than age and performance status; however, it does not predict the risk of relapse. Detailed explanation of the HCT-CI has been published (Sror ML. Blood 2013;121:2854-2863). See HCT-Cl score calculator: http://hctci.org.

References on HCT-A(8 of 10)

Continued

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF CONDITIONING FOR HEMATOPIETIC CELL TRANSPLANT

Examples of Commonly Used Conditioning Regimens

●This list is not comprehensive. Other options can be considered.

● See Suggested Doses/Modifications by Weight(HCT-A7 of 10)

|MA Regimens|MA Regimens|Busulfan-BasedF| |---|---|---| |Allegeneic Transplant|TBI-Based Cyclophosphamide + TBI1 - Cyclophosphamide 60 mg/kg/day for 2 daysC - TBI 12-13.2 Gy fractionated|Busulfan-Based F Busulfan + Cyclophosphamide9,15 ● Busulfan 3.2 mg/kg/day for 4 days ● Cyclophosphamide 60 mg/kg/day for 2 daysC ●Fludarabine+TBI12 ●Fludarabine+30mg/m2/day for 4 days ●TBI 12-13.2 Gy fractionated ●Fludarabine 30-32 mg/m2/day for 4-5 days| |Umilbolic Cord Blood (UCB)d,e|Fludarabine+TBI1 - TBI 12-22 ●Fludarabine+40mg/m2/day for 2 days; Fludarabine 30 mg/kg/day for 4 days ●TBI 13.2 Gy fractionated|Fludarabine+ Busulfan16 ● Busulfan 3.2 mg/kg/day(12.8 mg/kg total) for 4 days ●Fludarabine 30-32 mg/m2/day for 4-5 days ●Fludarabine+ Busulfan+ Thiotepa17,18 ●Fludarabine 30-40 mg/m2/day for 4 days OR 50 mg/m2/day for 3 days ●Busulfan 3.2 mg/kg/day total for 3-4 days; ●Thiotepa 5 mg/kg/day for 1-2 days ●Clofarabine+ Busulfan19,20 ●Clofarabine 20-40 mg/m2/day for 4-5 days ●Busulfan AUC 4000-5500 (or 3.2 mg/kg/day) for 4 days| |Umbilonic Cord Blood (UCB)d,e|TBI-Based F Busulfan-Based Fludarabine+ Cyclophosphamide + TBI12 ●Fludarabine+ Busulfan+ Thiotepa23 ●Cyclophosphamide 60 mg/kg/day for 2 days ● Busulfan 3.2 mg/kg/day for 3 days ●TBI 13.2 Gy fractionated ●Fludarabine 50 mg/m2/day for 3 days ●TBI 13.2 Gy fractionated||

|NMA Regimens|NMA Regimens|Other| |---|---|---| |Allogeneic Transplant|TBI-Based Fludarabine + TBI24 ●Fludarabine 30 mg/m2/day for 3 days ●TBI 2 Gy|Fludarabine + Cyclophosphamide $\pm$ Rituximab $\pm$ Rituximab 30 mg/m2/day for 3 days $\bullet$ Cyclophosphamide 750 mg/m2/day for 3 days $\bullet$ Rituximab $\pm$ 375 mg/m2 IV for 1 day before transplant; and 1000 mg/m2 IV on days 1,8, and 15 after transplant|

C If using post-transplant cyclophosphamide(PTCy) for GVHD prophylaxis, carefully evaluate cyclophosphamide doses used for conditioning.

d Referral to a center with experience in UCB transplants is strongly recommended.

e If an MA conditioning regimen is planned for a recipient of UCB, omidubicel-onlv has been shown to shorten the time to engraftment and reduce the risk of some infections. Horwitz ME,et al. Blood 2021;138:1429-1440.

f These recommendations are for IV busulfan, which is the preferred route of administration due to more favorable pharmacokinetic and toxicity profiles. Oral busulfan may be considered in select cases but tends to exhibit more pharmacokinetic variability and requires different dosing.

9 Cyclophosphamide/busulfan is different than busulfan/cyclophosphamide(Rezvani AR, et al.Biol Blood Marrow Transplant 2013;19:1033-1039).

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

Examples of Commonly Used Conditioning Regimens

•This list is not comprehensive. Other options can be considered.

● See Suggested Doses/Modifications by Weight (HCT-A 7 of 10)

|RIC Regimens|Fludarabine + Melphalan26 ●Fludarabine + Cyclophosphamide + TBI29 ●Fludarabine 20-36 mg/m2/day for 4-5 days ● Melphalan 100-140 mg/m2 over 1-2 days ● Cyclophosphamide 14.5 mg/kg/day for 2 days ● TBI 2-4 Gy ●Fludarabine + Melphalan + TBI1,30 ● Busulfan 3.2 mg/kg/day IV for 2-3 days OR 25 mg/m2/day for 6 days ● Melphalan 100-140 mg/m2 over 1-2 days ● Busulfan 2.3 mg/kg/day IV for 2-3 days OR 25 mg/m2/day for 6 days ● Melphalan 100-140 mg/m2 over 1-2 days ● TBI 2-4 Gy| |---|---| |Allogeneic Transplant|Fludarabine + Melphalan + Thiotepa31,32 ●Fludarabine 40 mg/m2/day for 4 days ● Melphalan 140 mg/m2 for 1 day ● Thiotepa 10 mg/m2 for 1 day ● Fludarabine+ Busulfan+ Thiotepa17 ● Thiotepa 5 mg/kg/day for 1 day ● Busulfan 130 mg/m2/day IV for 2 days ● Fludarabine 30-40 mg/m2/day for 4 days| |UCBd|Fludarabine + Cyclophosphamide + Tiotepa + TBI33 ● Tiotepa 10 mg/kg/day ● TBI 4 Gy Fludarabine + Cyclophosphamide + TBI34 ● Fludarabine 200 mg/m2 ● Cyclophosphamide 50 mg/kg ● TBI 2 Gy|

d Referral to a center with experience in UCB transplants is strongly recommended.

h See RIC regimens without fludarabine(HCT-A 5 of 10).

If using PTCy for GVHD prophylaxis, carefully evaluate melphalan and TBI doses. Gaballa S, et al. Cancer 2016;122:3316-3326.

j Typically, this is equivalent to 3.2 mg/kg/day.

References on HCT-A(8 of 10)

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PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

Conditioning Regimens Without Fludarabine

●The following is a non-inclusive list of non-fludarabine RIC regimens given the intermittent drug shortage in the United States. However, because of lack of comparative data with fludarabine-based regimens, choice of regimen should be based on institutional preference and experience. See Update on FDA Drug Shortages

● See Suggested Doses/Modifications by Weight(HCT-A 7 of 10)

●Please refer to corresponding published data for GVHD prophylaxis.

|RIC Regimens Without Fludarabine|| |---|---| |Pentostatin-based|●Pentostatin+ busulfan35 ●Pentostatin+ busulfan + cyclophosphamide36 ●Pentostatin+ TBI 4 Gy37| |Clofarabine-basedk|●Clofarabine+ busulfan38,39 ●Clofarabine + melphalan40±thiotepa41 ●Clofarabine + TBI 2 Gy42 ●Clofarabine + cyclophosphamide + TBI 2 Gy43 (with PTCy)| |Cladribine-basedl|●Cladribine+ busulfan +ATG44,45 ●Cladribine + busulfan +TBI 2 Gy46| |Cyclophosphamide-based|Cyclophosphamide + TBI 5.5 Gy47|

kA systemic inflammatory syndrome has been reported with clofarabine use. Concomitant steroid use may mitigate this risk.The use of busulfan±TBI 2 Gy may be associated with risk of engraftment failure.

Note: All recommendations are category 2A unless otherwise indicated.

References on HCT-A(8 of 10)

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PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

Examples of Commonly Used Conditioning Regimens

●This list is not comprehensive.Other options can be considered.

● See Suggested Doses/Modifications by Weight(HCT-A7 of 10)

|Autologous Regimens by Disease Type|| |---|---| |NHL(without central nervous system disease) or HL|●BEAM(carmustine+etoposide+cytarabine +melphalan)48 ●BEAC(carmustine+etoposide+cytarabine + cyclophosphamide)49-51 ●Carmustine + thiotepa52 ● Busulfan + cyclophosphamide + etoposide53 ●TEAMal Nervous System or NHL(with central nervous system disease)| |$$\text{Multiple Myeloma/Plasma Cell}$$ Leukemia|●Melphalan(200 mg/m^{2})56 ●Melphalan(70-140 mg/m^{2} for select patients)m,57-59 ● Melphalan+ busulfan(high risk)60| |Germ Cell Tumors|●Carboplatin +etoposide 61,62| |Acute Promyelocytic Leukemia|●Busulfan + melphalan63-65 ● Cyclophosphamide + TBl65 ● Busulfan + cyclophosphamide65|

m Lower dose melphalan can be considered for amyloidosis, older age, high HCT-CI, low KPS, and chronic kidney disease.

Note:All recommendations are category 2A unless otherwise indicated.

References on HCT-A(8 of 10)

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HCT-A 6 OF 10

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PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT

|Suggested Doses/Modifications by Weight66|| |---|---| |Busulfan|● Adults: mg/kg dosing: dose based on 25% adjusted body weight Body surface area (BSA) dosing: dose based on total body weight ● Pediatrics: dose based on total body weight ● Risk of SOS/VOD is correlated with higher busulfan exposure (higher AUC)| |Carmustine|● Dose adults on BSA ●Total body weight ≤120% ideal body weight: dose based on total body weight ●Total body weight >120% ideal body weight: dose based on 25% adjusted body weight ●Pulmonary toxicity >50% at 600 mg/m2 with multiple agent regimens. Maximum tolerated dose of 1200 mg/m2 as single agent with 9.5% pulmonary toxicity| |Cyclophosphamide|● Cy200 regimen: dose based on the lesser of total body weight or ideal body weight ● Cy120 regimen: dosing can be either ideal body weight or total body weight until >120% ideal body weight, then dose based on 25% adjusted body weight| |Cytarabine|Dose adults and children on BSA based on total body weight| |Etoposide|● Mg/kg dosing: dose based on 25% adjusted body weight ● BSA dosing: dose based on total body weight| |Fludarabine|Dose adults on BSA based on total body weight| |Melphalan|● Dose adults on BSA based on total body weight ●Adjustments for age and renal function are not standardized| |Thiotepa|● Dose adults on BSA if total body weight≤120% ●Total body weight≤120% ideal body weight dose on BSA based on total body weight| |Treosulfan|Dose adults and children on BSA based on total body weight|

n25% adjusted body weight indicates ideal body weight +0.25 (total body weight - ideal body weight); 40% adjusted body weight indicates ideal body weight + 0.4 (total body weight - ideal body weight).

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PRINCIPLES OF CONDITIONING FOR HEMATOPIETIC CELL TRANSPLANT REFERENCES

1Bacigalo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009;15:1628-1633.

2 Scott BL, Pasquini MC, Logan BR, et al. Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol 2017;35:1154-1161.

3 Cutler C, Stevenson K, Kim HT, et al. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood 2008;114:4225-4431.

4 Cutler C, Logan B, Nakamura R,et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood 2014;124:1372-1377.

5 Pidala J, Kim J, Jim H, et al. A randomized phase ll study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation. Haematologica 2012;97:1882-1889.

6 Khimani,Fim J,Chen L,et al. Predictors of overall survival among patients treated with sirolimus/tacrolimus vs methotrexate/tacrolimus for GvHD prevention. Bone Marrow Transplant 2017;52:1003-1009.

7ljax A,Khan AY, Malik SU,et al. Significant risk of graft-versus-host disease with exposure to checkpoint inhibitors before and after allogeneic transplantation transplantation.

8 Merrman RW, Kim HT, Zinzani PL, et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapse/refractory lymphoma. Blood 2017;129:1380-1388.

9 Kamada Y,Arima N,Hayashida M,et al. Prediction of the risk for graft versus host disease after allogeneic hematopoietic stem cell transplantation in patients treated with magomulizumab. Leuk Lymphoma 2022;27:1-7.

10Merryman RW,Castagna L,Giordano L,et al.Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma. Leukemia 2021;35:2672-2683.

11 Dusenbery KE, Daniels KA, McClure JS, et al. Randomized comparison of cyclophosphamide-total body irradiation versus busulfan-cyclophosphamide conditioning in autologous bone marrow transplantation for acute myeloid leukemia.Int J Radiat Oncol Biol Phys 1995;31:119-128.

12 Al Malki MM, Tsai NC, Palmer J, et al. Posttransplant cyclophosphamide as GVHD prophylaxis for peripheral blood stem cell HLA-mismatched unrelated donor transplant. Blood Adv 2021;5:2650-2659.

13 Blume KG, Forman SJ, O'Donnell MR, et al. Total body irradiation and high-dose etoposide: a new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies. Blood 1987;69:1015-1020.

14 Beelen DW,Tenschel R,Stelljes M,et al.Treosulfan or busulfan plus fludabarine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukemia or myelodysplastic syndrome(MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol 2020;7:e28-e39.

15 Lee JH, Joo YD, Kim H, et al. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine.J Clin Oncol 2013;31:701-709.

16 de Lima C, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood 2004;104:857-864.

17 Pagliardini T,Castagna L,Harbi S,et al.Thiotepa,fludarabine,and busulfan conditioning regimen for T cell-replete haploidentical transplantation with post-transplant cyclophosphamide for acute myeloid leukemia: A bicentric experience of 100 patients. Biol Blood Morrow Transplant 2019;25:1803-1809.

18 Sora F, Grazia CD, Chiusolo P, et al. Allogeneic hemopoietic stem cell transplants in patients with acute myeloid leukemia(AML) prepared with fusulfan and fludarabine(BUFLU) or thiotepa, busulfan, and fludarabine(TBF): A retrospective study. Biol Blood Marrow Transplant 2020;26:698-703.

19 Magenau J,Tobai H,Pawarade et al. Clofarabine and busulfan conditioning facilitates engraftment and provides significant antitumor activity in nonremission hematologic malignancies. Blood 2011;118:4258-4264.

20 Kebriaei P, Bassett R, Lyons G,et al. Clofarabine plus busulfan is an effective conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia: Long-term study results. Biol Blood Marrow Transplant 2017;23:285-292.

21 Horwitz ME, Stiff PJ, Cutler C, et al. Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study. Blood 2021;138:1429-1440.

22 Anand S,Thomas S,Corbet K,et al.Adult umbilical cord blood transplantation using myeloablative thiotepa, total body irradiation, and fludarabine conditioning.Biol Blood Marrow Transplant 2017;23:1949-1954.

23 Sanz J, Boluda JC, Martin C, et al. Single-unit umbilical cord blood transplantation from unrelated donors in patients with hematological malignancy using busulfan, thiotepa, fludarabine and ATG as myeloablative conditioning regimen. Bone Marrow Transplant 2012;47:1287-1293.

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF CONDITIONING FOR HEMATOPOIETIC CELL TRANSPLANT REFERENCES

24 Kornblit B, Maloney DG, Storb R, et al. Fludarabine and 2-Gy TBl is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. Biol Blood Marrow Transplant 2013;19:1340-1347.

25 Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allageneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 2001;98:3595-3599.

26 Ciurea SO, Kongtim P, Varma A, et al. Is there an optimal conditioning for older patients with AML receiving allogeneic hematopoietic cell transplantation? Blood 2020;135:449-452.

27 Lee SS, Jung SH, Do YR, et al. Reduced-intensity conditioning with busulfan and drudarbine for allogeneic hematopoietic stem cell transplantation in acute lymphoblastic leukemia. Yonsei Med J 2020;61:452-459.

28 Chen YB,Coughlin E,Kennedy KF,et al. Busulfan dose intensity and outcomes in reduced-intensity allogeneic peripheral blood stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia. Biol Blood Marrow Transplant 2013;19:981-987.

29 Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008;14:641-650.

30 Choe HK, Gergus U, Mayer SA, et al. The addition of low-dose total body irradiation to fludarabine and melphalan conditioning in haplocord transplantation for high-risk hematological malignancies.Transplantation 2017;101:e34-e38.

31 Ciurea SO, Saliba R, Rondon G, et al. Reduced-intensity conditioning using fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT. Bone Marrow Transplant 2010;45:429-436.

32 Gaballa S, Ge I, El Fakih R, et al. Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation. Cancer 2016;122:3316-3326.

33 Sharma P, Pollyea DA, Smith CA, et al. Thiotepa-based intensified reduced-intensity conditioning adult double-unit cord blood hematopoietic stem cell transplantation results in decreased relapse rate and improved survival compared with transplantation following standard reduced-intensity conditioning: A retrospective cohort comparison. Biol Blood Marrow Transplant 2018;24:1671-1677.

34 Brunstein CG, Barker JN, Weisdorf DJ, et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood 2007;110:3064-3070.

35 Kharfan-Dabaja M, Anasetti C, Fernandez H,et al.Phase II study of CD4+guided pentostatin lymphodepletion and pharmacokinetically targeted busfunal as conditioning for hematopoietic cell allografting. Biol Blood Marrow Transplant 2013;19:1087-93.

36 Dimitrova D, Gea-Banacloche J, Steinberg S, et al. Prospective study of a novel, radiation-free, reduced-intensity bone marrow transplantation platform for primary immunodeficiency diseases. Biol Blood Marrow Transplant 2020;26:94-106.

37 Gvajia A, Langston A, Esiashvil N, et al. Pentostatin/TBI conditioning is well-tolerated and permits engraftment of a second allogeneic stem cell transplant following primary or secondary rejection of an allogeneic hematopoietic stem graft[abstract]. Blood 2019;134(Suppl):Abstract 5657.

38 Chevallier P, Labopin M, de La Tour RP,et al. Clofarabine versus fludabine-based reduced-intensity conditioning regimen prior to allogeneical transplantation in adults with AML/MDS. Cancer Med 2016;5:3068-3076.

39 El-Jawahri A, Li S, Ballen KK, et al. Phase II trial of reduced-intensity busulfan/clofarabine conditioning with allogeneic hematopoietic stem cell transplantation for patients with acute myeloid leukemia, myelodysplastic syndromes, and acute lymphoid leukemia. Biol Blood Marrow Transplant 2016;22:80-85.

40 Kirschbaum MH, Stein AS, Popplewell L, et al. A phase I study in adults of clofarabine combined with high-dose melphalan as reduced-intensity conditioning for allogeneic transplantation. Biol Blood Marrow Transplant 2012;18:432-440.

41 Spitzer B, Perales MA, Kernan NA, et al. Second allogeneic stem cell transplantation for acute leukemia using a chemotherapy-only cytoreduction with clofarabine, melphalan, and thiotepa. Biol Blood Marrow Transplant 2016;22:1449-1454.

42 Krakow EF, Gyurkocza B, Storer BE, et al. Phase I/ll multisite trial of optimally dosed clofarabine and low-dose TBI for hematopoietic cell transplantation in acute myeloid leukemia. Am J Hematol 2020;95:48-56.

43 Chevallier P, Peterlin P, Garnier A, et al. Clofarabine-based reduced intensity conditioning regimen with peripheral blood stem cell graft and post-transplant cyclophosphamide in adults with myeloid malignancies. Oncotarget 2018;9:33528-33535.

44 Saito T, Kanda Y, Kami M, et al. Therapeutic potential of a reduced-intensity preparative regimen for allogeneic transplantation with cladribine, busulfan, and antithymocyte globulin against advanced/refractory acute leukemia/lymphoma.Clin Cancer Res 2002;8:1014-1120.

Note: All recommendations are category 2A unless otherwise indicated.

Continued

HCT-A 9 OF 10

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PRINCIPLES FOR MEMATOPIETIC CELL TRANSLANT REFERENCES

45 Saito T, Kanda Y, Nakai K, et al. Immune reconstitution following reduced-intensity transplantation with cladribine, busulfan, and antithymocyte globulin:serial comparison with conventional myeloablative transplantation. Bone Marrow Transplant 2003;32:601-608.

46 Markova M, Barker JN, Miller JS, et al. Fludarabine vs cladramine plus busulfan and low-dose TBI as reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation: a prospective randomized trial. Bone Marrow Transplant 2007;39:193-199.

47 Halmeier C, Girgis M, Blum W, et al. Outcomes of adults with acute myelogenous leukemia in remission given 550 cGy of single-exposure total body irradiation, cyclophosphamide, and unrelated donor bone marrow transplants.Biol Blood Marrow Transplant 2004;10:310-319.

48 Mills W, Chopra R, McMillan A, et al. BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol 1995;13:588-595.

49 Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC+ autologous stem-cell support: still very long survival but late relapses do occur[published correction appears in Br J Haematol 2012;158:815-816]. Br J Haematol 2012;158:355-362.

50 Jo,Cang BW,Jang G,et al.BEAC or BEAM high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin's lymphoma patients: comparative analysis of efficacy and toxicity, Ann Hematol 2008;87:43-48.

51 Sakellari I, Gavilriaki E, Bouziana S, et al. BEAC(carmustine, etoposide,cyctarabine, and cyclophosphamide) in autologous hematopoietic cell transplantation: a safe and effective alternative conditioning regimen for Hodgkin and non-Hodgkin lymphoma. Bone Marrow Transplant 2019;54:921-923.

52 Ferrari AJ, Illerhaus G. The role of autologous stem cell transplantation in primary central nervous system lymphoma. Blood 2016;127:1642-1649.

53 Hyung J, Hong JY, Yoon DH, et al. Thiotepa, busulfan, and cyclophosphamide or busulfan, cyclophosphamide, and etopide high-dose chemotherapy followed by autologous stem cell transplantation for consolidation of primary central nervous system lymphoma. Ann Hematol 2019;98:1657-1664.

54 Sellner L, Boumendil A, Finel H, et al. Thiotepa-based high-dose therapy for autologous stem cell transplantation in lymphoma: a retrospective study from the EBMT. Bone Marrow Transplant 2016;51:212-218.

55 Frankiewicz A, Sadu5-Wojciechowska M, Najda J, et al. Comparable safety profile of BeE(Bamendustine, etoposide, cytarabine, melphalan) and BEAM(carmustine, etoposide, cytarabine, melphalan) as conditioning before autologous haematopoietic cell transplantation. Contemp Oncol (Pozn) 2018;22:113-117.

56 Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003;348:1875-1883.

57 Badros A,Barlogie B,Siegel E,et al.Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol 2001;114:822-829.

58 Kumar SK, Dingli D, Lacy MQ, et al. Autologous stem cell transplantation in patients of 70 years and older with multiple myeloma: Results from a matched pair analysis. Am J Hematol 2008;83:614-617.

59 Bashir Q, Chamoun K, Milton DR, et al. Outcomes of autologous hematopoietic cell transplantation in myeloma patients aged≥75 years. Leuk Lymphoma 2019;60:3536-3543.

60 Bashir Q,Thal PF,Milton DR,et al. Conditioning with busfan plus melphan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial. Lancet Haematol 2019;6:e266-e275.

61 Adra N, Abonour R, Althouse SK, et al. High-dose chemotherapy and autologous peripheral-blood stem-cell transplantation for relapsed metastatic germ cell tumors: The Indiana University experience. J Clin Oncol 2017;35:1096-1102.

62 Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol 2010;28:1706-1713.

63 Yanada M, Tsuzuki M, Fujita H, et al. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood 2013;121:3095-3102.

64 Linker CA, Owzar K, Powell B, et al. Auto-SCT for AML in second remission:CALGB study 9620. Bone Marrow Transplant 2009;44:353-359.

65 de Botton S, Fawaz A, Chevret S, et al. Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 2005;23:120-126.

66 Bubalo J, Carpenter PA, Majhail N,et al. Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplant practice guideline committee. Biol Blood Marrow Transplant 2014;20:600-616.

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DIAGNOSIS/WORKUP OF GVHD

![WORKUP\nAdditional tests as clinically indicated to rule out non-GVHD causes^{a,b,c}\n●Additional tests as clinically indicated to rule out non-GVHD causes^{a,b,c}\n●Organ-directed biopsy, as clinically indicated, to support acute GVHD diagnosis\n●Skin rash: consider biopsy of suspicious skin sites\n●Diarrhea: consider biostinalian (GI) biopsya\n● Diarrhea: lower gastrointestinal (GI) biopsya\nNausea/vomiting: consider upper Gl biopsya\n● Nausea/vomiting: consider liver biopsy if elevated liver-associated enzymes or total/direct bilirubin and no evidence of acute GVHD elsewhere\n●Determine chronic GVHD; skin stage 1-2, CVH\n●Regine chronic GVHD grade\n●See Chronic GVHD: Grading(GVHD-C)\n●Determine chronic GVHD grade See Chronic GVHD: Grading(GVHD-C)\nManagement of Grade II-IV\n●Management of Grade II-IV\n●Acute CVHD(GVHD-3)\nGrade l-IVd (Moderate to severe acute GVHD) Acute GVHD(GVHD-3)\n](2/aj0YEe4oUhYkBdfpda0fYP/figuref5ab0f2b2f124dcc8a1e45ec0144354f_0_6.png)

suspected

Determine chronic GVHD grade Management of Chronic See Chronic GVHD: Grading(GVHD-C) GVHD(GVHD-4)

a Gl biopsy (esophagogastroduodenoscopy, colonoscopy, and/or flexible sigmoidoscopy) as clinically indicated to support the diagnosis of Gl acute GVHD. Stool testing may be used to rule out infectious etiology of diarrhea.

b Consider imaging as clinically indicated to evaluate the etiology of LFT abnormalities(eg, ultrasound and/or CT scan of the abdomen).

c Liver biopsy and/or viral reactivation testing may be used to rule out non-GVHD causes of liver dysfunction(ie, VOD/SOS, infection, effects of preparatory regimen,dug toxicity). Transjugular approach may be preferred, especially if thrombocytopenia or coagulopathy is present.

d Acute GVHD Grading Criteria(GVHD-A).

e While a biopsy may be done to confirm chronic GVHD, a biopsy is not always feasible and is not mandatory if the patient has at least one of the diagnostic findings of chronic GVHD(Jagasia MH, et al. Biol Blood Marrow Transplant 2015;21:389-401).

Note:All recommendations are category 2A unless otherwise indicated.

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MANAGEMENT OF ACUTE GVHD

FIRST-LINE THERAPYf

![Continue or consider restarting original immunosuppressive agent(s) and\n](2/aj0YEe4oUhYkBdfpda0fYP/figured59fa3a7e85442e1bf627896fbd1eee7_0_7.png) Acute GVHD Grade II-IVd

dAcute GVHD Grading Criteria (GVHD-A).

For recommendations on antibiotic prophylaxis during immunosuppressive therapy, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.Tap Topical steroids(eg, triamcinolone, clobetasol) and/or topical tacrolimus. Medium to high potency formulations are recommended except on the face or intertriginous areas where low potency hydrocortisone can be used.

h Antihistamines may be used for symptoms (eg, itching), as needed.

iGVHD Steroid Response Definitions/Criteria(GVHD-D).

Enrollment in well-designed clinical trials should be encouraged since no standard, effective therapy for steroid-refractory GVHD has been identified. The selection of therapy for steroid-refractory GVHD should be based on physician experience, agent's toxicity profile, the effect of prior treatment, drug interactions, convenience/accessibility, and patient tolerability.

Note:All recommendations are category 2A unless otherwise indicated.

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MANAGEMENT OF ACUTE GVHD

FIRST-LINE THERAPY ACTe First-LINE THERAPY GLAN 02001: laminosuppressive agne(or Response ${}^{o}$ $\rightarrow$ Taper steroids as clinically continuous monuppressive agent(or fully prednisoneol (or prednisone dose equivalent) -as clinically l'opital séorol 2020 - upper GI only: No response er $^{o}$ as clinically Grade II-IV $\left\{\right.$ grantive blood level if 1-2 mg/kg/day prednisoneol er $^{o}$ atopical steroids ${}^{o}$ $\rightarrow$ - topical steroids ${}^{o}$ No response1 2021 - lower high end (or Scientific acid l'empidosire 2020 - topical steroids ${}^{o}$ as clinically effective IRIDL 2021 - upper GL only: Responco Taper steroids for immunosuppressive stally - For el el el el el el el el el el el el el el el el el el el el el el el el el el el el el el el el el el el el el

9 Topical steroids (eg, triamcinolone, clobetasol) and/or topical tacrolimus.Medium to high potency formulations are recommended except on the face or intertriginous areas where low potency hydrocortisone can be used.

i GVHD Steroid Response Definitions/Criteria(GVHD-D).

Enrollment in well-designed clinical trials should be encouraged since no standard, effective therapy for steroid-refractory GVHD has been identified.The selection of therapy for steroid-refractory GVHD should be based on physician experience, agent's toxicity profile, the effect of prior treatment,drug interactions, convenience/accessibility, and patient tolerability.

k Addition of other systemic agents in conjunction with systemic steroids as initial therapy for acute GVHD should not be done outside the context of a well-designed clinical trial.

In a phase III randomized controlled trial, initial treatment with systemic prednisone at 0.5 mg/kg/day in conjunction with Gl topical steroids(beclomethasone dipropionate[available as a compounded agent]± budesonide) was safe and effective for upper Gl symptoms(ie, nausea, vomiting, anorexia), with or without skin involvement(<50% BSA), in patients with diarrhea volumes of<1000 mL/day effective at treating the upper Gl tract.

There is no role for escalation of methylprednisolone dose beyond 2 mg/kg/day.n Standard-risk acute GVHD as defined by clinical risk score and biomarker status.(CTN1501 trial: Pidala J,et al.Blood 2020;135:97-107.)

●Complete resolution of GVHD or improvement in at least one organ without any progression in any other organs.

P If response, taper systemic steroids to mitigate long-term steroid side effects and risk of infection, as clinically feasible.

Note:All recommendations are category 2A unless otherwise indicated.

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figureb3b9370dcb3f46beb40a3840612c7c78_0_1.png) National Comprehensive Cancer Network®

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NCCN Guidelines Index Table of Contents Discussion

![MANAGEMENT OF CHRONIC GVHD\nFIRST-LINE THERAPY\nClinical trial\nor\nContinue or consider restarting original immunosuppressive agent and/or\n2661/8974111\nTaper steroids as immunosuppressive agent\n)\n2662/89741111\n2663/89741111\nControl or consider restarting original immunosuppressive agent\n)\n2663/897411111\n2664/897411111\n2665/897411111\n2665/897411111\n2665/897411111\n2665/897411111\n2665/8974111111\n2665/8974111111\n2665/8974111111\n2665/89741111111\n2665/89741111111\n2665/89741111111\n2665/89741111111\n2665/897411111111\n2665/897411111111\n2665/89741111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/897411111111\n2665/8974111111111\n2665/897411111111\n2665/8974111111111\n2665/8974111111111\n2665/8974111111111\n2665/8974111111111\n2665/8974111111111\n2665/8974111111111\n2665/8974111111111\n2665/8974111111111\n2665/8974111111111\n2665/8974111111111\n2665/89741111111111\n2665/897411111111111\n2665/89741111111111\n2665/89741111111111\n2665/89741111111111\n2665/89741111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111\n](2/aj0YEe4oUhYkBdfpda0fYP/figure0ee958a28fa6447ea023fe3891742436_0_5.png) iGVHD Steroid Response Definitions/Criteria(GVHD-D).

Enrollment in well-designed clinical trials should be encouraged since no standard, effective therapy for steroid-refractory GVHD has been identified. The selection of therapy for steroid-refractory GVHD should be based on physician experience, agent's toxicity profile, the effect of prior treatment, drug interactions,convenience/accessibility, and patient tolerability.

Pf response, taper systemic steroids to mitigate long-term steroid side effects and risk of infection, as clinically feasible.

q Multidisciplinary care aimed at avoiding organ damage and preserving function is recommended.

r Initial dose may vary depending on organs involved,GVHD severity, patient comorbidities, and overlapping syndromes.

s Carpenter PA,et al. Haematologica 2018;103:1915-1924.

${}^{t}$ Topical steroids(eg, triamcinolone, clobetasol), topical estrogen(vulvovaginal GVHD), topical tacrolimus, or dexamethasone oral rinse(oral GVHD). Medium- to high-potency formulations are recommended except on the face or intertriginous areas where low-potency hydrocortisone can be used.

${}^{u}$ Examples of acceptable inhaled steroids include budesonide or fluticasone.

v Azithromycin should only be used for treatment of bronchiolitis obliterans syndrome(BOS), not for prophylaxis, due to a suggestion of an increased risk of leukemic relapse or secondary neoplasms in recent clinical trials. Bergeron A,et al. JAMA 2017;318:557-566. Cheng GS, et al. Biol Blood Marrow Transplant 2020;26:392-400.

W Patients with progression/worsening of lung chronic GVHD following 2-3 lines of therapy may be evaluated for lung transplant.

×PFT at onset of chronic GVHD and subsequently as clinically indicated.

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ACUTE GVHD: STAGING AND GRADING

Commonly used criteria for the staging/grading of adults with acute GVHD include:

●Keystone (modified Glucksberg) criteria (see below)

● MAGIC criteria(GVHD-A,2 of 2)

●Minnesota criteriaa

Modified Glucksberg Criteria: Staging and Grading of Acute GVHD*

|Stage|Extent of Organ Involvement||| |---|---|---|---| |Stage|Skin|Liver|Gut| |1|Rash on <25% of skinb|Bilirubin 2-3 mg/dlc|Diarrhea >500 ml/day or persistent nausea| |2|Rash on 25-50% of skin|Bilirubin 3-6 mg/dl|Diarrhea >1000 ml/day| |3|Rash on >50% of skin|Bilirubin 6-15 mg/dl|Diarrhea >1500 ml/day| |4|Generalized erythroderma with bullous formation|Bilirubin >15 mg/dl|Severe abdominal pain with or without ileus| |Gradef|||| |I|Stage 1-2|None|None| |II|Stage 3|Stage 1|Stage 1| |III|-|Stage 2-3|Stage 2-4| |IV9|Stage 4|Stage 4|-|

*Used with permission: Przepiorka D, Weisdorf D, Martin P, et al.1994 Consensus Conference on Acute GVHD Grading.Bone Marrow Transplant 1995;15:825-828.

a MacMillan ML,et al.Biol Blood Marrow Transplant 2015;21:761-767;https://z.umn.edu/MNAcuteGVHDRiskScore

b Use 'Rule of Nines' or burn chart to determine extent of rash.

cRange given as total bilirubin. Downgrade one stage if an additional cause of elevated bilirubin has been documented.

d Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on BSA. Gut staging criteria for pediatric patients was not discussed at the consensus conference. Downgrade one stage if an additional cause of diarrhea has been documented.

e Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.

fCriteria for grading given as minimum degree of organ involvement required to confer that grade.

9 Grade IV may also include lesser organ involvement but with extreme decrease in performance status.

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ACUTE GVHD Targetor Organ Staging & Overall Clinical Gradeh

MAGIC Criteria: Acute GVHD Target Organ Staging & Overall Clinical Gradeh

|Stage|Skin (active erythema only)|Liver (bilirubin)|Upper Gl|Lower Gl (stool output/day)| |---|---|---|---|---| |0|No active (erythematous) GVHD rash|<2 mg/dL|No or intermittent nausea, vomiting, or anorexia|Adult: <500 mL/day or <3 episodes/day vomiting, or anorexia| |1|Maculopapular rash <25% BSA|2-3 mg/dL|Persistent nausea, vomiting or anorexia|Adult: <500 mL/day or <3 episodes/day Variable: vanomusea, vomiting or anorexia| |2|Maculopapular rash 25%-50% BSA|3.1-6 mg/dL||Child: 10-19.9 mL/kg/day or 4-6 episodes/day| |3|Maculopapular rash >50% BSA|6.1-15 mg/dL||Adult: 1000-1500 mL/day or 5-7 episodes/day Child: 20-30 mL/kg/day or 7-10 episodes/day| |4|Generalized erythroderma (>50% BSA) plus bullous formation and desquamation >5% BSA|>15 mg/dL||Adult: >500 mL/day or >7 episodes/day Child: >30 mL/kg/day or >10 episodes/day|

Grade(based on most severe target organ involvement)

0 No stage 1-4 of any organ.

1 Stage 1-2 skin without liver, upper Gl, or lower Gl involvement.

Ⅱ Stage 3 rash and/or stage 1 liver and/or stage 1 upper Gl and/or stage 1 lower Gl.

Ⅲ Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI.

${}^{h}$ Reproduced with permission from Elsevier: Harris AC, Young R, Devine S, et al. International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant 2016;22(1):4-10. DOI: 10.1016/j.bmt.2015.09.001. This article is published under the terms of the Creative Commons Attribution-NonCommercial-No Derivatives License (CC BY NC ND).

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CHRONIC GVHD: DIAGNOSIS

|Signs and Symptoms of Chronic GVHDa|Distinctive_b (seen in chronic GVHD, but insufficient to establish a diagnosis)|Other features for unclassified entitiesc|Commond (seen with both acute and chronic GVHD)|| |---|---|---|---|---| |Organ Site|Distinctive_b (seen in chronic GVHD, but insufficient to establish a diagnosis)|Other features for unclassified entitiesc|Commond (seen with both acute and chronic GVHD)|Diagnostic (sufficient to establish the diagnosis of chronic GVHD)| |Skin|●Pokiloderma ● Lichen planus-like features ●Sclerotic features ● Morphea-like features|●Depigmentation ● Papulosquamous lesions|●Sweat impairment ● Ichthyosis ●Lichthyosis ● Keratosis pilaris ● Hypopigmentation ● Hyperpigmentation|●Erythema ● Maculopapular rash ● Pruritus| |Nails||●Dystrophy ● Longitudinal ridging, splitting or brittle features ● Onycholysis ● Pterygium unguis ● Nail loss (usually symmetric, affects most nails)|● Normalding (seen with both acute and chronic GVHD)|| |Scalp and Body Hair||● New onset of scarring or non-scarring scalp the alloperia(after recovery from chemoradiotherapy) ● Loss of body hair ● Scaling|● Thinning scalp hair, typically patchy, coarse, or dull(not explained by endocrine or other causes) ● Premature gray hair|●Erythema ● Maculopapular rash ● Pruritus| |Mouth|● Lichen planus-like changes|● Xerostomia ● Muccoles ● Mucosal atrophy ● Ulcers ● Pseudomembranes|● McGivitis ● Mucositis ● Erythema ● Pain|| |Eyes||● New onset dry,gritty, or painful eyes ● Cicatricial conjunctivitis ● Keratoconjunctivitis sicca|● Photophobia ● Periorbital hyperpigmentation ● Blepharitis(erythema of the eye lids with edema|| |||● Confluent areas of punctate keratopathy|b In all cases, infection, drug effect, malignancy, or other causes must be excluded. c Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed. c Common refers to shared features by both acute and chronic GVHD.||

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.

b In all cases, infection, drug effect, malignancy, or other causes must be excluded.cCan be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed.

<EndOfPara>Common refers to shared features by both acute and chronic GVHD.

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CHRONIC GVHD: DIAGNOSIS

|Signs and Symptoms of Chronic GVHDa|||| |---|---|---|---| |Signs and Symptoms of Chronic GVHDa|||| |Organ Site|Diagnostic|Distinct6b (seen in chronic GVHD, but insufficient to establish a diagnosis)|Other features for unclassified entitiesc| |Genitalia|(sufficient to establish the diagnosis of chronic GVHD)|·Erosions ●Fissures ●Vaginal scarring or clitoral/labial agglutination ●Phimosis or urethral/meatus scarring or stenosis|| |Gl Tract|||●Exocrine pancreatic insufficiency ● Exocrine pancreatic insufficiency ● Nausea ● Stricatures or stenosis in the upper to insufficiency ● Diarrhea ● Weight loss ●Failure to thrive (infants and children)| |Liver|||●Failure to thrive (infants and children)| |Lung|· Bronchiolitis obliterans diagnosed with lung biopsy ●BOSe|●Air trapping and bronchiectasis ● Cryptogenic organizing pneumonia(cOP)f ●Restrictive lung diseasef|●Alanine transaminase(ALT)>2 x ULN|

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I.The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.

b In all cases, infection, drug effect, malignancy, or other causes must be excluded.

cCan be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed.

d Common refers to shared features by both acute and chronic GVHD.

eBOS can be diagnostic for lung chronic GVHD only if distinctive signs or symptoms of chronic GVHD are present in another organ. BOS diagnosis requires the following criteria:

1.Forced expiratory volume in the first second (FEV1)/vital capacity (VC) ratio<0.7 or the fifth percentile predicted.

2.FEV1<75% of predicted with≥10% decline within 2 years.FEV1 should not be corrected to>75% of predicted after ultralon inhalation, and the absolute decline for the corrected values should still remain at≥10% over 2 years.

3.Absence of infection in the respiratory tract, documented with investigations directed by clinical symptoms, such as chest radiographs, CT scans, or microbiologic cultures(sinus aspiration, upper respiratory tract viral screen, sputum culture, bronchoalveolar lavage).

4.One of the 2 supporting features of BOS: Evidence of air trapping by expiratory CT or small airway thickening or bronchiectasis by high-resolution chest CT; or evidence of air trapping by PFT: residual volume>120% of predicted or residual volume/total lung capacity elevated outside the 90% confidence interval.

If a patient already carries the diagnosis of chronic GVHD by virtue of organ involvement elsewhere, then only the first 3 criteria above are necessary to document chronic GVHD lung involvement.

f Pulmonary entities under investigation or unclassified.

Continued

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CHRONIC GVHD: DIAGNOSIS

|Signs and Symptoms of Chronic GVHDa||||| |---|---|---|---|---| |Organ Site|Diagnostic|Distinctiveb|Other features for unclassified entitiesc|Commond (seen with both acute and chronic GVHD)| ||(sufficient to establish the diagnosis of chronic GVHD)|(seen in chronic GVHD, but insufficient to establish a diagnosis)||| |Muscles, Fascia, Joints|● Fascitis ● Joint stiffness or contractures secondary to fascitis or sclerosis|●Myositis or polymositis9 ● Acute cramps ● Arthralgia or arthritis||| |Hematopoietic and Immune||||●Thrombocytopenia ●Eosinophilia ● Lymphopenia ●Hypo-or hyper- gammaglobulinemia ●Autoantibodies(autoimmune hemolytic anemia[AIHA], immune thrombocytopenia[ITP]) ● Raynaud's phenomenon| |Other||||●Pericardial or pleural effusions ● Ascites ● Peripheral neuropathy ● Nephrotic syndrome ● Myasthenia gravis ● Cardiac conduction abnormality or cardiomyopathy|

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I.The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.

b In all cases, infection, drug effect, malignancy, or other causes must be excluded.

cCan be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed.

d Common refers to shared features by both acute and chronic GVHD.

9Diagnosis of chronic GVHD requires biopsy.

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CHRONIC GVHD: GRADING

|Organ Scoring of Chronic GVHDa||||| |---|---|---|---|---| |Performance Score: KPS ECOG(circle one)|Score 0|Score 1|Score 2|Score 3| |Performance Score: KPS ECOG(circle one)|Asymptomatic and fully active(ECOG 0, KPS 100%)|Symptomatic, fully ambulatory, restricted only in physically strenuous activity(ECOG 1, KPS 80-90%)|Symptomatic, ambulatory, capable of self-care, >50% of waking hours out of bed (ECOG 2, KPS 60-70%)|Symptomatic, limited self-care, >50% of waking hours in bed (ECOG 3-4, KPS <60%)| |Skinb||||| |Score % BSA:|No BSA involved|1-18% BSA|19-50% BSA|>50% BSA| |GVHD features to be scored by BSA (check all that apply):||||| |O Maculopapular rash/erythema Lichen planus-like features||||| |O Sclerotic features||||| |O Papulosquamous lesions or ichthyosis||||| |O Keratosis pilaris-like GVHD||||| |Skin Features|No sclerotic features||Superficial sclerotic features|Check all that apply:| |Score: $\_$|||"not hidebound" (able to pinch)|O Deep sclerotic features "Hidebound" (unable to pinch)| |||||O Impaired mobility| |Other skin GVHD features, NOT scored by BSA (check all that apply):||||O Ulceration| |O Hyperpigmentation||||| |O Hypopigmentation||||| |O Poikiloderma||||| |O Severe or generalized pruritus||||| |O Hair involvement||||| |O Nail involvement||||| |O Abnormality present but explained entirely by non-GVHD documented cause(specify):|||||

b Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists between the percentage of BSA score and the skin feature score, OR if superficial sclerotic features are present(Score 2), but there is impaired mobility or ulceration (Score 3), the higher level should be used for the final skin scoring.

Continued

Note:All recommendations are category 2A unless otherwise indicated.

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CHRONIC GVHD: GRADING

|Organ Scoring of Chronic GVHDa||||| |---|---|---|---|---| ||Score 0|Score 1|Score 2|Score 3| |Mouth||||| ||No symptoms|Mild symptoms with disease signs but not limiting oral intake significantly|Moderate symptoms with disease signs with partial limitation of oral intake|Severe symptoms with disease signs on examination with major limitation of oral intake| |lichen planus-like features present: Yes||||| |ONo||||| |OAbnormality present but explained entirely by non-GVHD documented cause(specify):||||| |Eyes||||| |Keratoconjunctivitis sicica(KCS) confirmed by ophthalmologist Yes|No symptoms|Mild dry eye symptoms not affecting ADL (requirement of lubricant eye drops ≤3x per day)|Moderate dry eye symptoms partially affecting ADL (requiring lubricant eye drops >3x per day or punctal plugs), WITHOUT new vision impairment due to KCS|Severe dry eye symptoms significantly affecting ADL (special eyeware to relieve pain) OR unable to work because of ocular symptoms OR loss of vision due to KCS| |O Not examined||||| |O Abnormality present but explained entirely by non-GVHD documented cause (specify):||||| |GI Tract||||| |Check all that apply: Esophageal web/proximal stricture or ring|No symptoms|Symptoms without significant weight loss ${ }^{\circ} $|Symptoms associated with mild to moderate weight loss ${ }^{\circ} $ (5-15%) OR moderate diarrhea without significant interference with daily living|Symptomes associated with significant weight loss ${ }^{\circ} $ >15%, requires nutritional supplement| |O Anerxia||||for most calorie needs OR esophageal dilation OR severe diarrhea with significant interference with daily living| |O Vomiting||||diarrhea with significant interference with daily living| |O Diarrhea||||| |Weight loss $\ge$ 5%||||| |O Failure to thrive||||| ||Abnormality present but explained entirely by non-GVHD documented cause (specify):||||

c Weight loss within 3 months.

Continued

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CHRONIC GVHD: GRADING

||CHRONIC GVHD:GRADING|CHRONIC GVHD:GRADING|CHRONIC GVHD:GRADING|CHRONIC GVHD:GRADING| |---|---|---|---|---| ||Score 0|Score 1|Score 2|Score 3| |Liver||||| ||Normal total bilirubin and ALT or AP< 3 x ULN|Normal total bilirubin with ALT ≥ 3 to 5 x ULN or AP≥ 3 x ULN|Elevated total bilirubin but ≤ 3 mg/dL or ALT>5xULN|Elevated total bilirubin >3 mg/dL| |OAbnormality present but explained entirely by non-GVHD documented cause(specify):||||| |Lungsd||||| |Symptom score:|No symptoms|Mild symptoms (shortness of breath after climbing one flight of steps)|Moderate symptoms (shortness of breath after walking on flat ground)|Severe symptoms (shortness of breath at rest; requiring $O_{2}$)| |Lung score:$\_$ % FEV1|FEV1≥80%|FEV1 60-79%|FEV1 40-59%|FEV1 ≤39%| |Pulmonary function tests: Not performed||||| |Abnormality present but explained entirely by non-GVHD documented cause(specify):||||| |Joints and Fascia||||| |P-ROM score (see GVHD-C.5 of 5) Shoulder (1-7):|No symptoms|Mild tightness of arms or legs, normal or mild decreased range of motion (ROM) AND not affecting|Tightness of arms or legs OR joint contractures, erythema thought due to fasciitis, moderate decrease ROM AND mild to moderate limitation of ADL|Contractures WITH significant decrease of ROM AND significant limitation of ADL (unable to tie shoes, button shirts, dress self, etc)| |Elbow (1-7):||||| |Wrist/finger (1-7):||||| |Ankle(1-4):||||| |OAbnormality present but explained entirely by non-GVHD documented cause (specify):||||| |Genital Tracte||||| |O Not examined Currently sexually active: No signs|Mild signs and females with or without discomfort on exam|Moderate signs and may have symptoms with discomfort on exam|Severe signse with or may have symptoms with|Severe signse with or without symptoms| |O No||||| |OAbnormality present but explained entirely by non-GVHD documented cause (specify):|||||

a Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I.The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.

d Lung scoring should be performed using both the symptoms and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is discrepancy between symptoms and FEV1 scores.

e Referral and close surveillance by a specialist is recommended for early detection of chronic GVHD and full assessment of disease.

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CHRONIC GVHD: GRADING

|Organ Scoring of Chronic GVHD|| |---|---| |Other indicators, clinical features or complications related to chronic GVHD(checkd all that apply and assign a score to severity (0-3) based on functional impact where applicable none-0,mild-1, moderate-2, severe-3)|| |O Ascites (serositis)|| |O Pericardial effusion|| |O Weight loss >5% without GI symptoms|| |O Pleural effusion(s)|| |O Eosinophilia >500/μl|| |O Nephrotic syndrome _|| |O Myasthenia gravis _|| |O Peripheral neuropathy _|| |Overall GVHD Severity|| |Opinion of the evaluator: O No GVHD O Mild||

|NIH Global Severity of Chronic GVHa|||| |---|---|---|---| |Mild chronic GVHD|Moderate|ChVHD|Severe chronic GVHD| |1 or 2 organs involved with no more than score 1 plus|3 or more organs involved with no more than score 1 OR At least 1 organ (not lung) with a score of 2|At least 1 organ with a score of 3 OR|At least 1 organ with a score of 3 OR| |Lung score 0|Lung score 1|Lung score of 2 or 3|| |Key points:|Key points:|Key points:|Key points:| |1.In skin: higher of the two scores to be used for calculating global severity. 2.In lung: FEV1 is used instead of clinical score for calculating global severity. 3. If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD documented cause, that organ is not included for calculation of the global severity.|||| |4. If the abnormality in an organ is attributed to multifactorial causes(GVHD plus other causes) the scored organ will be used for calculation of the global severity should of the contributing causes (no downgrading of organ severity score).||||

Note:All recommendations are category 2A unless otherwise indicated.

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CHRONIC GVHD: GRADING

![Photographic Range of Motion (P-ROM)a\n!nckn\n1(Worst)22\n1(Worst)3\n1(Worst)2\n5\n4\n3\n4\n5\n6\n7(Normal)\nElbow\n1(Worst)2\n1(Worst)2\nNewt/finger\nAnkle\n1\nJagasia MH,GreinixHT,Arora M,et al.National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease:1.The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.\nWrist/finger\nAnkle\n1(Worst\n2\n2\n3\n4\n5\n3\n4\n(Normal)\n6\n7(Normal)\n6\nWikn/finger\n](2/aj0YEe4oUhYkBdfpda0fYP/figure8765f0fe56a3492dab5926f08f046b8f_0_6.png) a Jagasia MH, Grein HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.

Note:All recommendations are category 2A unless otherwise indicated.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Graft-Versus-Host Disease

NCCN Guidelines Index Table of Contents Discussion

GVHD STEROID RESPONSE DEFINITIONS/CRITERIA

Response Criteria for GVHD Clinical Trials

||Acute GVHD Steroid Response|Chronic GVHD Steroid Response| |---|---|---| |Steroid Refractoriness or Resistance|Progression of acute GVHD within 3-5 days of therapy onset with ≥2 mg/kg/day of prednisone OR Failure to improve within 5-7 days of treatment initiation OR Incomplete response after more than 28 days of immunosuppressive treatment including steroids|Chronic GVHD progression while on prednisone at ≥1 mg/kg/day for 1-2 weeks OR Stable GVHD disease while on ≥0.5 mg/kg/day (or 1 mg/kg every other day) of prednisone for 1-2 months| |Steroid Dependence|Inability to taper prednisone below 2 mg/kg/day OR A recurrence of acute GVHD activity during steroid taper|Inability to taper prednisone below 0.25 mg/kg/ day (or >0.5 mg/kg every other day) in at least two unsuccessful attempts separated by at least 8 weeks| |Steroid Intolerance|Emergence of unacceptable toxicity due to the use of corticosteroids||

a Schoemans HM, Lee SJ,Ferrara JL,et al.EBMT-NIH-CIBMTR Task Force position statement on standardized terminology& guidance for graft-versus-host disease assessment. Bone Marrow Transplant 2018;53:1401-1415.

Note:All recommendations are category 2A unless otherwise indicated.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Graft-Versus-Host Disease

NCCN Guidelines Index Table of Contents Discussion

GHVHD STEROID RESPONSE DEFINITIONS/CRITERIA

Chronic GVHD Response Criteriab

|Organ|Complete Response|Partial Response|Progression| |---|---|---|---| |Skin|NIH Skin Score 0 after previous involvement|Decrease in NIH Skin Score by 1 or more points|Increase in NIH Skin Score by 1 or more points, except 0 to 1| |Eyes|NIH Eye Score 0 after previous involvement|Decrease in NIH Eye Score by 1 or more points|Increase in NIH Eye Score by 1 or more points, except 0 to 1| |Mouth|NIH Modified Oral Mucosa Rating Score 0 after previous involvement|Decrease in NIH Modified Oral Mucosa Score of 2 or more points|Increase in NIH Modified Oral Mucosa Rating Score of 2 or more points| |Esophagus|NIH Esophagus Score 0 after previous involvement|Decrease in NIH Esophagus Score by 1 or more points|Increase in NIH Esophagus Score by 1 or more points, except 0 to 1| |Upper GI|NIH Upper GI Score 0 after previous involvement|Decrease in NIH Upper GI Score by 1 or more points|Increase in NIH Upper GI Score by 1 or more points, except 0 to 1| |Lower GI|NIH Lower GI Score 0 after previous involvement|Decrease in NIH Lower GI Score by 1 or more points|Increase in NIH Lower Gl Score by 1 or more points, except from 0 to 1| |Liver|Normal ALT, alkaline phosphatase, and total bilirubin after previous elevation of one or more|Decrease by 50%|Increase by 2x ULN| |Lungs|-Normal %FEV1 after previous involvement -If PFTs not available, NIH Lung Symptom Score 0 after previous involvement|-Increase by 10% predicted absolute value of %FEV1 -If PFTs not available, decrease in NIH Lung Symptom Score by 1 or more points, except in NIH|-Decrease by 10% predicted absolute value of %FEV1 -If PFTs not available, increase in NIH Lung Symptom Score by 1 or more points, except 0 to 1| |Joints and Fascia|Both NIH Joint and Fascia Score 0 and P-ROM score 25 after previous involvement by at least one measure|Decrease in NIH Joint and Fascia Score by 1 or more points or increase in P-ROM score by 1 point for any site|Increase in NIH Joint and Fascia Score by 1 or more points or decrease in P-ROM score by 1 point for any site| |Global|Clinician overall severity score 0|Clinician overall severity score decreases by 2 or more points on a 0-10 scale|Clinician overall severity score increases by 2 or more points on a 0-10 scale|

${}^{b}$ Lee SJ, Wolff D, Kitko C, et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease: IV. The 2014 Response Criteria Working Group Report. Biol Blood Marrow Transplant 2015;21:984-999.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Graft-Versus-Host Disease

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED SYSTEMIC AGENTS FOR STEROID-REFRACTORY GVHD

●Participation in clinical trials is encouraged.

●The following systemic agents are used in conjunction with corticosteroids for steroid-refractory GVHD.There is insufficient evidence to recommend one systemic agent as preferred over another. However, these are the most commonly used agents among the NCCN Member Institutions.

●The selection of systemic agent should be based on institutional preferences, physician experience, agent's toxicity profile, the effect of prior treatment, drug interactions, convenience/accessibility, and patient tolerability.

|Suggested Systemic Agents for Steroid-Refractory GVHD3|Chronic GVHD| |---|---| |Acute GVHD1|Chronic GVHD| |The following agents are often used in conjunction with the original immunosuppressive agent.|While the following systemic agents may be used to treat chronic GVHD in any organ, some agents are used more commonly for certain sites involved with chronic GVHD based on available data(see Discussion).| |FDA-approved category 1 agents|FDA-approved category 1 agents| |●Ruxolitinib(category 1)c,2|●Ruxolitinib(category 1)c,24-26| |Alternative agents(listed in alphabetical order)|Other FDA-approved agents(listed in order by FDA approval date)| |●Alpha-1 antitrypsin|●Ibrutinibe,27,28| |●ATG6|●Belumosudifif,29| |●Basiliximab7|●Axatilimab-csfr$9,30| |●Calcineurin inhibitors(CNls)(eg,tacrolimus, cyclosporine)|| |●Extracorporeal photophereis(ECP)d,9|Alternative agents(listed in alphabetical order)| |●Infixlimab10|●Abatacept31| |●Mortrin inhibitors(eg, sirolimus) 11,12|●Almtuzumab32,33| |●Mocophenolate mofetil13,14|●CNls(eg,tacrolimus,cyclosporine)| |●Pentostatin15-17|●Hydroxychloroquine35| |●Tocilizumab18-21|$$\begin{array}{l}\cdot\quad\text{Imatinib}^{36,37} 36,37\\ \cdot\quad\text{Imerulin}^{2}\cdot\text{IL-2)38}\\ \end{array}$$| |●epidermal growth factor(uhCG/EGF)22|●Low-dose methotrexate 39-41| |●Vedolizumab23|●MTOR inhibitors(eg, sirolimus)42-44| ||●Mycophenolate mofetil45| |a For patients receiving immunosuppressive agents for GVHD, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.|●Pentostatin46-48|

a For patients receiving immunosuppressive agents for GVHD, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

c Ruxolitinib is FDA approved for the treatment of adult and pediatric patients(age≥12 years)with either steroid-refractory acute GVHD, or chronic GVHD after failure of one or two lines of systemic therapy.

d Psoralen and ultraviolet A irradiation(PUVA) may be used for sclerotic or cutaneous GVHD if ECP is not available or feasible.

eIbrutinib is FDA approved for the treatment of adult and pediatric patients≥1 year with chronic GVHD after failure of one or more lines of systemic therapy. Ibrutinib should be used with caution in patients with a history of heart arrhythmias or heightened risk of bleeding.

f Belumosudil is FDA approved for the treatment of adult and pediatric patients(age≥12 years)with chronic GVHD after failure of two or more prior lines of systemic therapy.

9 Axatlimab-csfr is FDA approved for the treatment of adult and pediatric patients weighing≥40 kg with chronic GVHD after failure of at least two prior lines of systemic therapy.

References

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-E 1 OF 3

NCCN

National Concomprehensive Network

NCCN Guidelines Version 3.2025 Graft-Versus-Host Disease

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED SYSTEMIC AGENTS FOR STEROID-REFRACTORY GVHD REFERENCES

1 Martin,PJ,Rizzo JD,Wingard JR,et al.First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplant. Biol Blood Marrow Transplant 2012;18:1150-1163.

13 Pidala J, Kim J, Perkins J, et al. Mycophenolate moftil for the management of steroid-refractory acute graft vs host disease. Bone Marrow Transplant 2010;45:919-924.

14 Furlong T, Martin P, Flowers ME, et al. Therapy with mycophenolate mofetil for refractory acute and chronic GVHD. Bone Marrow Transplant 2009;44:739-748.

2 Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocicidort-refractory acute graft-versus-host disease. N Engl J Med 2020;382:1800-1810.

15 Ragon BK, Mehta RS, Gulbis AM, et al. Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit. Bone Marrow Transplant 2018;53:315-325.

3 Gomez-Almaguer D, Ruiz-Arguelles GJ, del Carmen Tarin-Arzaga L, et al. Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2008;14:10-15.

16 Schmitt T, Luft T, Hegenbart U, et al. Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis. Bone Marrow Transplant 2011;46:580-585.

4 Schnitzler M, Hasslkar J, Egger M, et al. Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab. Biol Blood Marrow Transplant 2009;15:910-918.

17 Bolanos-Meade J, Jacobsbohn Da, Margolis J, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol 2005;23:2661-2668.

18 Rodny J, Haverkos BM, McBride A, et al. Tocilizumab for steroid refractory acute graft-versus-host disease. Leuk Lymphoma 2016;57:81-85.

5 Magenau JM, Goldstein SC, Peltier D, et al.alpha1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood 2018;131:1372-1379.

19 Drobyski WR, Pasquini M, Kovatovic K, et al. Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transplant 2011;17:1862-1868.

6 MacMillan ML, Weisdorf DJ, Davies SM, et al. Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host host disease. Biol Blood Marrow Transplant 2002;8:40-46.

20 Ganetsky A,Frey NV,Hexner EO,et al.Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower gastrointestinal tract. Bone Marrow Transplant 2019;54:212-217.

7 Schmidt-Hieber F, Fitzet T, Knauf W,et al.Efficacy of the interleukin-2 receptor antagonist basilimaxib in steroid-refractory acute graft-versus-host disease. Br J Haematol 2005;130:568-574.

21 Yucebay F, Matthews C, Puto M, et al. Tocilizumab as first-line therapy for steroid-refractory acute graft-versus-host disease: analysis of a single-center experience. Leuk Lymphoma 2019;60:2223-2229.

8 Busca A, Locatelli F, Marmont F, et al. Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation.Am J Hematol 2007;82:45-52.

22 Holtan SG,Hoeschen A,Cao Q,et al.Phase II,open-label clinical trial of urinary-derived human chorionic gonadotropin/epidermal growth factor for life-threatening acute graft-versus-host disease. Transplant Cell Ther 2023;29:509.e1-509.e8.

9 Abu-Dale l, Reljic T, Nishiri T, et al. Extracorporeal photophereesis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies. Biol Blood Marrow Transplant 2014;20:1677-1686.

10 Courriel D, Saliba R, Hicks K, et al. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood 2004;104:649-654.

23 Li ACW, Dong C, Tay ST, et al. Vedolizumab for acute gastrointestinal graft versus-host disease: A systematic review and meta-analysis. Front Immunol 2022;13:1025350.

11 Hoda D, Pidala J, Salgado-Vila N, et al. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant 2010;45:1347-1351.

24 Khoury HJ, Langston AA, Kota VK, et al. Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. Bone Marrow Transplant 2018;53:826-831.

12 Pidala J, Kim J, Anasetti C. Sirolimus as primary treatment of acute graft-versus-host disease following allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2009;15:881-885.

25 Modi B, Hernandez-Henderson M, Yang D, et al. Ruxolitinib as salvage therapy for chronic graft-versus-host disease. Biol Blood Marrow Transplant 2019;25:265-269.

26 Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med 2021;385:228-238.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Graft-Versus-Host Disease

NCCN Guidelines Index Table of Contents Discussion

SUGGESTED SYSTEMIC AGENTS FOR STEROID-REFRACTORY GVHD REFERENCES

27 Miklos D, Cutler CS, Arora M, et al. Irubinitin for chronic graft-versus-host disease after failure of prior therapy. Blood 2017;30:2243-2250.

28 Carpenter PA, Kang HJ, Yoo KH, et al. Irubinitin treatment of pediatric chronic graft-versus-host disease: Primary results from the Phase 1/2 iMAGINE study.Transplant Cell Ther 2022;28:771.e1.771.e10.

29 Cutler CS, Lee SJ, Arai S, et al. Belumosudui for chronic graft-versus-host disease(cGVHD) after 2 or more prior lines of therapy: The ROCKStar Study.Blood 2021;138:2278-2289.

30 Wolff D, Cutler C, Lee SJ, et al. Safety and efficacy of axilatimab at 3 different doses in patients with chronic graft-versus-host disease(AGAVE-201). Blood 2023;142:(Supplement 1):1.

31 Nahas MR,Soffer RJ,Kim HT,et al.Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. Blood 2018;131:2836-2845.

32 Nikiforow S, Kim HT, Bindra B, et al. Phase I study of alemutzumab for therapy of steroid-refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant 2013;19:804-811.

33 Gutierrez-Aguirre CH, Cantu-Rodriguez OG, Borjas-Almaguer OD, et al.Effectiveness of subcutaneous low-dose alemtuzumab and rituximab combination therapy for steroid-resistant chronic graft-versus-host disease.Haematologica 2012;97:717-722.

34 Yanik GA, Mineishi S, Levine JE, et al. Soluble tumor necrosis factor receptor:embrel(etanercept) for subcute pulmonary dysfunction following alogeneic stem cell transplantation. Biol Blood Marrow Transplant 2012;18:1044-1054.

35 Gilman AL, Chan KW, Mogul A, et al. Hydroxychloroquine for the treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2000;6:327-334.

36 Olivieri A, Cimminiello M, Corradini P, et al. Long-term outcome and prospective validation of NIH response criteria in 39 patients receiving imatinib for steroid-refractory chronic GVHD. Blood 2013;122:4111-4118.

37 Arai S, Pidalaj R, Pusic I, et al. A randomized phase II crossover study of imatinib or rituximab for cutaneous sclerosis after hematopoietic cell transplantation. Clin Cancer Res 2016;22:319-327.

38 Koreh J,Kim HT,Jones KT,et al.Efficacy,durability,and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood 2016;128:130-137.

39 Giaccone L, Martin P, Carpenter P,et al. Safety and potential efficacy of low-dose methotrexate for treatment of chronic graft-versus-host disease. Bone Marrow Transplantation 2005;36:337-341.

40 de Lavallade H, Moothy M, Faucher C, et al. Low-dose methotrexate as salvage therapy for refractory graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation. Haematologica 2006;91:1438-1440.

41 Huang XJ, Jiang Q, Chen H, et al. Low-dose methotrexate for the treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.Bone Marrow Transplant 2005;36:343-348.

42 Courriel DR, Saliba R, Escalon MP, et al. Sirolimus in combination with tacrolimus and corticosterols for the treatment of resistant chronic graft-versus-host disease. Br J Haematol 2005;130:409-417.

43 Johnston LJ, Brown J, Shizuru JA, et al. Rapamycin(sirolimus) for treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2005;11:47-55.

44 Jurado M, Vallejo C, Perez-Simon JA,et al. Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant 2007;13:701-706.

45 Lopez F, Parker P, Nademanee A, et al. Efficacy of mycophenolate mofetil in the treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2005;11:307-313.

46 Goldberg JD, Jacobsohn DA, Margolis J, et al. Pentostatin for the treatment of chronic graft-versus-host disease in children. J Pediatr Hematol Oncol 2003;25:584-588.

47 Jacobsohn DA, Chen AR, Zahurak M, et al. Phase II study of pentostin in patients with corticosteroid-refractory chronic graft-versus-host disease. J Clin Oncol 2007;25:4255-4261.

48 Saven A, Piro L. Newer purine analogues for the treatment of hairy-cell leukemia.N Engl J Med 1994;330:691-697.

49 Kharfan-Dabaja MA,Mhaskar AR,Djulbegovic B,et al.Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. Biol Blood Marrow Transplant 2009;15:1005-1013.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Graft-Versus-Host Disease

NCCN Guidelines Index Table of Contents Discussion

GVHD SUPPORTIVE CARE

All Patients

●Supportive care is essential for patients with GVHD.1

●Special attention is required for the following issues:

Appropriate antimicrobial prophylaxis should be used with escalating immunosuppressive therapy. See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

Surveillance for CMV reactivation is recommended in appropriate patients. Additional viral surveillance may be considered.

Vaccination:

Avoid live vaccines if patient is on immunosuppressive therapy or has active GVHD.

COVID-19 re-vaccination is recommended in all patients 3 months post-transplant. See the CDC for Use of COVID-19 Vaccines in the US.

IV immunoglobulin(IVIG) replacement: There may be subsets of patients where prophylactic immunoglobulin replacement after bone marrow transplant may be considered, such as in recipients of a UCB transplant,in children undergoing transplantation for inherited or acquired disorders associated with B-cell deficiency, and in patients with chronic GVHD with recurrent sinopulmonary infections.2

HD steroid therapy may be associated with glucose intolerance,hypertension, adrenal insufficiency, poor wound healing, myopathy,osteoporosis, vitamin D deficiency, and mood swings.

Vitamin D and calcium supplementation should be considered for patients on HD steroid. Monitoring of vitamin D level is recommended.

DEXA scan(in particular for patients with either current or past exposure to HD steroids) with treatment and repeat imaging as indicated based on results.

▶Dermatologic,dental,and ophthalmologic evaluation at appropriate intervals beginning 6-12 months post-transplant.

Ursodiol for patients with liver GVHD may be considered.3,4

Acute GVHD

●Skin

Avoid direct sunlight, use sunlight, and avoid photosensitizing agents.

Dermatologic assessment is recommended for advanced disease.

●GI Tract

Cautious use of opioid medications is recommended for severe abdominal pain(risk of ileus).

●Gl Tract(continued)

●Cautious use of octreotide is recommended for diarrhea control. It should be stopped once diarrhea resolves, or after 7 days of treatment(risk of ileus).

●Prolonged oral beclomethasonea or budesonide may cause adrenal insufficiency. Monitor for symptoms and evaluate as clinically necessary.

●Nutrition

●Patients may suffer from malnutrition and protein-losing enteropathy with deficiency of trace elements(eg,magnesium,zinc) and vitamins(eg,thiamine,vitamins B12 and D).

Total parenteral nutrition and bowel rest should be considered in patients with voluminous diarrhea or poor tolerance to oral intake.

●Monitoring for thiamine deficiency should be considered for patients with altered mental status.

Chronic GVHD

·Oral

Sialagogues(eg, cevimeline) may be considered with severe xerostomia.

▶Dental/oral surgery assessment is recommended for suspicious oral lesions(risk of malignancy).

Consider dexamethasone or CNI mouth rinses(swish and spit).

●Monitor for oral thrust and use appropriate antifungal topical therapy as indicated.

●Eyes

●Ophthalmologic assessment is recommended.

Patients may benefit from artificial tears, autologous serum drops, punctal plugs, or gas-permeable scleral lenses.

Patients with severe ocular sicca may benefit from cholinergic agents(cevimeline or pilocarpine).

●GI Tract

●Gl consultation is recommended for patients with esophageal stricture(may benefit from periodic dilatation).

Workup is recommended for malabsorption from prolonged diarrhea(patients with pancreatic atrophy may benefit from oral pancreatic enzymes).

●Genital Tract

Concerns around genitourinary symptoms(eg, urinary issues, erectile dysfunction, vulvovaginal symptoms) should be addressed with referrals as appropriate(ie, dermatology, urology, gynecology).

●Physical therapy may help patients with musculoskeletal, sclerotic, or neuromuscular disease.

Footnote and

References on

GVHD-F 1 OF 2

NCCN Guidelines Version 3.2025 Graft-Versus-Host Disease

NCCN Guidelines Index Table of Contents Discussion

GVHD SUPPORTIVE CARE

FOOTNOTE AND REFERENCES

Note: All recommendations are category 2A unless otherwise indicated.

GVHD-F 2 OF 2

Footnotea Oral beclomethasone is available as a compounded agent.

References

1 Carpenter P, Kitko C, Elad S, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 2015;21:1167-1187.

2 Bhella S, Majhail NS, Betcher J, et al. Choosing Wisely BMT: American Society for Blood and Marrow Transplantation and Canadian Blood and Marrow Transplant

Group's List of 5 Tests and Treatments to Question in Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2018;24:909-913.

3 Ruutu T, Juvonen E, Remberger M, et al. Improved survival with ursodeoxycholic acid prophylaxis in allogeneic stem cell transplantation: long-term follow-up of a

randomized study. Biol Blood Marrow Transplant 2014;20:135-138.

4 Ruutu T, Eriksson B, Remes K, et al. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood 2002;100:1977-

1983.

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figure67fe2c1c1aff40b6a2c84a060c0d0b48_0_1.png) National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

|BOS|BOS|BOS|BOS| |---|---|---|---| |ADL|activities of daily living|G-CSF|granulocyte colony-stimulating| |AIHA|autoimmune hemolytic anemia||| |ALT|alanine transaminase|GI|gastrointestinal| |AP|alkaline phosphatase|GVHD|graft-versus-host disease| |ATG|antithymocyte globulin|HBV|hepatitis B virus| |AUC|area under the curve|HCT|hematopoietic cell transplant| |BOS|bronchiolitis obliterans syndrome|HCV|HCT-CI| |BSA|body surface area|HD|hepatitis C virus| |CMV|cytomegalovirus|HIV|high-dose| |CNI|calcineurin inhibitor|HL|Hodgin lymphoma| |COP|cryptogenic organizing pneumonia|HL|human leukocyte antigen| |DEXA|dual-energy x-ray absorptiometry|HSV|STR| |DLCO|diffusing capacity of the lungs for carbon monoxide|ITP|immune thrombocytopenia intravenous immunoglobulin| |ECOG|Eastern Cooperative Oncology Group|KCS|keratoconjunctivitis sicca| |ECP|extracorporeal photopheresis|LFT|Karnofsky Performance Status| |FEV1|forced expiratory volume in the first second|LVEF|left ventricular ejection fraction| ||MA|myeloablative|VC VOD/SOS|

|NHL|non-Hodgkin lymphoma| |---|---| |non-myelaloablative|| |non-relapse mortality|| ||pulmonary function test| |photographic range of motion|| |post-transplant|cyclophosphamide| |psoralen and ultraviolet A irradiation|| |reduced-intensity conditioning range of motion|| |range of motion|| ||short tandem repeat| |TBI|total body irradiation|

non-Hodgkin lymphoma non-myeloablative NRM non-relapse mortality

|Pulmonary function test||| |---|---|---| |photographic range of motion||| |post-transplant||| |cyclophosphamide||| |psoralen and ultraviolet A||| |irradiation||| |reduced-intensity conditioning||| |range of motion||| |short tandem repeat||| |TBI|total body irradiation||

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation

NCCN Guidelines Index Table of Contents Discussion

|NCCN Categories of Evidence and Consensus|| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is NCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference|| |---|---| |Preferred intervention|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended intervention|Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.| |Useful in certain circumstances|Other interventions that may be used for selected patient populations (defined with recommendation).|

All recommendations are considered appropriate.

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figuredbc1d1ad9d1c41148747471c53d432d5_0_1.png) National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

Discussion

This discussion corresponds to the NCCN Guidelines for Hematopoietic Cell Transplantation. Last updated September 24, 2025.

Post-Transplant Follow-Up 10

Management of Graft-Versus-Host Disease $\ldots$ 10

Overview $\ldots$ 2

Acute Graft-Versus-Host Disease 10

Diagnosis and Grading.11

Guidelines Update Methodology $\ldots$ 3

First-Line Therapy of aGVHD 11

Literature Search Criteria.3

Chronic Graft-Versus-Host Disease 13

Sensitive/Inclusive Language Usage $\longdots$ 3

Diagnosis and Grading.13

Autologous Hematopoietic Cell Transplant $\ldots$ 3

First-Line Therapy of cGVHD 14

Allogeneic Hematopoietic Cell Transplant...4

Steroid-Refractory GVHD 14

Indications for Transplantation $\ldots$ 4

Suggested Agents for Steroid-Refractory aGVHD..14

Donor Source $\ldots$ 4

Suggested Agents for Steroid-Refractory cGVHD.21

Pre-Transplant Recipient Evaluation..5

GVHD Supportive Care.29

Hematopoietic Cell Mobilization.6

Supportive Care for All Patients with GVHD 29

Hematopoietic Cell Mobilization for Autologous Donors.6

Supportive Care for Acute GVHD $\ldots$ 30

Dosing and Administration 7

Supportive Care for cGVHD $\ldots$ 30

Additional Therapy $\ldots$ 7

Summary $\ldots$ 31

Hematopoietic Cell Mobilization for Allogeneic Donors $\ldots$ 7

References.32

Dosing and Administration 8

Additional Therapy $\ldots$ 8

Principles of Conditioning for HCT 8

Conditioning Regimens Without Fludarabine.9

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figure7de90c5d4e4a47cf80b2450d3d9aee73_0_1.png)

National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

Overview

Hematopoietic cell transplantation(HCT) involves the infusion of hematopoietic cells after preparation with cytotoxic conditioning regimens in order to eradicate disease and establish adequate hematopoietic and immune function.1 HCT is potentially curative for patients with certain types of hematologic malignancies and is also used to support patients undergoing high-dose chemotherapy for the treatment of certain solid tumors. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. An autologous HCT uses the patient's own cells while an allogeneic HCT uses hematopoietic cells from a human leukocyte antigen(HLA)-compatible related or unrelated donor. Prior to HCT, most patients receive chemotherapy, immunotherapy, and/or radiation therapy for pre-transplant conditioning(conditioning regimen). In allogeneic HCT,conditioning regimens are administered in order to eradicate malignant cells in the bone marrow(if using a myeloablative[MA] regimen) and to immunosuppress the recipient so that engraftment of healthy donor cells can occur.1 In autologous HCT, MA conditioning regimens are used to treat the malignancy. This is followed by rescue infusion of the patient's own cells, which are collected and stored before high-dose therapy, in order to restore hematopoiesis and reconstitute the immune system.1

The Center for International Blood and Marrow Transplant Research(CIBMTR) estimates a total of>20,000 allogeneic and autologous transplants were performed in the United States in 2022.2 Acute myeloid leukemia(AML), myelodysplastic syndromes(MDS), myeloproliferative neoplasms(MPN), and acute lymphoblastic leukemia(ALL) were the most common malignancies treated with allogeneic HCT, while autologous HCT was used most frequently in multiple myeloma(MM)/plasma cell disorders,non-Hodgkin lymphoma(NHL), and Hodgkin lymphoma(HL).2 Difficult logistics and high costs create significant barriers to access for many patients. Studies have found older age, lower socioeconomic status, lower

educational status, uninsured status, and non-white race to be associated with reduced access to HCT.3-6 In addition to reduced access to HCT,studies have revealed that Black individuals have worse transplant-related outcomes, with significantly higher transplant-related mortality (TRM)compared to white individuals, even when controlling for insurance coverage.4

Outcomes of HCT vary according to the type and stage of the disease being treated, the overall health and comorbidities of the patient, and for allogeneic HCT, the degree of HLA mismatch between donor and recipient, the source of the hematopoietic cells, and the immunosuppressive regimen given to prevent graft-versus-host disease(GVHD), a common complication of allogeneic HCT.1,

Hematopoietic cells can be obtained from peripheral blood, bone marrow,or umbilical cord blood (UCB). Several clinical factors should be considered when determining the optimal graft source for an individual patient, including disease type, disease stage, patient comorbidities, and the urgency for transplantation. ${ }^{8}$ The use of peripheral blood progenitor cells (PBPCs) has largely replaced the use of bone marrow grafts (in particular for autologous HCT) due to the ease of collection, avoidance of general anesthesia, more rapid engraftment rates, and reduced risk of graft failure.9-11 However, allogeneic PBPC transplants are associated with an increased risk of chronic graft-versus-host disease (cGVHD) compared to bone marrow transplants.11-13

Advantages of using UCB grafts include rapid cell procurement, lower incidence of cGVHD, and less stringent HLA-matching requirements;however, use of UCB is limited by the cell doses that can be achieved in recipients with higher body weights and is also associated with delayed engraftment, higher risk for graft failure, higher rates of infectious complications, and higher costs for procurement.14 Therefore, UCB transplantation is typically reserved for patients without an HLA-matched

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

donor and should be performed in centers with expertise in this procedure.Patients without an HLA-matched donor may also be candidates for HCT from a haploidentical, or half HLA-matched, related donor. Advantages of haploidentical HCT include lower costs for procurement and rapid availability of the cell products, while disadvantages include increased risk of graft failure and GVHD as compared to HLA-matched HCT.15 The use of post-transplant cyclophosphamide has been shown to reduce the incidence of GVHD in haploidentical HCT recipients.16 Several investigators have also advocated for the use of bone marrow grafts for haploidentical HCT and HLA-mismatched unrelated donor HCT to reduce the risk of GVHD.12,13,17

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are available at www.NCCN.org.

Literature Search Criteria

Prior to the update of the NCCN Guidelines® for Hematopoietic Cell Transplantation, an electronic search of the PubMed database was performed to obtain key literature in HCT published since the previous Guidelines update, using the following search terms: hematopoietic stem cell transplant; allogeneic cell transplant; autologous cell transplant; and graft-versus-host disease. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.18

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following types: Clinical Trial,Phase II; Clinical Trial,Phase III; Clinical Trial,Phase IV; Guideline;Practice Guideline; Meta-Analysis; Randomized Controlled Trial;Systematic Reviews; and Validation Studies.

The data from key PubMed articles as well as articles from additional sources deemed as relevant to these Guidelines as discussed by the Panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel's review of lower-level evidence and expert opinion.

Sensitive/inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity,inclusion, and representation.NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist,anti-misognist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive of individuals of all sexual orientations and gender identities.NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics,recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently.If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Autologous Hematopoietic Cell Transplant

Autologous HCT is performed to replace or“rescue” hematopoietic cells damaged by the high-dose chemotherapy used to treat certain advanced or high-risk hematologic malignancies and solid tumors. Hematopoietic

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cells collected from the patient prior to receipt of high-dose chemotherapy are infused back into the patient after administration of the preparative regimen.1 High-dose chemotherapy with autologous HCT is an effective treatment for several hematologic malignancies, including MM,19-23 relapsed/refractory(R/R) HL,24,25 and R/R NHL.26-28 While autologous HCT may prolong progression-free survival(PFS) and overall survival(OS) for patients with MM, it is not curative.29 Autologous HCT is also used in patients receiving high-dose chemotherapy for the treatment of certain solid tumors, including testicular germ cell tumors30-33 and some central nervous system tumors,34-38 for whom hematologic toxicity would otherwise limit chemotherapy administration. Additionally, autologous HCT is sometimes used as consolidation therapy for certain patients with AML.39

Since autologous HCT uses the patient's own cells, these patients do not typically develop GVHD. Additionally, these patients often have a lower risk of infectious complications since they do not receive post-transplant immunosuppression. Compared to allogeneic HCT,autologous HCT is associated with less morbidity and mortality but greater risk of disease relapse.1 There is no benefit to graft purging(ex vivo manipulation to eliminate residual neoplastic cells) prior to autologous HCT. 40,41

Allogeneic Hematopoietic Cell Transplant

Allogeneic HCT is performed to replace malignant(or defective)hematopoietic cells using those from a healthy donor. A preparative regimen consisting of chemotherapy (often high-dose), immunotherapy,and/or total body (or lymphoid) irradiation is given prior to allogeneic HCT to eliminate residual malignant cells and to suppress the recipient's immune system, which is necessary to allow for engraftment of the donor-derived cells and to prevent graft rejection.

Indications for Transplantation

Indications for HCT(allogeneic or autologous) vary by disease type and remission status. Information on indications for HCT can be found in disease-specific NCCN Guidelines, available at www.NCCN.org.The American Society for Transplantation and Cellular Therapy (ASTCT) has also published clinical practice guidelines on indications for autologous and allogeneic HCT.8

Allogeneic HCT improves outcomes in patients with many subtypes of AML42 and ALL43 patients with MDS,44 patients with relapsed and/or refractory HL45 and NHL46 and certain patients with chronic myeloid leukemia(CML),47 such as those with advanced-phase disease and those whose disease is refractory to tyrosine kinase inhibitor therapy, including patients with certain high-risk ABL kinase mutations. Allogeneic HCT has also been offered to some patients with chronic lymphocytic leukemia(CLL),48 MM,49 and primary and secondary myelofibrosis,50 although benefits for these patients are less clear and toxicity may be greater.Decisions regarding allogeneic HCT are always complex and should be carefully weighed as part of shared decision-making between the transplant team and patient. Donor-derived immune cells may exert an immune-mediated cytotoxic effect against the recipient's neoplastic cells(ie, graft-versus-tumor effect). This phenomenon was described several decades ago and its clinical impact was demonstrated in a seminal CIBMTR study of >2000 patients that showed a reduced relapse risk among patients with GVHD.51 The graft-versus-tumor effect is considered a major mechanism for sustained response following allogeneic HCT, in particular with reduced-intensity or non-MA (NMA) HCT. 52,53

Donor Source

There are three potential donor sources for hematopoietic cells: related donor(family members), unrelated volunteers(from donor registries), and

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UCB units.1 HLA matching is the most important factor when choosing a donor. An HLA-matched sibling remains the preferred donor source,although post-transplant survival is comparable among patients receiving hematopoietic cells from HLA-matched unrelated donors(MUDs) for several diseases.54,55

When a patient has no HLA-matched related or unrelated donors, a haploidentical donor or UCB may be used. A haploidentical donor is a first-degree relative who matches at least half of the HLA loci of the patient.Emerging data suggest that haploidentical HCT with post-transplant cyclophosphamide(PTCy) for GVHD prophylaxis yields comparable outcomes to HLA-matched HCT.56,57 Of note, a retrospective multicenter analysis found that use of haploidentical donors beyond first-degree relatives may negatively affect survival.58

UCB transplant was first reported to cure a child with Fanconi anemia,59 and has been subsequently used successfully in patients with hematologic malignancies.60,61 Outcomes of UCB transplants have been comparable to HLA-matched transplants in some reports.54,62-65 Although recipients of UCB transplants may experience delayed engraftment and delayed immune reconstitution, which may result in increased risks of infectious complications, UCB transplants are associated with less GVHD.54 Importantly, UCB provides a graft source for many patients who lack other donors, particularly for patients with mixed or non-white genetic ancestry.66,67

While the high degree of HLA disparity that typically occurs with haploidentical or UCB donors has been associated with an increased risk of graft failure, haploidentical and UCB transplants have increased access to HCT for individuals with otherwise limited donor availability. 54,62-65,68

Donor age is emerging as one of the most important predictors of outcomes in MUD and haploidentical donor HCTs.69-72 Retrospective data

from 1802 patients from the CIBMTR suggest increased risk with donor age>30 years.72 Data revealed a significant 3-year OS benefit with a donor age of 18 years compared to a donor age of≥34 years; however,there was minimal difference in OS with a donor age of 22 to 30 years compared to a donor age of 18 years.72

Pre-Transplant Recipient Evaluation

The pre-transplant recipient evaluation generates data to estimate the risks of relapse, non-relapse mortality (NRM), and OS. It also generates information that may inform other transplant-related decisions.Physiological age, as measured by performance/functional status and use of geriatric assessments, rather than chronological age, should be used to determine eligibility for HCT.8,73 Selected patients who are older with limited comorbidities and good functional status can safely receive HCT with a relatively low risk of NRM.74-77 Studies such as the recently completed BMT CTN 1704 are assessing the utility of geriatric assessment tools in predicting outcome of HCT in patients who are older.78 Determining functional status (Karnofsky or ECOG performance status) and HCT-Comorbidity Index (HCT-CI) score79 are essential to determine candidacy for HCT (in particular for allogeneic HCT). HCT-CI score has been validated to predict the risk of NRM and estimated survival after allogeneic transplant. 80,81 HCT-CI has also been shown to predict survival after autologous transplant. 82,83 Furthermore, an updated composite-age HCT-CI has also been shown to have the same utility. 84 Detailed clinical assessment of HCT-CI has been published. 85 For specific information on pre-transplant donor evaluation and HLA typing, refer to the Foundation for the Accreditation of Cellular Therapy and Joint Accreditation Committee- International Society for Cell and Gene Therapy(ISCT) and European Society for Blood and Marrow Transplant(EBMT)(JACIE) International Standards, 8th edition.86 For more

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information regarding pre-transplant recipient evaluation, see Pre-Transplant Recipient Evaluation in the algorithm.

Hematopoietic Cell Mobilization

Granulocyte-colony stimulating factors(G-CSF),including fibrastim, tobilgrastim, pegfilgrastim, and fibrastim/pegfilgrastim biosimilars, are commonly administered in the HCT setting for mobilization of PBPCs.Mobilization of PBPCs by G-CSF has largely replaced use of bone marrow grafts due to the ease of collection, avoidance of general anesthesia, more rapid engraftment rates, and lower TRM.9-11 For donor evaluation and follow-up recommendations, refer to the FACT-JACIE International Standards, 8th edition; https://www.factglobal.org/ctstandards).86

Hematopoietic Cell Mobilization for Autologous Donors

Effective mobilization regimens for autologous donors include G-CSF plus plerixafor, G-CSF plus cyclophosphamide with or without plerixafor,granulocyte-macrophage colony-stimulating factor(GM-CSF) plus cyclophosphamide with or without plerixafor, pegfilgrastim plus plerixafor,G-CSF alone, G-CSF plus disease-specific chemotherapy with or without plerixafor, and G-CSF plus mixofafortide(for patients with MM). Adequate PBPC collection depends on individual patient- and disease-related factors. The minimum target yield for PBPC collection is 2 to $5 \times 10^{6}$ $PD34+$ cells/kg, with a target of 4 to $5 \times 10^{6}$ $CD34+$ cells/kg may result in delayed engraftment, while larger cell doses have been associated with a more rapid time to platelet and neutrophil recovery. ${}^{87}$

Single-agent G-CSF(filgrastim,tbo-filgrastim,or filgrastim biosimilars) is effective in mobilizing PBPCs in the autologous setting.88-92 The addition of the CXCR4 inhibitor plerixafor to G-CSF mobilization accelerates the rise in PBPC count.93-101 In a phase III trial, the addition of plerixafor to G-CSF improved PBPC collection yields and reduced mobilization failure rates in

patients with heavily pre-treated NHL, with 59% of patients in the G-CSF plus plerixafor group collecting≥5 x 106 CD34+ cells/kg in≤4 apheresis days compared to 20% of patients in the G-CSF alone group ( P < .001).99 Another phase III trial found similar results in patients with MM, with 71.6%of patients in the plerixafor plus G-CSF group collecting≥6 x 106 CD34+cells/kg in≤2 apheresis days compared to 34.4% of patients in the G-CSF alone group ( P < .001). ${ }^{100}$ Therefore, G-CSF plus plerixafor as well as single-agent G-CSF are recommended for PBPC mobilization in the autologous setting. The addition of a novel cyclic-peptide CXCR4 inhibitor,motixafortide, to G-CSF may also improve PBPC collection yields in patients with MM, with 92.5% of patients in the motixafortide plus G-CSF group collecting≥6 x 106 CD34+ cells/kg in ≤2 apheresis days compared to 26.2% of patients in the G-CSF alone group ( P < .0001). ${ }^{102}$ Therefore,G-CSF plus mixotifaortide is a recommended PBPC mobilization option for patients with MM in the autologous setting.

The addition of chemotherapy agents such as cyclophosphamide to G-CSF may also result in higher PBPC collection yields with fewer days of apheresis compared to G-CSF alone and may reduce the burden of residual tumor.103,104 In a trial comparing chemotherapy+ G-CSF to G-CSF alone, the addition of chemotherapy resulted in higher total cells collected (18.6 x $106/kg vs.7.0 x $106/kg; P<.001), fewer days of apheresis (2.0 vs.2.9;P<.001), and fewer re-mobilizations (1.06 vs. 1.2;P=.01) but also required substantially more apheresis days (12.5 vs. 4.2 days; P<.001), with higher total cost ($19,614 vs. $16,852; P=.003).${}^{104} In a study of patients with MM comparing cyclophosphamide plus G-CSF to plerixa for plus G-CSF, the cyclophosphamide group had significantly lower total CD34+ collection yields (median 7 x 106/kg vs. 11.6 x 106/kg; P=.001) and higher mobilization failure rates (8.1% vs. 0), but significantly lower costs ($19,626.5 vs. $28,980; P<.0001).${}^{93}$ Another study showed no difference in mobilization efficacy between G-CSF plus cyclophosphamide and GM-CSF (sargramostim) plus cyclophosphamide

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in patients with NHL.105 Therefore, G-CSF or GM-CSF plus cyclophosphamide with or without plerixafor are recommended regimens for PBPC mobilization in the autologous setting. Chemomobilization regimens using other chemotherapy agents with disease-specific activity are also appropriate.

Although there are limited high-quality data supporting the use of pegfilgrastim in this setting, some small studies suggest that pegfilgrastim may have similar efficacy to filgrastim for mobilization. 106-111 Therefore,pegfilgrastim or pegfilgrastim biosimilars plus plerixafor are also appropriate options for mobilization in the autologous setting.

Dosing and Administration

The NCCN Panel recommends administration of filgrastim, tbo-filgrastim,or a filgrastim biosimilar as single agents, or as part of a chemomobilization regimen for 4 to 5 days after the completion of cyclophosphamide(or other disease-directed therapy), at a dose of 10 mcg/kg body weight per day in daily or twice-daily(split) dosing by subcutaneous injection. Sargramostim should be administered at a dose of 250 mcg/m2 per day either by intravenous infusion over 24 hours or by subcutaneous injection once daily for 4 to 5 days. Pegfilgrastim is given as a single dose of 6 mg by subcutaneous injection on Day 1. Apheresis usually commences on the fourth or fifth day following initiation of growth factor.Plerixafor is generally administered by subcutaneous injection 11 hours prior to hematopoietic cell collection. Plerixafor dosing is based on patient body weight and estimated creatinine clearance. Clinical judgment should be used when the white blood cell count is>50,000; these patients should be monitored carefully for splenic pain due to rare cases of splenomegaly or splenic rupture.

Additional Therapy

If CD34+ cell yield is inadequate(<2x106 CD34+ cells/kg), consider increasing G-CSF dose or changing dose schedule. If not administered prior to cell collection, the addition of plerixa for G-CSF or chemotherapy plus G-CSF is also recommended. The addition of plerixa for as preemptive(“just in time”) strategy in patients with poor mobilization after administration of G-CSF with or without chemotherapy has been highly successful.95,96,112-114 Risk factors associated with poor mobilization include older age, extensive prior therapy, prior radiation to marrow-containing regions, low white blood cell count(<4000), or multiple cycles of certain agents such as fludarabine or lenalidomide.97,115-124 Additional studies have suggested there may also be genetic parameters that contribute to mobilization outcome.125 However, predicting mobilization failure based on baseline patient characteristics or risk factors has historically been highly inaccurate.9 Bone marrow harvest can also be considered in the setting of poor mobilization.126 For bone marrow harvest recommendations, refer to the National Marrow Donor Program/Be the Match. If feasible, consider rest for 2 to 4 weeks before a remobilization attempt.Hematopoietic Cell Mobilization for Allogeneic Donors

Hematopoietic Cell Mobilization for Allogeneic Donors

G-CSF alone should be used to mobilize allogeneic donors. Initially, there were concerns about using G-CSF for mobilization in the allogeneic setting due to toxicity for the donor and the risk for GVHD in the recipient.However, studies have demonstrated filgrastim to be well-tolerated by donors without an effect on long-term survival in the recipient.127-129 Data supporting the use of filgrastim biosimilars in the allogeneic setting are sparse. Some studies have suggested that filgrastim biosimilars are effective for mobilization in healthy donors with no short-term safety issues,130-134 but long-term data are needed. In a study by the World Marrow Donor Association(WMDA), mobilization of CD34+ cells and incidence of treatment-related adverse events were found to be similar between filgrastim biosimilars and reference filgrastim in 1287 healthy

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volunteers, ${ }^{135}$ although the authors cite a lack of long-term follow-up for both. Tbo-filgrastim has also been shown to effectively mobilize PBPCs for allogeneic transplantation in healthy donors. ${ }^{92,136,137}$ Based on these data,the NCCN Panel endorses the use of filgrastim, to-filgrastim, and filgrastim biosimilars for the mobilization of PBPCs in healthy allogeneic donors, but cautions physicians to closely follow patients receiving tbo-filgrastim or filgrastim biosimilars during the follow-up period in order to identify any potential complications or unexpected outcomes.The minimum target yield for PBPC collection in allogeneic donors is 4 to 5 x 106 CD34+ cells/kg.87

Dosing and Administration

Single-agent filgrastim, to-filgrastim, or a filgrastim biosimilar should be administered at a dose of 10 mg/kg per day in daily or twice daily (split)dosing by subcutaneous injection for 4 to 5 days. Apheresis usually commences on the fourth or fifth day following mobilization initiation.

Additional Therapy

If CD34+ cell yield is inadequate(<4 x 106 CD34+ cells/kg), consider addition of plerixafor to G-CSF. Bone marrow harvest is an alternative option.126 For bone marrow harvest recommendations, refer to the National Marrow Donor Program/Be the Match.

Principles of Conditioning for HCT

Conditioning regimens are categorized into three groups based on their intensity.138 MA regimens cause irreversible(or near irreversible)pancytopenia. Hematopoietic cell support is required to rescue marrow function and prevent aplasia-related death. Regimens that include total body irradiation(TBI)(≥5 Gy single dose or≥8 Gy fractionated) or busulfan>8 mg/kg orally (>6.4 mg/kg IV) or busulfan plasma exposure unit(BPEU) equivalent are MA regimens.139 NMA conditioning regimens

produce moderate-to-minimal cytopenia, and graft rejection, if it occurs,would be followed by autologous hematopoietic recovery. Examples include TBI≤2 Gy± purine analog and total lymphoid irradiation +antithymocyte globulin(ATG). A reduced-intensity conditioning(RIC)regimen is one that does not fulfill the criteria for either an MA or NMA regimen.RIC regimens differ from NMA regimens in that they cause cytopenias that do require hematopoietic cell support, but the doses of alkylating agents or TBI is reduced in comparison to MA regimens.138

The choice among an MA, NMA, or RIC regimen is a nuanced decision that should be made by the transplant team at the time of pre-transplant recipient evaluation or upon review of pre-transplant organ testing,frailty/geriatricess assessment, or other evaluation. The selection of conditioning regimen intensity depends on many factors including patient age (chronologic and physiologic),84 performance status, HCT-Cl score,85 disease type, remission status(including measurable residual disease),and history of prior HCT. In patients who are young and fit, MA regimens may be preferred for ALL, AML, CML, and MDS.140 See HCT-A 3 of 10,Principles of Conditioning for Hematopoietic Cell Transplant, Examples of Commonly Used Conditioning Regimens, in the algorithm for a non-exhaustive list of MA regimens commonly used in autologous, allogeneic,and UCB transplants.

If UCB transplant is being used, referral to a center with experience in UCB transplants is strongly recommended. If an MA conditioning regimen is planned for a recipient of UCB,omidubicel-onlv, an ex vivo nicotinamide-modified allogeneic hematopoietic progenitor cell therapy derived from a single cord blood unit, has been shown to shorten the time to engraftment and reduce the risk of some infections.141 In a phase III trial, median time to neutrophil engraftment for UCB transplantation with omidubicel-onlv was 12 days compared to 22 days for standard UCB transplantation(P<.001).141 Similarly, platelet recovery was shorter in the

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omidubicel-onlv arm(55% vs.35% recovery at 42 days; P=.028). Grade 2-3 bacterial or invasive fungal infections were also less common in the omidubicel-onlv arm(37% vs.57%; P=.027).

NMA or RIC regimens may be preferred for patients undergoing allogeneic HCT for treatment of lymphoma (NHL or HL),CLL,and plasma cell disorders such as MM and plasma cell leukemia. NMA/RIC regimens may also be preferred for patients who have received a prior autologous HCT and patients who are not candidates for MA regimens. See HCT-A 3 of 10,Principles of Conditioning for Hematopoietic Cell Transplant, Examples of Commonly Used Conditioning Regimens, in the algorithm for a non-exhaustive list of NMA regimens commonly used in allogeneic transplant and HCT-A 4 of 10, Principles of Conditioning for Hematopoietic Cell Transplant, Examples of Commonly Used Conditioning Regimens, in the algorithm for a non-exhaustive list of RIC regimens commonly used in allogeneic and UCB transplants. Conditioning regimens commonly used in allogeneic and UCB transplants. Conditioning regimens commonly used in autologous transplants are listed by disease type on HCT-A 6 of 10,Principles of Conditioning for Hematopoietic Cell Transplant, Examples of Commonly Used Conditioning Regimens, in the algorithm). Suggested dose modifications by weight for many of the drugs commonly used in conditioning regimens are given in the Principles of Conditioning for Hematopoietic Cell Transplant: Suggested Doses/Modifications by Weight section of the algorithm. ${ }^{142}$

There are certain special situations that warrant more caution. For example, use of high-dose busulfan, cararmustine, or high-dose TBI in patients with significant pulmonary dysfunction should be carefully considered due to the substantial additional risk to the lungs. 143-145 The use of high-dose busulfan and high-dose TBI has been associated with an increased risk of sinusoidal obstruction syndrome(SOS) in patients with significant liver dysfunction. 146 An increased risk of SOS has also been associated with the use of dual alkylator-based regimens with pre-

transplant inotuzumab or gemutuzumab.147 Additionally, the alkylating agent thiotepa can be excreted through the skin and requires special skin care.148 The combination of sirolimus and tacrolimus may also be associated with higher risk of SOS and thrombotic microangiopathy(TMA), especially if used with MA regimens.149-152 Importantly, an increased risk of GVHD has been associated with pre-transplant treatment with immune checkpoint inhibitors (pre- or post-HCT) and mogamulizumab.153-156 Therefore, the Panel recommends considering a minimum 8- to 12-week window between these treatments and the start of transplant conditioning if clinically feasible.

Conditioning Regimens Without Fludarabine

There have been intermittent shortages of fludarabine, which is a component of many conditioning regimens.157 To address this, the Panel has developed recommendations for non-fludarabine RIC regimens for use during times of shortage(see Principles of Conditioning for Hematopoietic Cell Transplant: Conditioning Regimens Without Fludarabine in the algorithm for a non-inclusive list).The Panel suggests that the choice of regimen should be based on institutional preference and experience due to the lack of comparative data with fludarabine-based regimens.

Some of the regimens recommended by the Panel are associated with certain adverse events. For example, a systemic inflammatory syndrome has been reported with the use of clofarabine-based regimens, although concomitant steroid use may mitigate this risk.158 Additionally, use of certain cladribine-based regimens may be associated with increased risk of graft failure.159-161 The pentostatin+ busulfan+ cyclophosphamide regimen was reported with primary immunodeficiency disorders using post-transplant cyclophosphamide ${}^{162}$ and pentostatin+ TBI 4 Gy was reported for second transplant after engraftment failure.163

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Post-Transplant Follow-Up

Advances in HCT treatment paradigms, including supportive care, have led to improved survival.164 However, disease relapse and post-transplant complications continue to pose a major threat to HCT recipients. Disease relapse is more frequent in patients with advanced disease and in those receiving NMA conditioning regimens.165 Intensive supportive care is required for all post-transplant recipients until engraftment occurs. Post-transplant complications are common after both allogeneic and autologous HCT and are often caused by the conditioning regimen,166,167 delayed immune reconstitution, and/or GVHD(for allogeneic HCT and very rarely autologous HCT). The risk and type of complications are also influenced by patient-related factors such as age, performance status, and comorbidities.55,168,169 Early complications (generally occurring within the first 100 days post-HCT) include prolonged cytopenia/delayed engraftment, infections, hepatic venpo-occlusive disease(VOD)/SOS, and other organ toxicities such as cardiomyopathy or idiopathic pneumonia syndrome(IPS).166,170 Based on non-randomized trials, defibrotide is FDA approved for the treatment of hepatic VOD/SOS in patients with renal or pulmonary dysfunction following HCT(see defibrotide prescribing information for further details).

Late complications(after the first 100 days) include infections; late radiation-related toxicities(eg, cataracts, hypothyroidism); late chemotherapy-related toxicities(eg, heart failure); organ dysfunction;secondary malignancies including therapy-related myeloid neoplasms,breast and thyroid cancers, melanoma and non-melanoma skin cancers;endocrinopathies; and infertility, among others.166,170 GVHD is a common and significant risk in allogeneic HCT recipients. In GVHD, donor lymphocytes recognize the recipient's tissues as foreign, resulting in immune-mediated cellular injury. Acute GVHD(aGVHD) typically manifests in the skin, gastrointestinal(GI) tract, and/or liver, while chronic

GVHD may affect any organ but most commonly affects the eyes, mucosal surfaces, skin/joints/fascia, muscles, liver, and lungs.

Common causes of NRM after allogeneic HCT include GVHD, infections,cardiovascular disease, secondary malignancies, and organ toxicity.171-174 Common causes of NRM after autologous HCT include organ toxicity,cardiovascular disease, and infectious complications.175-177 Therefore,post-transplant care plans, including optimal supportive and survivorship care, are essential to optimize long-term outcomes in both autologous and allogeneic HCT recipients.

Management of Graft-Versus-Host Disease

GVHD is a common complication of allogeneic HCT and may be associated with significant morbidities and NRM.178-180 Despite advances in many aspects of allogeneic HCT, such as improved donor selection,more effective GVHD prophylaxis, increasing use of RIC, and ursodiol prophylaxis, GVHD remains a significant clinical problem. Mild manifestations of GVHD limited to a single organ are often managed with close observation, topical treatment, or by slowing tapering the immunosuppressive agents.181 More severe manifestations or multi-organ involvement typically require systemic corticosteroid treatment as the first-line approach; the addition of secondary agents may be required for patients who do not experience response to initial steroid therapy or who are unable discontinue steroids.180 GVHD management can be optimized with coordinated care from a multidisciplinary team, preferably in medical centers with access to specialized transplant services.

Acute Graft-Versus-Host Disease

Up to 50% of allogeneic HCT recipients will develop aGVHD.172,182,183 Risk factors include degree of HLA-matching, donor type, and choice of GVHD prophylaxis, which are often inter-related, as well as use of TBI in conditioning and graft source.180 The skin, Gl tract(upper and lower), and

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liver are the three organs primarily affected by aGVHD, which is generally characterized by maculopapular rash; Gl symptoms such as nausea,vomiting, and/or diarrhea; and hyperbilirubinemia as well as elevated transaminases.182,184 Pathologic confirmation of aGVHD should be considered whenever possible, especially before initiating or escalating systemic immunosuppression. Although biopsies are not absolutely sensitive or diagnostic, they may help exclude other diagnostic considerations.

Diagnosis and Grading

If aGVHD is suspected, organ-appropriate additional tests such as stool infectious disease testing, imaging studies, and/or viral testing should be performed to rule out non-GVHD causes of the symptoms. Organ-directed biopsies can then be performed as clinically indicated to support the presence of aGVHD or to exclude other diagnoses. GI biopsy (via esophagogastroduodenoscopy [EGD], colonoscopy, and/or flexible sigmoidoscopy) is recommended, whenever possible, for the diagnosis of GI aGVHD, particularly if stool infectious disease testing is unrevealing.Rectosigmoid biopsies were shown in one study to have higher sensitivity and negative predictive value than biopsies at other sites, whether the patient presented with diarrhea, nausea, or vomiting.185 Liver function tests(LFTs) should be routinely monitored after allogeneic HCT for early detection of hepatic aGVHD, which is often asymptomatic and can manifest with elevated transaminases without elevated bilirubin. Liver biopsy may be considered in patients presenting with unexplained abnormal LFTs without evidence of aGVHD elsewhere if the information would inform treatment. Once the diagnosis of aGVHD is made, the organ staging and overall grade of aGVHD should be determined to guide choice of therapy and disease monitoring.

Following an aGVHD diagnosis, clinicians should remain attuned to the possibility of alternative diagnoses causing persistent or worsening

symptoms. For example, persistent diarrhea in a patient with a history of Gl aGVHD may be related to mucosal denudation with delayed healing due to compromised gut epithelial stem cell function, yet without active GVHD. On a case-by-case basis, repeat EGD/colonoscopy may therefore be indicated to differentiate which patients may benefit from additional immunosuppressive agents. Similarly, if one affected organ system has shown improvement with aGVHD management and another is worsening on therapy, an alternative explanation should be investigated, as it is unusual to have disparate responses in different organ systems.

The clinical grade of aGVHD is predictive of survival. Glucksberg aGVHD grading criteria were first proposed in 1974.186 Modified Glucksberg(consensus or Keystone) criteria were developed in 1994 (see Acute GVHD: Staging and Grading in the algorithm for modified Glucksberg grading criteria). 178The IBMTR Severity Index was subsequently developed,187 and was shown to be more predictive of HCT outcome when compared with the original Glucksberg criteria.188 Minnesota criteria have also been devised to identify patients with "high-risk" aGVHD who could benefit from early escalated therapy.189,190 More recently, MAGIC(Mount Sinai Acute GVHD International Consortium) criteria were developed (see Acute GVHD: Staging and Grading in the algorithm for MAGIC grading criteria).191 A joint task force of the EBMT, National Institutes of Health(NIH), and CIBMTR has published a position statement on standardized terminology for GVHD.192 Furthermore, blood biomarkers are being investigated for their utility as a predictive tool in aGVHD.193-196

First-Line Therapy of aGVHD

Grade I

Grade I aGVHD affects only the skin (stage 1-2, <50% body surface area [BSA] non-bullous rash), with no Gl or liver involvement.178 First-line therapy options for these patients include continuing (or restarting) the

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original immunosuppressive agent(s) and administering topical steroids(eg, triamcinolone, clobetasol) and/or topical tacrolimus. Medium- to high-potency topical steroid formulations are recommended, except on the face or intertriginous areas where low-potency hydrocortisone is to be used(to avoid skin atrophy, telangiectasia, and acneiform eruptions).

Antihistamines may be used for symptomatic relief of itching as needed.Alternatively, the patient can be observed without treatment if the rash is asymptomatic and stable. If there is a response to first-line therapy, as indicated by a resolution of the rash and associated symptoms, the immunosuppressive agent(s) should be tapered as clinically feasible and topical steroids can be discontinued. Options for patients with no response to first-line therapy include enrollment in a well-designed clinical trial or continuing topical steroids (see GVHD Steroid Response Definitions/Criteria in the algorithm). Patients with progression and/or symptomatic rash (eg, purritus, pain, sloughing, increasing BSA involvement) should be treated according to the recommendations for grade II-IV aGVHD.

Grades II-IV

Enrollment in a well-designed clinical trial is encouraged for all patients presenting with grade II-IV aGVHD. The original immunosuppressive agent(s) may be restarted, continued, or escalated (with or without therapeutic drug monitoring) if aGVHD developed during tapering of immunosuppressive therapy; alternatively, additional agents may be initiated. Administration of systemic corticosteroids (± topical steroids) is the standard first-line treatment option (unless contraindicated or associated with severe intolerance) for patients with grades II-IV aGVHD.182,184,197 A phase III randomized controlled trial showed that initial treatment with low-dose systemic prednisone (0.5 mg/kg/day) in conjunction with Gl topical steroids (beclomethasone dipropionate± budesonide) was safe and effective for managing upper Gl symptoms (ie,nausea, vomiting, anorexia) in patients with grade II aGVHD, with or

<EndOfPara>without skin involvement (<50% BSA), with diarrhea volumes <1000 mL/day.197 Of note, budesdonide alone is less effective at treating the upper GI tract.In patients with higher grade aGVHD, use of low-dose prednisone was associated with an increased risk of requiring secondary immunosuppressive therapy, but with no difference in survival.Thus,patients with grade II aGVHD may be treated with 0.5-1 mg/kg/day of methylprednisone(or prednisone dose equivalent). Patients with higher grade aGVHD should be treated with higher doses of systemic steroids(1-2 mg/kg/day methylprednisone or prednisone dose equivalent). There is no role for escalation of methylprednisone above 2 mg/kg/day.198 The simultaneous addition of other systemic agents in conjunction with systemic corticosteroids as first-line therapy for aGVHD should only be done in the context of a well-designed clinical trial. Patients on high-dose steroids require significant supportive care(see Supportive Care for All Patients with GVHD).

The randomized phase II BMT CTN 1501 trial compared sirolimus to prednisone as initial treatment in 122 patients with standard-risk aGVHD as defined by the Minnesota GVHD Risk Score and Ann Arbor (AA1/2)biomarker status.199 At day 28, the overall response rates (ORR) for sirolimus and prednisone were similar (65% vs. 73%) and there were no differences in subsequent development of steroid-refractory aGVHD or any other key outcomes. Patients in the sirolimus group experienced less hyperglycemia and had reduced risk of infections but were at an increased risk for TMA as compared to patients in the prednisone group (10% vs.1.6%). Thus, sirolimus can be considered as an alternative to systemic corticosteroids as first-line therapy for patients with standard-risk aGVHD,as defined by clinical risk score and, if available, Ann Arbor biomarker status.

Alternative regimens have been investigated as first-line therapy for aGVHD. BMT CTN 0302 was a randomized, 4-arm, phase II clinical trial(n

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=180) that compared different agents(etanercept, mycophenolate mofetil,denileukin diftitox, and pentostatin) in combination with methylprednisolone at 2 mg/kg per day(or prednisone dose equivalent) for treatment of newly diagnosed aGVHD.200 The day 28 ORRs were:etanercept 26%, mycophenolate mofetil 60%, denileukin diftitox 53%, and pentostatin 38%. The corresponding 9-month OS rates were: 47%, 64%,49%, and 47%, respectively. Risk of severe infections were: etanercept 48%, mycophenolate mofetil 44%, denileukin 62%, and pentostatin 57%.These results indicated that mycophenolate mofetil plus corticosteroids could be a promising regimen for initial therapy of aGVHD. Accordingly, a phase III, multicenter, double-blinded clinical trial(BMT CTN 0802) was initiated comparing the combination of methylprednisolone at 1.6 mg/kg per day(or prednisone dose equivalent) plus mycophenolate mofetil versus methylprednisolone plus placebo as first-line therapy for aGVHD.201 A futility rule for GVHD-free survival at day 56 was met at a planned interim analysis after 235 patients(of 372) were enrolled. Outcomes of both arms were equivalent in OS, 1-year incidence of cGVHD, and infection risk. Therefore, mycophenolate mofetil provided no benefit when added to corticosteroids as first-line therapy for aGVHD.

If there is a response to first-line therapy, as indicated by a complete resolution of GVHD or improvement in at least one organ without progression in any other organ, steroids should be tapered as clinically feasible, as a standardized taper approach has yet to be defined. Options for patients with no response to first-line therapy include enrollment in a well-designed clinical trial202 or the addition of other systemic agent(s) to the corticosteroids, with steroid taper as clinically feasible. See Suggested Agents for Steroid-Refractory aGVHD below for more information.

Chronic Graft-Versus-Host Disease

cGVHD is the leading cause of NRM after allogeneic HCT.cGVHD is a profound detriment to quality of life and is associated with significant costs

and health care utilization. ${ }^{174,203-205}$ cGVHD usually develops within the first year after HCT, but it can occur years later. ${ }^{180}$ cGVHD may affect multiple organ systems, most commonly skin, oropharynx, ocular, musculoskeletal,and pulmonary, and is characterized by fibrosis, dryness, and ulceration of mucosal surfaces and variable clinical features resembling autoimmune disorders. ${ }^{206}$ The NIH Consensus Development Project has published detailed recommendations for the management of cGVHD including diagnosis, assessment of organ involvement, monitoring response to treatment, and supportive care interventions. ${ }^{181,207-210}$ A thorough understanding of the various clinical manifestations of cGVHD is essential for the early recognition of signs and symptoms. Multidisciplinary care aimed at avoiding organ damage and preserving function is strongly recommended.

Diagnosis and Grading

In all cases of suspected cGVHD, additional tests should be considered to rule out non-GVHD causes of the symptoms, such as infection, drug-induced injury or toxicity, or malignancy. While a biopsy may be done to confirm the presence of cGVHD, this is not always feasible and is not mandatory if the patient has at least one of the diagnostic findings of cGVHD defined by the NIH Consensus Development Project (see Chronic GVHD: Diagnosis in the algorithm for diagnostic signs and symptoms of cGVHD).181 Manifestations of cGVHD include bronchiolitis obliterans syndrome(BOS), an inflammatory lung condition. Unless it is pathologically diagnosed (via lung biopsy), clinical characteristics of BOS(assessed by pulmonary function tests [PFTs] and inspiratory and expiratory CT imaging of the lungs) are only diagnostic of lung cGVHD if distinctive features of cGVHD are present in another organ (see Chronic GVHD: Diagnosis, GVHD-B 2 of 3 in the algorithm for the complete criteria required for diagnosis of BOS). cGVHD grading is done according to the NIH Consensus Development Project criteria (see Chronic GVHD:Grading in the algorithm).181

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First-Line Therapy of cGVHD

Enrollment in a well-designed clinical trial is encouraged for all patients presenting with cGVHD. Options for first-line therapy include restarting,continuing, or escalating the original immunosuppressive agent(s) and/or administration of systemic corticosteroids (0.5-1 mg/kg/day methylprednisolone or prednisone dose equivalent). The initial corticosteroid dose may vary depending on the organs involved, the severity of GVHD, and patient comorbidities.

In lieu of systemic corticosteroids alone, sirolimus in combination with prednisone may be considered. A phase II/III randomized trial compared prednisone + sirolimus versus prednisone + sirolimus+ a calcineurin inhibitor (CNI) in patients with newly diagnosed cGVHD (defined as those receiving <14 days of corticosteroids) or those with cGVHD that did not respond adequately to ≤16 weeks of initial therapy (prednisone and/or a CNI +/- an additional agent other than sirolimus).211 The addition of a CNI did not improve 6-month complete or partial response rates(48.6% vs.50.0%; P=.87), 2-year complete response (CR) (14.7%vs. 15.5%; P=.90), and 2-year OS (81.5% vs. 74%; P=.28) rates. There was a lower incidence of renal dysfunction on the prednisone + sirolimus arm.

Topical steroids, such as triamcinolone or clobetasol, topical estrogen(for menopausal dryness and atrophy, which are often present and may complicate vulvovaginal cGVHD), topical tacrolimus, or dexamethasone oral rinse(for oral cGVHD) may be used as clinically indicated. Patients with lung involvement should receive inhaled steroids(eg, budesonide or FAM[fluticasone+ montelukast+ azithromycin]).212 Azithromycin should be used only for the treatment of BOS and not for BOS prophylaxis due to possible increased risk for leukemic relapse and secondary neoplasms in patients undergoing HCT receiving azithromycin for BOS prophylaxis.213,214 Patients with progressive or worsening lung

cGVHD following two to three lines of therapy may be evaluated for lung transplant.

If there is a response to first-line therapy according to the NIH Response Criteria,192 steroids should be slowly tapered as clinically feasible to mitigate long-term side effects of chronic steroid use. Options for patients with no response to first-line therapy include enrollment in a well-designed clinical trial202 or the addition of other systemic agent(s) to the corticosteroids, with steroid taper as clinically feasible. See GVHD Steroid Response Definitions/Criteria in the algorithm and Suggested Agents for Steroid-Refractory cGVHD below for more information. Supportive care interventions for controlling organ-specific symptoms or other risks and complications should be an integral part in the long-term care of patients with cGVHD.208

Steroid-Refractory GVHD

Approximately 40% to 50% of patients with acute or chronic GVHD experience steroid-refractory disease, which is associated with high mortality.182,215 The NIH has defined criteria for steroid-refractory acute and chronic GVHD(see GVHD Steroid Response Definitions/Criteria in the algorithm).192 Enrollment in a well-designed clinical trial is strongly encouraged for these patients. The selection of therapy for steroid-refractory GVHD should be based on randomized clinical trials when available, as well as institutional preferences, physician experience, the agent's toxicity profile, the effects of prior treatments, drug interactions,convenience/accessibility, and patient tolerability. Agent selection may also depend on organ involvement and overall grade of cGVHD.

Suggested Agents for Steroid-Refractory aGVHD

The following systemic agents, listed in alphabetical order(except for ruxolitinib, which has a category 1 recommendation), can be used in conjunction with the original immunosuppressive agent(s) and

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corticosteroids (typical first-line therapy) for steroid-refractory aGVHD.Slow taper of systemic corticosteroids is recommended if they are ineffective. In patients with steroid-dependent disease, corticosteroid therapy may be continued until an alternative steroid-sparing agent induces a response. Currently, ruxolitinib is the only therapy approved by the U.S. Food and Drug Administration (FDA) for treatment of steroid-refractory aGVHD.216 In patients whose disease does not respond to, or cannot tolerate or receive ruxolitinib, there are insufficient comparative data to recommend one systemic agent as preferred over another.184

Ruxolitinib

Ruxolitinib is a selective inhibitor of JAK1 and JAK2, which are intracellular tyrosine kinases that play critical roles in cytokine signaling as well as the development and function of several types of immune cells.217 In 2019, the FDA approved ruxolitinib for the treatment of steroid-refractory aGVHD in adult and pediatric patients aged≥12 years based on data from the single-arm phase II REACH1 trial in which 71 patients with grade II-IV steroid-refractory aGVHD were treated with 5 mg ruxolitinib twice daily with an optional increase to 10 mg.216 The ORR at day 28 was 55%, with 27% of patients achieving a CR. Responses were seen across the skin(61%), Gl tract(46%), and liver(27%). The randomized phase III REACH2 trial compared ruxolitinib (10 mg twice daily) to investigator's choice of regimen in 309 patients with steroid-refractory aGVHD.218 The ORR at day 28 was significantly higher in the ruxolitinib group compared to the control group(62%[34.4% CR] vs.39%[19.4% CR]; P<.001). Similar results were observed for the durable ORRs at day 56(40% vs.22%; P=.001).Median failure-free survival and median OS were substantially longer in the ruxolitinib arm compared to the control arm(5 vs.1 month; hazard ratio[HR], 0.46 and 11 vs. 6.5 months; HR, 0.83). The most common adverse events in the ruxolitinib group were thrombocytopenia(33%),anemia(30%), and cytomegalovirus infection(26%). Based on these data,

ruxolitinib is a category 1 recommended option for patients with steroid-refractory aGVHD.

Alemutuzumab

Alemutuzumab is a humanized anti-CD52 monoclonal antibody that has been successfully used as part of a pre-transplant preparative regimen for GVHD prophylaxis.219,220 The safety and efficacy of alemutzumab for the treatment of steroid-refractory aGVHD was evaluated in a prospective clinical study of 18 patients with grade II-IV steroid-refractory aGVHD treated subcutaneously with 10 mg alemtuzumab daily for 5 consecutive days.221 The ORR to alemtuzumab was 83%, with 33% of patients achieving CR. Importantly, univariate analyses of clinical characteristics between those who experienced response and those who did not experience response showed no differences in the main organ involved,grade of GVHD, or time between HCT and GVHD onset. After a median follow-up of 9 months, 78% of patients had one or more infectious episodes. In a retrospective analysis of 20 patients with steroid-refractory grade III-IV aGVHD receiving 10 mg of intravenous alemtuzumab weekly,the ORR was 70% with a CR of 35%.222 One-year OS was 50%. Although infectious complications were common, infection was not a significant predictor of survival in this study. These data suggest that alemtuzumab has favorable activity in the treatment of steroid-refractory aGVHD and emphasizes the need for anti-infective prophylaxis and close monitoring for patients receiving this therapy. Currently in the United States,alemtuzumab is only available via the Campath Distribution Program and drug supply is patient-specific.

Alpha-1 Antitrypsin

Alpha-1 antitrypsin (AAT) (also known as alpha-1 proteinase inhibitor) is a circulating protease inhibitor that inactivates serine proteases from neutrophils and macrophages to protect tissues from proteolytic

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degradation.223 AAT is most commonly used to treat patients with AAT deficiency, an inherited condition that causes lung and liver damage.224 The safety and efficacy of AAT to treat steroid-refractory aGVHD was evaluated in a prospective, multicenter phase II trial of 40 patients treated with intravenous AAT twice weekly for up to 4 weeks at a dose of 60 mg/kg/day.223 The ORR and CR rate at 28 days were 65% and 35%,respectively. After 60 days, responses were maintained in 73% of patients.OS at 6 months was 45% and did not differ by grade or site of organ involvement.Infectious mortality was 10% at 6 months. No infusion reactions or drug-related grade 3-4 toxicities were reported.These data suggest that AAT is an effective treatment option for patients with steroid-refractory aGVHD.

Anti-Thymocyte Globulin

Anti-thymocyte globulin is a T-cell-depleting antibody that has been commonly used for immunosuppression in the solid organ transplant setting and for GVHD prophylaxis. ${}^{225-232}$ Two non-interchangeable ATG products are currently approved by the FDA: anti-thymocyte globulin(rabbit), a polyclonal immunoglobulin G (lgG) derived from rabbits, and anti-thymocyte globulin(equine), a polyclonal IgG derived from horses. An early retrospective study analyzed the clinical response and survival outcomes of 79 patients with steroid-refractory aGVHD treated with 1 to 5 courses of equine ATG at a dose of 15 mg/kg/day twice daily for 5 days. 233 At day 28 of treatment, the ORR was 54%, with 20% of patients achieving a durable CR. Response to ATG was not associated with the initial grade of GVHD; however, it was associated with the site of GVHD. Patients with skin aGVHD were more likely to experience response to ATG. Of the 64 patients with skin involvement, 61% achieved a CR or partial response compared to 27% without skin involvement ( $P=.02$ ). The probability of survival at 1 year for all patients was 32% (95% CI, 22%-42%). Bacterial, viral, and fungal infections occurred in 37%, 10%, and 18% of patients,respectively. Another early retrospective study analyzed the efficacy of

rabbit ATG in 36 patients with steroid-refractory GVHD treated at a single institution. ${}^{234}$ Most patients (89%) had grade III-IV aGVHD and received rabbit ATG at 2.5 mg/kg/day for either 4 to 6 consecutive days (group 1; n=13) or on Days 1,3,5, and 7 (group 2; n=21).The ORR was 59%, with a CR rate of 38%. As seen in the aforementioned study, skin aGVHD was more responsive (96% of patients) than GI (46%) or liver aGVHD (36%).Common adverse events included hepatic dysfunction (25%), viral infections (26%), fungal infections (32%), and bacteremia (21%). Of the 36 original patients enrolled in the study, only 2 (6%) were alive 34 months post-HCT. These data suggest that ATG may be an effective treatment option for patients with steroid-refractory aGVHD, especially for those with skin involvement. However, long-term survival appears to be low, even in those who experience response. ${ }^{234}$ A comprehensive review on the use of ATG for GVHD treatment has been published. ${ }^{235}$

Basilimaximab

Basiliximab is a chimeric monoclonal antibody that functions as an immunosuppressive agent by binding to and blocking the interleukin-2(IL-2) receptor.236 IL-2 plays a key role in the development of aGVHD by stimulating the activation of donor T cells in the graft, which can attack the cells and tissues of the recipient.237 The efficacy and feasibility of basiliximab for the treatment of steroid-refractory aGVHD was evaluated in a prospective phase II trial of 23 patients treated with intravenous basiliximab at a dose of 20 mg on Days 1 and 4.237 The ORR was 83%,with 18% of patients achieving a CR. Basiliximab was most effective in those with skin GVHD (77% of these patients achieved response, versus 67% of patients with Gl involvement and 14% with liver involvement).Infections occurred in 65% of patients, and 1-year treatment-related mortality was 45%. Therefore, basiliximab appears to have some activity in the treatment of steroid-refractory aGVHD.

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Calcineurin Inhibitors

Calcineurin inhibitors, such as tacrolimus and cyclosporine, inhibit the action of calcineurin, an enzyme involved in the activation of T cells. CNI are commonly used for the prevention and initial treatment of GVHD, often in conjunction with other agents.152,238-246 However, there are limited data for their use in the treatment of steroid-refractory aGVHD. In a small phase II trial, 18 patients with aGVHD that developed or progressed during therapy with high-dose cyclosporine and/or other immunosuppressive agents were treated with tacrolimus at an initial dose of 0.05 mg/kg intravenously or 0.15 mg/kg orally twice daily (target trough, 15-25 ng/mL).247 In the 13 patients with evaluable data, the ORR was 54%. The most common adverse events were renal toxicity(53% of patients),followed by nausea and vomiting (31%). A retrospective analysis involving 42 patients with steroid-refractory aGVHD treated with tacrolimus (target concentration, 4-8 ng/mL) in combination with sirolimus reported an ORR of 49% (CR rate = 42%) for patients treated in the second-line (n =31)and an ORR of 27% (CR = 0) for patients treated in the third-line (n =11).248 One-year OS was 42% in patients treated in the second-line and 0% in patients treated in the third-line. Infectious complications occurred in 90% of patients. Therefore, CNI may be a reasonable option for the treatment of patients with steroid-refractory aGVHD, including when they have not been used in prophylaxis or initial therapy.

Etanercept

Etanercept is a recombinant tumor necrosis factor-alpha (TNF-a) receptor fusion protein.249 Etanercept acts by inhibiting the activity of TNF-a, a proinflammatory cytokine that acts as the master regulator of immune response and is a major mediator in the pathogenesis of aGVHD. ${}^{250}$ The efficacy of etanercept for the treatment of steroid-refractory aGVHD was retrospectively evaluated in a cohort of 13 patients.251 Etanercept at 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg

weekly for 4 weeks.The ORR was 46%, with 4 patients achieving CR.Responses correlated with the overall grade of aGVHD, with patients with grade II aGVHD showing higher response rates than those with grades III-IV aGVHD, and were most commonly observed in patients with Gl involvement (64% of clinical responses). No immediate treatment-related side effects were observed; however, bacterial and fungal infections occurred in 14% and 19% of patients, respectively. At a median follow-up of 429 days, OS was 67%. These results suggest that etanercept has favorable activity in steroid-refractory aGVHD.

Extracorporeal Photopheresis

Extracorporeal photopheresis (ECP) is a form of immunotherapy that involves ex vivo exposure of mononuclear cells obtained by apheresis to the photosensitizing agent 8-methoxypsoralen and ultraviolet A (UVA)light, followed by reinfusion of the cells back into the patient. 252 The clinical activity of ECP is thought to be mediated by the immunomodulatory effects of UV light. 253 The exact mechanism by which ECP ameliorates GVHD(acute or chronic) is unclear, but may involve the normalization of CD4+/CD8+ lymphocyte populations, an increase in the number of CD3-/CD56+ natural killer (NK) cells, and/or a decrease in circulating dendritic cells. $^{252,254}$

A phase ll trial in patients with grade II-IV steroid-refractory aGVHD found that weekly ECP therapy resulted in complete resolution of aGVHD symptoms in 82% of patients with skin involvement and 61% of patients with liver or Gl involvement.255 In a prospective single-center study involving 21 patients with grade III-IV aGVHD, second- or third-line treatment with ECP resulted in an ORR of 84%.256 After a median follow-up of 17 months, 1-year OS was 53% and was independently associated with a higher number of ECP sessions. A systematic review of prospective studies reported a pooled ORR of 69% for ECP in the treatment of steroid-refractory aGVHD.252 The ORR for skin manifestations was highest at

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84%, followed by 65% for Gl involvement. Reported rates of ECP-related mortality were extremely low. Another systematic review largely reached the same conclusions, reporting a pooled ORR of 71% and ORRs of 86%,60%, and 68% for skin, liver, and Gl involvement, respectively.257 These data suggest that ECP is an effective therapy for steroid-refractory aGVHD, especially for patients with skin involvement. Its relatively low potential for toxicity needs to be weighed against a delayed onset of the therapeutic effect.

Infliximab

Infliximab is a genetically constructed immunoglobulin G1 (lgG1) chimeric monoclonal antibody that binds to membrane-bound TNF-α, blocking its activity and triggering lysis of TNF-α-producing cells.250,258 In a retrospective evaluation of 21 patients with steroid-refractory aGVHD who had received treatment with single-agent infliximab (10 mg/kg once weekly for at least 4 doses), the ORR was 67%, with 62% of patients achieving CR.250 No toxic reactions to infliximab were observed; however, bacterial,fungal, and viral infections occurred in 81%, 48%, and 67% of patients,respectively. OS was 38% at a median follow-up of 21 months. Another retrospective analysis of 32 patients with steroid-refractory aGVHD treated with infliximab administered intravenously at a dose of 10 mg/kg once weekly for a median of three courses reported an ORR of 59%.259 Infections developed in 72% of patients. A third, more recent retrospective analysis involving 35 patients with steroid-refractory aGVHD reported an ORR of 40% for infliximab administered intravenously at 10 mg/kg weekly for a median of four doses, with 83% of patients developing infectious complications.260 These data suggest that infliximab is active in the treatment of steroid-refractory aGVHD; however, the potential for excessive infections should be evaluated.

mTOR Inhibitors

Sirolimus (rapamycin) is a macrolide compound derived from the bacteria Streptomyces hygroscopicus that possesses immunosuppressive,antibiotic, and antitumor properties. Sirolimus functions as a potent immunosuppressant by inhibiting the activity of mTOR, a serine/threonine kinase that acts as a master regulator of cell growth, proliferation,metabolism, and survival.261,262 By inhibiting mTOR, sirolimus disrupts the cytokine signaling that promotes the growth and differentiation of T cells.263 Sirolimus is also used for GVHD prophylaxis, often in conjunction with the CNI tacrolimus.152,243,244,264-267 The safety and efficacy of sirolimus in the treatment of steroid-refractory aGVHD was evaluated in a phase I trial involving 21 patients with grade III-IV steroid-refractory aGVHD.268 The ORR was 57%, with a CR rate of 24%. However, only 11 patients completed the full course of treatment due primarily to extensive toxicities including cytopenias, hyperlipidemia, severe TMA, and renal failure. In a retrospective analysis of 31 patients with steroid-refractory aGVHD treated with sirolimus (target therapeutic range, 4-12 ng/mL) in combination with tacrolimus, the ORR was 76% and 42% of patients achieved CR.269 Median OS was 5.6 months and 1-year OS was 44%.TMA and hyperlipidemia occurred in 21% and 44% of patients,respectively, but were manageable. Another retrospective study involving 22 patients with steroid-refractory aGVHD treated with sirolimus (target therapeutic range, 7-13 ng/mL) reported similar results.270 The ORR was 72% and OS was 41% after a median follow-up of 13 months. TMA occurred in 36% of patients when sirolimus was combined with tacrolimus or other CNI. A third, more recent retrospective analysis involving 42 patients with steroid-refractory aGVHD treated with sirolimus (target concentration, 4-8 ng/mL) and tacrolimus reported an ORR of 48.5%(CR rate=42%) for patients treated in the second-line setting (n=31) and an ORR of 27% for patients treated in the third-line setting (n=11).248 For patients treated in the second-line setting, 1-year OS was 42% (0% for

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patients treated in the third-line setting). Infectious complications were common(90% of patients). These data suggest that sirolimus is an effective option for the treatment of patients with steroid-refractory aGVHD, but may result in significant toxicities.

Mycophenolate Mofetil

Mycophenolate Mofetil is a prodrug of mycophenolic acid(MPA) that acts as an immunosuppressant by inducing apoptosis in lymphocytes through inhibition of the de novo synthesis of purines.271 Mycophenolate mofetil is indicated for the prevention of organ rejection in solid organ transplants and is a standard component of several GVHD prophylaxis regimens.272 In a prospective phase II trial completed in the mid-1990s, Furlong et al reported an ORR of 47% and a CR rate of 31% in 19 patients with steroid-refractory aGVHD treated with mycophenolate mofetil at an initial dose of 1 g twice daily for 35 days.273 OS at 6 and 12 months was 37% and 16%,respectively. Mycophenolate mofetil treatment was discontinued in four patients because of toxicities including neutropenia, abdominal pain, and pulmonary infiltrate. The same group conducted a retrospective analysis of more recent patients with steroid-refractory aGVHD (n = 29) and found a similar ORR to mycophenolate mofetil therapy (48%).273 However, OS at 6 and 12 months was much higher (55% and 52%, respectively). Possible explanations for the improved OS may include improved management of GVHD and longer experience with the use of mycophenolate mofetil. In another retrospective analysis of 13 patients with steroid-refractory aGVHD, the ORR to mycophenolate mofetil (1.5 or 2 g daily) was 31%and the estimated 2-year OS rate was 33%.274 Responses were achieved in 31% of patients with skin involvement, 44% with liver involvement, and 23% with GI involvement. Another retrospective study reported a 3-year OS rate of 40% and a CR rate of 26% in 27 patients with steroid-refractory aGVHD treated with mycophenolate mofetil at a dose of 1 to 1.5 g twice daily orally or intravenously.275 The CR rates observed with mycophenolate mofetil therapy were typically higher in patients with lower

grade GVHD(40% for grades I-II vs.8% for grades III-IV). These data suggest that mycophenolate mofetil has some efficacy for treating steroid-refractory aGVHD, especially in those with lower grade GVHD at the start of treatment.

Pentostatin

Pentostatin is a purine analogue that acts as an immunosuppressant by inducing lymphocyte apoptosis through inhibition of adenosine deaminase.276 A large retrospective analysis of 60 patients treated with pentostatin for steroid-refractory aGVHD reported an ORR of 33% and a CR rate of 18%.271 All patients received pentostatin at a dose of 1.5 mg/m2 on days 1 to 3, repeated every 2 weeks, for a median of three courses. OS at 18 months was 21% and NRM was 72%. Stratified analysis revealed that patients<60 years of age with isolated lower GI GVHD had the best outcomes with an ORR of 48% and 18-month OS of 42%. An earlier retrospective study reported similar results, with an ORR of 38% and 2-year OS of 17% in 24 patients treated with pentostatin at a daily dose of 1 mg/m2 given intravenously on 3 consecutive days.278 A smaller retrospective analysis of 12 patients reported a higher ORR of 50% and a CR rate of 33%.279 Discrepanant results among these studies may be attributed to variability in the patient populations, pentostatin doses and number of treatment cycles, use of additional therapies, or the assessment of treatment response.277

A phase I dose-escalation study involving 22 patients with steroid-refractory aGVHD reported a high CR rate of 63%.280 However, late infections observed at the 2 mg/m2/day dose used in the study were considered to be dose-limiting toxicities. In a follow-up phase II study of eight patients receiving a lower dose of 1.5 mg/m2/day of pentostatin, four patients died from progressive hepatic GVHD and three patients died from sepsis secondary to infections, pancytopenia, progressive hepatic GVHD,and/or acute renal failure.281 Two patients with renal insufficiency

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experienced excessive pentostatin exposure, as determined by measurement of the area under the curve (AUC), despite a 50% reduction in pentostatin dose. Although this trial was terminated before efficacy could be assessed, the data suggest that pentostatin is ineffective in treating liver manifestations of GVHD and may be inappropriate for patients with renal insufficiency. The limited available data suggest activity for pentostatin in the treatment of steroid-refractory aGVHD without liver involvement; however, serious adverse events (SAEs) have been reported. The renal function of patients receiving pentostatin should be monitored throughout the course of treatment.

Tocilizumab

Tocilizumab is a humanized anti-IL-6 receptor antibody that functions as an immunosuppressive agent by blocking IL-6 signaling.282 IL-6 is a pro-inflammatory cytokine produced by a variety of cell types that plays a key role in the development of aGVHD. Elevations of IL-6 have been detected in the serum of patients with GVHD, and polymorphisms that result in increased IL-6 production have been associated with an increase in GVHD severity.283,284 The efficacy of tocilizumab for the treatment of steroid-refractory aGVHD was evaluated in several studies.285-289 A small study of eight patients(6 patients had aGVHD, the majority of whom had grade IV)showed an ORR of 67%, with a CR rate of 33%.289 Tocilizumab was administered intravenously at a dose of 8 mg/kg once every 3 to 4 weeks.The most common adverse event was infection (69% were bacterial in origin). A retrospective study of nine patients with grade III-IV steroid-refractory aGVHD treated with the same dose and schedule of tocilizumab reported a lower ORR of 44% and a CR rate of 22%.288 Another retrospective analysis of 15 patients conducted at the same institution reported improved results with the use of tocilizumab for steroid-refractory aGVHD, with a CR rate of 40%.287 In this study, the patients received to tocilizumab every 2 to 3 weeks(majority received to tocilizumab every 2 weeks), compared to every 3 to 4 weeks as in the previous

studies. Patients with skin and/or Gl involvement had the greatest response, while those with liver involvement demonstrated no response.Another retrospective study conducted at a different institution reported a CR rate of 63% to tocilizumab(8 mg/kg given every 2 weeks) in 16 patients with steroid-refractory aGVHD of the lower Gl tract.285 These data suggest that tocilizumab has activity in the treatment of patients with steroid-refractory aGVHD, especially in patients with skin or Gl involvement. An FDA-approved biosimilar is an appropriate substitute for tocilizumab.

Urinary-Derived Human Chorionic Gonadotropin/Epidermal Growth Factor

Urinary-derived human chorionic gonadotropin/epidermal growth factor(uhCG/EGF) is a placenta-derived hormone supplement obtained from the urine of pregnant individuals. In a prospective phase II trial, uCG/EGF was added to first-line aGVHD therapy with methylprednisolone or second-line therapy of physician's choice in 44 patients with high-risk aGVHD per the Minnesota criteria.290 Seventy-five percent of patients had grade III-IV aGVHD and 52% had stage III-IV lower GI aGVHD. uhCG/EFG was administered every other day for 1 week with first-line therapy and for 2 weeks with second-line therapy. Maintenance dosing twice weekly for 5 weeks was available for patients with aGVHD who experienced response. At day 28, 68% of patients achieved a response, with 57% achieving CR,defined as resolution of aGVHD in all involved organs. CR rates at day 28 among patients receiving first- and second-line therapy were 64% and 50%, respectively.

Vedolizumab

Vedolizumab is a monoclonal antibody that is currently FDA approved for the treatment of moderate to severe inflammatory bowel disease.

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activation of a4β7 integrin, a process involved in the pathogenesis of Gl aGVHD.291-293

Several studies have investigated the safety and efficacy of vedolizumab for steroid-refractory GI aGVHD.291-293 In a small retrospective study that analyzed the outcomes of 29 patients, the ORR following vedolizumab was 79%, with a CR rate of 29% and a PR rate of 52%.292 ORR was 100%when vedolizumab was given as a second-line agent, compared to 63%when given as third-line or later(P=.012). When given early,vedolizumab was also associated with a greater likelihood of coming off of immunosuppression(69% vs. 19%; P=.007) as well as fewer fatal infections(38% vs.88%; P=.0006). In another small retrospective study analyzing the outcomes of 29 patients with steroid-refractory GI aGVHD,ORR was 64% at 6 to 10 weeks following vedolizumab administration.293 At 6 months, OS was 54%. There were 29 SAEs, 12 of which were infectious in nature(3 possibly related to vedolizumab) and 13 of which were fatal(1 possibly related to vedolizumab). In a more recent meta-analysis, the use of vedolizumab for Gl aGVHD was associated with significantly improved pooled ORR at 14 days(60.53%), 28 days(50%),and 12 months(76.92%).291 While improvement in CR rates at 14 and 28 days was not significant, improvement at 12 months was significant(pooled CR, 27.27%).

Suggested Agents for Steroid-Refractory cGVHD

The following systemic agents, listed in alphabetical order(except for the category 1 recommendation and FDA-approved recommendations), can be used in conjunction with corticosteroids for steroid-refractory cGVHD.Although prolonged systemic corticosteroid therapy is better avoided,some patients may require prolonged steroid therapy(preferably using ≤0.5 mg/kg/day) for steroid-dependent cGVHD. Currently, ruxolitinib,ibrutinib, belumosudil, and axatilimab-csfr are FDA-approved agents for treatment of steroid-refractory cGVHD.294-296

Ruxolitinib

In 2021, the FDA approved ruxolitinib for the treatment of steroid-refractory cGVHD after failure or one or two lines of systemic therapy in adult and pediatric patients aged≥12 years. The approval was based on data from the randomized phase III REACH3 trial, which compared ruxolitinib(10 mg twice daily) to investigator's choice of best available therapy in 329 patients with steroid-refractory or steroid-dependent cGVHD.295 At week 24, the ORR was higher in patients in the ruxolitinib group compared to those in the control group(50% vs.26%; P<.001).Ruxolitinib also led to longer median failure-free survival(>19 vs.6 months; HR=.37; P<.001) and higher symptom response(24% vs.11%;P=.001) than control. The median durations of response were 4.2 months and 2.1 months for the ruxolitinib and control arms, respectively. The median times from first response to death or new systemic therapies for cGVHD were 25 months and 5.6 months, respectively. The most common≥ grade 3 adverse events were thrombocytopenia(15% in the ruxolitinib group and 10% in the control group) and anemia(13% and 8%,respectively). Based on these data and the FDA approval, ruxolitinib is a category 1 recommended option for patients with steroid-refractory cGVHD.

Ibrutinib

Irbutinib is a potent and irreversible inhibitor of Bruton's tyrosine kinase(BTK), which regulates B-cell survival.294 It also inhibits IL-2-inducible T-cell kinase(ITK), which is involved in the selective activation of T-cell subsets.297 In 2017, ibrutinib was approved by the FDA for the treatment of adult patients with cGVHD after failure of one or more lines of systemic therapy and in 2022 was approved for pediatric patients≥1 year of age with the same indication. The initial approval in adults was based on data from a single-arm, phase ll multicenter trial that included 42 patients with steroid-refractory cGVHD.294 Patients received 420 mg of ibrutinib daily

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until cGVHD progression. The majority of patients(88%) had≥2 organs involved at baseline, the most common being mouth(86%), skin(81%),and GI tract(33%). At a median follow-up of 14 months, the ORR was 67% and the most commonly reported adverse events were fatigue,bleeding/bruising, diarrhea, muscle spasms, nausea, thrombocytopenia,and anemia. After a median follow-up of 26 months, the ORR was 69%,with 31% of patients achieving a CR.298 Sustained responses of ≥44 weeks were seen in 55% of the those who experienced response. Of the patients with multiorgan involvement, 73% of those with ≥2 organs involved showed responses in ≥2 organs and 60% of those with ≥3 organs involved showed responses in ≥3 organs reduced to <0.15 mg/kg/day in 64% of patients and was completely discontinued in 19% of patients. The most common grade 3 adverse events were pneumonia, fatigue, and diarrhea.

Pediatric for ibrutinib comes from a two-part, multicenter, phase I/II study that investigated the pharmacokinetics, safety, and efficacy of ibrutinib in patients aged $\geq$ 1 to <22 years with cGVHD. ${}^{299}$ Part A of the study determined the recommended pediatric equivalent dose of ibrutinib to be $240 mg / m^{2}$ once daily (up to a maximum of $420 mg$ , the recommended dose for pediatric patients $\geq$ 12 years) based on pharmacokinetic and safety data in children $\geq$ 1 to $<12$ years. In part B of the study, patients with either treatment-naive or R/R moderate to severe cGVHD received age-based dosing of ibrutinib as above, with dose modification for concomitant azole therapy as indicated. ORR at 24 weeks was 83% for patients with treatment-naive cGVHD and 60% for those with R/R cGVHD. Twelve-month duration of response was 60% and 58%，respectively, for those with treatment-naive and R/R cGVHD. Overall,safety of ibrutinib in pediatric patients was consistent with the known profile.

These data suggest that ibrutinib is effective and may produce durable responses in patients with steroid-refractory cGVHD. However, ibrutinib should be used with caution in patients with a history of heart arrhythmias,due to a heightened risk of atrial fibrillation, and in patients on anticoagulation or antiplatelet therapy, due to an increased risk of bleeding. Ibrutinib should be held for 3 to 7 days prior to and after surgical procedures to minimize bleeding complications.

Belumosudil

In 2021, belumosudil was approved by the FDA for the treatment of adult and pediatric patients aged ≥12 years with cGVHD after failure of ≥2 lines of systemic therapy. This approval was based on data from the randomized, multicenter phase II ROCKstar study, which evaluated the efficacy of belumosudil 200 mg taken once or twice daily in patients with cGVHD who had received two to five prior lines of therapy.296 After a median follow-up of 14 months, the ORR was 76%， with 5% of patients achieving a CR. Response,including CR, was observed in all organs,including pulmonary GVHD. The median duration of response was 54 weeks and 44% of patients remained on belumosudil therapy for >1 year.Adverse events were consistent with those observed in patients with cGVHD receiving immunosuppressants and included infections, asthenia,nausea,diarrhea,dyspnea,cough,edema,hemorrhage, abdominal pain,and musculoskeletal pain. Sixteen patients (12%) discontinued belumosudil due to possible drug-related adverse events. These data suggest that belumosudil is a promising therapy for steroid-refractory cGVHD that is well tolerated.

Axatilimab-csfr

In August 2024, axatilimab-csfr was approved by the FDA for the treatment of pediatric and adult patients with cGVHD weighing≥40 kg after failure of≥2 prior lines of systemic therapy. Approval was based on

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data from the randomized, multicenter phase II AGAVE-201 study, which investigated the efficacy and safety of 3 different doses (0.3 mg/kg every 2 weeks, 1 mg/kg every 2 weeks, or 3 mg/kg every 3 weeks) of axatilimab-csfr in 239 patients with recurrent or refractory cGVHD.300 Simultaneous use of corticosteroids, CNIs, or mTOR inhibitors was permitted. Median duration of response was not reached at any dose, with 60%, 60%, and 53% of patients at doses of 0.3 mg/kg, 1 mg/kg, and 3 mg/kg maintaining response at 12 months, respectively. However, ORR was superior in the 0.3 mg/kg arm, at 74%, compared to 67% and 50% with the 1 mg/kg and 3 mg/kg doses, respectively. Treatment-related adverse events, including fatal events, were also less common in the 0.3 mg/kg arm. The most common treatment-related adverse events included headache, elevation in LFTs and creatine kinase, and infections.

Of note, there are currently no randomized data comparing any of the above agents(ruxolitinib, ibrinitinib, berumosudil, and axatilimab-cfr) to one another or to other agents utilized for steroid-refractory cGVHD.

Abatacept

Abatacept is a T-cell costimulatory inhibitor. It is a recombinant soluble fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4(CTLA-4) linked to the modified fragment crystallizable(Fc) region of IgG1.301.302 Abatacept acts as an immunomodulatory drug by selectively inhibiting T-cell activation via binding to (blocking) the costimulation receptors (CD80 and CD86) on antigen-presenting cells (costimulation blockade). The safety and efficacy of abatacept in the treatment of steroid-refractory cGVHD were evaluated in a phase l clinical trial involving 16 patients.301 The study followed a 3+3 design with two escalating abatacept doses to determine the maximum tolerated dose (MTD). The partial response rate to abatacept was 44%and no dose-limiting toxicities were observed at the MTD of 10 mg/kg.The sites with greatest improvement were the mouth, Gl tract, joints, skin,

eyes, and lungs. The most common adverse events were pulmonary infections(all of which resolved), diarrhea, and fatigue. Importantly,mreatment with abatacept resulted in a 51% reduction in prednisone usage.These data suggest that abatacept is an effective treatment option for patients with steroid-refractory cGVHD.

Alemutzumab

The safety and efficacy of alemutzumab for the treatment of steroid-refractory cGVHD was evaluated in a phase I dose-escalation trial involving 13 patients.300 Six patients had moderate and seven patients had severe cGVHD per NIH consensus global scoring criteria; all patients had involvement of skin and subcutaneous tissues. Alemutzumab dosing was investigated in a 3+3 study design. The MTD of alemutzumab was 3 mg x 1, then 10 mg x 5 administered over 4 weeks. The most common adverse events were infections and hematologic toxicities. Of the 10 patients evaluable for response, the ORR was 70%, with a 30% CR rate.The median decrease in steroid dose at 1 year was 62%. A prospective study of 15 patients with steroid-refractory cGVHD treated with one cycle of subcutaneous alemtuzumab at 10 mg/day for 3 days followed by 100 mg intravenous rituximab on days+4,+11,+18,and+25 reported an ORR of 100% and a CR rate of 33% at day+30 evaluation.304 At day+90 evaluation, the partial response rate was 50%, the CR rate was 28%, and 21% of patients had relapsed cGVHD. Of the five patients with evaluable data at 1 year, two(40%) had a partial response, two had a CR, and one experienced cGVHD progression. These data indicate that alemtuzumab is active in steroid-refractory cGVHD. Currently in the United States,alemtuzumab is only available via the Campath Distribution Program and the drug supply is patient-specific.

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Calcineurin Inhibitors

Limited data exist for the efficacy of CNI, such as tacrolimus and cyclosporine, for the treatment of steroid-refractory cGVHD. The most common adverse events typically seen with CNI use are renal toxicity,hypomagnesemia, hypertension, and tremors.In a phase II trial,31 patients with cGVHD that developed or progressed during therapy with cyclosporine and/or other immunosuppressive agents were treated with tacrolimus at an initial dose of 0.05 mg/kg intravenously or 0.15 mg/kg orally twice daily(target trough, 15-25 ng/mL). In the 26 patients with evaluable data, the ORR was 46%.247 Another trial evaluated the efficacy of tacrolimus administered at 0.15 mg/kg twice daily orally or 0.15 mg/kg/day intravenously in 17 patients with severe steroid-refractory cGVHD.305 The ORR was 35% and OS was 65% at a median follow-up of 8.4 months. The greatest responses were observed in the skin, liver, and GI tract; musculoskeletal and lung cGVHD showed no response to treatment. Commonly reported adverse events included renal toxicity,hypertension, and infections. In a third report, 39 patients with cGVHD refractory to cyclosporine and prednisone were treated with tacrolimus.306 The ORR was 21% with a CR rate of 13%. However, 56% of patients discontinued tacrolimus due to progression/persistence of cGVHD or treatment-related toxicity and 23% died during continued tacrolimus treatment. Infectious complications were the most common adverse event followed by renal toxicity, which led to treatment discontinuation in two patients. Three-year estimated OS was 64% and 41% of patients had discontinued all immunosuppressive treatment at 3 years post-HCT.Therefore, CNI may provide clinical benefit for steroid-refractory cGVHD,in particular when they have not been used for GVHD prophylaxis or initial therapy.

Etanercept

The efficacy of etanercept for the treatment of steroid-refractory cGVHD was retrospectively evaluated in a cohort of eight patients treated with subcutaneous etanercept at 25 mg twice weekly for 4 weeks followed by 25 mg once weekly for 4 weeks.251 Patients were also continued on CNI,mycophenolate mofetil, and/or sirolimus.The ORR was 62%, with one patient achieving CR. Three of the eight patients(37%) treated with etanercept died of progressive disease or sepsis. In three of the five patients who experienced response to etanercept, corticosteroids were reduced by>50%. In a phase II trial, 34 patients with either obstructive(n= 25) or restrictive(n= 9) lung dysfunction following allogeneic HCT were treated with etanercept subcutaneously at 0.4 mg/kg/dose twice weekly for 4(group A) or 12(group B) weeks.307 Obstructive lung dysfunction is commonly associated with cGVHD, with BOS being the most common histopathology reported. All patients had clinical signs or symptoms of cGVHD at the onset of treatment with diffuse skin, oral mucosal, ocular,and/or hepatic involvement. All patients received concurrent immunosuppressive therapy with either CNI alone(n= 5), CNI plus corticosteroids± mycophenolate mofetil(n= 22), mycophenolate mofetil±corticosteroids(n= 5), or sirolimus(n= 2). Clinical response, defined as a≥10% improvement in the absolute value for forced expiratory volume(FEV1; for obstructive defects) or forced vital capacity(FVC; for restrictive defects), was obtained in 32% of patients. There was no difference in ORR based on the duration of treatment(29% in group A vs. 35% in group B;P=.99) or the presence of restrictive or obstructive lung dysfunction(33% vs.32%, respectively; P=.73). No bacterial or viral infections were observed. Thus, etanercept seems to be effective for treating steroid-refractory cGVHD of the lung(especially if associated with BOS).

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Extracorporeal Photopheresis

In a prospective single-center study involving 88 patients with extensive cGVHD, second- or third-line treatment with ECP resulted in an ORR of 73%.256 Cutaneous and sclerotic manifestations were associated with higher response rates. After a median follow-up of 68 months, 5-year OS was 65% and was independently associated with a higher number of ECP sessions and cutaneous manifestations. A multicenter randomized phase II trial involving 95 patients with cutaneous manifestations of steroid-refractory cGVHD found that 8% of patients receiving ECP therapy experienced at least a 25% reduction in total skin score from baseline compared to 0% of patients in the control group(P=.04).308 Treatment with ECP resulted in an ORR of 61% in a retrospective analysis of 71 patients with severe steroid-refractory cGVHD; the best responses were seen in the skin, liver, oral mucosa, and eyes.309 A systematic review of prospective studies reported a pooled ORR of 64% for ECP in the treatment of steroid-refractory cGVHD.252 Similar response rates were seen with skin and Gl involvement; however, the ORR for cGVHD with lung involvement was only 15%, suggesting that ECP may not effectively treat lung manifestations of cGVHD. Reported rates of ECP-related mortality were extremely low. Another systematic review largely reached the same conclusions, reporting a pooled ORR of 64% and pooled response rates of 74% and 48% for skin and lung involvement,respectively.310 This review also reported activity for ECP in treating cGVHD with GI involvement(ORR= 53%). These data suggest that ECP is an effective therapy for steroid-refractory cGVHD, especially in those with skin involvement. If ECP is not available or feasible, the NCCN Panel recommends the use of PUVA irradiation as an alternative treatment option for sclerotic or cutaneous steroid-refractory cGVHD.

Hydroxychloroquine

Hydroxychloroquine is a 4-aminoquinoline immunosuppressive and anti-parasitic agent that is commonly used for the treatment of malaria.311 Hydroxychloroquine is believed to exert its immunomodulatory effects by interfering with cytokine production and antigen processing and presentation.312,313 The efficacy of hydroxychloroquine for the treatment of steroid-refractory cGVHD was evaluated in a phase II trial involving 40 patients treated with hydroxychloroquine at 800 mg(12 mg/kg) per day.313 The ORR was 53% among the 32 patients with evaluable data, with three patients achieving a CR. All patients who experienced response tolerated a>50% reduction in their steroid dose while receiving hydroxychloroquine.The highest response rates were observed in patients with skin, oral,and/or liver involvement; efficacy in the treatment of Gl manifestations was limited.

One of the most SAEs reported with the long-term use (>2 years) of hydroxychloroquine is chloroquine retinopathy, a form of toxic retinopathy caused by the binding of hydroxychloroquine to melanin in the retinal pigment epithelium, which can result in vision loss. The retinal toxicity of hydroxychloroquine was evaluated in a cohort of 12 patients with cGVHD treated with 800 mg hydroxychloroquine per day for a median duration of 22.8 months.314 Seven patients developed vortex keratopathy and three patients developed retinal toxicity; retinal structure and color vision were abnormal in two of the three patients. These data suggest that hydroxychloroquine is an effective treatment option for patients with steroid-refractory cGVHD, especially in those with skin or oral involvement, but may not be appropriate for long-term use due to the risk of retinal toxicity. Periodic ophthalmologic assessment is recommended during treatment.

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Imatinib

Imatinib is a small molecule tyrosine kinase inhibitor indicated for the treatment of several types of cancer, including CML. ${ }^{315}$ Imatinib has activity against several tyrosine kinase enzymes, including platelet-derived growth factor receptor(PDGFR), which is implicated in skin fibrosis. ${ }^{316}$ Stimulatory antibodies against PDGFR have been identified in patients with cGVHD with cutaneous sclerosis; however, neither anti-PDGFR antibody level, nor phosphorylation of tissue PDGFR, correlated with response to imatinib in patients with cGVHD. ${ }^{317}$ The efficacy of imatinib to treat sclerotic manifestations of cutaneous steroid-refractory cGVHD was assessed in a pilot phase II trial involving 20 patients. ${ }^{316}$ Eight patients received a standard dose of 400 mg daily while 12 patients underwent a dose escalation study due to poor tolerability (100 mg daily initial dose up to 200 mg daily maximum). Of the 14 patients evaluated for primary response,5(36%) had a partial response,7(50%) had stable disease,and 2(14%) had progressive disease. After treatment with imatinib for 6 months, range of motion(ROM) deficit was improved in 79% of patients by an average of 24%. Common adverse events included hypophosphatemia, fatigue, nausea, diarrhea, and disrupted fluid homeostasis leading to edema. A randomized phase II crossover study compared imatinib(200 mg daily) to rituximab(375 mg/m ${ }^{2}$ intravenously weekly for 4 weeks) for the treatment of patients(n= 35) with cutaneous sclerosis associated with cGVHD. ${ }^{318}$ Significant clinical response, defined as quantitative improvement in skin sclerosis or joint ROM, was observed in 26% of patients randomized to imatinib and 27% of patients randomized to rituximab.Treatment success, defined as significant clinical response at 6 months without crossover, recurrent malignancy, or death, was achieved in 17% of patients on imatinib and 14% of patients on rituximab. In a prospective trial of 39 patients with steroid-refractory cGVHD treated with imatinib, the partial response rate was 36%.319 The best responses were seen in the skin (32%), Gl tract (50%), and lungs (35%). After a median

follow-up of 40 months, the 3-year OS and event-free survival rates were 72% and 46%, respectively. These data suggest that low-dose imatinib(200 mg) is active in the treatment of patients with steroid-refractory cGVHD, especially in those with cutaneous sclerosis.

Interleukin-2

IL-2 is a naturally occurring pleiotropic cytokine that regulates the growth of T cells and is a key mediator of immune response.320 The efficacy of IL-2 in the treatment of steroid-refractory cGVHD was evaluated in a phase I study involving 29 patients.321 Patients received daily subcutaneous IL-2 at escalating dose levels for 8 weeks. The MTD was determined to be 1 x 106IU/m2. Of the 23 patients evaluable for a response, 12 had a significant clinical response involving multiple organs. Clinical responses were sustained in patients who received IL-2 for an extended period, allowing their corticosteroid dose to be tapered by a mean of 60%. In a follow-up phase II trial, 35 patients with steroid-refractory cGVHD were treated with IL-2 at 1 x 106 IU/m2 for 12 weeks.320 The ORR in 33 patients with evaluable data was 61%. There were CRs and three patients developed progressive cGVHD. All those who experienced response experienced improvement in multiple sites of cGVHD, including the liver, skin, Gl tract,lungs, and joints/muscle/fascia. Extended IL-2 therapy for up to 2 years was well tolerated and resulted in durable clinical responses in most patients. However, two patients in this study withdrew and five required dose reductions of IL-2 due to adverse events including thrombocytopenia,fatigue, flu-like symptoms, malaise, and thrombocytopenia. A phase I dose-escalation trial showed that escalation above the previously defined MTD did not improve clinical response in 10 patients with steroid-refractory cGVHD.322 These data suggest that low-dose IL-2 has durable clinical activity in treating steroid-refractory cGVHD and is generally safe for long-term use.

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Low-Dose Methotrexate

Methotrexate is an antimetabolite that exerts immunosuppressive effects by inhibiting the activity of dihydrofolic acid reductase, resulting in impaired DNA synthesis and lymphocyte proliferation.323 In a retrospective 134 patients who had received low-dose methotrexate(7.5 mg/m2/week for 3-50 weeks) for the treatment of steroid-refractory cGVHD, 71% of patients were able to reduce their prednisone dose to <1 mg/kg every other day without the addition of other agents.324 In this study, the most frequently involved sites were the oral mucosa(n= 14) and skin(n= 11)and no grade ≥3 toxicities were observed. The steroid-sparing effects of methotrexate were also observed in a prospective study of eight patients with steroid-refractory cGVHD, which reported a reduction in corticosteroid dose in the range of 25% to 80% in patients treated with low-dose methotrexate(5 mg/m2/infusion).325 The ORR was 75% and few toxicities were observed, the most serious being grade 3-4 cytopenias reported in two patients. Another retrospective review of 21 patients with steroid-refractory cGVHD reported an ORR of 76% in patients treated with low-dose methotrexate(5 or 10 mg/m2 infusion every 3-4 days).326 The response rates were particularly high in patients with extensive cGVHD(ORR= 92%) and were significantly higher in patients with skin involvement (92%) compared to those with liver involvement (43%; P=.009). Among patients with cGVHD in a single organ (skin or liver), 58%experienced response compared to 100% of patients with ≥2 organs involved. Although this trial reported severe hematologic toxicities associated with methotrexate, these toxicities were reversible and did not result in treatment discontinuation. These data suggest that low-dose methotrexate is active in the treatment of patients with steroid-refractory cGVHD, especially in those with skin and oral manifestations.

mTOR Inhibitors

The safety and efficacy of sirolimus for the treatment of steroid-refractory cGVHD was evaluated in a phase II trial involving 35 patients.327 Patients with steroid-refractory cGVHD received sirolimus at a loading dose of 6 mg orally followed by a maintenance dose of 2 mg/day targeting a concentration between 7 to 12 ng/mL while continuing immunosuppressive treatment with tacrolimus and methylprednisolone. The ORR was 63%,with six patients achieving CR. The highest response rates were observed in patients with sclerotic skin involvement (73%) and involvement of the oral mucosa (75%), but responses were also observed in the lower GI tract (67%), liver (33%), and eyes (64%). Major adverse events included hyperlipidemia, renal dysfunction, cytopenias, TMA, and infectious complications. Median survival was 15 months and estimated actuarial survival at 2 years was 41%. In another phase II trial, 19 patients with steroid-refractory cGVHD were treated with sirolimus, CNI, and prednisone.328 Sirolimus was administered orally at a loading dose of 10 mg followed by a daily dose of 5 mg without a defined target range. Of the 16 patients with evaluable data, 15 had an initial clinical response.However, five patients discontinued treatment due to renal toxicity. Of the 10 patients who continued with this regimen, three had a prolonged response and were able to successfully taper off immunosuppressive agents. A retrospective study analyzed 47 patients with steroid-refractory cGVHD treated with sirolimus (2 mg/day, target concentration 5-10 ng/mL) in combination with other immunosuppressive agents (CNI [n=33], mycophenolate mofetil [n = 9], or prednisone [n = 5]). 329 The ORR was 81%, with a CR rate of 38%. The main toxicity was mild impairment of renal function, which was more common in patients receiving sirolimus and CNI (33%) compared to sirolimus and other immunosuppressive agents (7%). Estimated 3-year OS in all patients was 57%. These data suggest that sirolimus is an effective agent for the treatment of patients with steroid-refractory cGVHD and should be investigated further to find

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

the best dose schedule and combination of additional agents to optimize clinical response while limiting toxicity.

Although it has not been studied extensively, the sirolimus derivative everolimus has shown activity in the treatment of steroid-refractory cGVHD. Preliminary data from two retrospective studies showed that treatment with everolimus resulted in significant improvement in the NIH Severity Score and patient-reported quality of life.330,331 However, more data are necessary to confirm the role of everolimus in the treatment of steroid-refractory cGVHD.

Mycophenolate Mofetil

The safety and efficacy of mycophenolate mofetil for treatment of steroid-refractory cGVHD was evaluated in a retrospective study of 24 patients treated with mycophenolate mofetil at a dose of 500 mg twice daily(escalated to 1 g twice daily if tolerated) in combination with cyclosporine,tacrolimus, and/or prednisone.332 The ORR was 75%, with a CR rate of 21%. Only two patients experienced progressive disease. The highest response rates were seen in patients with skin or oral mucosa involvement. Of the 22 patients receiving prednisone, 14(64%) had their prednisone dose decreased by a median of 50% by the end of the 6-month observation period. The most common adverse events were abdominal cramps (which resulted in discontinuation of mycophenolate mofetil in 3 patients) and infections. At a median follow-up of 24 months,83% of patients were alive. In a prospective phase II trial involving 23 patients with steroid-refractory cGVHD, the cumulative incidence of disease resolution and withdrawal of all immunosuppressive treatment was 26% at 36 months after starting treatment with mycophenolate mofetil(initial dose of 1 g twice daily).273 After a median follow-up of 9.5 years,52% of patients remained alive with only one patient requiring continued treatment with immunosuppressive agents. In another retrospective analysis of 13 patients with steroid-refractory cGVHD, the ORR to

mycophenolate mofetil (1.5 or 2 g daily) was 77% and the estimated 2-year OS rate was 54%. The most common adverse events were Gl disturbances (27%) and infectious complications (23%). These data suggest that mycophenolate mofetil is an effective therapy option for patients with steroid-refractory cGVHD.

Pentostatin

In a phase ll trial involving 58 patients with steroid-refractory cGVHD,treatment with pentostatin at 4 mg/m2 given intravenously every 2 weeks for a median of 12 doses resulted in an ORR of 55%.333 Most patients had skin involvement and more than half had oral and Gl involvement.The highest response rates were observed in patients with lichenoid cutaneous manifestations(69%) followed by patients with oral involvement(62%);the lowest response rates were seen in patients with liver involvement. A total of 11 grade 3-4 infections was reported, and four patients withdrew from treatment due to adverse events including nausea/vomiting, renal toxicity,and fatigue. OS at 1 and 2 years was 78% and 70%, respectively. In a retrospective analysis of 18 patients with steroid-refractory cGVHD, 12 of whom had severe cGVHD, treatment with pentostatin at 4 mg/m2 every 2 weeks resulted in an ORR of 56%; CR was achieved in one patient.279 Activity was observed in all affected organs, with CRs observed in GI (CR=3), skin (CR=4), and muscle/fascia (CR=1) manifestations.The median decrease in corticosteroid dose over 24 months after pentostatin initiation was 38% and median OS was 5 months. Estimated 1-year OS was 34%. Common adverse events included renal toxicity and infections.These data suggest that pentostatin is active in the treatment of steroid-refractory cGVHD.

Rituximab

Rituximab is an anti-CD20 chimeric monoclonal antibody used to treat NHL and CLL that exerts immunosuppressive effects by binding to CD20

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on the surface of B cells, facilitating their destruction.334 Since B cells are implicated in the pathogenesis of cGVHD, the efficacy of rituximab in the treatment of steroid-refractory cGVHD has been evaluated in several studies.312,335 In a systematic review and meta-analysis of seven studies(3 prospective and 4 retrospective) including 111 patients, the pooled ORR to rituximab was 66%.335 The majority of studies used rituximab at a dose of 375 mg/m2 once per week for 4 to 8 infusions, although similar results were reported with rituximab administered at 50 mg/m2 per week for 4 weeks(ORR = 69%). The pooled ORR for patients with skin cGVHD was 60%,compared to 36% for oral mucosal cGVHD,29% for liver cGVHD,and 30% for lung cGVHD, suggesting that skin manifestations of cGVHD are particularly susceptible to rituximab treatment. However, it should be noted that the site-specific response rates varied greatly among studies.Administration of rituximab facilitated corticosteroid dose reductions in the range of 75% to 86%, depending on the study. The steroid-sparing effect of rituximab was more pronounced in patients with skin and oral mucosal GVHD. The most common adverse events were related to infusion reactions or infectious complications. Therefore, rituximab is an effective treatment option for patients with steroid-refractory cGVHD, especially those with skin involvement. An FDA-approved biosimilar is an appropriate substitute for rituximab.

GVHD Supportive Care

Supportive Care for All Patients with GVHD

Supportive care is essential for all patients with GVHD. Special attention is required for prevention of infection, as infection is the most common cause of death in those with cGVHD.208 The NCCN Panel recommends initiation of appropriate antimicrobial prophylaxis with escalating immunosuppressive therapy as outlined in the NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections. Surveillance for cytomegalovirus reactivation, which is associated with significant morbidity and mortality among allogeneic HCT recipients,208,336 is also

recommended in appropriate patients. Consideration can be made for additional viral surveillance. Live vaccines should be avoided for all patients on immunosuppressive therapy or those with active GVHD.208 Re-vaccination for COVID-19 is recommended in all allogeneic HCT recipients starting 3 months post-transplant given the likelihood of a blunted immune response affecting the efficacy of vaccination prior to this time point.337 Routine use of prophylactic intravenous immunoglobulin(IVIG)replacement is not recommended given lack of clear evidence of benefit,higher risks of SOS and thrombosis, and possible reduced efficacy of vaccinations post-transplant; however, there may be subsets of patients where prophylactic IVIG may be considered, such as in UCB transplant recipients, in children undergoing transplantation for inherited or acquired disorders associated with B-cell deficiency, and in patients with cGVHD with recurrent sinopulmonary infections.338

Prophylaxis with ursodiol, a hydrophilic bile acid, should be considered to help prevent hepatic complications of allogeneic HCT,including GVHD.In a randomized trial,ursodiol reduced the incidence of bilirubin elevation;severe aGVHD,liver GVHD,and GI GVHD;and improved survival.339,340

The use of high-dose steroid therapy for management of GVHD may be associated with infections (including viral, fungal, and bacterial), glucose intolerance, hypertension, adrenal insufficiency, poor wound healing,myopathy, osteoporosis, vitamin D deficiency,insomnia, anxiety, and mood swings.341 Vitamin D and calcium supplementation should be considered for patients on high-dose steroids. 341 Allogeneic HCT, even without the use of high-dose steroids, is associated with bone resorption and decreased bone formation, which can lead to osteoporosis. Thus,monitoring of vitamin D levels and measurement of bone mineral density by dual-energy x-ray absorptiometry (DEXA) scans is recommended for those with current or past exposure to high-dose steroids and those with

![NCCN\nNCCN\nControl Medicine\n](2/aj0YEe4oUhYkBdfpda0fYP/figuree1b971dfdc9e42b19de7eaf34c2bdff1_0_1.png) National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

cGVHD, with treatment and repeat imaging as indicated based on results.208

Dermatology,dental, and ophthalmology exams are recommended at baseline and at appropriate intervals beginning 6 to 12 months post-transplant for all patients with GVHD for both GVHD-related symptoms and other increased risk factors, such as increased risks of skin cancer and oral squamous cell carcinoma in those with cGVHD.208

Supportive Care for Acute GVHD

Acute GVHD of the Skin Supportive care recommendations for aGVHD of the skin include avoidance of direct sunlight and photosensitizing agents, such as voriconazole, as well as the use of sunscreen.342 Those with advanced skin aGVHD should be evaluated by a dermatologist.343

Acute GVHD of the GI Tract

aGVHD of the GI Tract aGVHD of the Gl tract can lead to symptoms such as severe abdominal pain and diarrhea. Abdominal pain from aGVHD can be difficult to treat and opioids are often required, though they should be used with caution given the increased risk of ileus associated with their use.344 Similarly, the use of octreotide can be considered for control of severe diarrhea.Because opioids may cause ileus, they should be stopped once diarrhea resolves, or after 7 days of treatment.345

Patients with aGVHD of the gut may suffer from malnutrition and protein-losing enteropathy with deficiency of trace elements (eg, magnesium and zinc) and vitamins(eg, thiamine, and vitamins B12 and D).344,346 In addition, bowel rest is a critical component of supportive care for high-grade aGVHD of the GI tract. Total parenteral nutrition should be considered in patients with voluminous diarrhea or poor tolerance to oral

intake.344,346 Monitoring for thiamine deficiency should be considered for patients with altered mental status.

Gl topical steroids such as oral beclomethasone or budesonide are frequently administered in the setting of aGVHD of the gut, but prolonged use can lead to adrenal insufficiency. Thus, it is critical for providers to be familiar with symptoms of adrenal insufficiency and to keep a high index of suspicion in the setting of non-specific symptoms, such as fatigue,malaise, and muscle aches.347

Supportive Care for cGVHD

Chronic Oral GVHD

Xerostomia is a common complication of oral cGVHD. Sialogogues such as cevimeline can be considered for severe xerostomia in the absence of contraindications.208 Patients with oral cGVHD are also at higher risk of developing oral squamous cell carcinoma208; thus, all suspicious oral lesions should be examined by a dentist or oral surgeon, in addition to routine surveillance dental examinations. Dexamethasone mouth rinses(swish and spit) can be considered,208 as can CNI mouth rinses; patients should be monitored for oral thrush and appropriate anti-fungal topical therapy should be initiated as indicated.

Chronic Ocular GVHD

Supportive care for ocular cGVHD centers around increasing ocular surface moisture to reduce dry eye and reduction of inflammation. ${}^{208}$ Autologous serum drops may improve ocular surface inflammation but are not widely available. Methods to alleviate dry eye include artificial tears and, in severe cases, punctal plugs or gas-permeable scleral lenses.Assessment and follow-up by an ophthalmologist, ideally with experience in GVHD or dry eye, is recommended.

Chronic Gut GVHD

![NCCN\nNATIONAL Cancer\nComprehensive Network\n](2/aj0YEe4oUhYkBdfpda0fYP/figure2dc420ad2cc54ae8bd2079b316689f10_0_1.png) National Comprehensive Cancer Network®

NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

Diarrhea is a well-known symptom of gct cGVHD, and a workup for malabsorption is indicated in patients with prolonged diarrhea. Pancreatic atrophy leading to fat malabsorption may occur in the setting of gut cGVHD and oral pancreatic enzyme supplementation may be beneficial.208,348

Upper intestinal cGVHD is associated with the development of esophageal webs and strictures, for which Gl consultation for endoscopic esophageal dilation may be beneficial. ${}^{208}$

cGVHD of the Genitalia

Vulvovaginal cGVHD often presents with symptoms of dryness,tenderness,dysuria,and dyspareunia.208All patients with vulovaginal symptoms should be assessed by a gynecologist. Urology and dermatology assessment may also be required for genitourinary symptoms or sclerotic changes. Differential diagnosis includes post-menopausal changes and consideration may be given to starting topical estrogen or systemic estrogen/progestin-combined hormone therapy (or referral to gynecology for further evaluation).349

Foreskin and penile cGVHD are uncommon but may lead to lichenoid skin lesions and erectile dysfunction.208,350 Appropriate referrals to urology and/or dermatology are recommended.

Musculoskeletal and Nervous System Manifestations of cGVHD Physical therapy consultation may be beneficial for patients experiencing myopathy and/or neuropathy from cGVHD, especially when symptoms such as muscle pain, weakness, or wasting or paresthesias limit activities of daily living or impair quality of life.208 Patients with limited ROM from sclerotic skin changes may also benefit from physical therapy consultation.

Summary

The NCCN Guidelines for Hematopoietic Cell Transplantation provide an evidence- and consensus-based approach for the use of HCT for the management of malignant disease in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies.However, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The leading cause of NRM in allogeneic HCT recipients is GVHD.174 Optimal GVHD care is best delivered by a multidisciplinary team, preferably in medical centers with access to specialized transplant services. Systemic corticosteroids are a mainstay of treatment for GVHD. However, approximately 50% of patients have steroid-refractory disease.215 There has been significant progress in the treatment of steroid-refractory GVHD, with recent FDA approval of several agents. However, steroid-refractory GVHD remains associated with significant morbidity, poor quality of life, increased health care costs, and significant mortality. Continued research to improve risk stratification, develop new therapies, and enhance supportive care is needed. Therefore, the NCCN Panel strongly encourages patients with steroid-refractory acute or cGVHD to participate in well-designed clinical trials to enable further advancements for the management of these diseases and ultimately increase the long-term survival of HCT recipients.

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

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30.Einhorn LH, Williams SD,Chamness A,et al.High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 2007;357:340-348. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17652649.

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33.Kilari D, D'Souza A, Fraser R, et al. Autologous hematopoietic stem cell transplantation for male germ cell tumors: improved outcomes over 3 decades. Biol Blood Marrow Transplant 2019;25:1099-1106. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30794931.

34. Dunkel J, Gardner SL, Garvin JH, Jr.,et al. High-dose carboplatin,thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma. Neuro Oncol 2010;12:297-303. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20167818.

35. Illerhaus G, Muller F, Feuerhake F,et al. High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system. Haematologica 2008;93:147-148. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18166803.

36. Kasenda B, Ihorst G, Schroers R, et al. High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group. Leukemia 2017;31:2623-2629. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28559537.

37.DeFilipp Z,Li S,El-Jawahari A,et al.High-dose chemotherapy with thiotepa, busulfan, and cyclophosphamide and autologous stem cell transplantation for patients with primary central nervous system lymphoma in first complete remission. Cancer 2017;123:3073-3079.Available at:https://www.ncbi.nlm.nih.gov/pubmed/28369839.

38. Soussain C, Hoang-Xuan K,Taillandier L,et al.Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Societe Francaise de Greffe de Moelle Osseuse-Therapie Cellulaire. J Clin Oncol 2008;26:2512-2518. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18413641.

39.Gorin NC. History and development of autologous stem cell transplantation for acute myeloid leukemia. Clin Hematol Int 2021;3:83-95. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34820613.

40. De Rosa L, Lalle M, Pandolfi A, et al. Autologous bone marrow transplantation with negative immunomagnetic purging for aggressive B-cell non-Hodgkin's lymphoma in first complete remission. Ann Hematol 2002;81:575-581. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12424539.

41. Bierman PJ, Sweetenham JW, Loberiza FR, Jr., et al. Syngeneic hematopoietic stem-cell transplantation for non-Hodgkin's lymphoma: a comparison with allogeneic and autologous transplantation--The Lymphoma Working Committee of the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation. J Clin Oncol 2003;21:3744-3753. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12963703.

42. Othus M, Appelbaum FR, Petersdorf SH, et al. Fate of patients with newly diagnosed acute myeloid leukemia who fail primary induction therapy. Biol Blood Marrow Transplant 2015;21:559-564. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25536215.

43. Yanada M, Matsuo K, Suzuki T, Naoe T. Allogeneic hematopoietic stem cell transplantation as part of postremission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia: a

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metaanalysis.Cancer 2006;106:2657-2663.Available at:https://www.ncbi.nlm.nih.gov/pubmed/16703597.

44. de Witte T,Bowen D,Robin M,et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood 2017;129:1753-1762. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28096091.

45. Sureda A, Robinson S, Canals C, et al. Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2008;26:455-462.Available at:https://www.ncbi.nlm.nih.gov/pubmed/18086796.

46.Rezvani AR, Norasetthada L, Gooley T, et al. Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse B-cell lymphoma: a multicentre experience. Br J Haematol 2008;143:395-403. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18759762.

47. Barrett J. Allogeneic stem cell transplantation for chronic myeloid leukemia. Semin Hematol 2003;40:59-71. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12563612.

48.Kharfan-Dabaja MA, Kumar A, Hamadani M, et al. Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia on behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplant. Biol Blood Marrow Transplant 2016;22:2117-2125. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27660167.

49. Bruno B, Rotta M, Patriarca F,et al. Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood 2009;113:3375-3382. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19064724.

50. Shanavas M, Messner HA, Atenafu EG, et al. Allogeneic hematopoietic cell transplantation for myelofibrosis using fludarabine-,

intravenous busulfan- and low-dose TBI-based conditioning. Bone Marrow Transplant 2014;49:1162-1169. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24978138.

51.Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990;75:555-562.Available at:https://www.ncbi.nlm.nih.gov/pubmed/2297567.

52. Corradini P, Dodero A, Zallio F, et al. Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin's lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol 2004;22:2172-2176. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15169805.

53. Weisdorf D, Zhang MJ, Arora M, et al. Graft-versus-host disease induced graft-versus-leukemia effect: greater impact on relapse and disease-free survival after reduced intensity conditioning. Biol Blood Marrow Transplant 2012;18:1727-1733. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22766220.

54. Weisdorf D, Eapen M, Ruggeri A, et al. Alternative donor transplantation for older patients with acute myeloid leukemia in first complete remission: a Center for International Blood and Marrow Transplant Research-Eurocord analysis. Biol Blood Marrow Transplant 2014;20:816-822. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24582782.

55. Servais S, Porcher R, Xhaard A, et al. Pre-transplant prognostic factors of long-term survival after allogeneic peripheral blood stem cell transplantation with matched unrelated/unrelated donors. Haematologica 2014;99:519-526. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24241489.

56. Rashidi A, Hamadani M,Zhang MJ,et al. Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission. Blood Adv 2019;3:1826-1836. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31201170.

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57. Meybodi MA, Cao W, Luznik L, et al. HLA-haploidentical vs matched-sibling hematopoietic cell transplantation: a systematic review and meta-analysis.Blood Adv 2019;3:2581-2585. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31484635.

58. Bazarachi A, Boumendil A, Finel H, et al. Influence of donor type,stem cell source and conditioning on outcomes after haploidentical transplant for lymphoma- a LWP-EBMT study. Br J Haematol 2020;188:745-756. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31498883.

59. Gluckman E, Broxmeyer HA, Auerbach AD, et al. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 1989;321:1174-1178. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2571931.

60. Wagner JE, Rosenthal J, Sweetman R, et al. Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood 1996;88:795-802. Available at:https://www.ncbi.nlm.nih.gov/pubmed/8704232.

61. Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005;105:1343-1347.Available at:https://www.ncbi.nlm.nih.gov/pubmed/15466923.

62. Warlick ED, Peffault de Latour R, Shanley R, et al. Allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia:similar outcomes regardless of donor type. Biol Blood Marrow Transplant 2015;21:357-363. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25452032.

63. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004;351:2265-2275. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15564543.

64. Marks DI, Woo KA, Zhong X, et al. Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors. Haematologica 2014;99:322-328. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24056817.

65.Rocha V, Labopin M, Sanz G,et al.Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia.N Engl J Med 2004;351:2276-2285. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15564544.

66.Fingrut WB, Gyurkocza B, Davis E, et al. Racial disparities in access to alternative donor allografts persist in the era of "donors for all". Blood Adv 2022;6:5625-5629. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2571931.

67. Kosuri S, Wolff T,Devlin S,Devlin S,et al.Prospective evaluation of unrelated donor cord blood and haploidentical donor access reveals graft availability varies by patient ancestry: Practical implications for donor selection. Biol Blood Marrow Transplant 2017;23:965-970. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28263918.

68.Khaddour K, Mewawalla P. Hematopoietic stem cell transplantation.StatPearlears. Treasure Island(FL); 2019.

69.Mehta RS,Marin D,Alousi A,et al.Haploidentical vs matched unrelated donors for patients with ALL: donor age matters more than donor type. Blood Adv 2023;7:1594-1603. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36630564.

70.Mehta RS,Ramdial J, Marin D,et al. Impact of donor age in haploidentical-post-transplantation cyclophosphamide versus matched unrelated donor post-transplantation cyclophosphamide hematopoietic stem cell transplantation in patients with acute myeloid leukemia.Transplant Cell Ther 2023;29:377 e371-377 e377. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36990221.

71. Marcoux C, Marin D, Ramdial J,et al. Younger haploidentical donor versus older matched unrelated donor for patients with AML/MDS. Am J

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Hematol 2023;98:712-719. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36734029.

72. Sparapani RA, Maiers MJ, Spellman SR, et al. Is the youngest donor always the best choice to optimize outcomes for matched unrelated allogeneic transplant? Improving precision using novel statistical methodology. Blood 2023;142:3552-3552. Available at:https://doi.org/10.1182/blood-2023-181884.

73. Artz AS. Biologic vs physiologic age in the transplant candidate.Hematology Am Soc Hematol Educ Program 2016;2016:99-105.Available at: https://www.ncbi.nlm.nih.gov/pubmed/27913468.

74. Muffy L, Pasquini MC, Martens M, et al. Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States. Blood 2017;130:1156-1164. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28674027.

75. Ciurea SO, Shah MV, Saliba RM, et al. Haploidentical transplantation for older patients with acute myeloid leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant 2018;24:1232-1236. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28918304.

76. Mohyuddin GR, Romanelli N, Shune L, et al. Autologous hematopoietic stem cell transplant is safe for elderly lymphoma patients.Hematol Oncol Stem Cell Ther 2019;12:124-125. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30075096.

77.Antonioli E, Nozzoli C, Buda G,et al. Autologous stem cell transplantation is safe in selected elderly multiple myeloma patients. J Haematol 2020;104:138-144. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31762088.

78. Artz A, Logan BR, Saber W, et al. The composite health risk assessment model (CHARM) to predict 1-year non-relapse mortality(NRM) among older recipients of allogeneic transplantation: A prospective BMT-CTN Study 1704. Blood 2023;142:109-109. Available at:https://doi.org/10.1182/blood-2023-173855.

79. Sorro ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106:2912-2919.Available at:https://www.ncbi.nlm.nih.gov/pubmed/15994282.

80. Sror ML, Logan BR, Zhu X, et al. Prospective validation of the predictive power of the hematopoietic cell transplantation comorbidity index: a Center for International Blood and Marrow Transplant research study. Biol Blood Marrow Transplant 2015;21:1479-1487. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25862591.

81.EISawy M, Storer BE,Pulsipher MA,et al.Multi-centre validation of the prognostic value of the haematopoietic cell transplantation- specific comorbidity index among recipient of allogeneic haematopoietic cell transplantation. Br J Haematol 2015;170:574-583. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25945807.

82.Saad A,Mahindra A,Zhang MJ,et al.Hematopoietic cell transplant comorbidity index is predictive of survival after autologous hematopoietic cell transplantation in multiple myeloma. Biol Blood Marrow Transplant 2014;20:402-408 e401. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24342394.

83. Berro M, Arbelbide JA, Rivas MM, et al. Hematopoietic cell transplantation-specific comorbidity index predicts morbidity and mortality in autologous stem cell transplantation. Biol Blood Marrow Transplant 2017;23:1646-1650. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28669923.

84. Sror ML, Storb RF, Sandmaier BM, et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation.J Clin Oncol 2014;32:3249-3256. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25154831.

85. Sror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood 2013;121:2854-2863. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23355537.

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86. Foundation for the Accreditation of Cellular Therapy and Joint Accreditation Committee-ISCT and EBMT. FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection,Processing, and Administration (8th edition). 2021. Available at:https://www.factglobal.org/ctstandards/.

87. Jillela AP, Ustun C. What is the optimum number of CD34+peripheral blood stem cells for an autologous transplant? Stem Cells Dev 2004;13:598-606. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15684827.

88. Kroger N, Zeller W, Fehse N, et al. Mobilizing peripheral blood stem cells with high-dose G-CSF alone is as effective as with Dexa-BEAM plus G-CSF in lymphoma patients. Br J Haematol 1998;102:1101-1106.Available at:https://www.ncbi.nlm.nih.gov/pubmed/9734664.

89.Elayan MM, Horowitz JG, Magraner JM, et al. Tbo-filgrastim versus filgrastim during mobilization and neutrophil engraftment for autologous stem cell transplantation. Biol Blood Marrow Transplant 2015;21:1921-1925. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26033279.

90. Trifilio S, Zhou Z, Galvin J, et al. Filgrastim versus TBO-filgrastim to reduce the duration of neutropenia after autologous hematopoietic stem cell transplantation: TBO, or not TBO, that is the question. Clin Transplant 2015;29:1128-1132. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26493022.

91. Neme K, Henkin D, Mikulandric N, et al. Outcomes of tbo-filgrastim,filgrastim-sndz or filgrastim for mobilization in patients undergoing an autologous hematopoietic stem cell transplant: A single center experience. Journal of Clinical Oncology 2019;37:e19000-e19000.Available at:https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15 suppl.e19000.

92. Schmitt M, Hoffmann JM, Lorenz K, et al. Mobilization of autologous and allogeneic peripheral blood stem cells for transplantation in haematological malignancies using biosimilar G-CSF. Vox Sang 2016;111:178-186. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27509033.

93. Chaudhary L, Awan F, Cumpston A, et al. Peripheral blood stem cell mobilization in multiple myeloma patients treat in the novel therapy-era with plerixafor and G-CSF has superior efficacy but significantly higher costs compared to mobilization with low-dose cyclophosphamide and G-CSF.J Clin Apher 2013;28:359-367. Available at:http://www.ncbi.nlm.nih.gov/pubmed/23765597.

94. Dugan MJ, Maziarz RT, Bensinger WI,et al. Safety and preliminary efficacy of plerifaxor(Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin's lymphoma undergoing stem cell mobilization. Bone Marrow Transplant 2010;45:39-47. Available at:http://www.ncbi.nlm.nih.gov/pubmed/19483760.

95.Gopal AK, Karami M, Mayor J, et al. The effective use of pleroxia for a real-time rescue strategy for patients poorly mobilizing autologous CD34(+) cells. J Clin Aperh 2012;27:81-87. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2298418.

96. Milone G, Tripepi G, Martino M, et al. Early measurement of CD34+cells in peripheral blood after cyclophosphamide and granulocyte colony-stimulating factor treatment predicts later CD34+ mobilisation failure and is a possible criterion for guiding" on demand" use of plerixafor. Blood Transfus 2013;11:94-101. Available at:

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97.Giralt S, Costa L, Schriber J, et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol Blood Marrow Transplant 2014;20:295-308. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24141007

98.Becker PS.Optimizing stem cell mobilization: lessons learned.J Natl Compr Canc Netw 2014;12:1443-1449. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25313183.

99.DiPersio JF,Micallef IN,Stiff PJ,et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus

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granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma.J Clin Oncol 2009;27:4767-4773.Available at:https://www.ncbi.nlm.nih.gov/pubmed/19720922.

100. DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma.Blood 2009;113:5720-5726. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19363221.

101. Duong HK, Savani BN, Copelan E, et al. Peripheral blood progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2014;20:1262-1273. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24816581.

102. Crees ZD, Rettig MP, Jayasinghe RG, et al. Motifaxiorfide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial. Nat Med 2023;29:869-879. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37069359.

103. Haynes A, Hunter A, McQuaker G, et al. Engraftment characteristics of peripheral blood stem cells mobilised with cyclophosphamide and the delayed addition of G-CSF. Bone Marrow Transplant 1995;16:359-363. Available at:https://www.ncbi.nlm.nih.gov/pubmed/8535307.

104.Chao NJ,Grima DT,Carrum G,et al.Chemo-mobilization provides superior mobilization and collection in autologous stem cell transplants but with less predictability and at a higher cost. Blood 2011;118:4040-4048. Available at:

https://ashpublications.org/blood/article/118/21/4048/68992/Chemo-Mobilization-Provides-Superior-Mobilization.

105. Gazitt Y, Callander N, Freytes CO, et al. Peripheral blood stem cell mobilization with cyclophosphamide in combination with G-CSF, GM-CSF, or sequential GM-CSF/G-CSF in non-Hodgkin's lymphoma patients: a randomized prospective study. J Hematother Stem Cell Res

2000;9:737-748. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11091498.

106.Kobbe G, Bruns I, Fenk R, et al. Pegfilgrastim for PBSC mobilization and autologous haematopoietic SCT. Bone Marrow Transplant 2009;43:669-677. Available at:http://www.ncbi.nlm.nih.gov/pubmed/19308043.

107. Costa LJ, Kramer C, Hogan KR, et al. Pegfilgrastim- versus filgrastim-based autologous hematopoietic stem cell mobilization in the setting of preemptive use of plerixafor: efficacy and cost analysis.Transfusion 2012;52:2375-2381. Available at:http://www.ncbi.nlm.nih.gov/pubmed/22404694.

108. Herbert KE, Demosthenous L, Wiesner G, et al. Plerixafor plus pegfilgrastim is a safe, effective mobilization regimen for poor or adequate mobilizers of hematopoietic stem and progenitor cells: a phase I clinical trial. Bone Marrow Transplant 2014;49:1056-1062. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24887382.

109.Abid MB,De Mel S,Abid MA,E.glyal in Pegfilgrastim versus filgrastim for stem cell mobilization in multiple myeloma after novel agent induction.Clin Lymphoma Myeloma Leuk 2018;18:174-179. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29398647.

110. Herbert KE, Gambell P, Link EK,et al. Pegfilgrastim compared with filgrastim for cytokine-alone mobilization of autologous haematopoietic stem and progenitor cells. Bone Marrow Transplant 2013;48:351-356.Available at:https://www.ncbi.nlm.nih.gov/pubmed/22858510.

111. Partanen A, Valtola J, Ronpponen A, et al. Preemptive plerixafor injection added to pegfilgrastim after chemotherapy in non-Hodgkin lymphoma patients mobilizing poorly. Ann Hematol 2017;96:1897-1906.Available at: https://www.ncbi.nlm.nih.gov/pubmed/28879595.

112. Micallef IN, Stiff PJ, DiPersio JF,et al. Successful stem cell remobilization using plerixafor(mozobil) plus granulocyte colony-stimulating factor in patients with non-hodgkin lymphoma: results from the plerixafor NHL phase 3 study rescue protocol. Biol Blood Marrow

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Transplant 2009;15:1578-1586. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19896082

113. Li J, Hamilton E,Vaughn L,et al.Effectiveness and cost analysis of"just-in-time" salvage pleroxifar administration in autologous transplant patients with poor stem cell mobilization kinetics. Transfusion 2011;51:2175-2182. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21492180.

114.Worel N,Fritsch G,Agis H,et al.Plerixafor as preemptive strategy results in high success rates in autologous stem cell mobilization failure.J Clin Apher 2017;32:224-234. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27578390.

115. Tournilac O, Cazin B, Lepretre S, et al. Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia.Blood 2004;103:363-365. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12969985.

116. Kuittinen T, Nousiainen T, Halonen P, et al. Prediction of mobilisation failure in patients with non-Hodgkin's lymphoma. Bone Marrow Transplant 2004;33:907-912. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15034543.

117. Kumar S, Giralt S, Stadtmauer EA, et al. Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens. Blood 2009;114:1729-1735. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19561323.

118. Micallef IN, Apostolidis J, Rohatiner AZ, et al. Factors which predict unsuccessful mobilisation of peripheral blood progenitor cells following G-CSF alone in patients with non-Hodgkin's lymphoma. Hematol J 2000;1:367-373. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11920216.

119. Hosing C, Saliba RM, Ahlawat S, et al. Poor hematopoietic stem cell mobilizers: a single institution study of incidence and risk factors in

patients with recurrent or relapsed lymphoma. Am J Hematol 2009;84:335-337. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19384931.

120. Wuchter P, Ran D, Bruckner T, et al. Poor mobilization of hematopoietic stem cells-definitions, incidence, risk factors, and impact on outcome of autologous transplantation. Biol Blood Marrow Transplant 2010;16:490-499. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19925876.

121.Paripati H, Stewart AK, Cabou S, et al. Compromised stem cell mobilization following induction therapy with lenalidomide in myeloma.Leukemia 2008;22:1282-1284. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18216870.

122. Mazumder A, Kaufman J, Niesvizky R, et al. Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients. Leukemia 2008;22:1280-1281;author reply 1281-1282. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18033320

123. Waterman J, Rybicki L, Bolwell B, et al. Fludarabine as a risk factor for poor stem cell harvest, treatment-related MDS and AML in follicular lymphoma patients after autologous hematopoietic cell transplantation.Bone Marrow Transplant 2012;47:488-493. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21572461.

124.Ogunniyi A,Rodriguez M,Devlin S,et al.Upfront use of plerixafor and granulocyte-colony stimulating factor (GCSF) for stem cell mobilization in patients with multiple myeloma: efficacy and analysis of risk factors associated with poor stem cell collection efficiency. Leuk Lymphoma 2017;58:1123-1129. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27735212.

125. Shin S, Kim J, Kim-Wanner SZ, et al. A novel association between relaxin receptor polymorphism and hematopoietic stem cell yield after mobilization. PLoS One 2017;12:e0179986. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28666004.

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126.Kanate AS, Watkins K, Cumpston A, et al. Salvage bone marrow harvest in patients failing plerixafor-based stem cell mobilization attempt:feasibility and autologous transplantation outcomes. Biol Blood Marrow Transplant 2013;19:1133-1135. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23635452.

127. Bensinger WI, Weaver CH, Appelbaum FR, et al. Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor. Blood 1995;85:1655-1658.Available at: https://www.ncbi.nlm.nih.gov/pubmed/7534140.

128. Cavallaro AM, Lilleby K, Majolino I, et al. Three to six year follow-up of normal donors who received recombinant human granulocyte colony-stimulating factor. Bone Marrow Transplant 2000;25:85-89. Available at:https://www.ncbi.nlm.nih.gov/pubmed/10654020.

129. Rinaldi C, Savignano C, Pasca S, et al. Efficacy and safety of peripheral blood stem cell mobilization and collection: a single-center experience in 190 allogeneic donors. Transfusion 2012;52:2387-2394.Available at:https://www.ncbi.nlm.nih.gov/pubmed/22452363.

130. Azar N, Choquet S, Garnier A. Use of a biosimilar G-CSF in allogeneic stem cell mobilisation. Bone Marrow Transplant 2012;47:S316(P727). Available at:

http://www.nature.com/bmt/journal/v47/n1s/pdf/bmt201237a.pdf

131. Antelo M, Zabalza A, Sanchez P. Safety and efficacy of a G-CSF biosimilar(Zarzio(R)) for haematopoietic progenitor cell mobilization in allogeneic healthy donors. Bone Marrow Transplant 2013;48:S102(P491). Available at:

http://www.nature.com/bmt/journal/v48/n2s/pdf/bmt201323a.pdf

132. Becker P, Schwebig A, Brauninger S, et al. Healthy donor hematopoietic stem cell mobilization with biosimilar granulocyte-colony-stimulating factor: safety, efficacy, and graft performance. Transfusion 2016;56:3055-3064. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27633122.

133. Antelo ML,Zabalza A, Sanchez Anton MP,et al. Mobilization of hematopoietic progenitor cells from allogeneic healthy donors using a new biosimilar G-CSF(Zarzio(R)). J Clin Apher 2016;31:48-52.Available at: http://www.ncbi.nlm.nih.gov/pubmed/26011178.

134.Farhan R, Urbanowska E, Zborowska H, et al. Biosimilar G-CSF versus figigrastim and lenograstim in healthy unrelated volunteer hematopoietic stem cell donors. Ann Hematol 2017;96:1735-1739.Available at:https://www.ncbi.nlm.nih.gov/pubmed/28801752.

135. Pahnke S,Egeland T, Halter J,et al. Current use of biosimilar G-CSF for haematopoietic stem cell mobilisation. Bone Marrow Transplant 2019;54:858-866. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30283148.

136. Schmitt M, Xu X, Hilgendorf I, et al. Mobilization of PBSC for allogeneic transplantation by the use of the G-CSF biosimilar XM02 in healthy donors. Bone Marrow Transplant 2013;48:922-925. Available at:http://www.ncbi.nlm.nih.gov/pubmed/23318540.

137. Danylesko I, Sareli R, Bloom-Varda N, et al. Biosimilar frilastrimin(Tevagrastim, XMO2) for allogeneic hematopoietic stem cell mobilization and transplantation in patients with acute myelogenous leukemia/myelodysplastic syndromes. Biol Blood Marrow Transplant 2016;22:277-283. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26343949.

138. Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009;15:1628-1633. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19896087.

139. McCune JS, Quinones CM, Ritchie J, et al. Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement. Biol Blood Marrow Transplant 2019;25:1890-1897. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31136799.

140.Scott BL, Pasquini MC, Logan BR, et al. Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid

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leukemia and myelodysplastic syndromes. J Clin Oncol 2017;35:1154-1161.Available at:https://www.ncbi.nlm.nih.gov/pubmed/28380315.

141.Horwitz ME,Stiff PJ,Cutler C,et al.Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study. Blood 2021;138:1429-1440. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34157093.

142. Bubalo J, Carpenter PA, Majhail N, et al. Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation practice guideline committee. Biol Blood Marrow Transplant 2014;20:600-616. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24462742.

143. Hagenburg J, Savale L, Lechartier B, et al. Pulmonary hypertension associated with busfan. Pulm Circ 2021;11:20458940211030170.Available at:https://www.ncbi.nlm.nih.gov/pubmed/34616544.

144.Till BG, Madtes DK. BCNU-associated pneumonitis: portrait of a toxicity. Leuk Lymphoma 2012;53:1019-1020. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22220936.

145. Vogel J, Hui S, Hua CH, et al. Pulmonary toxicity after total body irradiation- critical review of the literature and recommendations for toxicity reporting.Front Oncol 2021;11:708906. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34513689.

146. Mohty M, Malard F, Abcassis M, et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation(EBMT). Bone Marrow Transplant 2015;50:781-789.Available at:https://www.ncbi.nlm.nih.gov/pubmed/25798682.

147. Ladha A, Mannis G, Muffly L. Hepatic veno-occlusive disease in allogeneic stem cell transplant recipients with prior exposure to gemutuzumab ozogamicin or intotuzumab ozogamicin. Leuk Lymphoma 2021;62:257-263. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32988266.

148. Van Schandevyl G, Bauters T. Thiotepa-induced cutaneous toxicity in pediatric patients: Case report and implementation of preventive care guidelines. J Oncol Pharm Pract 2019;25:689-693. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30185131.

149. Pidala J, Kim J, Jim H, et al. A randomized phase ll study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation. Haematologica 2012;97:1882-1889. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22689677.

150.Khimani F,Kim J,Chen L,et al. Predictors of overall survival among patients treated with sirolimus/tacrolimus vs methotrexate/tacrolimus for GvHD prevention. Bone Marrow Transplant 2017;52:1003-1009. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28368376.

151. Cutler C, Stevenson K, Kim HT, et al. Sirolimus is associated with veno-occlusive disease of the liver after myelolative allogeneic stem cell transplantation. Blood 2008;112:4425-4431. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18776081.

152. Cutler C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood 2014;124:1372-1377. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24982504.

153.Ijaz A,Khan AY,Malik SU,et al.Significant risk of graft-versus-host disease with exposure to checkpoint inhibitors before and after allogeneic transplantation. Biol Blood Marrow Transplant 2019;25:94-99.Available at:https://www.ncbi.nlm.nih.gov/pubmed/30195074.

154. Merrman RW, Kim HT, Zinzani PL, et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood 2017;129:1380-1388. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28073785.

155. Kamada Y, Arima N, Hayashida M, et al. Prediction of the risk for graft versus host disease after allogeneic hematopoietic stem cell

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transplantation in patients treated with mogulamizumab. Leuk Lymphoma 2022;63:1701-1707.Available at:

https://www.ncbi.nlm.nih.gov/pubmed/35225126.

156. Merry RW, Castagna L, Giordano L, et al. Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.Leukemia 2021;35:2672-2683. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33658659.

157. Maziarz RT, Diaz A, Miklos DB, Shah NN. Perspective: An International Fludarabinage Shortage: Supply Chain Issues Impacting Transplantation and Immune Effector Cell Therapy Delivery.Transplantation and Cellular Therapy, Official Publication of the American Society for Transplantation and Cellular Therapy 2022;28:723-726. Available at:https://doi.org/10.1016/j.jtct.2022.08.002.

158. Chevallier P, Peterlin P, Garnier A, et al. Clofarabinar-based reduced intensity conditioning regimen with peripheral blood stem cell graft and post-transplant cyclophosphamide in adults with myeloid malignancies. Oncotarget 2018;9:33528-33535. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30323896.

159.Saito T, Kanda Y, Kami M, et al. Therapeutic potential of a reduced-intensity preparative regimen for allogeneic transplantation with cladribine, busulfan, and antihymocyte globulin against advanced/refractory acute leukemia/lymphoma. Clin Cancer Res 2002;8:1014-1020. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11948108.

160.Saito T, Kanda Y, Nakai K, et al. Immune reconstitution following reduced-intensity transplantation with cladibrine, busulfur, and antithymocyte globulin: serial comparison with conventional myeloablative transplantation. Bone Marrow Transplant 2003;32:601-608. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12953133.

161. Markova M, Barker JN, Miller JS, et al. Fludarabine vs cladibine plus busulfan and low-dose TBI as reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation: a prospective

randomized trial. Bone Marrow Transplant 2007;39:193-199. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17220905.

162.Dimitrova D, Gea-Banacloche J, Steinberg SM, et al. Prospective study of a novel, radiation-free, reduced-intensity bone marrow transplantation platform for primary immunodeficiency diseases. Biol Blood Marrow Transplant 2020;26:94-106. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31493539.

163.Gvajaia A, Langston A, Esiashvil N, et al. Pentotstatin/TBI conditioning is well-tolerated and permits engraftment of a second allogeneic stem cell transplant following primary or secondary rejection of an allogeneic hematopoietic stem graft[abstract]. Blood 2019;134(Suppl 1):Abstract 5657. Available at:https://ashpublications.org/blood/article/article/134/Supplement 1/5657/425387/Pentotstatin-TBI-Conditioning-ls-Well-Tolerated?

164. McDonald GB, Sandmaier BM, Mielcarek M, et al. Survival,nonrelapse mortality, and relapse-related mortality after allogeneic hematopoietic cell transplantation: comparing 2003-2007 versus 2013-2017 cohorts. Ann Intern Med 2020;172:229-239. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31958813.

165. Levine JE, Uberti JP, Ayash L,et al. Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy. Biol Blood Marrow Transplant 2003;9:189-197.Available at:https://www.ncbi.nlm.nih.gov/pubmed/12652470.

166. Majhail NS,Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012;18:348-371.Available at:https://www.ncbi.nlm.nih.gov/pubmed/22178693.

167.Jim HS, Syrjala KL, Rizzo D. Supportive care of hematopoietic cell transplant patients. Biol Blood Marrow Transplant 2012;18:S12-16.Available at: https://www.ncbi.nlm.nih.gov/pubmed/22226095.

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168. Giebel S, Labopin M, Socie G,et al.Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica 2017;102:139-149. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27686376.

169. Ribera JM. Allogeneic stem cell transplantation for adult acute lympholastic leukemia: when and how. Haematologica 2011;96:1083-1086. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21810970.

170. Trajkovska I, Georgievski B, Cevreska L, et al. Early and late complications in patients with allogeneic transplantation of hematopoietic stem cell. Open Access Maced J Med Sci 2017;5:340-343. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28698754.

171. Bacigalupo A, Sormani MP, Lamparelli T, et al. Reducing transplant-related mortality after allogeneic hematopoietic stem cell transplantation. Haematologica 2004;89:1238-1247. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15477210.

172. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010;363:2091-2101.Available at:https://www.ncbi.nlm.nih.gov/pubmed/21105791.

173.Tanaka Y,Kurosawa S,Tajima K,et al. Analysis of non-relapse mortality and causes of death over 15 years following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2016;51:553-559. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26752142.

174. Wingard JR, Majhail NS, Brazauskas R, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 2011;29:2230-2239. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21464398.

175. D'Souza A, Fretham C, Lee SJ, et al. Current use of and trends in hematopoietic cell transplantation in the United States. Biol Blood

Marrow Transplant 2020;26:e177-e182. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32438042.

176. Marchesi F,Pimpinelli F,Di Domenico EG,et al.Association between CMV and invasive fungal infections after autologous stem cell transplant in lymphoproliferative malignancies: opportunistic partnership or cause-effect relationship? Int J Mol Sci 2019;20. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30893777.

177.Jantunen E,Itala M,Lehtinen T,et al.Early treatment-related mortality in adult autologous stem cell transplant recipients: a nation-wide survey of 1482 transplanted patients. Eur J Haematol 2006;76:245-250. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16412136.

178.Przepioka D, Weisdorf D, Martin P, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995;15:825-828. Available at:https://www.ncbi.nlm.nih.gov/pubmed/7581076.

179.Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11:945-956. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16338616.

180.Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood 2015;125:606-615. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25398933.

181.Jagasia MH,Greinix HT,Arora M,et al.National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant 2015;21:389-401 e381.

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182. Zeiser R, Blazar BR. Acute graft-versus-host disease - biologic process,prevention,and therapy.N Engl J Med 2017;377:2167-2179.Available at:https://www.ncbi.nlm.nih.gov/pubmed/29171820.

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183. McDonald GB, Sandmaier BM, Mielcarek M, et al. Survival,nonrelapse mortality, and relapse-related mortality after allogeneic hematopoietic cell transplantation: Comparing 2003-2007 cerus 2013-2017 cohorts. Ann Intern Med 2020;172:229-239. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31958813.

184. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplant. Biol Blood Marrow Transplant 2012;18:1150-1163. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22510384.

185. Ross WA, Ghosh S, Dekovich AA, et al. Endoscopic biopsy diagnosis of acute gastrointestinal grafting-versus-host disease:rectosigmoid biopsies are more sensitive than upper gastrointestinal biopsies. Am J Gastroenterol 2008;103:982-989. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18028511.

186. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974;18:295-304. Available at:https://www.ncbi.nlm.nih.gov/pubmed/4153799.

187. Rowlings PA, Przepioka D, Klein JP, et al. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol 1997;97:855-864. Available at:https://www.ncbi.nlm.nih.gov/pubmed/9217189.

188. Martino R, Romero P, Subira M, et al. Comparison of the classic Glucksberg criteria and the IBMTR Severity Index for grading acute graft-versus-host disease following HLA-identical sibling stem cell transplantation. International Bone Marrow Transplant Registry. Bone Marrow Transplant 1999;24:283-287. Available at:https://www.ncbi.nlm.nih.gov/pubmed/10455367.

189. MacMillan ML, DeFor TE, Weisdorf DJ. What predicts high risk acute graft-versus-host disease(GVHD) at onset?: Identification of those at highest risk by a novel acute GVHD risk score. Br J Haematol

2012;157:732-741. Available at:

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190. MacMillan ML, Robin M, Harris AC,et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy,survival, and transplant-related mortality. Biol Blood Marrow Transplant 2015;21:761-767. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25585275.

191. Harris AC, Young R, Devine S, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant 2016;22:4-10. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26386318.

192.Schoemans HM, Lee SJ, Ferrara JL, et al. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology& guidance for graft-versus-host disease assessment. Bone Marrow Transplant 2018;53:1401-1415. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29872128.

193. Major-Monfried H, Renteria AS, Pawoarde A, et al. MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD.Blood 2018;131:2846-2855. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29545329.

194. Ali AM, DiPersio JF, Schroeder MA. The role of biomarkers in the diagnosis and risk stratification of acute graft-versus-host disease: a systematic review. Biol Blood Marrow Transplant 2016;22:1552-1564.Available at:https://www.ncbi.nlm.nih.gov/pubmed/27158050.

195. Levine JE, Braun TM, Harris AC,et al. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study.Lancet Haematol 2015;2:e21-29. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26687425.

196. Socie G, Niederwieser D, von Bubnoff N, et al. Prognostic value of blood biomarkers in steroid-refractory or steroid-dependent acute graft-

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versus-host disease: a REACH2 analysis. Blood 2023;141:2771-2779.Available at:https://www.ncbi.nlm.nih.gov/pubmed/36827620.

197. Mielcarek M, Furlong T, Storer BE, et al. Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial. Haematologica 2015;100:842-848. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25682602.

198. Van Lint MT, Uderzo C, Locasciull A, et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood 1998;92:2288-2293. Available at:https://www.ncbi.nlm.nih.gov/pubmed/9746766.

199. Pidala J, Hamadani M, Dawson P, et al. Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CN 1501 trial. Blood 2020;135:97-107. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31738834.

200.Alousi AM, Weisdorf DJ, Logan BR, et al. Etanercept,mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. Blood 2009;114:511-517.Available at:https://www.ncbi.nlm.nih.gov/pubmed/19443659.

201. Bolarnos-Meade J, Logan BR, Alousi AM, et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood 2014;124:3221-3227; quiz 3335.Available at: https://www.ncbi.nlm.nih.gov/pubmed/25170121.

202. Martin PJ, Inamoto Y, Flowers ME, Carpenter PA. Secondary treatment of acute graft-versus-host disease: a critical review. Biol Blood Marrow Transplant 2012;18:982-988. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22510383.

203. Csanadi M, Agh T, Tordai A, et al. A systematic literature review of incidence, mortality, and relapse of patients diagnosed with chronic graft versus host disease. Expert Rev Hematol 2019;12:311-323. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30955381.

204. Maziarz RT,Devine S, Garrison LP, et al. Estimating the lifetime medical cost burden of an allogeneic hematopoietic cell transplantation patient. Transplant Cell Ther 2023;29:637 e631-637 e639. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37364775.

205. Avenoso D, Davidson JA, Larvin H, et al. Healthcare resource utilization and associated costs in patients with chronic graft-versus-host disease post-allegeneic hematopoietic stem cell transplantation in England. Transplant Cell Ther 2024;30:1207 e1201-1207 e1211.Available at:https://www.ncbi.nlm.nih.gov/pubmed/39389467.

206.Pidala J,Kurland B,Chai X,et al. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood 2011;117:4651-4657. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21355084.

2017. Lee SJ, Wolff D, Kitko C, et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 response criteria working group report. Biol Blood Marrow Transplant 2015;21:984-999. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25796139.

208. Carpenter PA, Kitko CL, Elad S,et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: V. The 2014 ancillary therapy and supportive care working group report. Biol Blood Marrow Transplant 2015;21:1167-1187.Available at:https://www.ncbi.nlm.nih.gov/pubmed/25838185

209. Shulman HM, Cardona DM, Greenson JK, et al. NIH Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 pathology working group report. Biol Blood Marrow Transplant 2015;21:589-603. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25639770.

210. Paczesny S, Hakim FT, Pidala J, et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: III. The 2014 biomarker working group report.

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Biol Blood Marrow Transplant 2015;21:780-792. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25644957.

211. Carpenter PA, Logan BR, Lee SJ, et al. A phase II/III randomized, multicenter trial of prednisone/sirrolimus versus prednisone/sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica 2018;103:1915-1924.Available at:https://www.ncbi.nlm.nih.gov/pubmed/29954931.

212. Williams KM, Cheng GS, Pusic I,et al. Fluticasone, azithromycin,and montelukast treatment for new-onset bronchiolitis obitransy syndrome after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2016;22:710-716. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26475726.

213. Bergeron A, Chevret S, Granata A, et al. Effect of azithromycin on airflow decline-free survival after allogeneic hematopoietic stem cell transplant: the ALLOZITHRO randomized clinical trial. JAMA 2017;318:557-566. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28787506.

214.Cheng GS,Bondeelle L,Gooley T,et al.Azithromycin use and increased cancer risk among patients with bronchiolitis obliterans after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2020;26:392-400. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31682980.

215.Pidala J,Anasetti C. Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2010;16:1504-1518.Available at:https://www.ncbi.nlm.nih.gov/pubmed/20096359.

216.Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD(REACH1): a multicenter,open-label phase 2 trial. Blood 2020;135:1739-1749. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32160294.

217.Jagasia M, Zeiser R, Arbushites M, et al. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the

REACH trials. Immunotherapy 2018;10:391-402. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29316837.

218. Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med 2020;382:1800-1810.Available at:https://www.ncbi.nlm.nih.gov/pubmed/32320566.

219.Prescribing information for alemutuzumab injection, for intravenous use.2023. Available at:

https://www.accessdata.fda.gov/drugsatfda docs/label/2023/103948s51881bl.pdf.Accessed July 28, 2023.

220.Khouri IF, Albitar M, Saliba RM, et al. Low-dose alemtuzumab(Campath) in myeloablative algeogene stem cell transplantation for CD52-positive malignancies: decreased incidence of acute graft-versus-host disease with unique pharmacokinetics. Bone Marrow Transplant 2004;33:833-837. Available at:https://www.ncbi.nlm.nih.gov/pubmed/14755312.

221.Gómez-Almager D, Ruiz-Arguelles GJ, del Carmen Tarin-Arzaga L,et al.Alemutuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2008;14:10-15.Available at:https://www.ncbi.nlm.nih.gov/pubmed/18158956.

222.Schnitzler M, Hasskarl J, Egger M, et al. Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab. Biol Blood Marrow Transplant 2009;15:910-918. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19589480.

223. Magenau JM, Goldstein SC, Peltier D, et al. alpha1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood 2018;131:1372-1379. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29437593.

224.Pye A,Turner AM. Experimental and investigational drugs for the treatment of alpha-1 antitrypsin deficiency. Expert Opin Investig Drugs 2019;28:891-902. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31550938.

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

225. Arai Y, Jo T, Matsui H, et al. Efficacy of antithymocyte globulin for allogeneic hematopoietic cell transplantation: a systematic review and meta-analysis. Leuk Lymphoma 2017;58:1840-1848. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27951736.

226. Alousi AM, Brammer JE, Saliba RM, et al. Phase II trial of graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide after reduced-intensity busulfan/fludarabine conditioning for hematological malignancies. Biol Blood Marrow Transplant 2015;21:906-912. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25667989.

227. Czerw T, Labopin M, Giebel S, et al. Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBTM. Cancer 2018;124:2523-2533. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29603136.

228.Kroger N, Solano C, Wolschke C, et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med 2016;374:43-53. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26735993.

229.Kumar A,Reljic T, Hamadami N,et al. Antithymocyte globulin for graft-versus-host disease prophylaxis: an updated systematic review and meta-analysis. Bone Marrow Transplant 2019;54:1094-1106. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30446739.

230.Ziakas PD,Zervou FN,Zacharioudakis IM,Mylonakis E.Graft-versus-host disease prophylaxis after transplantation: a network meta-analysis.PLoS One 2014;9:e114735. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25485632.

231. Cho BS, Min GJ, Park SS, et al. Low-dose thymoglobulin for prevention of chronic graft-versus-host disease in transplantation from an HLA-matched sibling donor. Am J Hematol 2021;96:1441-1449.Available at:https://www.ncbi.nlm.nih.gov/pubmed/34390504.

232.Khanolkar RA, Kalra A, Kinzel M, et al. A biomarker-guided,prospective, phase 2 trial of pre-emptive graft-versus-host disease therapy using anti-thymocyte globulin. Cytotherapy 2021;23:1007-1016.Available at:https://www.ncbi.nlm.nih.gov/pubmed/34373186.

233. MacMillan ML, Weisdorf DJ, Davies SM, et al. Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host disease. Biol Blood Marrow Transplant 2002;8:40-46.Available at:https://www.ncbi.nlm.nih.gov/pubmed/11858189.

234. McCaul KG, Nevill TJ, Barnett MJ, et al. Treatment of steroid-resistant acute graft-versus-host disease with rabbit antihymocyte globulin. J Hematother Stem Cell Res 2000;9:367-374. Available at:https://www.ncbi.nlm.nih.gov/pubmed/10894358.

235. Ali R, Ramdial J, Algaze S, Beitinjaneh A. The role of anti-thymocyte globulin or altemuzumab-based serotherapy in the prophylaxis and management of graft-versus-host disease. Biomedicines 2017;5:67. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29186076.

236. Prescribing information for basilimoxim and docs/label/2003/basnov0102 https://www.accessdata.fda.gov/drugsatfda docs/label/2003/basnov010203LB.htm.Accessed July 28, 2023.

237.Schmidt-Hieber M, Fietz T, Knauf W, et al.Efficacy of the interleukin-2 receptor antagonist basilimax in steroid-refractory acute graft-versus-host disease. Br J Haematol 2005;130:568-574. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16098072.

238. Prescribing information for tacrolimus capsules, for oral use;injection, for intravenous use; granules(tacrolimus for oral suspension).2022. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/050708s054,050709s047,204096s010lbl.pdf.Accessed July 28,2023.

239. Prescribing information for cyclosporine, capsules; oral solution;injection. 2015. Available at:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/050573s041,050574s051,050625s0551bl.pdf.Accessed July 28, 2023.

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

240. Moiseev IS, Pirogova OV, Alyanski AL, et al. Graft-versus-host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus,and mycophenolate mofetil. Biol Blood Marrow Transplant 2016;22:1037-1042. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26970381.

241.Kanda Y, Kobayashi T, Mori T, et al. A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations after unrelated bone marrow transplantation. Bone Marrow Transplant 2016;51:103-109. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26437063.

242. Mielcarek M, Furlong T, O'Donnell PV, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood 2016;127:1502-1508. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26764356.

243.Torlen J, Ringden O, Garming-Legert K, et al. A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation. Haematologica 2016;101:1417-1425. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27662016.

244.Al-Kadhimi Z,Gul Z,Abidi M,et al.Low incidence of severe cGvHD and late NRM in a phase II trial of thymoglobulin, tacitrogimus and sirolimus for GvHD prevention. Bone Marrow Transplant 2017;52:1304-1310.Available at:https://www.ncbi.nlm.nih.gov/pubmed/28581472.

245.Gao L,Liu J,Zhang Y,et al.Low incidence of acute graft-versus-host disease with short-term tacrolimus in haploid identical hematopoietic stem cell transplantation. Leuk Res 2017;57:27-36. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28273549.

246.Deeg HJ, Loughran TP, Jr., Storb R, et al. Treatment of human acute graft-versus-host disease with antihymocyte globulin and cyclosporine with or without methylprednisolone. Transplantation

1985;40:162-166. Available at:https://www.ncbi.nlm.nih.gov/pubmed/3895622.

247.Kanamaru A,Takemoto Y,Kakishita E,et al.FK506 treatment of graft-versus-host disease developing or exacerbating during prophylaxis and therapy with cyclosporin and/or other immunosuppressants.Japanese FK506 BMT Study Group. Bone Marrow Transplant 1995;15:885-889.Available at:https://www.ncbi.nlm.nih.gov/pubmed/7581086.

248.Xhaard A, Launay M, Sicre de Fontrune F, et al. A monocentric study of steroid-refractory acute graft-versus-host disease treatment with tacitrolus and mTOR inhibitor. Bone Marrow Transplant 2020;55:86-92.Available at:https://www.ncbi.nlm.nih.gov/pubmed/31413313.

249. Prescribing information for etanercept injection, for subcutaneous use.2023. Available at:

https://www.accessdata.fda.gov/drugsatfda docs/label/2023/103795s5594lbl.pdf. Accessed July 28,2023.

250.Couriel D,Saliba R,Hicks K,et al.Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood 2004;104:649-654.Available at:https://www.ncbi.nlm.nih.gov/pubmed/15069017.

251. Busca A, Locatelli F, Marmont F, et al. Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2007;82:45-52. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16937391.

252. Abu-Dalle I, Reljic T, Nishihori T, et al. Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies. Biol Blood Marow Transplant 2014;20:1677-1686. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24867779.

253.Smith EP, Sniecinski I, Dagis AC, et al. Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs.-host

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disease. Biol Blood Marrow Transplant 1998;4:27-37. Available at:https://www.ncbi.nlm.nih.gov/pubmed/9701389.

254. Alcondir T,Gorgun G,Miller KB,et al.Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease. Blood 2001;98:1622-1625. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11520818.

255. Greinix HT, Knobler RM, Wolre N, et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica 2006;91:405-408. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16531267.

256. Sakellari I, Gavriilaki E, Batsis I, et al. Favorable impact of extracorporeal photopheresis in acute and chronic graft versus host disease: prospective single-center study. J Clin Apher 2018;33:654-660.Available at:https://www.ncbi.nlm.nih.gov/pubmed/30394564.

257.Zhang H, Chen R, Cheng R, J et al. Systematic review and meta-analysis of prospective studies for ECP treatment in patients with steroid-refractory acute GVHD. Patient Prefer Adherence 2015;9:105-111.Available at:https://www.ncbi.nlm.nih.gov/pubmed/25653504.

258. Prescribing information for infliximab for injection, for intravenous use.2021. Available at:https://www.accessdata.fda.gov/drugsatfda docs/label/2021/103772s5401lbl.pdf. Accessed July 28,2023.

259. Patriarca F,Sperotto A, Damiani D, et al. Infliximab treatment for steroid-refractory acute graft-versus-host disease. Haematologica 2004;89:1352-1359. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15531458.

260.Yalniz FF,Hefazi M, McCullough K, et al. Safety and efficacy of infliximab therapy in the setting of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2017;23:1478-1484.

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261.Goral S, Helderman JH. Chapter 36- Current and emerging maintenance immunosuppressive therapy. In: Himmelfarb J, Sayegh MH,eds. Chronic Kidney Disease, Dialysis, and Transplantation (Third Edition). Philadelphia: W.B. Saunders; 2010:516-525.

262.Hsieh A.mTOR: The master regulator. Cell 2012;149:955-957.Available at:

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263. Dumont FJ,Su Q.Mechanism of action of the immunosuppressant rapamycin.Life Sci 1996;58:373-395. Available at:https://www.ncbi.nlm.nih.gov/pubmed/8594303.

264.Armand P, Kim HT, Sainvil MM, et al. The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial. Br J Haematol 2016;173:96-104. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26729448.

265.Kornblit B, Maloney DG, Storer BE, et al. A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation. Haematologica 2014;99:1624-1631. Available at:

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266.Pidala J,Kim J,Alsina M,et al. Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease.Haematologica 2015;100:970-977. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25840599.

267.Wang L,Gu Z,Zhai R,et al.The efficacy and safety of sirolimus-based graft-versus-host disease prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials. Transfusion 2015;55:2134-2141. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25857725.

268. Benito Al, Furlong T, Martin PJ, et al. Sirolimus(rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease.

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

Transplantation 2001;72:1924-1929. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11773890.

269.Hoda D, Pidala J, Salgado-Vila N, et al. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant 2010;45:1347-1351. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19966849.

270. Ghez D, Rubio MT, Maillard N, et al. Rapamycin for refractory acute graft-versus-host disease. Transplantation 2009;88:1081-1087.

Available at: https://www.ncbi.nlm.nih.gov/pubmed/19898203.

271. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000;47:85-118. Available at:https://ncbi.nlm.nih.gov/pubmed/10878285.

272. Prescribing information for mycophenolate mofetil. 2022. Available at:

https://www.accessdata.fda.gov/drugsatfda docs/label/2022/050722s050,050723s050,057058s048,050759s055lbl.pdf.Accessed July 28,2023.

273.Furlong T, Martin P, Flowers ME, et al. Therapy with mycophenolate mofetil for refractory acute and chronic GVHD. Bone Marrow Transplant 2009;44:739-748. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19377515.

274.Kim JG,Sohn SK,Kim DH,et al. Different efficacy of mycophenolate mofetil as salvageage treatment for acute and chronic GVHD after allogeneic stem cell transplant. Eur J Haematol 2004;73:56-61.Available at:https://www.ncbi.nlm.nih.gov/pubmed/15182339.

275. Pidala J, Kim J, Perkins J, et al. Mycophenolate mofetil for the management of steroid-refractory acute graft vs host disease. Bone Marrow Transplant 2010;45:919-924. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19767783.

276. Prescribing information for pentostatin for injection. 2019. Available at:

https://www.accessdata.fda.gov/drugsatfda docs/label/2019/020122s015lbl.pdf.Accessed July 28, 2023.

277.Ragon BK,Mehta RS,GulbisAM,et al.Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit. Bone Marrow Transplant 2018;53:315-325. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29269797.

278.Schmitt T, Luft T, Hegenbart U, et al. Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis.Bone Marrow Transplant 2011;46:580-585. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19898203.

279.Pidala J,Kim J,Roman-Diaz J,et al.Pentostatin as rescue therapy for glucocorticoid-refractory acute and chronic graft-versus-host disease.Ann Transplant 2010;15:21-29. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21183872.

280.Bolaos-Meade J, Jacobsobsohn DA, Margolis J, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol 2005;23:2661-2668. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15837980.

281.Poi MJ, Hofmeister CC, Johnston JS, et al. Standard pentostatin dose reductions in renal insufficiency are not adequate: selected patients with steroid-refractory acute graft-versus-host disease. Clin Pharmacokinet 2013;52:705-712. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23588536.

282. Prescribing information for tocilizumab injection, for intravenous or subcutaneous use.2022. Available at:

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283. lmamura M, Hashino S, Kobayashi H, et al. Serum cytokine levels in bone marrow transplantation: synergistic interaction of interleukin-6,interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host disease. Bone Marrow Transplant 1994;13:745-751. Available at:https://www.ncbi.nlm.nih.gov/pubmed/7920309.

![NCCN\nNCC\n](2/aj0YEe4oUhYkBdfpda0fYP/figure38357d3b7aca4b158e7b8ce849ec6f02_0_1.png)

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

284. Cavet J, Dickinson AM, Norden J, et al. Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 2001;98:1594-1600. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11520812.

285. Ganetsky A, Frey NV, Hexner EO, et al. Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower gastrointestinal tract. Bone Marrow Transplant 2019;54:212-217. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29795429.

286. Gergis U, Arnason J, Yantiss R, et al. Effectiveness and safety of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in a patient with refractory Gl graft-versus-host disease. J Clin Oncol 2010;28:e602-604. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20713858.

287. Yucebay F, Matthews C, Puto M, et al. Tocilizumab as first-line therapy for steroid-refractory acute graft-versus-host-disease: analysis of a single-center experience. Leuk Lymphoma 2019;60:2223-2229.Available at: https://www.ncbi.nlm.nih.gov/pubmed/30764681.

288. Roddy JV, Haverkos BM, McBride A, et al. Tocilizumab for steroid refractory acute graft-versus-host disease. Leuk Lymphoma 2016;57:81-85. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26140610.

289.Drobyski WR, Pasquini M, Kovatovic K, et al. Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transplant 2011;17:1862-1868. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21745454.

290.Holtan SG,Hoeschen A,Cao Q,et al.Phase II,open-label clinical trial of urinary-derived human chorionic gonadotropin/epidermal growth factor for life-threatening acute graft-versus-host disease. Transplant Cell Ther 2023;29:509 e501-509 e508. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37279855.

291. Li AC, Dong C, Tay ST, et al. Vedolizumab for acute gastrointestinal graft-versus-host disease: A systematic review and meta-analysis. Front

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292. Danylesko I, Bukauskas A, Paulson M, et al. Anti-alphabeta7 integrin monoclonal antibody(vedolizumab) for the treatment of steroid-resistant severe intestinal acute graft-versus-host disease. Bone Marrow Transplant 2019;54:987-993. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30356163.

293.Floisand Y, Lazarevic VL, Maertens J, et al. Safety and effectiveness of vedolizumab in patients with steroid-refractory gastrointestinal acute graft-versus-host disease: a retrospective record review. Biol Blood Marrow Transplant 2019;25:720-727. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30468919.

294. Miklos D,Cutler CS,Arora M,et al.lbrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood 2017;130:2243-2250. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28924018.

295. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med 2021;385:228-238. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34260836.

296.Cutler CS, Lee SJ, Arai S, et al. Belumosuilad for Chronic Graft-versus-Host Disease After 2 or More Prior Lines of Therapy: The ROCKstar Study. Blood 2021;138:2278-2289. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34265047.

297. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013;122:2539-2549. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23886836.

298. Waller EK,Miklos D, Cutler C,et al. lbrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-year update of a phase 1b/2 study. Biol Blood Marrow Transplant 2019;25:2002-2007.Available at:https://www.ncbi.nlm.nih.gov/pubmed/31260802.

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

299. Carpenter PA,Kang HJ,Yoo KH,et al.Ibrutinib treatment of pediatric chronic graft-versus-host disease: Primary results from the Phase 1/2 iMAGINE study.Transplant Cell Ther 2022;28:771 e771-771 e710.Available at:https://www.ncbi.nlm.nih.gov/pubmed/36044977.

300. Wolff D, Cutler C, Lee SJ, et al. Safety and efficacy of axitalimab at 3 different doses in patients with chronic graft-versus-host disease(AGAVE-201). Blood 2023;142:1-1. Available at:https://doi.org/10.1182/blood-2023-186963.

301. Nahas MR, Soiffer RJ, Kim HT, et al. Phase 1 clinical trial evaluating abatcept in patients with steroid-refractory chronic graft-versus-host disease. Blood 2018;131:2836-2845. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29549175.

302. Prescribing information for abatacept injection. 2021. Available at:https://www.accessdata.fda.gov/drugatsfda docs/label/2021/125118s240 lbl.pdf. Accessed July 28, 2023.

303. Nikiforow S, Kim HT, Bindra B, et al. Phase I study of alemtuzumab for therapy of steroid-refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant 2013;19:804-811. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23416855.

304.Gutierrez-Aguirre CH,Cantu-Rodriguez OG, Borjas-Almaguer OD,et al. Effectiveness of subcutaneous low-dose alemtuzumab and rituximab combination therapy for steroid-resistant chronic graft-versus-host disease. Haematologica 2012;97:717-722. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22133770.

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

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326.Huang XJ,Jiang Q,Chen H,et al.Low-dose methotrexate for the treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2005;36:343-348.Available at:https://www.ncbi.nlm.nih.gov/pubmed/15968295.

327.Couriel DR,Saliba R,Escalon MP,et al.Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol 2005;130:409-417. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16042691.

328. Johnston LJ, Brown J, Shizuru JA, et al. Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2005;11:47-55. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15625544.

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NCCN Guidelines Version 3.2025 Hematopoietic Cell Transplantation (HCT)

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331. Mielke S, Lutz M, Schmidhuber J, et al. Salvage therapy with everolimus reduces the severity of treatment-refractory chronic GVHD without impairing disease control: a dual center retrospective analysis.Bone Marrow Transplant 2014;49:1412-1418. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25089598.

332. Lopez F, Parker P, NademaneA, et al. Efficacy of mycophenolate mofetil in the treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2005;11:307-313. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15812396.

333. Jacobsohn DA, Chen AR, Zahurak M, et al. Phase II study of pentostatin in patients with corticosterof-refractory chronic graft-versus-host disease. J Clin Oncol 2007;25:4255-4261. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17878478.

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336. Stern L, Withers B, Avdic S, et al. Human cytomegalovirus latency and reactivation in allogeneic hematopoietic stem cell transplant recipients. Front Microbiol 2019;10:1186. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31191499.

337. ASH-ASTCT COVID-19 vaccination for HCT and CAR T cell recipients: Frequently asked questions. 2022. Available at:https://www.hematology.org/covid-19/ash-astct-covid-19-vaccination-for-hct-and-car-t-cell-recipients. Accessed July 10,2023.

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339. Ruutu T, Eriksson B, Remes K, et al. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood 2002;100:1977-1983. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12200355.

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表 1
三Critical care medicine/ Pulmonary medicine ＵHematology �s Hematology	p Internal medicine ／ Medical oncology ［ Patient advocacy
○ Hematopoietic cell	∑ Pharmacology * Discussion Section
transplantation	Writing Committee

表 2
MA Regimens	MA Regimens	Busulfan-BasedF
Allegeneic Transplant	TBI-Based Cyclophosphamide + TBI1 - Cyclophosphamide 60 mg/kg/day for 2 daysC - TBI 12-13.2 Gy fractionated	Busulfan-Based F Busulfan + Cyclophosphamide9,15 ● Busulfan 3.2 mg/kg/day for 4 days ● Cyclophosphamide 60 mg/kg/day for 2 daysC ●Fludarabine+TBI12 ●Fludarabine+30mg/m2/day for 4 days ●TBI 12-13.2 Gy fractionated ●Fludarabine 30-32 mg/m2/day for 4-5 days
Umilbolic Cord Blood (UCB)d,e	Fludarabine+TBI1 - TBI 12-22 ●Fludarabine+40mg/m2/day for 2 days; Fludarabine 30 mg/kg/day for 4 days ●TBI 13.2 Gy fractionated	Fludarabine+ Busulfan16 ● Busulfan 3.2 mg/kg/day(12.8 mg/kg total) for 4 days ●Fludarabine 30-32 mg/m2/day for 4-5 days ●Fludarabine+ Busulfan+ Thiotepa17,18 ●Fludarabine 30-40 mg/m2/day for 4 days OR 50 mg/m2/day for 3 days ●Busulfan 3.2 mg/kg/day total for 3-4 days; ●Thiotepa 5 mg/kg/day for 1-2 days ●Clofarabine+ Busulfan19,20 ●Clofarabine 20-40 mg/m2/day for 4-5 days ●Busulfan AUC 4000-5500 (or 3.2 mg/kg/day) for 4 days
Umbilonic Cord Blood (UCB)d,e	TBI-Based F Busulfan-Based Fludarabine+ Cyclophosphamide + TBI12 ●Fludarabine+ Busulfan+ Thiotepa23 ●Cyclophosphamide 60 mg/kg/day for 2 days ● Busulfan 3.2 mg/kg/day for 3 days ●TBI 13.2 Gy fractionated ●Fludarabine 50 mg/m2/day for 3 days ●TBI 13.2 Gy fractionated

表 3
NMA Regimens	NMA Regimens	Other
Allogeneic Transplant	TBI-Based Fludarabine + TBI24 ●Fludarabine 30 mg/m2/day for 3 days ●TBI 2 Gy	Fludarabine + Cyclophosphamide $\pm$ Rituximab $\pm$ Rituximab 30 mg/m2/day for 3 days $\bullet$ Cyclophosphamide 750 mg/m2/day for 3 days $\bullet$ Rituximab $\pm$ 375 mg/m2 IV for 1 day before transplant; and 1000 mg/m2 IV on days 1,8, and 15 after transplant

表 4
RIC Regimens	Fludarabine + Melphalan26 ●Fludarabine + Cyclophosphamide + TBI29 ●Fludarabine 20-36 mg/m2/day for 4-5 days ● Melphalan 100-140 mg/m2 over 1-2 days ● Cyclophosphamide 14.5 mg/kg/day for 2 days ● TBI 2-4 Gy ●Fludarabine + Melphalan + TBI1,30 ● Busulfan 3.2 mg/kg/day IV for 2-3 days OR 25 mg/m2/day for 6 days ● Melphalan 100-140 mg/m2 over 1-2 days ● Busulfan 2.3 mg/kg/day IV for 2-3 days OR 25 mg/m2/day for 6 days ● Melphalan 100-140 mg/m2 over 1-2 days ● TBI 2-4 Gy
Allogeneic Transplant	Fludarabine + Melphalan + Thiotepa31,32 ●Fludarabine 40 mg/m2/day for 4 days ● Melphalan 140 mg/m2 for 1 day ● Thiotepa 10 mg/m2 for 1 day ● Fludarabine+ Busulfan+ Thiotepa17 ● Thiotepa 5 mg/kg/day for 1 day ● Busulfan 130 mg/m2/day IV for 2 days ● Fludarabine 30-40 mg/m2/day for 4 days
UCBd	Fludarabine + Cyclophosphamide + Tiotepa + TBI33 ● Tiotepa 10 mg/kg/day ● TBI 4 Gy Fludarabine + Cyclophosphamide + TBI34 ● Fludarabine 200 mg/m2 ● Cyclophosphamide 50 mg/kg ● TBI 2 Gy

表 5
RIC Regimens Without Fludarabine
Pentostatin-based	●Pentostatin+ busulfan35 ●Pentostatin+ busulfan + cyclophosphamide36 ●Pentostatin+ TBI 4 Gy37
Clofarabine-basedk	●Clofarabine+ busulfan38,39 ●Clofarabine + melphalan40±thiotepa41 ●Clofarabine + TBI 2 Gy42 ●Clofarabine + cyclophosphamide + TBI 2 Gy43 (with PTCy)
Cladribine-basedl	●Cladribine+ busulfan +ATG44,45 ●Cladribine + busulfan +TBI 2 Gy46
Cyclophosphamide-based	Cyclophosphamide + TBI 5.5 Gy47

表 6
Autologous Regimens by Disease Type
NHL(without central nervous system disease) or HL	●BEAM(carmustine+etoposide+cytarabine +melphalan)48 ●BEAC(carmustine+etoposide+cytarabine + cyclophosphamide)49-51 ●Carmustine + thiotepa52 ● Busulfan + cyclophosphamide + etoposide53 ●TEAMal Nervous System or NHL(with central nervous system disease)
$$\text{Multiple Myeloma/Plasma Cell}$$ Leukemia	●Melphalan(200 mg/m^{2})56 ●Melphalan(70-140 mg/m^{2} for select patients)m,57-59 ● Melphalan+ busulfan(high risk)60
Germ Cell Tumors	●Carboplatin +etoposide 61,62
Acute Promyelocytic Leukemia	●Busulfan + melphalan63-65 ● Cyclophosphamide + TBl65 ● Busulfan + cyclophosphamide65

表 7
Suggested Doses/Modifications by Weight66
Busulfan	● Adults: mg/kg dosing: dose based on 25% adjusted body weight Body surface area (BSA) dosing: dose based on total body weight ● Pediatrics: dose based on total body weight ● Risk of SOS/VOD is correlated with higher busulfan exposure (higher AUC)
Carmustine	● Dose adults on BSA ●Total body weight ≤120% ideal body weight: dose based on total body weight ●Total body weight >120% ideal body weight: dose based on 25% adjusted body weight ●Pulmonary toxicity >50% at 600 mg/m2 with multiple agent regimens. Maximum tolerated dose of 1200 mg/m2 as single agent with 9.5% pulmonary toxicity
Cyclophosphamide	● Cy200 regimen: dose based on the lesser of total body weight or ideal body weight ● Cy120 regimen: dosing can be either ideal body weight or total body weight until >120% ideal body weight, then dose based on 25% adjusted body weight
Cytarabine	Dose adults and children on BSA based on total body weight
Etoposide	● Mg/kg dosing: dose based on 25% adjusted body weight ● BSA dosing: dose based on total body weight
Fludarabine	Dose adults on BSA based on total body weight
Melphalan	● Dose adults on BSA based on total body weight ●Adjustments for age and renal function are not standardized
Thiotepa	● Dose adults on BSA if total body weight≤120% ●Total body weight≤120% ideal body weight dose on BSA based on total body weight
Treosulfan	Dose adults and children on BSA based on total body weight

表 8
Stage	Extent of Organ Involvement
Stage	Skin	Liver	Gut
1	Rash on <25% of skinb	Bilirubin 2-3 mg/dlc	Diarrhea >500 ml/day or persistent nausea
2	Rash on 25-50% of skin	Bilirubin 3-6 mg/dl	Diarrhea >1000 ml/day
3	Rash on >50% of skin	Bilirubin 6-15 mg/dl	Diarrhea >1500 ml/day
4	Generalized erythroderma with bullous formation	Bilirubin >15 mg/dl	Severe abdominal pain with or without ileus
Gradef
I	Stage 1-2	None	None
II	Stage 3	Stage 1	Stage 1
III	-	Stage 2-3	Stage 2-4
IV9	Stage 4	Stage 4	-

表 9
Stage	Skin (active erythema only)	Liver (bilirubin)	Upper Gl	Lower Gl (stool output/day)
0	No active (erythematous) GVHD rash	<2 mg/dL	No or intermittent nausea, vomiting, or anorexia	Adult: <500 mL/day or <3 episodes/day vomiting, or anorexia
1	Maculopapular rash <25% BSA	2-3 mg/dL	Persistent nausea, vomiting or anorexia	Adult: <500 mL/day or <3 episodes/day Variable: vanomusea, vomiting or anorexia
2	Maculopapular rash 25%-50% BSA	3.1-6 mg/dL		Child: 10-19.9 mL/kg/day or 4-6 episodes/day
3	Maculopapular rash >50% BSA	6.1-15 mg/dL		Adult: 1000-1500 mL/day or 5-7 episodes/day Child: 20-30 mL/kg/day or 7-10 episodes/day
4	Generalized erythroderma (>50% BSA) plus bullous formation and desquamation >5% BSA	>15 mg/dL		Adult: >500 mL/day or >7 episodes/day Child: >30 mL/kg/day or >10 episodes/day

表 10
Signs and Symptoms of Chronic GVHDa	Distinctive_b (seen in chronic GVHD, but insufficient to establish a diagnosis)	Other features for unclassified entitiesc	Commond (seen with both acute and chronic GVHD)
Organ Site	Distinctive_b (seen in chronic GVHD, but insufficient to establish a diagnosis)	Other features for unclassified entitiesc	Commond (seen with both acute and chronic GVHD)	Diagnostic (sufficient to establish the diagnosis of chronic GVHD)
Skin	●Pokiloderma ● Lichen planus-like features ●Sclerotic features ● Morphea-like features	●Depigmentation ● Papulosquamous lesions	●Sweat impairment ● Ichthyosis ●Lichthyosis ● Keratosis pilaris ● Hypopigmentation ● Hyperpigmentation	●Erythema ● Maculopapular rash ● Pruritus
Nails		●Dystrophy ● Longitudinal ridging, splitting or brittle features ● Onycholysis ● Pterygium unguis ● Nail loss (usually symmetric, affects most nails)	● Normalding (seen with both acute and chronic GVHD)
Scalp and Body Hair		● New onset of scarring or non-scarring scalp the alloperia(after recovery from chemoradiotherapy) ● Loss of body hair ● Scaling	● Thinning scalp hair, typically patchy, coarse, or dull(not explained by endocrine or other causes) ● Premature gray hair	●Erythema ● Maculopapular rash ● Pruritus
Mouth	● Lichen planus-like changes	● Xerostomia ● Muccoles ● Mucosal atrophy ● Ulcers ● Pseudomembranes	● McGivitis ● Mucositis ● Erythema ● Pain
Eyes		● New onset dry,gritty, or painful eyes ● Cicatricial conjunctivitis ● Keratoconjunctivitis sicca	● Photophobia ● Periorbital hyperpigmentation ● Blepharitis(erythema of the eye lids with edema
		● Confluent areas of punctate keratopathy	b In all cases, infection, drug effect, malignancy, or other causes must be excluded. c Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed. c Common refers to shared features by both acute and chronic GVHD.

表 11
Signs and Symptoms of Chronic GVHDa
Signs and Symptoms of Chronic GVHDa
Organ Site	Diagnostic	Distinct6b (seen in chronic GVHD, but insufficient to establish a diagnosis)	Other features for unclassified entitiesc
Genitalia	(sufficient to establish the diagnosis of chronic GVHD)	·Erosions ●Fissures ●Vaginal scarring or clitoral/labial agglutination ●Phimosis or urethral/meatus scarring or stenosis
Gl Tract			●Exocrine pancreatic insufficiency ● Exocrine pancreatic insufficiency ● Nausea ● Stricatures or stenosis in the upper to insufficiency ● Diarrhea ● Weight loss ●Failure to thrive (infants and children)
Liver			●Failure to thrive (infants and children)
Lung	· Bronchiolitis obliterans diagnosed with lung biopsy ●BOSe	●Air trapping and bronchiectasis ● Cryptogenic organizing pneumonia(cOP)f ●Restrictive lung diseasef	●Alanine transaminase(ALT)>2 x ULN

表 12
Signs and Symptoms of Chronic GVHDa
Organ Site	Diagnostic	Distinctiveb	Other features for unclassified entitiesc	Commond (seen with both acute and chronic GVHD)
	(sufficient to establish the diagnosis of chronic GVHD)	(seen in chronic GVHD, but insufficient to establish a diagnosis)
Muscles, Fascia, Joints	● Fascitis ● Joint stiffness or contractures secondary to fascitis or sclerosis	●Myositis or polymositis9 ● Acute cramps ● Arthralgia or arthritis
Hematopoietic and Immune				●Thrombocytopenia ●Eosinophilia ● Lymphopenia ●Hypo-or hyper- gammaglobulinemia ●Autoantibodies(autoimmune hemolytic anemia[AIHA], immune thrombocytopenia[ITP]) ● Raynaud's phenomenon
Other				●Pericardial or pleural effusions ● Ascites ● Peripheral neuropathy ● Nephrotic syndrome ● Myasthenia gravis ● Cardiac conduction abnormality or cardiomyopathy

表 13
Organ Scoring of Chronic GVHDa
Performance Score: KPS ECOG(circle one)	Score 0	Score 1	Score 2	Score 3
Performance Score: KPS ECOG(circle one)	Asymptomatic and fully active(ECOG 0, KPS 100%)	Symptomatic, fully ambulatory, restricted only in physically strenuous activity(ECOG 1, KPS 80-90%)	Symptomatic, ambulatory, capable of self-care, >50% of waking hours out of bed (ECOG 2, KPS 60-70%)	Symptomatic, limited self-care, >50% of waking hours in bed (ECOG 3-4, KPS <60%)
Skinb
Score % BSA:	No BSA involved	1-18% BSA	19-50% BSA	>50% BSA
GVHD features to be scored by BSA (check all that apply):
O Maculopapular rash/erythema Lichen planus-like features
O Sclerotic features
O Papulosquamous lesions or ichthyosis
O Keratosis pilaris-like GVHD
Skin Features	No sclerotic features		Superficial sclerotic features	Check all that apply:
Score: $\_$			"not hidebound" (able to pinch)	O Deep sclerotic features "Hidebound" (unable to pinch)
				O Impaired mobility
Other skin GVHD features, NOT scored by BSA (check all that apply):				O Ulceration
O Hyperpigmentation
O Hypopigmentation
O Poikiloderma
O Severe or generalized pruritus
O Hair involvement
O Nail involvement
O Abnormality present but explained entirely by non-GVHD documented cause(specify):
	Score 0	Score 1	Score 2	Score 3
Mouth
	No symptoms	Mild symptoms with disease signs but not limiting oral intake significantly	Moderate symptoms with disease signs with partial limitation of oral intake	Severe symptoms with disease signs on examination with major limitation of oral intake
lichen planus-like features present: Yes
ONo
OAbnormality present but explained entirely by non-GVHD documented cause(specify):
Eyes
Keratoconjunctivitis sicica(KCS) confirmed by ophthalmologist Yes	No symptoms	Mild dry eye symptoms not affecting ADL (requirement of lubricant eye drops ≤3x per day)	Moderate dry eye symptoms partially affecting ADL (requiring lubricant eye drops >3x per day or punctal plugs), WITHOUT new vision impairment due to KCS	Severe dry eye symptoms significantly affecting ADL (special eyeware to relieve pain) OR unable to work because of ocular symptoms OR loss of vision due to KCS
O Not examined
O Abnormality present but explained entirely by non-GVHD documented cause (specify):
GI Tract
Check all that apply: Esophageal web/proximal stricture or ring	No symptoms	Symptoms without significant weight loss ${ }^{\circ} $	Symptoms associated with mild to moderate weight loss ${ }^{\circ} $ (5-15%) OR moderate diarrhea without significant interference with daily living	Symptomes associated with significant weight loss ${ }^{\circ} $ >15%, requires nutritional supplement
O Anerxia				for most calorie needs OR esophageal dilation OR severe diarrhea with significant interference with daily living
O Vomiting				diarrhea with significant interference with daily living
O Diarrhea
Weight loss $\ge$ 5%
O Failure to thrive
	Abnormality present but explained entirely by non-GVHD documented cause (specify):

表 15
	CHRONIC GVHD:GRADING	CHRONIC GVHD:GRADING	CHRONIC GVHD:GRADING	CHRONIC GVHD:GRADING
	Score 0	Score 1	Score 2	Score 3
Liver
	Normal total bilirubin and ALT or AP< 3 x ULN	Normal total bilirubin with ALT ≥ 3 to 5 x ULN or AP≥ 3 x ULN	Elevated total bilirubin but ≤ 3 mg/dL or ALT>5xULN	Elevated total bilirubin >3 mg/dL
OAbnormality present but explained entirely by non-GVHD documented cause(specify):
Lungsd
Symptom score:	No symptoms	Mild symptoms (shortness of breath after climbing one flight of steps)	Moderate symptoms (shortness of breath after walking on flat ground)	Severe symptoms (shortness of breath at rest; requiring $O_{2}$)
Lung score:$\_$ % FEV1	FEV1≥80%	FEV1 60-79%	FEV1 40-59%	FEV1 ≤39%
Pulmonary function tests: Not performed
Abnormality present but explained entirely by non-GVHD documented cause(specify):
Joints and Fascia
P-ROM score (see GVHD-C.5 of 5) Shoulder (1-7):	No symptoms	Mild tightness of arms or legs, normal or mild decreased range of motion (ROM) AND not affecting	Tightness of arms or legs OR joint contractures, erythema thought due to fasciitis, moderate decrease ROM AND mild to moderate limitation of ADL	Contractures WITH significant decrease of ROM AND significant limitation of ADL (unable to tie shoes, button shirts, dress self, etc)
Elbow (1-7):
Wrist/finger (1-7):
Ankle(1-4):
OAbnormality present but explained entirely by non-GVHD documented cause (specify):
Genital Tracte
O Not examined Currently sexually active: No signs	Mild signs and females with or without discomfort on exam	Moderate signs and may have symptoms with discomfort on exam	Severe signse with or may have symptoms with	Severe signse with or without symptoms
O No
OAbnormality present but explained entirely by non-GVHD documented cause (specify):

表 16
Organ Scoring of Chronic GVHD
Other indicators, clinical features or complications related to chronic GVHD(checkd all that apply and assign a score to severity (0-3) based on functional impact where applicable none-0,mild-1, moderate-2, severe-3)
O Ascites (serositis)
O Pericardial effusion
O Weight loss >5% without GI symptoms
O Pleural effusion(s)
O Eosinophilia >500/μl
O Nephrotic syndrome _
O Myasthenia gravis _
O Peripheral neuropathy _
Overall GVHD Severity
Opinion of the evaluator: O No GVHD O Mild

表 17
NIH Global Severity of Chronic GVHa
Mild chronic GVHD	Moderate	ChVHD	Severe chronic GVHD
1 or 2 organs involved with no more than score 1 plus	3 or more organs involved with no more than score 1 OR At least 1 organ (not lung) with a score of 2	At least 1 organ with a score of 3 OR	At least 1 organ with a score of 3 OR
Lung score 0	Lung score 1	Lung score of 2 or 3
Key points:	Key points:	Key points:	Key points:
1.In skin: higher of the two scores to be used for calculating global severity. 2.In lung: FEV1 is used instead of clinical score for calculating global severity. 3. If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD documented cause, that organ is not included for calculation of the global severity.
4. If the abnormality in an organ is attributed to multifactorial causes(GVHD plus other causes) the scored organ will be used for calculation of the global severity should of the contributing causes (no downgrading of organ severity score).

表 18
	Acute GVHD Steroid Response	Chronic GVHD Steroid Response
Steroid Refractoriness or Resistance	Progression of acute GVHD within 3-5 days of therapy onset with ≥2 mg/kg/day of prednisone OR Failure to improve within 5-7 days of treatment initiation OR Incomplete response after more than 28 days of immunosuppressive treatment including steroids	Chronic GVHD progression while on prednisone at ≥1 mg/kg/day for 1-2 weeks OR Stable GVHD disease while on ≥0.5 mg/kg/day (or 1 mg/kg every other day) of prednisone for 1-2 months
Steroid Dependence	Inability to taper prednisone below 2 mg/kg/day OR A recurrence of acute GVHD activity during steroid taper	Inability to taper prednisone below 0.25 mg/kg/ day (or >0.5 mg/kg every other day) in at least two unsuccessful attempts separated by at least 8 weeks
Steroid Intolerance	Emergence of unacceptable toxicity due to the use of corticosteroids

表 19
Organ	Complete Response	Partial Response	Progression
Skin	NIH Skin Score 0 after previous involvement	Decrease in NIH Skin Score by 1 or more points	Increase in NIH Skin Score by 1 or more points, except 0 to 1
Eyes	NIH Eye Score 0 after previous involvement	Decrease in NIH Eye Score by 1 or more points	Increase in NIH Eye Score by 1 or more points, except 0 to 1
Mouth	NIH Modified Oral Mucosa Rating Score 0 after previous involvement	Decrease in NIH Modified Oral Mucosa Score of 2 or more points	Increase in NIH Modified Oral Mucosa Rating Score of 2 or more points
Esophagus	NIH Esophagus Score 0 after previous involvement	Decrease in NIH Esophagus Score by 1 or more points	Increase in NIH Esophagus Score by 1 or more points, except 0 to 1
Upper GI	NIH Upper GI Score 0 after previous involvement	Decrease in NIH Upper GI Score by 1 or more points	Increase in NIH Upper GI Score by 1 or more points, except 0 to 1
Lower GI	NIH Lower GI Score 0 after previous involvement	Decrease in NIH Lower GI Score by 1 or more points	Increase in NIH Lower Gl Score by 1 or more points, except from 0 to 1
Liver	Normal ALT, alkaline phosphatase, and total bilirubin after previous elevation of one or more	Decrease by 50%	Increase by 2x ULN
Lungs	-Normal %FEV1 after previous involvement -If PFTs not available, NIH Lung Symptom Score 0 after previous involvement	-Increase by 10% predicted absolute value of %FEV1 -If PFTs not available, decrease in NIH Lung Symptom Score by 1 or more points, except in NIH	-Decrease by 10% predicted absolute value of %FEV1 -If PFTs not available, increase in NIH Lung Symptom Score by 1 or more points, except 0 to 1
Joints and Fascia	Both NIH Joint and Fascia Score 0 and P-ROM score 25 after previous involvement by at least one measure	Decrease in NIH Joint and Fascia Score by 1 or more points or increase in P-ROM score by 1 point for any site	Increase in NIH Joint and Fascia Score by 1 or more points or decrease in P-ROM score by 1 point for any site
Global	Clinician overall severity score 0	Clinician overall severity score decreases by 2 or more points on a 0-10 scale	Clinician overall severity score increases by 2 or more points on a 0-10 scale

表 20
Suggested Systemic Agents for Steroid-Refractory GVHD3	Chronic GVHD
Acute GVHD1	Chronic GVHD
The following agents are often used in conjunction with the original immunosuppressive agent.	While the following systemic agents may be used to treat chronic GVHD in any organ, some agents are used more commonly for certain sites involved with chronic GVHD based on available data(see Discussion).
FDA-approved category 1 agents	FDA-approved category 1 agents
●Ruxolitinib(category 1)c,2	●Ruxolitinib(category 1)c,24-26
Alternative agents(listed in alphabetical order)	Other FDA-approved agents(listed in order by FDA approval date)
●Alpha-1 antitrypsin	●Ibrutinibe,27,28
●ATG6	●Belumosudifif,29
●Basiliximab7	●Axatilimab-csfr$9,30
●Calcineurin inhibitors(CNls)(eg,tacrolimus, cyclosporine)
●Extracorporeal photophereis(ECP)d,9	Alternative agents(listed in alphabetical order)
●Infixlimab10	●Abatacept31
●Mortrin inhibitors(eg, sirolimus) 11,12	●Almtuzumab32,33
●Mocophenolate mofetil13,14	●CNls(eg,tacrolimus,cyclosporine)
●Pentostatin15-17	●Hydroxychloroquine35
●Tocilizumab18-21	$$\begin{array}{l}\cdot\quad\text{Imatinib}^{36,37} 36,37\\ \cdot\quad\text{Imerulin}^{2}\cdot\text{IL-2)38}\\ \end{array}$$
●epidermal growth factor(uhCG/EGF)22	●Low-dose methotrexate 39-41
●Vedolizumab23	●MTOR inhibitors(eg, sirolimus)42-44
	●Mycophenolate mofetil45
a For patients receiving immunosuppressive agents for GVHD, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.	●Pentostatin46-48

表 21
BOS	BOS	BOS	BOS
ADL	activities of daily living	G-CSF	granulocyte colony-stimulating
AIHA	autoimmune hemolytic anemia
ALT	alanine transaminase	GI	gastrointestinal
AP	alkaline phosphatase	GVHD	graft-versus-host disease
ATG	antithymocyte globulin	HBV	hepatitis B virus
AUC	area under the curve	HCT	hematopoietic cell transplant
BOS	bronchiolitis obliterans syndrome	HCV	HCT-CI
BSA	body surface area	HD	hepatitis C virus
CMV	cytomegalovirus	HIV	high-dose
CNI	calcineurin inhibitor	HL	Hodgin lymphoma
COP	cryptogenic organizing pneumonia	HL	human leukocyte antigen
DEXA	dual-energy x-ray absorptiometry	HSV	STR
DLCO	diffusing capacity of the lungs for carbon monoxide	ITP	immune thrombocytopenia intravenous immunoglobulin
ECOG	Eastern Cooperative Oncology Group	KCS	keratoconjunctivitis sicca
ECP	extracorporeal photopheresis	LFT	Karnofsky Performance Status
FEV1	forced expiratory volume in the first second	LVEF	left ventricular ejection fraction
	MA	myeloablative	VC VOD/SOS

表 22
NHL	non-Hodgkin lymphoma
non-myelaloablative
non-relapse mortality
	pulmonary function test
photographic range of motion
post-transplant	cyclophosphamide
psoralen and ultraviolet A irradiation
reduced-intensity conditioning range of motion
range of motion
	short tandem repeat
TBI	total body irradiation

表 23
Pulmonary function test
photographic range of motion
post-transplant
cyclophosphamide
psoralen and ultraviolet A
irradiation
reduced-intensity conditioning
range of motion
short tandem repeat
TBI	total body irradiation

表 24
NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is NCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

表 25
NCCN Categories of Preference
Preferred intervention	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended intervention	Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances	Other interventions that may be used for selected patient populations (defined with recommendation).

图示：HEMATOPOIETIC CELL MOBILIZATION MBTREATMENTn,o Granulocyte colony-stimulating factor (G-CSF)+ plerixafor or Granulocyte colony-stimulating or clerish for granulocyte-macrophage colony-stimulating or Granulocyte-macrophage colony-stimulating or Granul30 colony-stimulating or Granul30 cells/kg (preferred)^P HEMATOPOIETIC CELL MOBILIZATION MBTREATMENTn,o0 Granulocyte colony-stimulating or Granul30 cells-stimulating or Granul30234 cells/kg (preferred)^P Stem cell collection with minimum target yield of 2-5x10°CD34 cells/kg (preferred)^P CD34 count (preferred)^CD34 cells/kg (preferred)^P If insufficient collection, consider: Increasing G-CSF dose or changing dose schedule or Addition of plerixafor to G-CSF or for G-CSF + mix of plerixafor + Target yield of 2-5x10°CD34 cells/kg (preferred)^P Chemo-mobilization± Bremmat. FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product, Processing, and Administration (8th edition); 2021. OAlternative chemo-mobilization depends on individual patient, and disease-related factors. Lower yields may be adequate, but>2 x 10° CD34 cells/kg is strongly preferred, with a target of 4-5 x 10° CD34 cells/kg. Stem cell yields <2 x 10° CD34 cells/kg may result in delayed engraftment, while larger cell doses have been associated with a more rapid time to platelet and neutrophil recovery. For bone marrow harvesto g CD34 = BHene marrow harvesto g Conditioning HCT (HCT-5)

图示：Conditioning for allogeneic transplant based on disease Infusion of hematopoietic cells Conditioning for autologous transplant based on disease

图示：WORKUP Additional tests as clinically indicated to rule out non-GVHD causes^{a,b,c} ●Additional tests as clinically indicated to rule out non-GVHD causes^{a,b,c} ●Organ-directed biopsy, as clinically indicated, to support acute GVHD diagnosis ●Skin rash: consider biopsy of suspicious skin sites ●Diarrhea: consider biostinalian (GI) biopsya ● Diarrhea: lower gastrointestinal (GI) biopsya Nausea/vomiting: consider upper Gl biopsya ● Nausea/vomiting: consider liver biopsy if elevated liver-associated enzymes or total/direct bilirubin and no evidence of acute GVHD elsewhere ●Determine chronic GVHD; skin stage 1-2, CVH ●Regine chronic GVHD grade ●See Chronic GVHD: Grading(GVHD-C) ●Determine chronic GVHD grade See Chronic GVHD: Grading(GVHD-C) Management of Grade II-IV ●Management of Grade II-IV ●Acute CVHD(GVHD-3) Grade l-IVd (Moderate to severe acute GVHD) Acute GVHD(GVHD-3)

图示：Continue or consider restarting original immunosuppressive agent(s) and

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图示：MANAGEMENT OF CHRONIC GVHD FIRST-LINE THERAPY Clinical trial or Continue or consider restarting original immunosuppressive agent and/or 2661/8974111 Taper steroids as immunosuppressive agent ) 2662/89741111 2663/89741111 Control or consider restarting original immunosuppressive agent ) 2663/897411111 2664/897411111 2665/897411111 2665/897411111 2665/897411111 2665/897411111 2665/8974111111 2665/8974111111 2665/8974111111 2665/89741111111 2665/89741111111 2665/89741111111 2665/89741111111 2665/897411111111 2665/897411111111 2665/89741111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/897411111111 2665/8974111111111 2665/897411111111 2665/8974111111111 2665/8974111111111 2665/8974111111111 2665/8974111111111 2665/8974111111111 2665/8974111111111 2665/8974111111111 2665/8974111111111 2665/8974111111111 2665/8974111111111 2665/89741111111111 2665/897411111111111 2665/89741111111111 2665/89741111111111 2665/89741111111111 2665/89741111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111

图示：Photographic Range of Motion (P-ROM)a !nckn 1(Worst)22 1(Worst)3 1(Worst)2 5 4 3 4 5 6 7(Normal) Elbow 1(Worst)2 1(Worst)2 Newt/finger Ankle 1 Jagasia MH,GreinixHT,Arora M,et al.National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease:1.The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401. Wrist/finger Ankle 1(Worst 2 2 3 4 5 3 4 (Normal) 6 7(Normal) 6 Wikn/finger

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引用 / 出处

（2025.V3）NCCN临床实践指南：造血细胞移植. 2025.