（2026.V1）NCCN临床实践指南：霍奇金淋巴瘤

指南血液内科· 淋巴瘤与骨髓瘤 · 2026

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

*Ranjana H. Advani, MD/Chair † Stanford Cancer Institute

*Christopher R. Kelsey, MD/Vice Chair §Duke Cancer Institute

Philippe Armand, MD, PhD $\ddagger$ Dana-Farber/Brigham and Women's Cancer Center

Celeste M. Bello, MD, MSPH †Moffitt Cancer Center

Cecil M. Benitez, MD, PhD¥§UCLA Jonsson Comprehensive Cancer Center

David Bond, MD p\$

The Ohio State University Comprehensive Center-James Cancer Hospital and Solove Research Institute

Weina Chen, MD, PhD # UT Southwestern Simmons Comprehensive Cancer Center

Sheen Cherian, MD §

Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

Magdalena Czader, MD, PhD $\neq$ Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Bouthaina Dabaja,MD§

The University of Texas MD Anderson Cancer Center

Megan E.Daly,MD§

UC Davis Comprehensive Cancer Center

Zachary Frosch,MD,MSHP

Fox Chase Cancer Center

Leo I. Gordon, MD‡

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Neil Hansen, MD $\phi$

Fred & Pamela Buffett Cancer Center

Alex F. Herrera, MD ‡ξ

City of Hope

National Medical Center

Ephraim P. Hochberg, MD t

Mass General Cancer Center

*Richard T. Hoppe, MD §

Iris usfi, MD$

Yale Cancer Center/Smilow Cancer Hospital

Patrick B. Johnston, MD PhD † p

Mayo Clinic Comprehensive Cancer Center

Kara Kelly,MD€

Roswell Park Comprehensive Cancer Center

Vaishalee P.Kenkre,MD‡

University of Wisconsin

Carbone Cancer Center

Justin Kline,MD

The UChicago Medicine

Comprehensive Cancer Center

Ryan C. Lynch, MD †

Fred Hutchinson Cancer Center

Jonathan McConathy,MD,PhD

O'Neal Comprehensive

Cancer Center at UAB

David Morgan, MD †$\varepsilon$

Vanderbilt-Ingram Cancer Center

Alex Niu, MD P++

Roswell Park Comprehensive

Cancer Center

Suman Paul, PhD, MBBS $\ddagger$

Johns Hopkins Kimmel Cancer Center

Rachel Rabinovitch, MD §

University of Colorado Cancer Center

Ali Salavati,MD,MPH $\phi $

UCLA Jonsson

Comprehensive Cancer Center

Dahlia Sano, MBChB‡

University of Michigan

Rogel Cancer Center

Harsh Shah,DO ⋯

Huntsman Cancer Institute at the University of Utah

Michael Spinner, MD‡

UCSF Helen Diller Family

Comprehensive Cancer Center

Jakub Svoboda, MD †

Abramson Cancer Center

at the University of Pennsylvania

Jane N. Winter, MD $†

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Joachim Yahalom, MD

Memorial Sloan Kettering Cancer Center

*.Joanna C. Yang, MD, MPH $\S$

Siteman Cancer Center at Barnes-

Jewish Hospital and Washington

University School of Medicine

NCCN

Sarah Montgomery,BA

Katie Stehman, PA-C, MMS

$\xi$ Bone marrow

transplantation

Diagnostic radiology

Hematology/

Hematology oncology

B Internal medicine

† Medical oncology

$\dagger$ Nuclear medicine

≠ Pathology

≠ Patient advocacy

€ Pediatric oncology

SRIadiation oncology

B Internal medicine

† Medical oncology

* Discussion writing

Discussion committee

NCCN Guidelines Version 1.2026

Hodgkin Lymphoma (Age ≥18 years)

Version 1.2026, 10/22/25 © 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.

NCCN Guidelines Index Table of Contents Discussion

NCCN Hodgkin Lymphoma Panel Members Summary of Guidelines Updates

Diagnosis and Workup (HODG-1)

Staging/Risk Classification of Classic Hodgkin Lymphoma (CHL) (HODG-2)

Unfavorable Risk Factors (HODG-3)

Primary Treatment of Classic Hodgkin Lymphoma (CHL):

• Important Considerations (HODG-4)

• Stage IA/IIA Favorable Disease by GHSG Criteria (HODG-5)

• Stage IA/IIA Favorable Disease by EORTC Criteria (HODG-5A)

• Stage IA/IIA Favorable by GHSG or EORTC criteria with Deauville 4–5 After 2 Cycles of ABVD (HODG-5B)

• Stage I/II Unfavorable with B Symptoms, Bulky Mediastinal Disease and/or >10 cm Adenopathy, ≥4 Nodal Sites, and/or ESR ≥50 mm/hr (HODG-6)

• Stage III–IV (HODG-7)

Management of CHL in Adults Age >60 Years or Adults Unfit for Intensive Therapy (HODG-9)

Management of CHL During Pregnancy (HODG-10)

Primary Treatment of Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL):

• Stage IA–IV (HODG-11)

Follow-up After Completion of Treatment and Monitoring for Late Effects (HODG-12)

Relapsed or Refractory Disease:

• Primary Refractory CHL or Relapse Within 3 Months: Candidate for High-Dose Therapy and Autologous

Stem Cell Rescue (HDT/ASCR) (HODG-13)

• Suspected Biopsy Proven Relapse of CHL After ≥3 Months: Candidate for HDT/ASCR (HODG-14)

• Relapsed/Refractory CHL: Not a Candidate for HDT/ASCR (HODG-15)

• Refractory or Suspected Relapse of NLPHL (HODG-16)

Principles of FDG-PET/CT (HODG-A)

Principles of Systemic Therapy (HODG-B)

Principles of Radiation Therapy (HODG-C)

• General Principles (HODG-C 1 of 16)

• RT Dose Constraint Guidelines for Lymphoma (HODG-C, 3 of 16)

• General Principles of RT Dose Constraints (HODG-C, 7 of 16)

Staging (ST-1)

Abbreviations (ABBR-1)

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.

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

See the NCCN Guidelines for Pediatric Hodgkin Lymphoma for additional recommendations for pediatric patients

(including adolescents and young adults [AYAs]).

NCCN Guidelines Version 1.2026

Hodgkin Lymphoma (Age ≥18 years)

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

Global Changes

• References updated throughout the guideline.

Updates in Version 1.2026 of the NCCN Guidelines for Hodgkin Lymphoma from Version 2.2025 include:

HODG-1

• Diagnosis/Workup

Useful in selected cases, footnote f added: Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health.

See NCCN Guidelines for Distress Management (DIS-A).

Useful in selected cases, bullet 7 revised: Echocardiogram or multigated acquisition (MUGA) scan and consideration of atorvastatin if anthracyclinebased chemotherapy is indicated.

HODG-2

• Page has been significantly revised.

HODG-3• Unfavorable Risk Factors for Stage I-II Hodgkin Lymphoma

GHSG

◊ ESR and B symptoms modified: greater than or equal to 50 mm/hr if A; greater than or equal to ≥30 mm/hr if B.

◊ # Nodal regions modified: >2 ≥3

EORTC

◊ ESR and B symptoms modified: greater than or equal to 50 mm/hr if A; greater than or equal to ≥30 mm/hr if B.

◊ # Nodal regions modified: >3 ≥4

NCCN, # Nodal regions modified: >3 ≥4

HODG-4

• New page added: Primary Treatment of CHL: Important Considerations

HODG-5

• Page has been significantly revised.

HODG-5A

• Page has been significantly revised.

HODG-5B

• Page has been significantly revised.

HODG-6

• Page has been significantly revised.

HODG-6A

• Page has been significantly revised.

HODG-6B

• Page has been significantly revised.

HODG-7

• Page has been significantly revised.

HODG-7A

• Page has been significantly revised.

HODG-7B

• Page has been significantly revised.

NCCN Guidelines Version 1.2026

Hodgkin Lymphoma (Age ≥18 years)

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

Updates in Version 1.2026 of the NCCN Guidelines for Hodgkin Lymphoma from Version 2.2025 include:

HODG-7C• Page has been significantly revised.

HODG-7D

• Page has been significantly revised.

HODG-10

• First trimester, bullet 2 modified: If severe symptoms or organ compromise: consider referral to center with expertise, consider pregnancy termination and urgent treatment, or single-agent vinblastine followed by ABVD after end of first the start of the second trimester

HODG-12

• Follow-up after completion of treatment up to 5 years

Laboratory Studies

◊ Bullet 1 modified: CBC, platelets, ESR (if elevated at time of initial diagnosis), chemistry profile as clinically indicated.

◊ Bullet 2 modified: Thyroid-stimulating hormone (TSH) Thyroid function tests (TFTs) at least annually if RT to neck thyroid gland was in the RT field.

Row added: Cardiovascular Toxicity Screening

◊ Bullet added: ECHO at 1 year after completion of anthracycline therapy.

HODG-12A

• Follow-up and monitoring after 5 years

Bullet 2, sub-bullet 1 modified: Consider stress test/ECHO at 5- to 10-year intervals or per institutional guidelines after treatment is completed.

Bullet 3, sub-bullet 2 modified: TSH TFTs at least annually if RT to neck thyroid was in the RT field

HODG-13

• Page has been significantly revised.

HODG-14

• Page has been significantly revised.

HODG-15

• Pathway added: Patients who received abbreviated chemotherapy (3-4 cycles) without RT.

HODG-B (1 of 8)

• Footnote i added to all instances of BV-containing regimens: Utilize with caution in those with neuropathy. (Also for HODG-B 2 of 8 and HODG-B 5 of 8)

• Footnote j added to all instances of BV-containing regimens: PJP prophylaxis is recommended for all BV-containing regimens. (Also for HODG-B 2 of 8 and HODG-B 5 of 8)

HODG-B (2 of 8)

• Primary Systemic Therapy Regimens, Age >60 Years and Candidate for Anthracycline Row added: Stage I-II Favorable Disease by GHSG Criteria

◊ Regimen added: A(B)VD (2 cycles) + ISRT 20 Gy

Row modified: Stage I–II Favorable Disease by EORTC Criteria

◊ Regimen removed: A(B)VD (2 cycles) + ISRT

◊ Regimen modified: A(B)VD (3 cycles) ± + ISRT 30 Gy (if CR)

Stage III-IV Disease

◊ Nivolumab-AVD x 6 cycles (preferred): Category of evidence changed to category 1

NCCN Guidelines Version 1.2026

Hodgkin Lymphoma (Age ≥18 years)

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

Updates in Version 1.2026 of the NCCN Guidelines for Hodgkin Lymphoma from Version 2.2025 include:

HODG-B (5 of 8)

• Primary Refractory Disease or Relapse (within any time frame) (Candidate for or Not a Candidate for HDT/ASCR)Second-Line and Subsequent Therapy

◊ CPI-containing regimen added: GEMOX-tislelizumab-jsgr

Therapy for Disease Refractory to at Least 3 Prior Lines of Subsequent Therapy

◊ Regimen added: Nivolumab

◊ Regimen added: Pembrolizumab

◊ Note added: Consider referral for allogeneic HCT in appropriate patients

HODG-B (6 of 8)

• Footnote r modified: Subsequent systemic therapy options include second-line chemotherapy options that were not previously used.

HODG-C (1 of 16)

• General Principles, bullet 2 modified: Advanced RT technologies such as intensity-modulated RT (IMRT)/volumetric modulated arc therapy (VMAT),

deep-inspiratory breath hold (DIBH) or respiratory gating, image-guided RT (IGRT), and proton therapy may offer significant and clinically relevant

advantages in specific instances to spare important normal organs at risk (OARs) and decrease the risk for both acute and long-term toxicity late,

normal tissue damage while still achieving the primary goal of local tumor control.

HODG-C (2 of 16)• ISRT: Dose

CMT, sub-bullet 1 modified: Non-bulky disease (stage I–II): 20–30 Gy (if treated with ABVD); 1.5–2.0 Gy per fraction

CMT, sub-bullet 4 modified: Partial response/refractory disease (Deauville 4–5): 36–45 40 Gy

• ISRT: Volumes

Bullet 2 modified: ISRT in the setting of CMT targets the site of the originally involved lymph node(s).

Bullet 4, sub-bullet 2 modified: CMT: Similar to CHL after chemotherapy [treating encompass originally involved lymph node(s) only]

HODG-C (3 of 16)

• Head and Neck

OAR added: Pituitary gland

◊ Dose Recommendation added: Mean <30 Gy

◊ Toxicity added: Hormone deficiencies

OAR added: Optic nerves and chiasm

◊ Dose Recommendation added: Dmax <45 Gy

◊ Toxicity added: Optic neuropathy

OAR added: Retina

◊ Dose Recommendation added: Dmax <35 Gy

◊ Toxicity added: Retinopathy

• Footnote d added: For NK/T-cell lymphoma, nasal type, and other high-grade lymphomas in the periorbital region, a Dmax of 50 Gy may be required to allow adequate target coverage.

HODG-C (4 of 16)

• Header added to Heart, Left ventricle, and LAD artery: The most important cardiac constraints are mean heart dose and dose to the left anterior

descending artery and left ventricle

• Header added to remaining thoracic OARs: Limiting dose to the following cardiac substructures is also recommended

NCCN Guidelines Version 1.2026

Hodgkin Lymphoma (Age ≥18 years)

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for Hodgkin Lymphoma from Version 2.2025 include:

HODG-C (5 of 16)

• Row title modified: Pelvis/Other

OAR added: Ovaries

◊ Dose Recommendation added: Mean <2 Gy (recommended); <10 Gy (acceptable)◊ Toxicity added: Acute ovarian failure

OAR added: Testes

◊ Dose Recommendation added: Mean <2 Gy (recommended); <12 Gy (acceptable)◊ Toxicity added: Azoospermia

HODG-C (6 of 16)

• Secondary Malignancies

Lung, dose recommendation modified: Minimize volume >95 Gy Pancreas, dose recommendation modified: Minimize volume >5–10 Gy

HODG-C (8 of 16)

• Heart, bullet 2, sentence 3 modified: The relative risk appears to be linear, without a clear safe threshold dose, with the risk of heart disease increasing by 4.1%–7.4% per 1 Gy of cardiac radiation dose administered.

HODG-C (9 of 16)

• Bullet 1 modified: "...This data set is too small to be a basis of radiation dose constraints, but does support the general notion of a dose-response effect in the clinical range of lymphoma radiation prescriptions. Another study by Hahn et al used a sample of 125 patients with HL treated with mediastinal

RT and analyzed various dosimetry parameters of whole heart and coronary segments, looking for a relationship to cardiac events.78 Multivariable

competing risk regression models found that when any adverse cardiac event was the outcome, models using coronary artery variables did not perform better than models using whole heart variables. However, in a subanalysis of ischemic cardiac events only, the model using coronary artery variables was superior to the whole heart. Major findings for this study were that the V5 Gy for the LAD and the V20 Gy for the LCx had predictive value when

looking at ischemic endpoints such as need for coronary revascularization, myocardial infarction, or cardiac death. The modeling analysis was not

robust enough to yield specific guidance on dose constraints to specific coronary arteries."

• Bullet 3 modified: "...Those receiving at least 20 Gy to any part of the heart also were at increased risk. A follow up study using the CCSS database

demonstrated mean doses of 5–9.9 Gy to the right coronary artery (rate ratio, 2.6) and left ventricle (rate ratio, 2.2) increased risk of coronary artery disease and mean doses of 5–9.9 Gy to the tricuspid valve (RR, 5.5) and right ventricle (RR, 8.4) increased risk of valvular disease."

HODG-C (12 of 16)

• Section added: Ovaries

• Section added: Testicles

MS-1

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

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

DIAGNOSIS/WORKUP

CLINICAL PRESENTATION

|Excisional biopsy Core needle biopsy|Essential: -38℃; drenching night sweats; or weight loss >10% of body weight within 6 mo of diagnosis), alcohol intolerance, pruritus, fatigue, performance status, and examination of lymphoid regions, spleen, and liver|Classic Hodgkin lymphoma (CHL)k HODG-2|HODG-2 lymphoma|| |---|---|---|---|---| |Excisional biopsy Core needle biopsy|●Complete blood count (CBC), differential ●Erythrocyte sedimentation rate (ESR) ●Comprehensive metabolic panel, lactate dehydrogenase (LDH), and liver function test (LFT) ●Human immunodeficiency virus (HIV) testing (See NCCN Guidelines for Cancer in People with HIV) ●Pregnancy test for those of childbearing potential prior to cytotoxic chemotherapy or radiation therapy (RT)|Classic Hodgkin lymphoma (CHL)k HODG-2||| |Excisional biopsy (recommended)|-Pregnancy test for those of childbearing potential prior to cytotoxic chemotherapy) or radiation therapy (RT)|||| |Core needle biopsy|-FDG-PET/CT scan (skull base to mid-thigh or vertex to feet in selected cases)|-S-counsl: Fertility/psychosocial $^{e}$ and smoking cessation (See NCCN Guidelines for Smoking Cessation)||| |Immunohistochemistry evaluationb|●Counseling: Fertility/psychosocial $^{e}$ and smoking cessation (See NCCN Guidelines for Smoking Cessation)|||| |Useful in selected cases:|-|||Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) per WHO 5th edition1| |-Fertility preservation $^{e}$||||| |-Pulmonary function tests ([PFTs] including diffusing capacity of the lung for carbon monoxide [DLCO])$^{h}$ if ABVD is being used||||HODG-11| |-Pulmonary B/C testing (encouraged)||||Hodgkin lymphoma (NLPHL) per WHO 5th edition1| |-Diagnostic CTi (contrast-enhanced)||||| |-Chest x-ray (encouraged, especially if large mediastinal mass)||||| |●Adequate bone marrow biopsy if there are unexplained cytopenias other than anemia and negative FDG-PETj||||| |●Echocardiogram or multigated acquisition (MUGA) scan if anthracycline-based chemotherapy is indicated||||| |●MRI of select sites, with contrast unless contraindicated ●FDG-PET/MRI (skull base to mid-thigh) without contrast|||||

NCCN Guidelines Version 1.2026

Hodgkin Lymphoma (Age ≥18 years)

NCCN Guidelines Index Table of Contents Discussion

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

HODG-1A

a Fine-needle aspiration (FNA) alone, in distinction from a core biopsy, is generally insufficient for diagnosis. b Typical immunophenotype for CHL: CD15+, CD30+, PAX-5+ (weak); CD3-, CD20- (majority), CD45-, CD79a-. Typical immunophenotype for NLPHL: CD20+, CD45+, CD79a+, BCL6+, PAX-5+; CD3-, CD15-, CD30- (Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues.

Lyon, France: IARC; 2017). Epstein-Barr encoding region in situ hybridization (EBER-ISH) is recommended at initial diagnosis (CHL: EBER+/-; NLPHL: EBER-). An

expanded panel of markers (eg, MUM-1, BOB-1, OCT-2) may be required, especially if equivocal diagnosis. See NCCN Guidelines for B-Cell Lymphomas. For NLPHL, immunoarchitectural pattern should be specified as A or B (typical) versus C–F (variant).

c Principles of FDG-PET/CT (HODG-A).d Consider measures to reduce brown fat activation to minimize false-positive findings.e See NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology for more details on fertility/fertility preservation and psychosocial assessments in AYA patients.f Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management (DIS-A).g Fertility preservation options include: semen cryopreservation, in vitro fertilization (IVF), or ovarian tissue or oocyte cryopreservation. h In general, a DLCO threshold of ≥60% is acceptable for use of bleomycin.i Imaging should be obtained in accordance with the American College of Radiology (ACR) practice guidelines. CT is considered diagnostic if it is enhanced with oral and/or IV contrast. CT component of a conventional FDG-PET/CT is often not IV contrast-enhanced. Although the diagnostic CT will often be of the neck/chest/

abdomen/pelvis, at minimum include the areas identified as abnormal on FDG-PET/CT.

j In most instances, if the FDG-PET/CT displays a homogeneous pattern of marrow uptake (thought to be secondary to cytokine release) bone marrow involvement is

not assumed. If there are multifocal (three or more) skeletal FDG-PET/CT lesions, marrow may be assumed to be involved. In general, bone marrow biopsies are no

longer indicated.

k CHL includes nodular sclerosis (NSHL), mixed cellularity (MCHL), lymphocyte-depleted (LDHL), and lymphocyte-rich (LRHL) subtypes. If grey-zone, see NCCN

Guidelines for B-Cell Lymphomas.

l Referred to as nodular lymphocyte predominant B-cell lymphoma (NLPBL) in ICC. See HODG-11.

FOOTNOTES

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

STAGING/RISK CLASSIFICATION OF CHLm

|Stage|Bulky Mediastinal Diseaseem or>10 cm Adenopathy|# of Nodal Regions|ESR ≥50 mm/hr|E-lesion(s)|Type|Guidelines Page| |---|---|---|---|---|---|---| |IA/IIA|No|≤2|No|No|Favorable Disease by GHSG Criteria|HODG-5| |IA/IIA|No|≤3|No|Yes/No|Favorable Disease by EORTC Criteria|HODG-5A| |IA/IIA|Yes|Any|Yes/No|Yes/No|Unfavorable Disease|HODG-6| |IB/IIB|Yes/No|Any|Yes/No|Yes/No|Unfavorable Disease|HODG-6| |III-IV|Yes/No|Any|N/A|Yes/No|Advanced Disease|HODG-7|

●HODG-4 for Primary Treatment of CHL: Important Considerations

●HODG-9 for the Management of CHL in Adults Age>60 Years or Adults Unfit for Intensive Therapy

●HODG-10 for the Management of CHL During Pregnancy

m For definitions of bulky disease and lymph node regions, see HODG-3.

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

NCCN Guidelines Index

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age $\geq$ 18 years)

UNFAVORABLE RISK FACTORS

Unfavorable Risk Factors for Stage I-II Hodgkin Lymphoma

|Risk Factor|GHSG|EORTC|NCCN| |---|---|---|---| |Age|||≥50 mm/hr| |ESR and B symptoms|≥50 mm/hr if A;≥30 mm/hr if B|≥50 mm/hr if A;≥30 mm/hr if B|≥50 mm/hr or any B symptoms| |Mediastinal massn|MMR >0.33|MTR >0.35|MMR >0.33| |# Nodal regions|≥3^{*}|≥4^{*}|≥4| |E lesion|any||| |Bulkyn||||

GHSG = German Hodgkin Study Group EORTC = European Organization for Research and Treatment of Cancer

MMR = Mediastinal mass ratio, maximum width of mass/maximum intrathoracic diameter as measured on chest radiograph (CXR)

MTR = Mediastinal thoracic ratio, maximum width of mediastinal mass/intrathoracic diameter at T5-6 as measured on CXR

International Prognostic Score (IPS) 1 point per factor (advanced disease)$^{\dagger}$

● Album <4 g/dL

• Hemoglobin <10.5 g/dL

· Male

• Age ≥ 45 years

● Stage IV disease

●Leukocytosis (white blood cell count≥15,000/mm3)

● Lymphocytopenia (lymphocyte count <8% of white blood cell count, and/or lymphocyte count <600/mm3)

$^{\dagger}$ From: Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International

Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 1998;339:1506-

* Note that the EORTC includes the infraclavicular/subpectoral area with the axilla while the GHSG includes it with the cervical. Both EORTC and GHSG combine the mediastinum and bilateral hila as a single region.

${}^{n}$ The definition of mediastinal bulk is best assessed with a standard CXR, as practice-changing studies utilized this staging modality. If a staging CXR is not obtained,disease bulk can also be assessed with CT. In this scenario, a single mass or nodal conglomerate measuring(in any direction)>1/3 the maximum transverse diameter of the chest, or any tumor mass or nodal conglomerate>10 cm(also measured in any direction) should be considered"bulky."

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

UNFAVORABLE RISK FACTORS

Definitions of Lymph Node Regions*

|||Ann Arbor Nodal Sites|EORTC Nodal Regions|GHSG Nodal Regions| |---|---|---|---|---| |Supradiaphragmatic|R Cervical/Supraclavicular|||| |Supradiaphragmatic|R ICL/Subpectoral|||| |Supradiaphragmatic|R Axilla|||| |Supradiaphragmatic|L Cervical/Supraclavicular|||| |Supradiaphragmatic|L Infraclavicular/Subpectoral|||| |Supradiaphragmatic|L Axilla|||| |Supradiaphragmatic|Mediastinum|||| |Supradiaphragmatic|R Hilum|||| |Supradiaphragmatic|L Hilum|||| |Infradiaphragmatic|Celiac/Spleen hilar|||| |Infradiaphragmatic|Para-aortic|||| |Infradiaphragmatic|Mesenteric|||| |Infradiaphragmatic|R Iliac|||| |Infradiaphragmatic|L Iliac|||| |Infradiaphragmatic|R Inguinal/Femoral|||| |Infradiaphragmatic|L Inguinal/Femoral||||

*Note that the EORTC includes the infraclavicular/subpectoral area with the axilla while the GHSG includes it with the cervical. Both EORTC and GHSG combine the mediastinum and bilateral hila as a single region.

NCCN Guidelines Version 1.2026

Hodgkin Lymphoma (Age ≥18 years)

NCCN Guidelines Index Table of Contents Discussion

PRIMARY TREATMENT OF CHL:

IMPORTANT CONSIDERATIONS

• All patients will benefit from multidisciplinary team (including radiation oncology) input prior to final treatment decisions.

• Treatment with combined modality therapy (CMT) provides for a better progression free survival (PFS)/freedom from progression (FFP), but no difference in overall survival.

• Selection of treatment (CMT or chemotherapy alone) should be based on patient age, sex, family history of cancer or cardiac disease,

comorbid conditions, and sites of involvement (especially within mediastinum or axilla).

• For patients assigned female at birth with intact breast tissue:

Chemotherapy alone may be preferred for those <30 years where recommended breast dose-volume histogram (DVH) constraints are

exceeded, if cardiac constraints cannot be met, or in the presence of high-risk comorbidities.

CMT may be preferred if the doxorubicin dose would exceed 200 mg/m2 provided that breast and cardiac constraints can be met.

Special Considerations

ABVD

• Neutropenia is not a factor for delay of treatment or reduction of dose intensity with ABVD.

• Routine use of growth factors is not recommended with ABVD.o

• Consider PFTs after 4 cycles of ABVD.

Deauville 4–5 Treatment Responses

• The degree of abnormality of both Deauville 4 and 5 scores are quite variable and clinical judgment is often necessary in such settings.

If disease is responding well to chemotherapy, but an interim FDG-PET/CT shows a Deauville 4 or 5 response, it may be appropriate to

continue with the same chemotherapy regimen and repeat an FDG-PET/CT after 2 additional cycles.

• Similarly, if a post-chemotherapy FDG-PET/CT is only focally positive, consolidation RT may be appropriate, especially if a biopsy is not

feasible. See Principles of Radiation Therapy (HODG-C 2 of 16).

• Use clinical judgement if a new lymph node can be explained by alternative etiology (eg, inflammation or infection) or if residual FDG-uptake may be related to treatment (eg, immunotherapy). Repeating a short-interval FDG-PET/CT may be preferred in such scenarios.

• At any point, if there is concern for refractory disease, a biopsy is appropriate to inform subsequent therapy.

o Evens AM, et al. Br J Haematol 2007;137:545-552.

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

HODG-4

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma:Stage IA/IIA Favorable Disease by GHSG Criteria

PRIMARY TREATMENT(see Important Considerations on HODG-4)

ADDITIONAL THERAPY

![\nDeauville\nAbeV's 1-39\nPreferred combined modality therapy: ISRT 20 Gyr' (adapted from GHSG HD16)1\nUseful in Certain Circumstances Chemotherapy alone (see important considerations on HODG-4): ABVD x 2 cycles (total 4) (adapted from H10F, CALGB)^{s,2,3} or\n\nADPU6-1\n8\nTop to 2\n2 cycles with FDG-(category 1)^p\nFDG-\nREastage\nFDG-\nwith\nFDG-\ncategory 1)^p\nPET/CT^c\nDeauville 4-5°\nHODG-5\nHODG-5\n](2/aj0YEe4oUhYkBdfpda0fYP/figuref4f7b65a314045b8a4624ddc31d98e89_0_7.png) Principles of FDG-PET/CT (HODG-A).

P Principles of Systemic Therapy (HODG-B 1 of 8).

9FDG-PET 5-Point Scale (Deauville Criteria) (HODG-A 2 of 2).

Principles of Radiation Therapy(HODG-C).

s Consider PFTs after 4 cycles of ABVD.

${}^{t}$ Outcomes for patients with Deauville 3 imaging participating in the CALGB 50604 trial were suboptimal. Straus DJ, et al. Blood 2018;132:1013-1021.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma:Stage IA/IIA Favorable Disease by EORTC Criteria

Important Considerations:

●All patients will benefit from multidisciplinary team (including radiation oncology) input prior to final treatment decisions. ● Treatment with CMT provides for a better PFS/FFP, but no difference in overall survival.2

●Selection of treatment (CMT or chemotherapy alone) should be based on patient age, sex, family history of cancer or cardiac disease, comorbid conditions, and sites of involvement (especially within mediastin or axilla).

●For patients assigned female at birth with intact breast tissue:

Chemotherapy alone may be preferred for those <30 years where recommended breast DVH constraints are exceeded, if cardiac constraints cannot be met, or in the presence of high-risk comorbidities.

CMT may be preferred if the doxorubic in dose would exceed 200 mg/m2 provided that breast and cardiac constraints can be met.

![PRIMARY TREATMENT\nDeauville 1-29\nCombined modality therapy ABVD x 1 cycle (total 3) + ISRT 30 Gyr'(adapted from RAPID, H10F) = 2.5\,Chemotherapy alone ABVD x 2 cycles (total 4) ABVD x 2 cycles (total 4) 2,3,3,4 Combined modality therapy ABVD x 2 ISRT 30 Gy' (adaptated from favorable disease (category 1) \rightarrow 2 cycles with FDG-84 yprC 39 J Chemotherapy alone AVD x 4 cycles (adapted from CALGB, RATHL)3,4 Deauville Deauville 3.4 and CADG constraints\nFollow-up(HODG-12)\nStage I/IA/IA favorable disease by EORTC criteria\n2 cycles (category 1) 0\nDeauville 2 - 9\nThallow FET/CTC\nRestage with FDG-1 copy (1) PET/CT°C\nDeauville 39\nALDvoiles play a better potential to recover the detection and detection\nH10F) 2.5 Chemotherapy alone AVD x 1 cycle (total 3) + ISRT 30 Gy' (adaptated from CALGB, RATHL)3,4\nCombined modality therapy ABVD x 2 cycles (total 4) ISRT 30 Gy' (adaptated from RAPID) 3.4\nDeauville 4-59 - HODG-5B\n](2/aj0YEe4oUhYkBdfpda0fYP/figure59d05ede2c464f51b37e8b1341b61b5d_0_11.png) Principles of FDG-PET/CT(HODG-A).

P Principles of Systemic Therapy (HODG-B 1 of 8).

9 FDG-PET 5-Point Scale(Deauville Criteria)(HODG-A 2 of 2).

Principles of Radiation Therapy(HODG-C).

s Consider PFTs after 4 cycles of ABVD.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma: Stage IA/IIA Favorable by GHSG or EORTC criteria with Deauville 4-5 After 2 Cycles of ABVD

Special Considerations for Deauville 4-5 Treatment Responses:

● The degree of abnormality of both Deauville 4 and 5 scores are quite variable and clinical judgment is often necessary in such settings. If disease is responding well to chemotherapy, but an interim FDG-PET/CT shows a Deauville 4 or 5 response, it may be appropriate to continue with the same chemotherapy regimen and repeat an FDG-PET/CT after 2 additional cycles.

● Similarly, if a post-chemotherapy FDG-PET/CT is only focally positive, consolidation RT may be appropriate, especially if a biopsy is not feasible. See Principles of Radiation Therapy(HODG-C 2 of 16).

•Use clinical judgement if a new lymph node can be explained by alternative etiology(eg, inflammation or infection) or if residual FDG-uptake may be related to treatment(eg, immunotherapy). Repeating a short-interval FDG-PET/CT may be preferred in such scenarios.

•At any point, if there is concern for refractory disease, a biopsy is appropriate to inform subsequent therapy.

ADDITIONAL THERAPY

![Stage IA/IIA favorable CHL by GSHG or EORTC GHSG or RORTC criteriaV with deauville 4-5 after 2 Deauville 5q,u\nABVD 4q,u\nDecuille 4-5\nReageville 1-3q\nISRT 30 Gyr (adaptated from RAPID, H10)2,5\nNovelet 4-59u\nDeauville 5q,u\nABVD 4-5q,u\nReagelet 5\nDeauville 6-5 u\nRegelikeva Positive of Primary Refractory Disease (HODG-13)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure02c48d7be67c45f88f1891b9af7012f1_0_11.png) Principles of FDG-PET/CT(HODG-A).

9FDG-PET 5-Point Scale (Deauville Criteria) (HODG-A, 2 of 2).

Principles of Radiation Therapy(HODG-C).

s Consider PFTs after 4 cycles of ABVD.

v See Staging/Risk Classification of CHL (HODG-2).

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

Version 1.2026,10/22/25 © 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.

References on HODG-8

HODG-5B

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma: Stage I/II Unfavorable with B Symptoms, Bulky Mediastinal Disease and/or>10 cm Adenopathy,24 Nodal Sites, and/or ESR≥50 mm/hr

``` tSpecial Considerations for Deauville 4-5 Treatment Responses:

•Use clinical judgement if a new lymph node can be explained by alternative etiology(eg, inflammation or infection) or if residual FDG-uptake may be related to treatment(eg, immunotherapy). Repeating a short-interval FDG-PET/CT may be preferred in such scenarios.

•At any point, if there is concern for refractory disease, a biopsy is appropriate to inform subsequent therapy.

PRIMARY TREATMENT(see Important Considerations)

![PRIMARY TREATMENT(see Important Considerations) on HODG-4)\nABVD\nx 2\ncyclesP\nADFD\nPET/CT\nDeauville 4-5q,u\nADneophary(EG-6A\nOther Regimens\nADG-6A\nRestage\nwith FDG-PET/CT°C\nABVD\ncyclesp\nADuville\nADneopharyosis\n·24 Nodal sites\nASR\nESR ≥50 mm/hr\nABVD\nABVD 4-7c\nRestage\nABE\nRestage\nwith\nFDG-PET/CT°C\nADuville\nADneopathy\n●24 Nodal sites\n·\nAD/or\nESR ≥50 mm/hr\n](2/aj0YEe4oUhYkBdfpda0fYP/figure826e2b82b4104601aef277a412b0fdc8_0_11.png)

ADDITIONAL THERAPY

Combined modality therapy

ABVDx2 cycles(total 4S+ISRT 30 Gyr(adapted from H10U)2 Chemotherapy alone AVD x 4 cycles(adapted from RATHL, H10U)2,4

![ABVD\nx 2 cycles (total 4)s\nABCD A 399(1-3q\nDisauville) or BrECADD + 496(r) 44\nBrECADD previously used)*x\nADauville (1-3q\nDisauville) 449(1) 5q, u\nA\nC\nB\nA\nDueville (1-3q\nBiopsy \nReGECADD previously used)*x\nCombined modality therapy ISRT 36-40 Gyr (adapted from H10U) 2\nFrom H10U) 2\nA\nDueville (1-4q, u\nA\nDuev-259(94) 44\nDeauville 59, u\nA\nDueville (1-3q) 449(1) 5q, u\nA\nDuev-259(104) 2\nAnnoine therapy Refractory Disease (HODG-13)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure5e234792a98d4e5aa5d92fe5d49610a2_0_15.png) cPrinciples of FDG-PET/CT(HODG-A).

P Principles of Systemic Therapy (HODG-B 1 of 8).

9FDG-PET 5-Point Scale(Deauville Criteria)(HODG-A 2 of 2).

rPrinciples of Radiation Therapy(HODG-C).

s Consider PFTs after 4 cycles of ABVD.

While BrECADD+ G-CSF has not been formally tested in this setting, its use as escalation therapy is reasonable given its improved safety profile compared to escalated BEACOPP in the frontline setting for advanced-stage CHL. Borchmann P, et al. Lancet 2024;404:341-352. Ongoing clinical trials that utilize escBEACOPP with dacarbazine substitution for procarbazine may be appropriate.

×Utilize with caution in those with neuropathy.

y Pneumocystis jirove precne pneumonia (PJP) prophylaxis is recommended for all BV containing regimens.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma: Stage I/II Unfavorable with B Symptoms, Bulky Mediastinal Disease and/or>10 cm Adenopathy, 24 Nodal Sites, and/or ESR≥50 mm/hr

Special Considerations for Deauville 4-5 Treatment Responses:

•Use clinical judgement if a new lymph node can be explained by alternative etiology(eg, inflammation or infection) or if residual FDG-uptake may be related to treatment(eg, immunotherapy). Repeating a short-interval FDG-PET/CT may be preferred in such scenarios.

•At any point, if there is concern for refractory disease, a biopsy is appropriate to inform subsequent therapy.

PRIMARY TREATMENT ADDITIONAL THERAPY

![Stage I/II unfavorable CHL: •or •B Symptoms\nor\nBV-AVD+G-CSF\t5 cycles,p,y\n(adapted from BREACH)^7\nRestage with FDG-PET/CT\nDisauvalville:4,9\n→Biopsy\nNegative\nNegative →ISRT°→\n→Deauville 1-4,9\n→Biopsy\nPositive\n→Primary Refractory Disease(HODG-13)\nPositive\nPrimary Refractory Disease(HODG-13)\n](2/aj0YEe4oUhYkBdfpda0fYP/figurebbec07c5e56f46fc8902b4c0ed681d8e_0_12.png) Principles of FDG-PET/CT(HODG-A).

P Principles of Systemic Therapy (HODG-B 1 of 8).

9 FDG-PET 5-Point Scale (Deauville Criteria) (HODG-A 2 of 2).

rPrinciples of Radiation Therapy(HODG-C).

xUtilize with caution in those with neuropathy.

y PJP prophylaxis is recommended for all BV containing regimens.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma: Stage I/II Unfavorable with B Symptoms, Bulky Disease and/or>10 cm Adenopathy,≥4 Nodal Sites, and/or ESR≥50 mm/hr

Special Considerations for Deauville 4-5 Treatment Responses:

● Similarly, if a post-chemotherapy FDG-PET/CT is only focally positive, consolidation RT may be appropriate,especially if a biopsy is not feasible. See Principles of Radiation Therapy(HODG-C 2 of 16).

● Use clinical judgement if a new lymph node can be explained by alternative etiology(eg, inflammation or infection) or if residual FDG-uptake may be related to treatment(eg, immunotherapy). Repeating a short-interval FDG-PET/CT may be preferred in such scenarios.

•At any point, if there is concern for refractory disease, a biopsy is appropriate to inform subsequent therapy.

PRIMARY TREATMENT

ADDITIONAL THERAPY

![BrECADD+G-CSF x 2 cycles 1-39\nDeauville+G-CSF with FDG-PET/CTC\nBrECADD+G-CSF x 2 cycles 4-c5-u\nDeauville→G-CSF x 4 cycles 4-5 q,u\nReastage\nFDG-PET/CTC\nBrECADD+G-CSF x 4 cycles 4-6 u\nDeauville→G-CSF x 4 cycles 4-6 u\nFDG-PET/CTC\nBiopsy\nDeauville→G-CSF x 49 q-u\nDeauville→HCHUCAN\nRedstage 494-1-3\nReustage\nFDG-PET-CTC\nDeauville→HCHUCAN\nISRT r\nDeauville→HCHUCN\nBiopsy\nDiauville\nBiopsy\n(+)\nNegative→ISRT'→\nFollow-up(HODG-12)\nPositive→ISRT'→\nPrimary Refractory Disease (HODG-13)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure7ca88e106602409ca666f611287a10c2_0_12.png) Principles of FDG-PET/CT(HODG-A).

P Principles of Systemic Therapy (HODG-B 1 of 8).

9 FDG-PET 5-Point Scale(Deauville Criteria)(HODG-A 2 of 2).

Principles of Radiation Therapy(HODG-C).

xUtilize with caution in those with neuropathy.

y PJP prophylaxis is recommended for all BV containing regimens.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma: Stage III-IV

PRIMARY TREATMENT(see Important Considerations on HODG-4)

![Preferred:\n Nivolumab-AVD^{p} (category 1) → HODG-7A\nor\nBrECADD + G-CSFP^{p} (category 1) → HODG-7B\nUseful in Certain Circumstances:\nBV-AVD + G-CSFP^{p} (category 1) → HODG-7C\nor\nABVDP^{p} (category 1) → HODG-7D\n](2/aj0YEe4oUhYkBdfpda0fYP/figured72ff3f7623647c786170d07dccda459_0_7.png) P Principles of Systemic Therapy (HODG-B 1 of 8).

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

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma: Stage III-IV

PRIMARY TREATMENT(continued from HODG-7)

Special Considerations for Deauville 4-5 Treatment Responses:

•At any point, if there is concern for refractory disease, a biopsy is appropriate to inform subsequent therapy.

Preferred:

![Nivolumab-706°C/cyclesp,z,aa (category)from SWOG from SWOG S1826)9\nReastage FDG-PET/CTC\nDeauville 1-39\nDeauville 4-59,u,bb\nRepeat FDG-PET/CT at 12 weeks' 0\nNegative\nDeauville 1-39\n+Deauville 4-59,u,bb\nNegative\nDeauville 3-9\nNegative\nDeauville 1-39\n+Deauville 4-59,u,bb\nNegative\nDeauville 2-4\nNegative\nPositive\nPrimary\nRefractory\nDisease\n(HODG-13)\nHODG-12)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure663d01915a89450687c63cbb308c8ce7_0_13.png) ${}^{c}$ Principles of FDG-PET/CT(HODG-A).

P Principles of Systemic Therapy (HODG-B 1 of 8).

9 FDG-PET 5-Point Scale(Deauville Criteria)(HODG-A 2 of 2).

$^{2}$ Neutropenia is not a factor for delay of treatment or reduction of dose intensity with nivolumab-AVD.

aa In the SWOG S1826 trial, growth factor support was optional. N Engl J Med 2024;391:1379-1389.

bb Some patients received ISRT 30 Gy on SWOG S1826. Criteria for RT included Deauville 4-5(only 1-2 lesions),≥30% reduction in transverse diameter, residual nodal mass≥2.5 cm in axial diameter, or residual extranodal lesion>1 cm in axial diameter. Patients with≥3 Deauville 4-5 lesions and/or a lesion that did not achieve≥30% reduction in transverse diameter were considered to have refractory disease. Patients with a Deauville 5 score due to new PET avid lesions were also considered to have refractory disease.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma: Stage III-IV

PRIMARY TREATMENT(continued from HODG-7)

Special Considerations for Deauville 4-5 Treatment Responses:

•Use clinical judgement if a new lymph node can be explained by alternative etiology(eg, inflammation or infection) or if residual FDG-uptake may be related to treatment(eg, immunotherapy). Repeating a short-interval FDG-PET/CT may be preferred in such scenarios.

•At any point, if there is concern for refractory disease, a biopsy is appropriate to inform subsequent therapy.

![Preferred:\nBrECADD + G-CSF 1-3^9\nDeauville + G-CSF with FDG-FET/total 4)xY\nRestage (category 1) with (adapted from HD21)^8\n/FDG-PET/CTC\nDeauville 4-5^9,u\nBrECADD + G-CSF x 4 cycles (total 6)xY\nDeauville 59,u\nBiopsy - Diauville - Di abopey (i) Positive for reference of the following experimental or for reference for inflation or reference for subsequent therapy\nDeauville 1-3^9\nRe板ADD + G-CSF 4-5^9,u\n,Chen (total 6)xY\nDeauville 1-3^9\nDeauville → Di abope y (total 4) Y\nReastage with FDG-FET/CTC\nEndage (1-4) 2\nDeauville 1-3^9\nFDG-FET/CTC\nEndage (1-5,1)\nDisauville 1-3^9\nRe板ADD + G-CSF x 4 cycles (total 6)xY\nDisauville 1-3^9\nDeauville → Di abope y (total 6)xY\n](2/aj0YEe4oUhYkBdfpda0fYP/figure797963375acb405fac35a362624a3e83_0_11.png) Principles of FDG-PET/CT(HODG-A).

P Principles of Systemic Therapy (HODG-B 1 of 8).

9 FDG-PET 5-Point Scale(Deauville Criteria)(HODG-A, 2 of 2).

rPrinciples of Radiation Therapy(HODG-C).

xUtilize with caution in those with neuropathy.

y PJP prophylaxis is recommended for all BV containing regimens.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma: Stage III-IV

PRIMARY TREATMENT(continued from HODG-7)

Special Considerations for Deauville 4-5 Treatment Responses:

•Use clinical judgement if a new lymph node can be explained by alternative etiology(eg, inflammation or infection) or if residual FDG-uptake may be related to treatment(eg, immunotherapy). Repeating a short-interval FDG-PET/CT may be preferred in such scenarios.

•At any point, if there is concern for refractory disease, a biopsy is appropriate to inform subsequent therapy.

Useful in Certain Circumstances:

![BV-AVD + G-CSF x 6 cycles (category 1)b,x,y,cc (adapted from ECHELON-1)10\n](2/aj0YEe4oUhYkBdfpda0fYP/figure257bfde89d6d4b84810123fecbc4c339_0_13.png) C Principles of FDG-PET/CT(HODG-A).

P Principles of Systemic Therapy (HODG-B 1 of 8).

9 FDG-PET 5-Point Scale(Deauville Criteria)(HODG-A 2 of 2).

xUtilize with caution in those with neuropathy.

y PJP prophylaxis is recommended for all BV containing regimens.

cc An interim FDG-PET/CT after 2 cycles may be helpful in further defining therapy.If performing an interim FDG-PET/CT before completion of 6 cycles, and FDG-PET is positive(Deauville 5), conduct a biopsy; if biopsy positive, change therapy.

dd Consider ISRT to initially bulky or remaining FDG-PET-positive sites at the end of therapy. See Principles of Radiation Therapy(HODG-C).

National Comprehensive Cancer Network®

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Classic Hodgkin Lymphoma: Stage III-IV

PRIMARY TREATMENT(continued from HODG-7)

Special Considerations for Deauville 4-5 Treatment Responses:

● Similarly, if a post-chemotherapy therapy FEDG-PET/CT is only focally positive, consolidation RT may be appropriate, especially if a biopsy is not feasible. See Principles of Radiation Therapy(HODG-C 2 of 16).

•Use clinical judgement if a new lymph node can be explained by alternative etiology(eg, inflammation or infection) or if residual FDG-uptake may be related to treatment(eg, immunotherapy). Repeating a short-interval FDG-PET/CT may be preferred in such scenarios.

•At any point, if there is concern for refractory disease, a biopsy is appropriate to inform subsequent therapy.

Useful in Certain Circumstances:

![ABVD x 2 cyclesp\nRestage with FDG-PET/CT\ncct,ee\nDeauville $\to$ AVD x 4 cyclesdd\n1-39\nAdapted from RATHL $4^{4}\nDeauville $\to$ BRECADD $+5^{9}\nDeauville $\to$ BRECADD $+6\text { CSF }x 3 \to \to PET / CT^c\ndycle $+5^{9},u\nu\end{aligned}$$\nDeauville $\to$ Angeville by $\to$ Angeville by $\to$ Angeville\nFollow-up (HODG-C 12)\nHODG-12)\nAVD ble\nBrECADD $+1-3^9\nDeauville $\to$ Angeville by $\to$ Angeville by $\to$ Angeville\n$4-5^9,u\nu\end{aligned}$$\nAddageleft\n$HODG-C-2$\nJapanese, which should be a significant following of the following is a significant change is $\to$ 9\nCnN, which should be a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a sign\n](2/aj0YEe4oUhYkBdfpda0fYP/figure7eb578013c0c4e24912ba7ad951440dd_0_11.png) c Principles of FDG-PET/CT(HODG-A).

P Principles of Systemic Therapy (HODG-B 1 of 8).

9 FDG-PET 5-Point Scale(Deauville Criteria)(HODG-A 2 of 2).

wWhile BrECADD+ G-CSF has not been formally tested in this setting, its use as escalation therapy is reasonable given its improved safety profile compared to escalated BEACOPPP in the frontline setting for advanced-stage CHL. Borchmann P, et al. Lancet 2024;404:341-352.

×Utilize with caution in those with neuropathy.

y PJP prophylaxis is recommended for all BV containing regimens.

dd Consider ISRT to initially bulky or remaining FDG-PET-positive sites at the end of therapy. See Principles of Radiation Therapy(HODG-C).

ee The value of interim FDG-PET imaging is unclear for many clinical scenarios. All measures of response should be considered in the context of management decisions.

Note: All recommendations are category 2A unless otherwise indicated. NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age 18-60 years) NCCN Guidelines Index Table of Contents Discussion

References

NCCN Guidelines Version 1.2026

Hodgkin Lymphoma (Age >60 Years)

NCCN Guidelines Index Table of Contents Discussion

MANAGEMENT OF CHL IN ADULTS AGE >60 YEARS OR ADULTS UNFIT FOR INTENSIVE THERAPY

• CHL in patients who are older is associated with poorer disease outcomes.1 B symptoms, poor performance status, mixed cellularity

histologic subtype, EBV+ disease, and medical comorbidities are more frequent in this population.2

• Standard chemotherapy regimens are associated with dose reductions, treatment toxicity, and treatment-related mortality in patients who

are older.3-6

• There are limited prospective data evaluating alternatives to standard therapies for patients >60 years. Selection of standard versus alternate first-line therapy for a patient >60 years should be based on clinical judgment, with the goal of minimizing toxicity while maximizing efficacy.

• The regimens listed in Principles of Systemic Therapy (HODG-B 2 of 8) should be considered in patients >60 years or those unfit for

intensive therapy to lessen/minimize toxicity. These regimens have not been proven to overcome the poorer disease outcomes observed in patients >60 years.

• Clinical trial is recommended when available.

• ISRT or extended-field radiation therapy (EFRT) alone are options when systemic therapy is not considered feasible or safe.

HODG-9

1 Jagadeesh D, Diefenbach C, Evens AM. XII. Hodgkin lymphoma in older patients: challenges and opportunities to improve outcomes. Hematol Oncol 2013;31 Suppl

1:69-75.

2 Evens AM, Sweetenham JW, Horning SJ. Hodgkin lymphoma in older patients: an uncommon disease in need of study. Oncology (Williston Park) 2008;22:1369-1379.3 Ballova V, Rüffer JU, Haverkamp H, et al. A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol 2005;16:124-131.

4 Halbsguth TV, Nogová L, Mueller H, et al. Phase 2 study of BACOPP (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) in older patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG). Blood 2010;116:2026-2032.

5 Böll B, Görgen H, Fuchs M, et al. ABVD in older patients with early-stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD10 and HD11 trials. J Clin Oncol 2013;31:1522-1529.

6 Evens AM, Hong F, Gordon LI, et al. The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma

patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol 2013;161:76-86.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Abstract

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

References

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION:Nodular Lymphocyte Predominant Hodgkin Lymphoma@ff,gg PRIMARY TREATMENT

![Stage IA, IIA\n(non-bulky)\nIsRT^{r} (preferred for stage IA or contiguous stage IIA) or\n(non-bulky)\nOserve\ii{\,}\\\end{array} \nStage\text{Stage IB,},{hh}\nIIB,or\nStage\text{IA-IIA}(\text{bulky})\nO\text{~\text{~\text{~\text{~\text{~}}}}}\text{Stage IB,},{h}\text{~\text{~\text{~\text{~}}}\text{~\text{I}}}\text{Stage IIA}(\text{non-contiguous})\text{~\text{Observe}\text{~\text{I}}\text{~\text{I}}\text{SRT}^{\text{r}}(\text{non-}\text{~\text{I}}\text{I})\text{~\text{I}}\text{SRT}^{\text{r}}(\text{non-}\text{I}}\text{~\text{I}}\text{S}\text{S}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\\n](2/aj0YEe4oUhYkBdfpda0fYP/figure2b53d43976fe4705b054d3ba264f241a_0_5.png) c Principles of FDG-PET/CT(HODG-A).

Principles of Radiation Therapy(HODG-C).

ff NLPHL has a different natural history and response to therapy than CHL, especially stages I-II. For that reason, separate guidelines are presented for NLPHL. Patients who present with bulky disease, subdiaphragmatic disease, or splenic involvement have a high risk for initial or later transformation to large cell lymphoma. Data suggest outcomes differ for typical immunoarchitectural patterns (A/B) versus variant patterns(C/D/E/F).(Swerdlow SH,Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC; 2017).

hh For select patients with Stage IB, or Stage IIA non-contiguous disease, ISRT alone may be an option.

${}^{i}$ Observation may be an option for patients with stage IA disease with a completely excised solitary lymph node. See Follow-up(HODG-12)

${}^{i}$ Principles of Systemic Therapy (HODG-B, 3 of 8).

kk Generally, a brief course of chemotherapy(2-4 mo) would be given with RT.

llRituximab monotherapy can be used for palliation in select cases.mm Borchmann S, et al. Blood 2019;133:2121-2129.

mm Biopsy is recommended for sites of progressive disease, especially subdiaphragmatic sites, to rule out transformation.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

FOLLOW-UP AFTER COMPLETION OF TREATMENT AND MONITORING FOR LATE EFFECTS

●Complete response (CR) should be documented including reversion of FDG-PET/CT to "negative" within 3 months following completion of therapy.

●It is recommended that the patient be provided with a treatment summary at the completion of therapy, including details of RT, organs at risk(OARs), and cumulative anthracycline dosage given.

●Follow-up with an oncologist is recommended and should be coordinated with the primary care physician (PCP), especially during the first 5 years after treatment to detect recurrence, and then annually due to the risk of late complications including second cancers and cardiovascular disease (see NCCN Guidelines for Survivorship).00,1 Late relapse or transformation to large cell lymphoma may occur in NLPHL.

●The frequency and types of tests may vary depending on clinical circumstances: age and stage at diagnosis, social habits, treatment modality, etc. There are few data to support specific recommendations; these represent the range of practice at NCCN Member Institutions.

||Follow-up After Completion of Treatment Up to 5 Years| |---|---| |Interim H&P|●Every 3-6 months for 1-2 years, then every 6-12 months until year 3, then annually.| |Vaccines|●Annual influenza vaccine and other vaccines as clinically indicated (see NCCN Guidelines for Survivorship).| |Laboratory studies2:|CBC,ESR (if elevated at time of initial diagnosis), chemistry profile as clinically indicated. Thyroid function tests (TFTs) at least annually if thyroid gland was in the RT field.| |Counseling|Reproduction, health habits, psychosocial, cardiovascular, breast awareness, skin cancer risk, end-of-treatment discussion (see NCCN Guidelines for Survivorship).| |Cardiovascular Toxicity Screening|●ECHO at 1 year after completion of anthracycline therapy. ●Imaging should only be obtained if significant clinical concern for relapse or as mandated if enrolled in an active protocol. ●If imaging is necessary, it may include diagnostic CT at 3- to 6-month intervals for up to 2 years as clinically indicated, or after 2 years if relapse is suspected. FDG-PET/CT should only be done if last FDG-PET/CT was Deauville 4-5, to confirm CR at the end of all prescribed therapy including RT. Once negative, repeat FDG-PET/CT should not be done unless evaluating suspicious findings on H&P or CT.| ||●Surveillance FDG-PET/CT should not be done routinely due to risk for false positives. Management decisions should not be based on FDG-PET scan alone; clinical or pathologic correlation is needed.|

1Mauch P, Ng A, Aleman B, et al. Report from the Rockefeller Foundation Sponsored International Workshop on reducing mortality and improving quality of life in long-term survivors of Hodgkin's disease:July 9-16,2003,Bellagio,Italy.Eur J Haematol Suppl 2005;(66):68-76.

2 Lynch RC, Sundaram V, Desai M, et al. Utility of routine surveillance laboratory testing in detecting relapse in patients with classic Hodgkin lymphoma in first remission: Results from a large single-institution study. JCO Oncol Pract 2020;16:e902-e911.

oo Appropriate medical management should be instituted for any abnormalities.

Suspected Relapse CHL (HODG-15) or NLPHL (HODG-16)Follow-up and Monitoring After 5 Years (HODG-12A)

NCCN Guidelines Version 1.2026

Hodgkin Lymphoma (Age ≥18 years)

NCCN Guidelines Index Table of Contents Discussion

HODG-12A

FOLLOW-UP AFTER COMPLETION OF TREATMENT AND MONITORING FOR LATE EFFECTS

oo Appropriate medical management should be instituted for any abnormalities.pp There is limited data on screening in individuals with increased risk assigned male at birth (AMAB).

Follow-up and Monitoring After 5 Yearsoo,1

• Interim H&P: Annually

Annual blood pressure, aggressive management of cardiovascular risk factors.

Annual influenza vaccine and other vaccines as clinically indicated (see NCCN Guidelines for Survivorship).

For guidance on COVID-19 vaccination, please see the CDC for Use of COVID-19 Vaccines in the US.

For guidance on general recommendations for vaccination in patients with cancer, see NCCN Guidelines for the Prevention and Treatment

of Cancer-Related Infections.

For guidance on the adolescent and young adult population, see NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology.

• Cardiovascular symptoms may emerge at a young age.

Consider ECHO at 5- to 10-year intervals or per institutional guidelines after treatment is completed.

Consider carotid ultrasound at 10-year intervals or per institutional guidelines if neck irradiation.

• Laboratory studies:

CBC, platelets, chemistry profile annually

TFTs at least annually if thyroid was in the RT field

Biannual lipids

Annual fasting glucose

• Annual breast screening: The NCCN Hodgkin Lymphoma Guidelines Panel recommends annual breast screening (mammography and MRI)for individuals assigned female at birth with intact breast tissuepp who received irradiation to the mediastinum or axilla between ages 10–

30 years, which is consistent with the American Cancer Society (ACS) Guidelines. Neither MRI nor mammography should be pursued until a patient is at least 25 years of age. Consider referral to a breast specialist. Standard screening is recommended for individuals assigned

female at birth with intact breast tissue treated with irradiation to the mediastinum or axilla after age 30.

• Perform other routine surveillance tests for cervical, colorectal, endometrial, lung, and prostate cancer as per the NCCN Guidelines for

Detection, Prevention, and Risk Reduction and the ACS Cancer Screening Guidelines.

• Counseling: Reproduction, health habits, psychosocial, cardiovascular, breast awareness, and skin cancer risk (see NCCN Guidelines for

Survivorship).

• Treatment summary and consideration of transfer to PCP.

• Consider a referral to a survivorship clinic.

1 Mauch P, Ng A, Aleman B, et al. Report from the Rockefeller FoundationSponsored International Workshop on reducing mortality and improving quality of

life in long-term survivors of Hodgkin's disease: July 9-16, 2003, Bellagio, Italy.

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

Eur J Haematol Suppl 2005;(66):68-76.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

![PRIMARY REFRACTORY CHL49 OR RELAPSE WITHIN 3 MONTHS: CANDIDATE FOR HIGH-DOSE THERAPY AND AUTOLOGOUS STEM CELL RESCUE (HDT/ASCR)\nACSR)\nSecond-LINE THERAPYtt\nReception\nHDT/ASCR\n±RT/r3,tt(category 1)\nObserve\nConsider BV maintenance for patients with high risk of relapse\nor and no prior BV exposure$x,y,vv,ww\n$DHT/ASCR$\nBe $$\pm RT,tt$$\pm R^{T,r}$$\nHDT/ASCR\nObserve\nor\nConsider BV maintenance for patients with high risk of relapse\nFollow-up(HODG-12)\nObserve\nConsider BV maintenance for patients with high risk of relapse\n(HTDG-12)\nHDT/ASCR\nor\nConsider BV assessment who is subsequent and no prior BV exposure$x,y,vv,ww\n$D7,tt$$\pm RT,tt$$\nVTP$\nReception\n OR\nConsider BV maintenance for patients with high risk of relapse\nHDT/ASCR\nor\nConsider BV assessment who is subsequent and no prior BV exposure$x,y,vv,ww\n$D7,tt$$\pm RT,tt$$\nVTP$\nAb\nHDT/ASCR\nReception\nRRT$\n▲\nObserve\nor\nConsider BV maintenance for patients with high risk of relapse\nHDT/ASCR\n+ no prior BV exposure$x,y,vv,ww\n$D7,tt$$\pm RT,tt$$\nObserve\nor\nConsider BV assessment for patients who underwent HDT/\nrisk of relapse\n\nexposurex,y,vv,ww\nVTR,tt\nVTP$\n▲\nObserve\nor\nConsider BV assessment for patients with high risk of relapse\nHDT/ASCR\n\nSubsequent systemic therapy\nSDequent\n→\nHDT/ASCR\n→\nEXU4\n→\nObserve\nor\nConsider BV assessment for patients with high risk of relapse\nVTR,tt\nVTP$\alpha$\n](2/aj0YEe4oUhYkBdfpda0fYP/figure9bb6b058366a49ca9fc2006b5d10ee84_0_4.png) ×Utilize with caution in those with neuropathy.

y PJP prophylaxis is recommended for all BV containing regimens.

qq Primary refractory refers to inability to achieve CR following front-line therapy.

rPrinciples of Systemic Therapy for Relapsed or Refractory Disease: CHL(HODG-B 5 of 8).

ss Strongly consider RT for selected sites that have not been previously irradiated. In patients without prior history of RT, total lymphoid irradiation(TLI) may be an appropriate component of HDT.

$\underline{U}$ Subsequent systemic therapy options include second-line therapy options that were not previously used (HODG-B 5 of 8).

vV Patients with 2 or more of the following risk factors are considered to be at high risk: Remission duration<1 year, extranodal involvement, FDG-PET-positive response at time of transplant, B symptoms, and/or>1 second-line/subsequent

The role of maintenance BV has not been well-defined in patients who received BV prior to maintenance therapy.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

![CHL BIPSY PROVEN RELAPSE AFTER ≥23 MONTHS: CANDIDATE FOR HDT/ASCR\nSECOND-LINE THERAPYY\nADDITIONAL THERAPYY\nHDT/ASCR\nDeauville 1-39\nHDT/ASCR\nUseful in Certain Circumstances ISRT (localized relapse & limited prior treatment only)×\n1-39\nAddutional THERAPYY\nHDT/ASCR ± ISRT,ss,tt\nObserve or Consider BV maintenance for patients with high risk of relapse and no prior BV exposure x,y,vv,ww\nHDT/ASCRY\nObserve\nHDT/ASCRY\nObserve BV maintenance for patients with high risk of relapse and no prior BV exposure x,y,vv,ww\nHDT/ASCRY\nObserve BVaintenance\nHDT/G-12\nObserve Vtreatment for patients with high risk of relapse\nChL BIopsy-reformance by 23 months:\nDeauville 1-39\nHDT/ASCR± ISRT,ss,tt\nObserve BVt maintenance for patients with high risk of relapse and no prior BV exposure x,y,vv,ww\nHDT/ASCRY\nObserve BVtreatment for patients with high risk of relapse\nChL BIopsy-reformance by 23 months:\nObserve Vtreatment for patients with high maintenance behavior and no prior BV exposure x,y,vv,ww\nObODU-12\nHODG-12\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figure84e8bfd1b8014a84b872d99a41b36d1d_0_4.png) c Principles of FDG-PET/CT(HODG-A).

9FDG-PET 5-Point Scale (Deauville Criteria) (HODG-A, 2 of 2).

r-Principles of Radiation Therapy (HODG-C).

${}^{w}$ Patients with 2 or more of the following risk factors are considered to be at high risk:Remission duration<1 year, extranodal involvement,FDG-PET-positive response at time of transplant,B symptoms, and/or>1 second-line/subsequent therapy regimen.AETHERA Trial: Moskowitz CH,et al. Blood 2018;132:2639-2642.

×Utilize with caution in those with neuropathy.

y PJP prophylaxis is recommended for all BV containing regimens.

rPrinciples of Systemic Therapy for Relapsed or Refractory Disease: CHL(HODG-B,5 of 8).

ss Strongly consider RT for selected sites that have not been previously irradiated. In patients without prior history of RT, TLI may be an appropriate component of HDT.

ww The role of maintenance BV has not been well-defined in patients who received BV prior to maintenance therapy.

XX For patients with stage IA-IIA disease who received abbreviated chemotherapy(3-4 cycles) without prior RT, and with relapse only at initial sites of disease.

tt Timing of RT may vary.

$u u$ Subsequent systemic therapy options include second-line therapy options that were not previously used (HODG-B, 5 of 8).

yy There are no data to support a superior outcome with any of the treatment modalities. Individualized treatment is recommended.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

![RELAPSED/ REFRACTORY CHL: NOT A CANDIDATE FOR HDT/ASCR\nNCCIN\nNational Comprehensive Neural Guidelines 2022.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2\n](2/aj0YEe4oUhYkBdfpda0fYP/figure2e6426fff43649de829bcd02f101511d_0_4.png) cPrinciples of FDG-PET/CT(HODG-A).

9FDG-PET 5-Point Scale (Deauville Criteria) (HODG-A, 2 of 2).

Principles of Radiation Therapy(HODG-C).

rPrinciples of Systemic Therapy for Relapsed or Refractory Disease: CHL(HODG-B 5 of 8).

tt Timing of RT may vary.

uu Subsequent systemic therapy options include second-line therapy options that were not previously used (see HODG-B 5 of 8).

yy There are no data to support a superior outcome with any of the treatment modalities. Individualized treatment is recommended.

zz If CPI- or BV-containing regimen contraindicated, an alternative second-line therapy option should be utilized(see HODG-B 5 of 8)

aaa Repeat imaging no more than every 3 months unless there is concern for progression.

bbb Choice depends on prior therapies, prior toxicities, and comorbidities.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

NLPHL REFRAFACTORY OR SUSPECTED RELAPSE

SECOND-LINE THERAPYY

![Refractory and disease or transected cyclIsCT$\longrightarrow$ Biopsy by Biopsy negative\n\n 口 observe with short-interval follow-up (HODG-12)\nRefractory or Disuspected $\boldsymbol{\in}$ Suspected $\boldsymbol{\in}$ CTc$\longrightarrow$ 信息系统\nRefractory Disease)\nNCCN Guidelines for B-Cell Lymphomas for B-Cell Lymphomas for B-Cell Lymphomas for Reractory Disease)\nAggressive B-cell lymphoma\n+ Diuse large B-cell lymphoma - Relapsed/Refractory Disease)\nSee NCCN Guidelines for B-Cell Lymphomas for B-Cell Lymphomas for Reractory Disease)\n](2/aj0YEe4oUhYkBdfpda0fYP/figureaacbd3ef7a1848a0bef87756e9cf7396_0_6.png) CPrinciples of FDG-PET/CT(HODG-A).

yy There are no data to support a superior outcome with any of the treatment modalities. Individualized treatment is recommended.

CCC At relapse, biopsy should be considered because of risk for transformation,especially if intra-abdominal or splenic disease. Some patients with NLPHL have a chronic indolent course that may not require aggressive re-treatment.These asymptomatic patients may be observed.

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

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age $\geqslant$ 18 years)

NCCN Guidelines Index Table of Contents Discussion

NLPHL REFRAFACTORY OR SUSPECTED RELAPSE

SECOND-LINE THERAPYXX

![NLPHL\nAsymptomatic and non-bulky\nObserve\nor\nRituximabccc\nor\nISRT^{\dagger}\nSecond-line therapy(HODG-B 6 of 8)\nIakouge\nRistage with FDG-PET/CT after treatmentc\n±\nHDT/ASCR\nProgressive disease\ndded\nObserve if asymptomatic\n(HODG-12)\nor\nHDT/ASCR(if not done previously)\nSymptomatic or bulky\nISRT^{\dagger}\nStandard-line therapy\nProgressive disease\nHodG-B 6 of 8)\nSubsequent therapy${}^{eee}$ （HODG-B 6 of 8）\nSubsequent therapy${}^{eee}$ （HODG-B 6 of 8）\n](2/aj0YEe4oUhYkBdfpda0fYP/figuree3eebf53e2894b589aec762c7ee1d4e5_0_6.png) ${}^{c}$ Principles of FDG-PET/CT(HODG-A).

Principles of Radiation Therapy(HODG-C).

XX There are no data to support a superior outcome with any of the treatment modalities. Individualized treatment is recommended.

ccc In some patients treated with rituximab alone, maintenance rituximab may be considered for 2 years(Schulz H, et al. Blood 2008;111:109-111; Advani RH, et al.J Clin Oncol 2014;32:912-918).

ddd Consider biopsy to rule out transformation.

eee Subsequent systemic therapy options include second-line therapy options that were not previously used (see HODG-B 6 of 8).

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

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF FDG-PET/CT

Technique

FDG-PET/CT interpretation, including the requirement that FDG-PET/CT examinations should be performed under the supervision of and interpreted by a physician with the following qualifications:

●An integrated FDG-PET/CT or an FDG-PET with a diagnostic CT is recommended for initial diagnosis and restaging.

Board certification in radiology or diagnostic radiology, nuclear radiology, or nuclear medicine OR

●For FDG-PET/CT performed in the staging or response assessment in Hodgkin lymphoma(HL), image acquisition should be obtained in accordance with the American College of Radiology (ACR)practice parameter guidelines1 or the Society of Nuclear Medicine and Molecular Imaging (SNMMI), which adopted the European Association of Nuclear Medicine (EANM) procedure guidelines for tumor imaging: version 2.0 (with the exception that the"standardized uptake value (SUV) max" is used in the United States as the quantitative measurement).2

Completion of a formal Accreditation Council for Graduate Medical Education(ACGME)-approved general nuclear medicine program in addition to 1000 hours of clinical training in general nuclear medicine, 20 hours of continuing medical education(CME) in FDG-PET, and at least 150 oncologic FDG-PET/CT examinations interpreted or multi-read during the previous 3 years.1

FDG-PET/CT should be performed with the patient on a flat table with arms up, if possible. In cases of FDG-PET positivity where disease sites are inconsistent with usual presentation of HL or if an unusual disease presentation(ie, HIV), additional clinical evaluation may be required for staging. See (ST-1).

●Continuing experience/education should include interpretation of a minimum of 150 FDG-PET/CT examinations in 3 years (multi-read is acceptable) and completion of 150 hours (including 75 hours of Category 1 CME) during the preceding 3 years pertinent to the physician's practice patterns, including FDG-PET imaging.1

●FDG-PET/CT scans obtained outside of these parameters(eg, in outdated mobile tomographs) can result in both false-negative and false-positive tests, and lead to inappropriate disease management. In these cases, consideration should be made for repeating the study on an acceptable FDG-PET/CT tomograph.

●The interpreting radiology or nuclear medicine physician should have adequate training and CME/experience in interpreting FDG-PET/CT for patients with lymphoma, including use of the Deauville 5-point scoring system.

Timing

●Initial staging of FDG-PET/CT for patients with lymphoma should be obtained no longer than 1 month prior to the initiation of therapy.

●The initial study should include a contrast-enhanced diagnostic CT if it is expected that RT may be a component of initial treatment.

Interpretation

●The Panel supports the ACR1 and SNMMI2 recommendation for

1American College of Radiology.ACR-SPR Practice Parameters for Performing FDG-PET/CT in Oncology.2016. Available at: https://www.acr.org/-/media/ACR/Files/Practice-Parameters/FDG-PET-CT.pdf?la=en. Accessed November 19, 2021.

2 Boellaard R, Delgado-Bolton R, Oyen WJG, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging 2015;42:328-354.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age $\geq$ 18 years)

NCCN Guidelines Index Table of Contents Discussion

PET 5-POINT SCALE (DEAUVILLE CRITERIA)

|Score|Score|PET/CT Scan Result| |---|---|---| |Negative|1|No uptake| |Negative|2|Uptake ≤ mediastinum| |Negative|3|Uptake > mediastinum but ≤ liver| |Positive|4|Uptake moderately higher than liver and visually above adjacent background activity| |Positive|5|Uptake markedly higher than liver and/or new lesions| |Positive|xa|New areas of uptake unlikely to be related to lymphoma|

Adapted with kind permission from Springer International Publishing: Barrington SF,Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 2014;32:3048-3058.

a Watchful waiting, biopsy, or additional imaging tests may be appropriate depending on clinical circumstances. Obtaining a second opinion/overread of the imaging may be beneficial.

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

NCCN Guidelines Index Table of Contents Discussion

National Comprehensive Cancer Network®

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPYa Primary Systemic Therapy Regimens

Classic Hodgkin Lymphoma in Adults 18-60 Years

Primary Systemic Therapy Regimensb(Listed in Alphabetical Order)

•ABVDc,d,e(Doxorubicin/Bleomycin/Vinblastine/Dacarbazine)± ISRTf,1,2,3,4,5

•ABVDc,d,e followed by BrECADD (BV/Etoposide/Cyclophosphamide/Doxorubicin/Dacarbazine/Dexamethasone)+ G-CSF9,h,i,j± ISRTf,5

•BrECADD+ G-CSF$^{h}$ (Brentuximab-vedotin/Etoposide/Cyclophosphamide/Doxorubicin/Dacarbazine/Dexamethasone)±ISRT$^{f,g,i,j,6}$

$\cdot$ BV-AVD+ G-CSFh (Brentuximab-vedotin/Doxorubicin/Vinblastine/Dacarbazine/Dexamethasone) $\pm$ ISRT${}^{f,g,i,j,6}$

•Nivolumab-AVD^{d},1,9,10

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

b Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics.The chart on this page delineates the systemic therapy regimens that can be used and provides some additional details.

cRoutine use of growth factors is not recommended with ABVD. Evens AM, Killey J,Ortiz T,et al.G-CSF is not necessary to maintain over 99% dose-intensity with ABVD in the treatment of Hodgkin lymphoma: low toxicity and excellent outcomes in a 10-year analysis. Br J Haematol 2007;137:545-552.

d Neutropenia is not a factor for delay of treatment or reduction of dose intensity with ABVD or nivolumab-AVD.

e In times of vinblastine shortage, consider capping the dose at 10 mg to avoid wasting a vial. Consideration can also be made for substituting vinblastine with vincristine 1 mg. In times of both vinblastine and dacarbazine shortage,consideration can be made for substituting ABVD with CHOP temporarily.

Principles of Radiation Therapy(HODG-C).

9 All cycles include growth factor support. See NCCN Guidelines for Hematopoietic Growth Factors.

h Tbo-filgrastim is an appropriate substitute for G-CSF.

iUtilize with caution in those with neuropathy.

jPJP prophylaxis is recommended for all BV-containing regimens.

${}^{k}$ In times of vinblastine shortage, consideration can be made for substituting BV+ AVD with BV-CHP(BV, cyclophosphamide, doxorubicin, prednisone) temporarily.

In the SWOG S1826 trial, growth factor support was optional. Herrera AF, et al.N Engl J Med 2024;391:1379-1389.

Principles of Systemic Therapy for Relapsed or Refractory CHL(HODG-B 5 of 8)References on HODG-B 4 of 8

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

NCCN Guidelines Index

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age >60 Years or Unfit for Intensive Therapy)

PRINCIPLES OF SYSTEMIC THERAPYa Primary Systemic Therapy Regimens

Classic Hodgkin Lymphoma in Adults Age>60 Years or Adults Unit for Intensive Therapy

|Primary Systemic Therapy Regimens|Primary Systemic Therapy Regimens (Listed in Alphabetical Order)||| |---|---|---|---| |Stage I-II Favorable Disease by GHSG Criteria|●A(B)VDC,d,e,m (2 cycles)+ISRT 20 Gyf,1,11,12||IsRT 20 Gyf,1,11,12| |Stage I-II Favorable Disease by EORTC Criteria|●A(B)VDC,d,e,m (3 cycles)+ISRT 30 Gyf,1,11,12||| |Stage I-II Unfavorable|●A(B)VDC,d,e,m (2 cycles) followed by AVD (4 cycles), if FDG-PET scan is negative after 2 cycles of ABVD.133 patients with a positive FDG-FET scan after 2 cycles of ABVD need individualized treatment. ●A(B)VDC,d,e,m x 4 cycles+ISRTf,14 ●BV x 2 cycles followed by AVD x 6 cycles, conditionally followed by BVX 2 cycles in patients with CR or PR and no neuropathy-I,j,k,15||Any Age and Not a Candidate for Anthracycline| |Stage III-IV Disease|●Nivolumab-AVD x 6 cyclesd,I,16,17 (category 1, preferred) ●If contraindications to CPI: BV x 2 cycles followed by AVD x 6 cycles, conditionally followed by BVX (4 cycles) in AVD x 6 cycles, conditionally followed by CVR and no neuropathy-I,j,15||●BV-Nivolumab± ISRTf,i,j,20 ●Nivolumab or Pembrolizumab± ISRTf (if contraindications to BV)|

|Primary Systemic Therapy Regimens (Listed in Alphabetical Order)||| |---|---|---| ||Any Age and Not a Candidate for Anthracycline|| |Stage I-IV|●BV-DTIC (Dacarbazine) ± ISRTf,i,j,18,19 ●BV-Nivolumab ± ISRTf,i,j,20|| ||●Nivolumab or Pembrolizumab ± ISRTf (if contraindications to BV)||

Principles of Radiation Therapy(HODG-C).

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

c Routine use of growth factors is not recommended with ABVD. Evans AM, Killey J, Ortiz T, et al. G-CSF is not necessary to maintain over 99% dose-intensity with ABVD in the treatment of Hodgkin lymphoma: low toxicity and excellent outcomes in a 10-year analysis. Br J Haematol 2007;137:545-552.

hTbo-filgrastim is an appropriate substitute for G-CSF.

iUtilize with caution in those with neuropathy.

d Neutropenia is not a factor for delay of treatment or reduction of dose intensity with with ABVD or nivolumab-AVD.

j PJP prophylaxis is recommended for all BV-containing regimens.

${}^{k}$ In times of vinblastine shortage, consideration can be made for substituting BV+AVD with BV-CHP(BV, cyclophosphamide, doxorubicin, prednisone) temporarily.

In the SWOG S1826 trial, growth factor support was optional. Herrera AF, et al.N Engl J Med 2024;391:1379-1389.

m Bleomycin should be used with caution as it may not be tolerated in patients>60 years, and it should not be used beyond 2 cycles.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPYa Primary Systemic Therapy Regimens

Nodular Lymphocyte-Predominant Hodgkin Lymphoma

●The most common chemotherapy regimens used at NCCN Member Institutions for NLPHL are listed below

Primary Systemic Therapy Regimens(listed in alphabetical order)

•ABVD°C,e,o (Doxorubicin/Bleomycin/Vinblastine/Dacarbazine)+Rituximabp,21,22

●CHOP (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone) + Rituximabp,23,24

●CVbP (Cyclophosphamide/Vinblastine/Prednisolone) + Rituximabp,25

●Rituximabp,26-31

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

${}^{n}$ Ongoing clinical trials will help to clarify the role of a watch-and-wait strategy or systemic therapy, including anthracycline(epirubicin or doxorubicin), bleomycin,and vinblastine-based chemotherapy or antibody-based approaches, in the treatment of these patients.

o Neutropenia is not a factor for delay of treatment or reduction of dose intensity with ABVD.

P Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

Principles of Systemic Therapy for Relapsed or Refractory NLPHL (HODG-B 6 of 8)

References on HODG-B 4 of 8

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma(Age≥18 years)

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAP PRIMARY PRIMARY GHERIMES REFERENCES

1Fuchs M, Goergen H, Kobe C, et al. Positron emission tomography-guided treatment in early-stage favorable Hodgkin lymphoma: Final results of the international, randomized phase III HD16 trial by the German Hodgkin Study Group. J Clin Oncol 2019;37:2835-2845.

2Rordford J, Lichou S, Counselell, N. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med 2015;372:1598-1607.

3 Federico M, Fortied C,Stepanishyna Y,et al.Long-term follow-up of the Response-Adapted Intergroup EORT/LYSA/FIL H10 trial for localized Hodgkin lymphoma. J Clin Oncol 2024;42:19-25.

Eich HT, Diehl V Gorgen H, E. et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol 2010;28:4199-4206.

5 Straus DJ, Jung SH, Pitcher B, et al. CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET. Blood 2018;132:1013-1021.

6 Borchmann P, Ferdinandus J, Schneider G,et al. Assessing the efficacy and tolerability of PET-guided BrECADg versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma(HD21):a randomised, multicentre, parallel, open-label, phase 3 trial. Lancet 2024:404:341-352.

7 Ansell SM, Radford J, Connors JM, et al. Overall survival with breuxintum vedotin in stage III or IV Hodgkin's lymphoma. N Eng J Med 2022;387:310-320.

Fornecker LM, Lazarovici J, Aurer I, et al. Brentarydum avodin plus AVD for first-line treatment of early-stage unfavorable Hodgkin lymphoma(BREACH): A multicenter, open label, randomized, phase II trial. J Clin Oncol 2023;41:327-335.

9Herrera AF,LeBlanc M, Castellino SM,et al.Nivolumab+AVD in advanced-stage classic Hodgkin's lymphoma. N Engl J Med 2024;391:1379-1389.

10Brockenram P, Buhren I, Meissner J, et al. Nivolumab and doxorubicin, vinblastine,and dacarbazine in early-stage unfavorable Hodgkin lymphoma: Final analysis of the Randomized German Hodgkin Study Group phase II NIVAlH trial. J Clin Oncol 2023;41:1193-1199.

11 Stamatoulas A, Brice P, Bouabdallah R, et al. Outcome of patients older than 60 years with classical Hodgkin lymphoma treated with front line ABVD chemotherapy: frequent pulmonary events suggest limiting the use of bleomycin in the elderly. Br J Haematol 2015;170:179-184.

12 Behringer K, Goergen H, Hitz F,et al. Omission of dacarbazine or bleomycin, or both,from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma(GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet 2015;385:1418-1427.

13 13 Luminari S, Fossa A, Trotman J, et al. Long-term follow-up of the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma trial. J Clin Oncol 2024;42:13-18.

14 Federico M, Fortpied C, Stepanishyna Y,et al. Long-term follow-up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 trial for localized Hodgkin lymphoma. J Clin Oncol 2024;42:19-25.

15 Evens AM, Advani RH, Helenowski IB, et al. Multicenter phase II study of sequential bentuximab vedotin and doxorubicin, vinblastine, and dacarbazine chemotherapy for older patients with untreated classical Hodgkin lymphoma. J Clin Oncol 2018;36:3015-3022.

16 Rutherford SC, Li H, Herrera AF, et al. Nivolumab- versus Brentximab vedotin-AVD in older patients with advanced-stage classic Hodgkin lymphoma enrolled on S1826.J 17 Clin Oncol 2025;43:2986-2973.

17 Torka P, Feldman T, Savage K, et al. Phase 2 trial of nivolumab plus adriamycin,vinblastine, dacarbazine (N-AVD) as frontline therapy in older adults with Hodgkin lymphoma [abstract]. Hemolat Oncol 2023;41:161-162.

18Friedberg JW, Forero-Torres A, Bordoni RE, et al. Frontline brextumabod in combination with dacarbazine or bendamustine in patients aged≥60 years with HL.Blood 2017;130:2829-2837.

19 Friedberg JW, Forero-Torres A, Holkova B, et al. Long-term follow-up of brentuximab vedotin $\_$ dotacbarazine as first line therapy in elderly patients with Hodgkin lymphoma[Abstract]. J Clin Oncol 2018;36(Suppl 15):Abstract 7542.

20 Friedberg JW, Bordoni R, Patel-Donnelly D, et al. Brentuximab vedotin with dacarbazine or nivolumab as frontline ch LCH therapy for older patients ineligible for chemotherapy. Blood 2024;143:786-795

21 Savage KJ, Skinnider B, Al-Mansour M, et al. Treating limited stage nodular lymphocyte predominant Hodgkin lymphoma similarly to classical Hodgkin lymphoma with ABVD may improve outcome. Blood 2011;118:4585-4590.

22 Canellos GPa, Mauch P. What is the appropriate systemic chemotherapy for lymphocyte-horporant Hodgkin lymphoma? J Clin Oncol 2010;28:e8.

23.Fanale MA, Cheah CY, Rich A, et al. Encouraging activity for R-CHOP in advanced stage 20 nodular lymphocyte-predominant Hodgkin lymphoma. Blood 2017;130:472-477.

24 Binkley MS, Advani, RH. SOHO State of the Art Updates and Next Questions [Treatment Approaches for Nodular Lymphocyte-Predominant Hodgkin Lymphoma. Clin Lymphoma Myeloma,Leuk2023:23:471-476.

25 Shankar A, Hall GW, Gordeles-Srojean S, et al. Treatment outcome after low intensity chemotherapy [CVP] in children and adolescents with early stage nodular lymphocyte predominant Hodgkin's lymphoma- an Anglo-French collaborative report. Eur J Cancer 2012;48:1700-1706.

26 Advani RH, Hoppe RT. How I treat nodular lymphocyte predominant Hodgkin lymphoma. J Clin Oncol 2014;32:142:4182-4188.

27 Advani RH,Horning SJ,Hoppe RT,et al. Mature results of a phase II study of rituximab therapy for nodular lymphocyte-predominant Hodgkin lymphoma. J Clin Oncol 2014;32:912-918.

28 Eichenauer DA, Fuchs M, Pluetschow A, et al. Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood 2011;118:4363-4365.

29 Eichenauer DA, Plütschow A, Fuchs M, et al. Long-term course of patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma: A report from the German Hodgkin Study Group.J Clin Oncol 2015;33:2857-2862.

30 Davies A,Merli F, Mihaljevic B,et al.Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma(SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol 2017;4:e272-e282.

31 Lugtenburg P, Avivi I, Berenschine H, et al. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica 2017;102:1913-1922.

NCCN Guidelines Index Table of Contents Discussion

NCCN

National Comprehensive Cancer Network®

PRINCIPLES OF SYSTEMIC THERAPY Relapsed or Refractory Disease

Classic Hodgkin Lymphoma

●Consider the following when selecting re-induction or subsequent therapy:

Clinical trial enrollment

▶ Referral to a center with expertise

|Primary Refractory Disease or Relapse(within any time frame)(Candidate for or Not a Candidate for HDT/ASCR)|Additional Considerations for Relapsed/ Refractory CHL (Not a Candidate for HDT/ ASCR)|| |---|---|---| |Second-Line and Subsequent Therapyq,r(in alphabetical order)|Therapy for Disease Refractory to at Least 3 Prior Lines of Subsequent Therapy(in alphabetical order)|●Individualized treatment is necessary. ● For localized relapse, consolidative ISRT should be strongly considered.f ● Refer to or consult a center with expertise. ●Single-agent palliative therapy options include: CPI: □Nivolumab24,25 Non-CPI-containing regimens: □Bendamustum82,27 Non-CPI containing regimen: ▶▶Voinostat-Pembrolizumab28 Everolimus29 √ISRTf| |CPI-containing regimens ●BV-Nivolumab1,1|● Bendamustine17|●Individualized treatment is necessary. ● For localized relapse, consolidative ISRT should be strongly considered.f ● Refer to or consult a center with expertise. ●Single-agent palliative therapy options include: CPI: □Nivolumab24,25 Non-CPI-containing regimens: □Bendamustum82,27 Non-CPI containing regimen: ▶▶Voinostat-Pembrolizumab28 Everolimus29 √ISRTf| |CPI-containing regimens ●BV-Nivolumab1,1|● Bendamustine/carbolopatin/etoposide18 ● GEMOC-tislelizumab-jsgr2 ●GVD-Pembrolizumab3 ●ICE-Nivolumab4,5 ●ICE-Pembrolizumab6|● Single-agent palliative therapy options include: □Nivolumab24,25 口Pembrolizumab26,27 Non-CPI containing regimen: ▶▶Bendamustine17 Bendamustum82,27 Non-CPI containing regimens: ▶▶ISRTd,17 Everolimus29 √ISRTf| |Non-CPI-containing regimens ●BV-Bendamustine1,1,8|● Nivolumab24,25 ●Pembrolizumab26,27|For 1,39,30| |●BV-Bendamustine1,1,8|● Vorinostat-Pembrolizumab28|For 1,49| |●DHAP(Dexamethasone/Cisplatin/High-Dose Cytarabine)9,10|Consider referral for allogeneic HCT in appropriate patients|◆ Gemcitabine30 √Lenalidomide31| |●GVD (Gemcitabine/Vinorelbine/Liposomal Doxorubicin)12|appropriate patients|◆ Vinblastine32|

General Guidelines for Checkpoint Inhibitors(CPI) for Relapsed or Refractory CHL33,34

●Post-allogeneic hematopoietic cell transplant(HCT), patients can receive either nivolumab or pembrolizumab. There are limited data regarding the use of CPI following allogeneic HCT. If a CPI is used, the HCT regimen will need to be carefully considered.

● Checkpoint inhibitors can be continued despite progression on imaging if patients are deriving clinical benefit, as imaging progression may be indicative of immune flare rather than true progression.

Principles of Radiation Therapy(HODG-C).

iUtilize with caution in those with neuropathy.

j PJP prophylaxis is recommended for all BV-containing regimens.

g Choice depends on prior therapies, prior toxicities, and comorbidities.

rSubsequent systemic therapy options include second-line therapy options that were not previously used.

NCCN Guidelines Index Table of Contents Discussion

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

PRINCIPLES OF SYSTEMIC THERAPYa Relapsed or Refractory Disease

Nodular Lymphocyte Predominant Hodgkin Lymphoma

●Consider the following when selecting reinduction or subsequent therapy:

Clinical trial enrollment

▶ Referral to a center with expertise

Relapsed or Refractory NLPHL

Second-Line and Subsequent Therapyr(s(in alphabetical order)

●R(Rituximab)p

$ \cdot \cdot $R $p+$ Bendamustine$36$

·R$^{p}$ + DHAP9,10

$ \cdot$ RP $+$ ICE $10,14$

● If not previously used37:

RP+ABVDc,e,o

RP+CHOP

° Neutropenia is not a factor for delay of treatment or reduction of dose intensity with ABVD.

P Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.

${}^{r}$ Subsequent systemic therapy options include second-line chemotherapy options that were not previously used.

${}^{s}$ Choice depends on prior therapies and prior toxicities. There are no preferred second-line or subsequent therapy options.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPY FRETORY RELAPSED OR REFRAFACTORY DISEASE REFERENCES

1Advani RH, Moskowitz AJ, Bartlett NL,et al. Brentximub vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. Blood 2021:138:427-438.

2Ding K, Liu H, Ma J, et al. Tisleizumab with gemcitabine and oxaloplatin in patients with relapsed or refractory classic Hodgkin lymphoma: a multicenter phase II trial.Haematologica 2023;108:2146-2154.

3 Moskowitz AJ, Shah G, Schöder H, et al. Phase II trial of pembrolizumab plus gemcitabine, voinreline, and liposomal doxorubicin as second-line therapy for relapsed or refractory classical Hodgkin lymphoma. J Clin Oncol 2021:39:3109-3117.

4 Mei MG, Lee HJ, Palmer J, et al. Response-adapted anti-PD1-based salvage therapy for Hodgkin lymphoma with nivolumab alone or in combination with ICE.Blood 2022;139:3605-3616.

5 Mei M, Palmer J, Lee HJ, et al. Nivolumab plus ifosfamide, carboplatin, and etoposide are a highly effective first salvage regimen in high-risk relapsed/refactory Hodgkin lymphoma. Hemasphere 2025;9:e70126.

6 Bryan LJ, Casulo C, Allen PB, et al. Pembrolizumab added to offosmide,carboplatin, and etoposide chemotherapy for relapsed or refractory classic Hodgkin lymphoma: A multi-institutional phase 2 investigator-initiated nonrandomized clinica I trial. JAMA Oncol 2023;93:683-691.

7 Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol 2012;30:2183-2189.

8'Connor OA, Lue JK, Sawas A, et al. Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm,phase 1-2 trial. Lancet Oncol 2018;19:257-266.

9 Josting A, Rudolph C, Reiser M, et al. Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin's disease. Ann Oncol 2002;13:1628-1635.

10Abali H, Urün Y, Oksuzoglu B, Budakoglu B,et al. Comparison of ICE(ifosfamide-carboplatin-etoposide) versus DHAP(cytosarine abinoside-cisplatin-dexamethasone)as salvage chemotherapy in patients with relapsed or refractory lymphoma. Cancer Invest 2008;26:401-406.

11 Santoro A, Mazza R, Pulsoni A, et al. Bendamustine in combination with gemcitabine and vinorelbine is an effective regimen as induction chemotherapy before autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma: final results of a multicenter phase II study. J Clin Oncol 2016;34:3293-3299.

12Bartlett N, Niedzwiecki D, Johnson J,et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin(GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804. Ann Oncol 2007;18:1071-1079.

13 Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood 2001;97:616-623.

14 Hertzberg MS, Crombie C, Benson W, et al. Outpatient fractionated ifosfamide, carboplatin and etoposide as salvage therapy in relapsed and refractory non-Hodgkin's and Hodgkin's lymphoma. Ann Oncol 2006;17 Suppl 4:iv25-30.

15 Lynch RC, Cassaday RD, Smith SD, et al. Dose-dense brentuximab vedotin plus ifosfamide, carboplatin, and etoposide for second-line treatment of relapsed or refractory classical Hodgkin lymphoma: a single centre, phase 1/2 study. Lancet Haematol 2021;8:e562-e571.

16 Santoro A, Magagnoli M, Spina M, et al. Ifosfamide, gemcitabine, and vinorebine: a new induction regimen for refractory and relapsed Hodgkin's lymphoma. Haematologica 2007;92:35-41.

17 Moskowitz AJ, Hamlin PA, Perales M-A, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol 2013;31:456-460.

18Budde LE, Wu D, Martin DB,et al. Bendamustine with rituximab, etoposide and carboplatin(T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial. Br J Haematol 2018;183:601-607.

19 Nie J, Wang C, Liu Y, et al. Addition of low-dose decitabine to anti-PD-1 antibody camrelizumab in relapsed/refractory classical Hodgkin lymphoma.J Clin Oncol.2019;37:1479-1489.

20 Lui Y, Wang C, Li X, et al. Improved clinical outcome in a randomized phase II study of anti-PD-1 camrelizumab plus decitabine in relapsed/refractory Hodgkin lymphoma.J Immunother Cancer 2021;9:e002347.

21 Wang C, Liu Y, Dong L, et al. Efficacy of decitabine plus anti-PD-1 camrelizumab in patients with Hodgkin lymphoma who progressed or relapsed after PD-1 blockade monotherapy. Clin Cancer Res.2021;27:2782-2791.

Note: All recommendations are category 2A unless otherwise indicated. NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥18 years) NCCN Guidelines Index Table of Contents Discussion HODG-B 8 OF 8 PRINCIPLES OF SYSTEMIC THERAPY FOR RELAPSED OR REFRACTORY DISEASE

References

NCCN Guidelines Version 1.2026

Hodgkin Lymphoma (Age ≥18 years)

NCCN Guidelines Index Table of Contents Discussion

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

HODG-C 1 OF 16

PRINCIPLES OF RADIATION THERAPY

• Treatment with photons, electrons, or protons may all be appropriate, depending on clinical circumstances.

• Advanced RT technologies such as intensity-modulated RT (IMRT)/volumetric modulated arc therapy (VMAT),1-3 deep-inspiratory breath

hold (DIBH) or respiratory gating,4,5 image-guided RT (IGRT),5 and proton therapy6-8 may offer significant and clinically relevant advantages in specific instances to spare important normal organs at risk (OARs) and decrease the risk for both acute and long-term toxicity while still

achieving the primary goal of local tumor control.

• Achieving significant dose-sparing for OARs reflect best clinical practice as it reduces the risk of late complications from normal tissue

damage. Achieving highly conformal dose distributions is especially important for patients who are being treated with curative intent or who have long life expectancies following therapy.

• In mediastinal HL, use of four dimensional (4D)-CT or DIBH at the time of simulation to deal with respiratory motion and minimize dose to

OARs is essential. DIBH, in particular, has been shown to decrease incidental dose to the heart, lungs, and other OARs in many disease

presentations.5 Further, IGRT during treatment delivery is essential to ensure accurate target localization. In certain circumstances, the

use of protons for mediastinal lymphoma provides dosimetric advantages that may reduce long-term toxicity. Proton therapy is particularly advantageous in the setting of mediastinal disease to reduce dose to the heart and cardiac substructures and in young patients to reduce

dose to breast tissue.9-11

• Although the advantages of tightly conformal dose techniques, such as IMRT, includes steep dose gradients between targets and OARs,

the "low-dose bath" to normal structures is often increased. Particular attention to treatment technique and adherence to dose constraints

is essential to minimize dose to high-risk OARs such as breast tissue in young premenopausal individuals. Target definition and treatment

delivery verification require careful monitoring to avoid the risk of tumor geographic miss and subsequent decrease in tumor control. Initial diagnostic imaging with contrast-enhanced CT, MRI, FDG-PET, and other imaging modalities facilitate target definition. Image guidance may be required to provide assurance of accurate daily delivery.

• Randomized studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which

take 10+ years to develop. In light of that, the modalities and techniques that are found to best reduce the doses to the OARs in a clinically

meaningful way without compromising target coverage should be considered.

References

General Principles

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National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF RADIATION THERAPY

Involved-Site Radiation Therapy (ISRT): Dose

ISRT alone: The CTV should be expanded to include potential microscopic disease in the immediate region of the FDG-PET-positive disease.

•Combined Modality Therapy (CMT)

Non-bulky disease(stage I-II): 20a-30 Gy; 1.5-2.0 Gy per fraction

Non-bulky disease(stage IB & IIB):30 Gy; 1.5-2.0 Gy per fraction

Bulky disease(all stages):30 Gy; 1.5-2.0 Gy per fraction

Partial response/refractory disease (Deauville 4-5): 36-40 Gy

●ISRT Alone(uncommon, except for NLPHL)

Involved regions: 30-36 Gy (the dose of 30 Gy is mainly used for NLPHL).1.5-2.0 Gy per fraction

Uninvolved regions: 25-30 Gy; 1.5-2.0 Gy per fraction. ISRT fields for NLPHL generally include adjacent but clinically uninvolved nodes when treated with RT alone.

● Palliative RT: 4-30 Gy

ISRT: Volumes

●ISRT principles should be followed when designing RT fields for HL12

▶Planning for ISRT requires modern CT-based simulation and treatment planning capabilities.

▶Incorporating other modern imaging such as FDG-PET and MRI often enhances treatment volume determination.13

●ISRT in the setting of CMT targets the site of the originally involved lymph node(s).

The clinical target volume (CTV) encompasses the original or suspected extent of disease prior to chemotherapy or surgery. This volume is then modified to account for tumor shrinkage and spares adjacent uninvolved organs(eg, lungs, bone, muscle, kidney) when lymphadenopathy regresses following chemotherapy.

●For CHL, the pre-chemotherapy or pre-biopsy gross tumor volume(GTV)provides the basis for determining the CTV.

● Concerns for questionable subclinical disease and uncertainties in original imaging accuracy or localization may lead to expansion of the CTV and are determined individually using clinical judgment.

●For NLPHL, the CTV will depend on whether treatment consists of ISRT alone or CMT.

CMT: Similar to CHL after chemotherapy [encompass originally involved lymph node(s) only]

●Possible movement of the target by respiration as determined by 4D-CT or fluoroscopy(internal target volume[ITV]) should also influence the final CTV.

●The planning target volume(PTV) is an additional expansion of the CTV that accounts only for setup variations and may differ by site and immobilization technique.

▶See ICRU definitions 14

●OARs should be outlined for optimizing treatment plan decisions.

●The treatment plan can be designed using 3-D conformal, proton therapy, or IMRT/VMAT techniques using clinical treatment planning considerations of coverage and normal tissue avoidance.

●The treatment of extranodal disease is individualized, but similar principles of GTV/CTV/PTV definition should be applied as for nodal disease.

Chest wall extension- Effort should be made to include regions of initial chest wall extension in the CTV.

●Lung involvement-Arcs of extension into the lung from mediastinal or hilar disease may be treated with lower doses (~15 Gy) unless the relative volume is small, in which case higher doses may be utilized.Careful consideration of partial lung tolerance is essential. Pulmonary nodular disease is usually not treated following chemotherapy unless residual disease is present.

●Pleural or pericardial effusions are not included in the GTV. Nodular pericardial involvement may be included with consideration of cardiac tolerance.

Bone-Areas of osseous disease may be treated with a CTV expansion beyond the GTV defined by imaging. In vertebral body disease, the entire vertebra is generally treated.

a A dose of 20 Gy following ABVD x 2 is sufficient if the patient has non-bulky stage I-IIA disease with an ESR<50 mm/hr, no extralymphatic lesions, and only 1 or 2 lymph node regions involved. See HODG-3 for definition of nodal sites according to GHSG.

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NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF RADIATION THERAPY

RT DOSE CONSTRAINT GUIDELINES FOR LYMPHOMAb

|OAR|OAR|Dose Recommendation (1.5-2 Gyfraction)|Toxicity| |---|---|---|---| |Head and Neck|Pituitary gland|Mean<30 Gy|Hormone deficiencies15| |Head and Neck|Optic nerves and chiasm|Dmax<45 Gyrd|Optic neuropathy16| |Head and Neck|Retina|Dmax<35 Gyrd|Retinopathy16| |Head and Neck|Lacrimal glands||Dry eye syndrome17| |Head and Neck|Parotid glandsc|Ipsilateral:Mean<11 Gy(recommended);<24 Gy (acceptable) Contralateral: as low as reasonably achievable (ALARA)|Xerostomia18,19| |Head and Neck|Submandibular glandsc|Ipsilateral:Mean<11 Gy(recommended);<24 Gy (acceptable) Contralateral: ALARA|Xerostomia20| |Head and Neck|Oral cavity (surrogate for minor salivary glands)|Mean<11 Gy|Xerostomia, dysgeusia, oral mucositis20| |Head and Neck|Thyroid|V25 Gy<63.5% Minimize V30 Gy|Hypothyroidism21| |Head and Neck|Larynx/Pharyngeal constrictors|Mean<25 Gy|Laryngeal edema, dysphagia22| |Head and Neck|Carotids|Ipsilateral: Avoid hotspots Contralateral: ALARA|Carotid artery atherosclerosis|

b General Principles of RT Dose Constraints, see HODG-C(7 of 16).

cIn many situations with low-dose consolidation RT, prioritizing avoidance of the salivary glands with IMRT can result in even lower doses than what are listed.

d For NK/T-cell lymphoma, nasal type, and other high-grade lymphomas in the periodorbital region, a Dmax of 50 Gy may be required to allow adequate target coverage.

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NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥ 18 years)

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF RADIATION THERAPY

RT DOSE CONSTRAINT GUIDELINES FOR LYMPHOMab

|OAR|OAR|Dose Recommendation (1.5-2 Gy/fraction)|Toxicity| |---|---|---|---| ||The most important cardiac constraints are mean heart dose and dose to the left anterior descending artery and left ventricle||| |Thorax|Hearte|Mean <8 Gy (recommended) Mean <15 Gy (acceptable); ALARA given increased risk with even lower doses|Major adverse cardiac events23-26| |Thorax|Left ventricle|Mean <8 Gy (recommended) Mean <15 Gy (acceptable)|Heart failure24, 27 Coronary artery disease28| |Thorax|Left anterior descending (LAD) artery|V15 Gy <10%e|Major adverse cardiac events29, 30| |Thorax|Limiting dose to the following cardiac substructures is also recommended||| |Thorax|Aortic and mitral valves|Dmax <25 Gy|Valvular heart disease24, 31, 32| |Thorax|Pulmonic valve|Dmax <30 Gy|Valvular heart disease24, 31, 32| |Thorax|Tricuspid valve|Mean <5 Gy (recommended); Dmax <30 Gy|Valvular heart disease28| |Thorax|Right ventricle|Mean <5 Gy (Nonimize the maximum dose to individual coronary arteries|Valvular heart disease28| |Thorax|Left circumflex artery|V15 Gy <14%|Major adverse cardiac events| |Thorax|Right coronary artery|Mean <5 Gy|Coronary artery disease28| |Thorax|Lungs|Mean <13.5 Gy V20 <20%(recommended); <30 Gy (acceptable)|Pneumonitis33- 35| |Thorax|||| |Thorax||||

b General Principles of RT Dose Constraints, see HODG-C(7 of 16).

e Mean heart dose may not be the most important DVH metric to reduce late cardiac complications. ${}^{36}$ As cardiac toxicity is related to dose to specific substructures, it is recommended that these are contoured, constraints are applied, and doses are recorded. Contouring atlases are available. ${ }^{37,38}$ It is recognized that contouring the coronary arteries is challenging given anatomical variations and lung/heart motion. This may warrant designing a planning OAR volume in some patients. Further, it is important to preferentially spare high-dose overlap with the proximal coronary arteries(left main, proximal LAD). For example, a plan may achieve an LAD V15 Gy and 10%, but it is not ideal if most of the 15 Gy or higher dose overlap is surrounding the proximal LAD while the distal LAD is spared to meet the volumetric dose goal. Reviewing both dose to the entire coronary tree and the individual components, particularly the proximal vessels, is important.

References

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

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|OAR|OAR|Dose Recommendation (1.5-2 Gy fraction)|Toxicity|| |---|---|---|---|---| |Abdomen|Liver|Mean <15 Gy V20 <30% V30 <20%|Hepatic toxicity39.40|| |Abdomen|Liver|Dmax <45 Gy|Dmax <45 Gy|Ulceration41| |Abdomen|Spleen|Mean <10 Gy V5 ≤30% V15 ≤20%|Late infections42 Lymphopenia43|| |Abdomen|Pancreas|Mean <21 Gy|Mean <21 Gy|Diabetes44-47| |Abdomen|Small bowel|V15 <120 cc Dmax <45 Gy|Diarrhea37 Obstruction,ulceration,fistula37|| |Abdomen|Kidney|Single organ Mean <5 Gy (recommended);<8 Gy (acceptable); (available) V10 <103% (recommended);<15% (recommended);<25% (acceptable)|Renal ins /58 %|| |Abdomen|Pelvis/ Other|Ovaries|Mean <2 Gy (recommended);<10 Gy (acceptable); <10 Gy (acceptable)|Acute ovarian failure51, 52| |Testes|Pelvis/ Other|Mean <2 Gy (recommended);<12 Gy (acceptable)|Azoospermia53|| |Bone marrow f|Pelvis/ Other|V5: ALARA V10 <50% V25 <25%|Acute cytopenias 54, 55 Chronic cytopenias 56|| |Long bone|Pelvis/ Other|V40 <64%|V40 <64%|Fracture57|

b General Principles of RT Dose Constraints, see HODG-C(7 of 16).

f Active bone marrow can be delineated using various imaging modalities and is most abundant in the pelvic bones, thoracic-lumbar spine, and sacrum.

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

References

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SECONDARY MALIGNANCIES9

|OAR|Dose Recommendation (1.8-2 Gy/fraction)|Secondary Malignancy| |---|---|---| |Breast|Minimize volume >4 Gy (ideally <10%)|Breast cancer (adenocarcinoma $)^{61}$| |Colon|Minimize volume >10 Gy|Colon cancer $62| |Lung|Minimize volume >5 Gy|Lung cancer $63| |Esophagus|Minimize volume >30 Gy|Esophageal cancer $64| |Stomach|Minimize volume >25 Gy|Gastric cancer $65| |Pancreas|Minimize volume >5 Gy|Pancreatic cancer $66|

b General Principles of RT Dose Constraints, see HODG-C(7 of 16).

9 The linear no-threshold model supports limiting RT dose to susceptible organs as low as reasonably achievable. The following dose guidelines, based on published data, may further guide treatment decisions.

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

References

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PRINCIPLES OF RADIATION THERAPY

RT DOSE CONSTRAINT GUIDELINES FOR LYMPHOMA

General Principles of RT Dose Constraints

• Patients with hematologic malignancies typically receive far lower doses than patients with epithelial or mesenchymal malignancies and generally

have more favorable long-term outcomes. Therefore, more stringent dose constraints, often proportionally reduced from acceptable thresholds in other malignancies, are recommended. Doses to OARs should follow principles of ALARA. In some scenarios, target coverage may require dose constraints

to be exceeded if the OAR is within, or adjacent to, the PTV. For example, it may be difficult to meet thyroid constraints in the setting of bilateral

supraclavicular lymphadenopathy.

• A relatively rare but serious complication of RT is induction of secondary malignancies. Most studies have shown that increasing dose is associated with increasing risk without a safe threshold dose (linear no-threshold model).67 Therefore, limiting radiation dose to susceptible organs as much as possible is vital. Disease- and patient-related factors are also contributory (eg, age, tobacco exposure).

• In addition to secondary malignancies, cardiac and pulmonary complications after RT are most concerning and are reviewed further in the following

sections.

Thyroid

• The thyroid gland, in close proximity to the cervical lymph node chains and the mediastinum, is commonly affected by RT in patients with lymphomas.

Functionally, hypothyroidism predominates and develops in up to 40% of long-term lymphoma survivors.68

• The risk of developing hypothyroidism persists long after treatment has concluded and lifetime screening is required.69 Both clinical and dosimetric

factors are associated with an increased risk. White individuals, females, and those with a prior history of thyroid surgery seem to be at increased risk of hypothyroidism after RT.70 Dosimetrically, a variety of different metrics have been associated with a higher risk, all of which are closely related

(V25 >63.5%,21 mean dose >28 Gy,71 V30 >62.5%72).

• As with other epithelial cancers, the risk of developing a secondary thyroid cancer is approximately linear (higher exposures lead to higher risks).

However, with doses above 20–30 Gy, the risk may begin to decline, presumably from cell death within the gland reducing the risk of malignant

degeneration.67 In addition to dose, younger age at exposure is another established risk factor.73 Papillary thyroid cancers predominate and behave

similarly to sporadic thyroid carcinomas.

• Thyroid nodules are common in the general population and also among lymphoma survivors.68 Given the ubiquitous nature of thyroid nodules, most

screening guidelines recommend obtaining an ultrasound only if a thyroid nodule is palpable on physical exam.

Heart

• Multiple cardiac complications can develop from mediastinal RT, including pericarditis, arrhythmias, coronary artery disease (CAD), valvular

heart disease (VHD), and cardiomyopathy/congestive heart failure.26,74 In addition to RT factors, the risk of cardiac events is also influenced by

chemotherapy administration (eg, doxorubicin), pre-existing cardiovascular disease, age, and other cardiac risk factors (eg, diabetes, hypertension,hyperlipidemia).26,36,75,76 While global heart metrics such as mean heart dose are most commonly used to assess risk, there is an increasing

recognition that radiation dose-fractionation to cardiac substructures must be accounted for. Atlases for radiation oncologists to assist with contouring cardiac substructures are available.37,38,77

Abstract

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

• Because of the long-term survival of thousands of patients with breast cancer and HL, many large cohort studies have been able to explore the relationship of heart RT dose with cardiac toxicity and death. Mediastinal RT for lymphomas, relative to breast cancer and other thoracic malignancies, is characterized by radiation exposures to larger volumes of the heart and substructures, albeit to lower doses (20-40 Gy). Common for both breast and lymphoma RT, there is typically a latency of > 20 years for secondary cardiac disease. 26,78-80 • As mentioned previously, most studies have associated cardiac events with either prescribed mediastinal radiation dose or mean heart dose. In both the breast cancer and lymphoma radiotherapy literature, mean heart dose has been related to the risk of cardiac events despite the variable volume of whole heart exposed in these two diseases. 9] [80] As such, radiation treatment planning should aim to decrease exposure to cardiac structures following ALARA principles. One of the best data sets relating radiation dose to cardiac disease risk in adult patients is an HL case-control study from the Netherlands. 26 Patients were treated prior to 1996 mainly using anteroposterior (AP)/PA fields. Using the metric of mean heart dose as a measure of cardiac toxicity risk, Van Nimwegen et al demonstrated an excess relative risk of 7.4% per Gy mean heart dose.

A statistically significant increased risk of coronary heart disease was demonstrated among patients getting a mean heart dose as low as 5-14 Gy (relative risk [RR], 2.31) compared with a mean heart dose of 0 Gy. This risk was even higher for a mean heart dose of 15 Gy or higher (RR, 2.83 for 15-19 Gy; RR, 2.9 for 20-24 Gy; and RR, 3.35 for 25-34 Gy). This study also explored different age-of-diagnosis cohorts and generally showed the same radiation dose-response relationships. • The number of studies evaluating specific dose constraints for cardiac substructures is rather limited. Dutch investigators demonstrated a relationship between heart failure and mean dose to the left ventricle. 27 Chemotherapy was a clear confounder in regards to the risk of heart failure. Among patients treated with anthracyclines, the 25-year cumulative risk of heart failure was 11.2% for mean left ventricle dose < 15 Gy, 15.9% for 16-20 Gy, and 32.9% for ≥21 Gy. • In regards to VHD, increasing mediastinal radiation dose, especially > 30 Gy, has been associated with an elevated risk of valvular dysfunction. 26, 79 sing a large Dutch cohort of adult patients treated with radiation to the mediastinum, Cutter et al demonstrated 30-year cumulative risks of VHD of 3%, 6.4%, 9.3%, and 12.4% for mean valvular doses of < 30, [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] and > 40 Gy. 31 VHD was related to aortic valve abnormalities in 71% of patients. Mitral valvular abnormalities, which can also be related to ischemic heart disease due to papillary muscle dysfunction after myocardial infarction, occurred in 50% of patients (some patients had multiple dysfunctional valves). Tricuspid valvular disease was uncommon and pulmonic valve dysfunction was not reported-perhaps due to right heart dysfunction tending to be less clinically problematic. Th re was no confounding effect of anthracycline chemotherapy on VHD risk in this study. In agreement with this Dutch study, the previously mentioned German-Austrian pediatric cohort showed that prescribed mediastinal radiation dose was the only independent risk factor for VHD. 32 No cases of VHD were observed for individuals with doses of 20 Gy, while the 25-year cumulative risks among individuals with prescribed doses of 25 Gy, 30 Gy, and 36 Gy were 2%, 1%, and 16%, respectively.

References

Abstract

Note: All recommendations are category 2A unless otherwise indicated. NCCN Guidelines Version 1.2026 Hodgkin Lymphoma (Age ≥18 years) NCCN Guidelines Index

Abstract

Table of Contents Discussion HODG-C 9 OF 16 References PRINCIPLES OF RADIATION THERAPY RT DOSE CONSTRAINT GUIDELINES FOR LYMPHOMA Heart (continued) • Radiation dose constraints for coronary arteries is a work in progress. Standard CT-simulation imaging, even with contrast, does not identify the entire coronary tree very well. There are resolution issues, acquisition time issues, and cardiac motion issues. Coronary anatomy is variable along with some individual variation with collateral blood flow. Proximal coronary arteries and the mid-trunk of the LAD are often visible, since the latter is located in the epicardial fat of the left anterolateral aspect of the global heart structure, apparently with minimal motion artifact. Even with research techniques to merge coronary CT angiograms, 81,82 the important branch vessels (diagonals off the LAD; obtuse marginals off the left circumflex (LCx), posterior descending branch of the right coronary artery (RCA) are not well demonstrated. Nevertheless, there have been studies in breast and lymphoma radiotherapeutic management to contour the major coronary arteries and try to relate coronary dosimetry to risk of CAD. Moignier et al analyzed 33 irradiated patients with HL-21 without coronary stenosis (controls) and 12 patients with critical coronary stenosis (cases) seen on CT angiography. 82

Abstract

Radiation dose to stenotic coronary segments and normal coronary segments was compared using a logistic regression. In this manner, the risk of stenosis was found to be increased by 4.9% per Gy over the median dose to the control segments. This data set is too small to be a basis of radiation dose constraints, but does support the general notion of a dose-response effect in the clinical range of lymphoma radiation prescriptions. • From the historical use of extended-field radiotherapy for HL, whole heart irradiation increases the risk of constrictive pericarditis, especially with doses > 15 Gy. 83 Modern radiotherapy for lymphomas rarely requires whole heart irradiation. • Patients who survived childhood cancers represent a unique high-risk group. In a French cohort study of pediatric survivors with HL, the relative risk of severe cardiac disease at age 40 years is 1.9 at a cardiac radiation dose of 1-5 Gy and increases to 19.5-75.2 at a dose > 15 Gy for survivors of childhood cancer. 23 There are at least two other notable pediatric survivorship study cohorts that provide insights to radiation dose relationship with subsequent cardiovascular disease. Schellong et al reported on 1132 survivors of HL treated on the German-Austrian pediatric cooperative group studies from 1978-1995. 32 Patients could be binned into mediastinal radiation dose exposures of 36 Gy, 30 Gy, 25 Gy, 20 Gy, and 0 Gy. Cardiac valvular defects were the most frequent late cardiac disease, followed by CAD, cardiomyopathy, conduction disorders, and pericardial abnormalities.

Abstract

The cumulative incidence of cardiac disease after 25 years correlated with radiation dose with incidence of 21% for 36 Gy, decreasing to 10%, 6%, 5%, and 3% for the lower dose groups, respectively (P < .001). Multivariate analysis of several putative risk factors showed that mediastinal radiation dose was the only significant variable predicting for cardiac disease-free survival (P = .0025). Mulrooney et al published the Childhood Cancer Survivor Study (CCSS) analysis of cardiovascular disease risk in pediatric cancer survivors (not just HL) and analyzed the confounding and independent effects of anthracycline and mediastinal radiation prescribed dose showing a dose-response effect for both chemotherapy and radiotherapy. 24 In this study of 14,358 patients, doses between 15 Gy and 35 Gy were not well distinguished, but there was a suggestion that 15 Gy might be a threshold dose associated with not only future VHD but also congestive heart failure and myocardial infarction. Bates et al recently updated the CCSS experience in a 2019 publication of 24,214 5-year survivors, providing further insights into the relationships between radiation and risk of long-term cardiac disease. 25 Mean heart doses > 10 Gy were associated with increasing cardiac disease risk in a dose-response manner. Volumes of the heart receiving radiation also were correlated with cardiac risk. Children receiving a heart V5 of > 50% had a 1.6-fold increased risk of late cardiac disease. Those receiving at least 20 Gy to any part of the heart also were at increased risk. A follow up study using the CCSS database demonstrated mean doses of 5-9.9 Gy to the right coronary artery (rate ratio, 2.6) and left ventricle (rate ratio, 2.2) increased risk of coronary artery disease and mean doses of 5-9.9 Gy to the tricuspid valve (RR, 5.5) and right ventricle (RR, 8.4) increased risk of valvular disease. 84

References

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Heart (continued)

• While the data regarding cardiac constraints for modern RT of lymphomas are imperfect, we recommend that the mean heart dose be kept as low as

possible, ideally <8 Gy, although in some patients a higher dose will be necessary given lymphoma extent. Conversely, treatment plans for patients

with superior mediastinal disease should achieve doses far less than 8 Gy. This also recognizes that patients with lymphoma tend to also receive

anthracycline chemotherapy, although cumulative chemotherapy doses in modern practice tend to be lower than historical cohorts. Rarely should mean heart dose exceed 15 Gy, unless patients are being treated in the second-line setting with curative intent where larger RT doses are necessary.23

Ideally, mean left ventricular dose should be kept lower than 8 Gy, although up to 15 Gy may be necessary in some circumstances. Aortic and mitral

valve doses should be kept below 25 Gy, and ideally even lower. Tricuspid and pulmonic valves may be less critical OAR and it is recommended that

doses be kept below 30 Gy. Constraints to coronary arteries are less well defined but should be as low as possible in terms of dose and volume/length.

Lungs

• The primary pulmonary toxicity related to mediastinal RT is radiation pneumonitis. Other complications, such as symptomatic fibrosis or bronchial

stenosis, are rarely encountered given the lower doses used for lymphoma management. Radiation pneumonitis is a clinical diagnosis consisting of dry cough, dyspnea, and occasionally low-grade fevers. Radiation pneumonitis must be distinguished from other entities such as infectious pneumonia,

acute bronchitis, and pulmonary embolism. Pulmonary complications, including pneumonitis, can arise from systemic modalities also, including

bleomycin and immunotherapy. Bleomycin pulmonary toxicity does not preclude consolidation thoracic radiation therapy.85

• The most important risk factor for radiation pneumonitis is lung dose–volume metrics including mean lung dose (MLD), V20, and V5. Such metrics have been associated with pneumonitis risk in both epithelial86 and hematologic malignancies.33,35 For epithelial malignancies, such as non-small cell lung cancer, guidelines generally recommend MLD <20 Gy and V20 <35%. In most circumstances, given the lower doses used in lymphoma management,much lower doses are generally achievable with careful planning.

• The Panel recommends limiting MLD <13.5 Gy and V20 <20%, though higher incidental dose to the lungs may occasionally be necessary. Rarely

should the lung V20 exceed 30%. More pertinent to IMRT or volumetric arc techniques, we recommend limiting the V5 <55%. DIBH can help meet MLD and V5 recommendations.87 Adherence to pulmonary constraints is particularly important in patients who have been heavily pre-treated, particularly

those who have received regimens with known lung toxicity.

• RT, and possibly some chemotherapy drugs such as alkylating agents,63 increase the risk of developing lung cancer.63,88 The risk increases linearly

with dose to the lung.58 The increased risk is most apparent in people who smoke, particularly those who continue to use tobacco after diagnosis.89 In fact, continuing to smoke after thoracic RT multiplies the risk of developing lung cancer. Therefore, a concerted effort should be made to help patients who currently smoke and require thoracic RT to stop smoking. Lung cancer screening with low-dose CT may also be appropriate depending upon

clinical circumstances including age, pack-year tobacco exposure history, and interval since quitting. See NCCN Guidelines for Lung Cancer Screening.

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Pancreas

• Diabetes mellitus (DM) can develop after RT due to parenchymal structural damage of the pancreas. A dose of ≥10 Gy has been shown in a pediatric study to increase the risk of latent DM.45 A retrospective study of adults treated for gastric lymphoma showed that a median dose of ≥21 Gy was

associated with an increased risk of DM.46 The 5-year cumulative incidence was 9.6% compared to 1.6% for those who did not receive RT. It also

demonstrated that a mean dose <21 Gy could be better achieved with IMRT compared with 3D-CRT. Recent data has shown that proton therapy can further reduce the dose compared to both 3D-CRT and IMRT.47

Breasts

• RT doses prescribed for thoracic lymphomas are significantly lower than doses utilized for epithelial breast cancer. As such, breast tissue exposure

resulting from lymphoma RT falls well within acceptable dose constraints for breast tissue toxicity and cosmesis.

• Breast tissue radiation exposure results in an increased lifetime risk for secondary malignancies. A minimum latency period of 8 years is considered

necessary before radiation induced cancers develop. After this latency period, routine breast exams 1–2 times per year are indicated. Individuals

assigned female at birthh previously treated with thoracic RT between ages 10 and 30 should begin annual screening mammography and MRI (typically alternating every 6 months) 8 years after undergoing treatment (but not before age 25) or by age 40, whichever comes first. See NCCN Guidelines for Breast Cancer Screening and Diagnosis (BSCR-3).

• Chemoprevention with selective estrogen receptor modulators and aromatase inhibitors have been demonstrated to reduce the risk of breast cancer

by 50%–60% in high-risk populations. These trials, however, did not include individuals who received prior breast radiation for non-epithelial breast

cancers. Patients should consider discussion of chemoprevention with their oncologist or breast specialist. See NCCN Guidelines for Breast Cancer

Risk Reduction.

Kidneys

• The kidneys are one of the most radiation-sensitive organs in the abdomen, necessitating careful planning to reduce the risk of long-term chronic renal

insufficiency after treatment. In a study of 40 patients with gastric/duodenal mucosal-associated lymphoid tissue (MALT) lymphoma treated with 3-D

conformal RT (median dose of 28 Gy), low-dose RT to both kidneys was most strongly associated with grade 2 or higher chronic kidney disease

(V5 ≥58%50). The 5-year cumulative incidence rate of grade 2 or higher chronic kidney disease was 15% and the median onset was 4.6 years. Half of the patients developed chronic kidney disease beyond 5 years after RT completion, which highlights the importance of longer follow-up.

• Another study included 38 patients with primary gastric diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy followed by 40 Gy of RT

to the whole stomach and perigastric lymph nodes.49 V20 Gy ≥27% and a D30% (minimum dose covering 30% of the kidney volume) ≥19 Gy were

associated with reduction of creatinine clearance and renal atrophy.

• Taken together, these data support the consideration of more restrictive dose constraints/goals to the kidneys during RT planning for lymphoma in the abdomen. The dose constraints used for gastrointestinal adenocarcinomas may not be applicable when the total RT dose is much higher and prognosis(eg, patients with pancreas cancer) affects the ability to fully capture late kidney toxicity. Dose constraints/goals in planning should include minimizing the low and intermediate doses (V5 Gy, V10 Gy) to the kidneys in addition to the commonly used constraints of V20 Gy and mean kidney dose.

h There is limited data on screening in individuals with increased risk AMAB.

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Ovaries

• Acute ovarian failure, defined as loss of function ≤5 years from diagnosis, and premature ovarian insufficiency (POI), are both associated with the mean radiation dose to the least affected ovary, chemotherapy doses, and age of the patient at treatment. There are strong data to suggest that AYAs are

at higher risk with lower doses of RT. The risk of acute ovarian failure also increases with alkylating agent cumulative dose and HCT. 2 Gy to the least affected ovary resulted in a risk of acute ovarian failure of 1% to 5% and increases with alkylator exposure. Acute ovarian failure risk is predicted to be≥50% with 20 Gy to the least affected ovary in a 20-year-old patient and 13 Gy with higher alkylator doses. Similarly, a 20-year-old patient would have a 12% risk of POI with <10 Gy to the least affected ovary without alkylating chemotherapy and a 41% risk with alkylating chemotherapy while a 40-yearold patient demonstrates higher risk in both scenarios: 50% without alkylating chemotherapy and 94% with alkylating chemotherapy.51,52

Testicles

• Even scatter radiation doses as low as 0.2–2 Gy may cause temporary azoospermia that typically recovers within 2 years. Similarly, scatter radiation doses >0.2 to 0.8 Gy and >0.5 Gy can cause follicle-stimulating hormone (FSH) and luteinizing hormone (LH) elevations, respectively, with not all

patients returning to baseline level at 2 years. In contrast, direct radiation to the testicles is associated with significant Leydig cell dysfunction at

even low doses of radiation. Testosterone levels can be abnormal after >0.2 Gy with doses >12 Gy associated with abnormal testosterone in 40% of patients.53

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26 Van Nimwegen FA, Schaapveld M, Cutter DJ, et al. Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol 2016;34:235-243.

27 Van Nimwegen FA, Nentas G, Darby SC, et al. Risk of heart failure in survivors of Hodgkin lymphoma: Effects of cardiac exposure to radiation and anthracyclines. Blood 2017;129:2257-2265.

28 Bates JE, Shrestha S, Liu Q, et al. Cardiac substructure radiation dose and risk of late cardiac disease in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.J Clin Oncol 2023;41:3826-3838.

29 Atkins KM, Chaunzwa TL, Lamba N, et al. Association of left anterior descending coronary artery radiation dose with major adverse cardiac events and mortality in patients with non-small cell lung cancer. JAMA Oncol 2021;7:206-219.

30McKenzie E,Zhang S,Zakaraee R,et al. Left anterior descending coronary artery radiation dose association with all-cause mortality in NRG oncology trial RTOG 0617. Int J Radiat Oncol Biol Phys 2023;115:1138-1143.

31Cutter DJ, Schaapveld M, Darby SC, et al. Risk for valvular heart disease after treatment for hodgkin lymphoma. J Natl Cancer Inst 2015;107:djv008.

32 Schollong G, Repenhausen M, Bruch C, et al. Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for hodgkin disease in children and adolescents: Report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD studies. Pediatr Blood Cancer 2010;55:1145-1152.

33nPinn CC,Smith GL,Milgrom S,et al. Predictors of radiation pneumonitis in patients receiving intensity modulated radiation therapy for Hodgkin and non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2015;92:175-182.

34 Fox AM, Dosoretz AP, Mauch PM,et al. Predictive factors for radiation pneumonitis in Hodgkin lymphoma patients receiving combined-modality therapy.Int J Radiat Oncol Biol Phys 2012;83:277-283.

35 Tseng YD, Hoppe BS, Dedeckova K, et al. Risk of pneumonitis and outcomes after mediastinal proton therapy for relapsed/refractory lymphoma: A PTCOG and PCG collaboration. Int J Radiat Oncol Biol Phys 2021;109:220-230.

36 Hoppe BS, Bates JE, Mendenhall NP, et al. The meaningless meaning of mean heart dose in mediastinal lymphoma in the modern radiotherapy era. Pract Radiat Oncol 2020;10:e147-e154.

37Milo MLH,Offersen BV, Bechmann T,et al. Delineation of whole heart and substructures in thoracic radiation therapy: National guidelines and contouring atlas by the Danish Multidisciplinary Cancer Groups. Radiother Oncol 2020;150:121-127.

38 Duane F, Aznar MC, Bartlett F, et al. A cardiac contouring atlas for radiotherapy. Radiother Oncol 2017;122:416-422.

39 Kim TH, Kim DY, Park JW,et al. Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 2007;67:225-231.

40 Cheng JC, Wu JK, Lee PC, et al. Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease.Int J Radiat Oncol Biol Phys 2004;60:1502-1509.

41 Kavanagh BD, Pan CC, Dawson LA, et al. Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys 2010;76:S101-107.

42 Weil BR, Madenc AL, Liu Q, et al. Late infection-related mortality in asplenic survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.J Clin Oncol 2018;36:1571-1578.

43 Chadha AS, Liu G, Chen HC, et al. Does unintentional splenic radiation predict outcomes after pancreatic cancer radiation therapy? Int J Radiat Oncol Biol Phys 2017;97:323-332.

44 van Nimwegen FA, Schaapveld M, Janus CP, et al. Risk of diabetes mellitus in long-term survivors of Hodgkin lymphoma. J Clin Oncol 2014;32:3257-3263.

45Lee J,Yoon HI, Kim J,et al. Risk of diabetes mellitus after radiotherapy for gastric mucosa-associated lymphoid tissue lymphoma. Cancers(Basel)2022;14:4110.

46 de Vathaire F,El-Fayech C,Ben Ayed FF,et al.Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol 2012;13:1002-1010.

47 Sachsman S, Hoppe BS, Mendenhall NP, et al. Proton therapy to the subdiaphragmatic region in the management of patients with Hodgkin lymphoma. Leuk Lymphoma 2015;56:2019-2024.

48 May KS,Khushalani NI,Chandrasekhar R,et al.Analysis of clinical and dosimetric factors associated with change in renal function in patients with gastrointestinal malignancies after chemoradiation to the abdomen. Int J Radiat Oncol Biol Phys 2010;76:1193-1198.

49 Inaba K, Okamoto H, Wakita A, et al. Long-term observations of radiation-induced creatinine clearance reduction and renal parenchymal volume atrophy.Radiother Oncol 2016;120:145-149.

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PRINCIPLES OF RADIATION THERAPY REFERENCES

50 Katsuta T, Matsuura K, Kashiwado K. Analysis of chronic kidney disease after radiation therapy for gastric/duodenal mucosa-associated lymphoid tissue lymphoma. Adv Radiat Oncol 2021;6:100788.

51 Milano MT, Marks LB, Olch AJ,et al. Comparison of risks of late effects from radiation therapy in children versus adults: Insights from the QUANTEC, HyTEC,and PENTEC efforts. Int J Radiat Oncol Biol Phys 2024;119:387-400.

52 Hill-Kayer C, Yorke E, Jackson A, et al. Effects of radiation therapy on the female reproductive tract in childhood cancer survivors: A PENTEC comprehensive review. Int J Radiat Oncol Biol Phys 2024;119:588-609.

53 Baliga S, Patel S, Naqa IE, et al. Testicular dysfunction in male childhood cancer survivors treated with radiation therapy: A PENTEC comprehensive review. Int J Radiat Oncol Biol Phys 2024;119:610-624.

54 Mell LK, Kochanski JD, Roeske JC, et al. Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy. Int J Radiat Oncol Biol Phys 2006;66:1356-1365.

55 Mell LK, Schomas DA, Salama JK, et al. Association between bone marrow dosimetric parameters and acute hematologic toxicity in anal cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2008;70:1431-1437.

56 McGuire SM, Bhatia SK, Sun W, et al. Using[(18)F]fluorothyidine imaged with positron emission tomography to quantify and reduce hematologic toxicity due to chemoradiation therapy for pelvic cancer patients. Int J Radiat Oncol Biol Phys 2016;96:228-239.

57 Dickie CI, Parent AL, Griffin AM,et al. Bone fractures following external beam radiotherapy and limb-preservation surgery for lower extremity soft tissue sarcoma:relationship to irradiated bone length,volume,tumor location and dose.Int J Radiat Oncol Biol Phys 2009;75:1119-1124.

58 Hayman JA, Callahan JW, Herschtal A, et al. Distribution of proliferating bone marrow in adult cancer patients determined using FLT-PET imaging. Int J Radiat Oncol Biol Phys 2011;79:847-852.

59 Liang Y, Bydder M, Yashar CM, et al. Prospective study of functional bone marrow-sparing intensity modulated radiation therapy with concurrent chemotherapy for pelvic malignancies. Int J Radiat Oncol Biol Phys 2013;85:406-414.

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

60 Basu S, Houseni M, Bural G,et al. Magnetic resonance imaging based bone marrow segmentation for quantitative calculation of pure red marrow metabolism using 2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography: A novel application with significant implications for combined structure-function approach. Mol Imaging Biol 2007;9:361-365.

61 Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 2003;290:465-475.

62 Geurts YM, Shakir R, Nentas G, et al. Association of radiation and procarbazine dose with risk of colorectal cancer among survivors of Hodgkin lymphoma. JAMA Oncol 2023;9:481-489.

63 Travis LB, Gosporarowicz M, Curtis RE,et al. Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J Natl Cancer Inst 2002;94:182-192.

64 Morton LM, Gilbert ES, Stovall M, et al.Risk of esophageal cancer following radiotherapy for Hodgkin lymphoma. Haematologica 2014;99:e193-e196.

65 Morton LM, Dores GM, Curtis RE,et al. Stomach cancer risk after treatment for Hodgkin lymphoma. J Clin Oncol 2013;31:3369-3377.

66 Dores GM, Curtis RE, van Leeuwen FE, et al. Pancreatic cancer risk after treatment of Hodgkin lymphoma. Ann Oncol 2014;25:2073-2079.

67 Berrington de Gonzalez A, Gilbert E, Curtis R, et al. Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship. Int J Radiat Oncol Biol Phys 2013;86:224-233.

68 Macklin-Doherty A, Jones M, Coulson P,et al. Risk of thyroid disorders in adult and childhood Hodgkin lymphoma survivors 40 years after treatment.Leuk Lymphoma 2022;63:562-572.

69 Inskip PD, Veiga LHS, Brenner AV,et al. Hypothyroidism after radiation therapy for childhood cancer: A report from the Childhood Cancer Survivor Study.Radiat Res 2018;190:117-132.

70 Vogelius IR, Bentzen SM, Maraldo MV,et al.Risk factors for radiation-induced hypothyroidism: a literature-based meta-analysis. Cancer 2011;117:5250-5260.

71Pravesh K, Sethi P, Kamalanathan SK, Manavalan M. An analytical study to determine dose-volume threshold for radiation induced hypothyroidism. Asian Pac J Cancer Prev 2023;24:3859-3866.

72 Cella L,Conson M, Caterino M, et al. Thyroid V30 predicts radiation-induced hypothyroidism in patients treated with sequential chemo-radiotherapy for Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys 2012;82:1802-1808.

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PRINCIPLES OF RADIATION THERAPY REFERENCES

73 Iglesias ML, Schmidt A, Ghuzlan AA,et al. Radiation exposure and thyroid cancer: a review. Arch Endocrinol Metab 2017;61:180-187.

85 Abou Yehia Z, Mikhaeel GN, Smith G, et al. Does bleomycin lung toxicity increase the risk of radiation pneumonitis in Hodgkin lymphoma? Int J Radiat Oncol Biol Phys 2016;96:951-958.

74 Wright JL, Yom S, Awan MJ, et al. Standardizing normal tissue contouring for radiation therapy treatment planning: An ASTRO consensus paper. Pract Radiat Oncol 2019;9:65-72.

86 Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys 2010;76:S70-S76.

75 Zamorano JL, Lancellotti P, Rodriguez Munoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology(ESC). Eur J Heart Fail 2017;19:9-42.

87 Pinnix CC, Huo J, Milgrom SA, et al. Using benchmarked lung radiation dose constraints to predict pneumonitis risk: Developing a nomogram for patients with mediastinal lymphoma. Adv Radiat Oncol 2018;3:372-381.

88 Schaapveld M, Aleman BM, van Eggermond AM, et al. Second cancer risk up to 40 years after treatment for Hodgkin's lymphoma. N Engl J Med 2015;373:2499-2511.

76 Totzeck M, Schuler M, Stuschke M, et al. Cardio-oncology- strategies for management of cancer-therapy related cardiovascular disease. Int J Cardiol 2019;280:163-175.

77 Kirli M, Akçay D, Baris MM, et al. A heart atlas for breast radiation therapy and the influence of delination education on both intra and interobserver variability. Jpn J Radiol 2019;37:420-430.

89 van Leeuwen FE, Klokan WJ, Stovall M, et al. Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 1995;87:1530-1537.

78 Darby Sc, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013;368:987-998.

79 Taylor C, Duane FK, Dodwell D, et al. Estimating the risks of breast cancer radiotherapy: Evidence from modern radiation doses to the lungs and heart and from previous randomized trials. J Clin Oncol 2017;35:1641-1649.

80 Maraldo MV, Giusti F, Vogelius IR, et al. Cardiovascular disease after treatment for Hodgkin's lymphoma: an analysis of nine collaborative EORTC-LYSA trials.Lancet Haematol 2015;2:e492-e502.

81 Milgrom SA, Varghese B, Gladish GW,et al. Coronary artery dose-volume parameters predict risk of calcification after radiation therapy. J Cardiovasc Imaging 2019;27:268-279.

82 Moignier A, Broggio D, Derreumaux S, et al. Coronary stenosis risk analysis following Hodgkin lymphoma radiotherapy: A study based on patient specific artery segments dose calculation. Radiother Oncol 2015;117:467-472.

83 Carmel RJ, Kaplan HS. Mantle irradiation in Hodgkin's disease. An analysis of technique, tumor eradication, and complications. Cancer 1976;37:2813-2825.

84 Bates JE, Shrestha S, Liu Q, et al. Cardiac substructure radiation dose and risk of late cardiac disease in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.J Clin Oncol 2023;41:3826-3838.

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Hodgkin Lymphoma (Age ≥18 years)

NCCN Guidelines Index Table of Contents Discussion

ST-1

Table 1

Definitions of Stages in Hodgkin Lymphoma2

Stage I Involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE).

Stage II Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph node(s), with or without involvement of other lymph node regions on the same side of the diaphragm (IIE).

Note: The number of lymph node regions involved may be indicated by a subscript (eg, II3).

Stage III Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an associated extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or by both (IIIE+S).

Stage IV Disseminated (multifocal) involvement of one or more extralymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement.

A No systemic symptoms present

B Unexplained fevers >38°C; drenching night sweats; or weight loss >10% of body weight (within 6 months prior to diagnosis)

Adapted with permission from the American Association for Cancer Research: Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on Hodgkin's

Disease Staging Classification. Cancer Res 1971;31:1860-1861.

1 For additional information regarding the staging of Hodgkin lymphoma, refer to: Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano Classification. J Clin Oncol

2014;32:3059-3068.

2 FDG-PET scans are useful for upstaging in stage I–II disease. If there is FDG-PET positivity outside of disease already identified, further clinical investigation is recommended to confirm or refute the observation. FDG-PET scans may demonstrate increased avidity in lymphoid tissue unrelated to lymphoma in persons with HIV, particularly if HIV is not well-controlled (ie, acute/subacute HIV infection, advanced

immunosuppression and or viremia) and in the presence of opportunistic infections.

HODGKIN LYMPHOMA STAGING1

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NCCN Guidelines Index Table of Contents Discussion

|4D-CT|four-dimensional computed tomography|EFRT| |---|---|---| |ACGME|Accreditation Council for Graduate Medical Education|ERORT| |ACS|American Cancer Society|ESR| |ALARA|as low as reasonably achievable|FDG| |AMAB|assigned male at birth|FNA| |AP|anteroposterior|FSH| |ASCR|autologous stem cell rescue|G-CSF| |AYA|adolescent and young adult|GHSG| |CAD|coronary artery disease|GTV| |CBC|complete blood count|H&P| |CCSS|Childhood Cancer Survivor Study|HCT| |CHL|classic Hodgkin lymphoma|HDT| |CME|continuing medical education|HIV| |CMT|combined modality therapy|HL| |CPI|checkpoint inhibitors|ICL| |CR|complete response|ICRU| |CTV|clinical target volume|| |CXR|chest radiograph|IGRT| |DIBH|deep-inspiratory breath hold|IMRT| |DLBCL|diffuse large B-cell lymphoma|IPS| |DLCO|diffusing capacity of the lung for|ISRT| |carbon monoxide|TVF|internal target volume| |DM|diabetes mellitus|IVF| |DVH|dose-volume histogram|LAD| |EANM|European Association of Nuclear Medicine|LCx| |EBER-|Epstein-Barr encoding region in situ hybridization|LDH| |ISH|hybridization|LDHL| |EBV|Epstein-Barr virus|LFT| |ECHO|echocardiogram||

|ABBREVIATIONS|ABBREVIATIONS|ABBREVIATIONS|ABBREVIATIONS| |---|---|---|---| |4D-CT|four-dimensional computed tomography|EFRT|extended-field radiation therapy| |ACGME|Accreditation Council for Graduate Medical Education|EORTC|European Organisation for Research and Treatment of Cancer| |ACGME|Accreditation Council for Graduate Medical Education|ESR|erythrocyte sedimentation rate| |ACS|American Cancer Society|FDG|fluorodeoxyglucose| |ACS|American Cancer Society|FPF|freedom from progression| |AMAB|assigned male at birth|FNA|fine-needle aspiration| |AMAB|assigned male at birth|FSH|follicle-stimulating hormone| |ASCR|autologous stem cell rescue|G-CSF|granulocyte colony-stimulating factor| |ASCR|AAYA|adolescent and young adult|GHSG| |CAD|coronary artery disease|GTV|gross tumor volume| |CAD|coronary artery disease|H&P|history and physical| |CCSS|Childhood Cancer Survivor Study|HCT|hematopoietic cell transplant| |CCSS|Childhood Cancer Survivor Study|HDT|high-dose therapy| |CME|continuing medical education|HIV|human immunodeficiency virus| |CME|continuing medical education|HL|Hodgkin lymphoma| |CPI|checkpoint inhibitors|ICL|infraclavicular| |CPI|CR|CR|CR| |CTV|complete response|complete response|complete response| |CTV|clinical target volume||| |CXR|chest radiograph|IGRT|image-guided radiation therapy| |DIBH|deep-inspiratory breath hold||| |DIBH|IMRT intensity-modulated radiation therapy||| |DLBCL|diffuse large B-cell lymphoma||| |DLBCL|diffusing capacity of the lung for||| |DLCO|diffusing capacity of the lung for||| |DLCO|carbon monoxide|carbon monoxide|carbon monoxide| |DM|diabetes mellitus||invitro fertilization| |DVH|dose-volume histogram|LAD|| |DVH|LAD|LAD|LAD| |EANM|European Association of Nuclear||| |EANM|Medicine|Medicine|Medicine| |EBER-ISH|Epstein-Barr encoding region in situ hybridization||| |EBER-ISH|LDHL|LDHL|LDHL| |EBV|Epstein-Barr virus|Epstein-Barr virus|Epstein-Barr virus| |EBV|LFT|LFT|LFT|

|LH|luteinizing hormone| |---|---| |LRHL|lymphocyte-rich Hodgkin lymphoma| |MALT|mucosal-associated lymphoid tissue| |MCHL|mixed cellularity Hodgkin lymphoma| |MLD|mean lung dose| |MMR|mediastinal mass ratio| |MTR|mediastinal thoracic ratio| |MUGA|multigated acquisition| |NLPBL|nodular lymphocyte-predominant B-Cell lymphoma| |NLPHL|nodular lymphocyte-predominant Hodgkin lymphoma| |NLPHL|nodular lymphocyte-predominant Hodgkin lymphoma| |NSHL|nodular sclerosis Hodgkin lymphoma| |OAR|organ at risk| |PA|posteroanterior| |PCP|primary care physician| |PFS|progression-free survival| |PFT|pulmonary function test| |PJP|nneumocystis jiroveci pneumonia| |POI|premature ovarian insufficiency| |PR|partial response| |PTV|planning target volume| |RATHL|risk-adapted therapy in Hodgkin lymphoma| |RCA|right coronary artery| |RR|relative risk| |SNMMI|Society of Nuclear Medicine and Molecular lmaging| |SUV|standardized uptake value| |TFT|thyroid function test| |TLLI|total lymphoid irradiation| |VHD|valvular heart disease| |VMAT|volumetric modulated arc therapy|

Version 1.2026,10/22/25©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.

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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|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended|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.

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NCCN Guidelines Version 1.2026 Hodgkin Lymphoma

Discussion

This discussion corresponds to the NCCN Guidelines for Hodgkin Lymphoma. Last updated: October 22, 2025.

Overview 2

Guidelines Update Methodology 2

Literature Search Criteria.2

Sensitive/Inclusive Language Usage $\ldots$ 3

Staging and Prognosis.3

The Role of FDG-PET Imaging in Management of CHL 4

Interim FDG-PET Imaging.5

Principles of Radiation Therapy 5

Principles of RT Dose Constraints.6

Heart.

Lungs.8

Breast.9

Thyroid.9

Pancreas..9

Kidneys 9

Ovaries 10

Testicles 10

Treatment Guidelines 11

Diagnosis and Workup $\ldots$ 11

Management of Classic Hodgkin Lymphoma in Adults Aged 18-60 Years...12

Management of Classic Hodgkin Lymphoma in Adults Aged >60 Years or Adults Unfit for Intensive Therapy..20

Management of Classic Hodgkin Lymphoma During Pregnancy $\ldots$ 22

Nodular Lymphocyte-Predominant Hodgkin Lymphoma...24

Follow-up After Completion of Treatment.28

Monitoring for Late Effects 28

Relapsed or Refractory Disease 31

Summary 37

References.39

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NCCN Guidelines Version 1.2026 Hodgkin Lymphoma

Overview

Hodgkin lymphoma(HL) is an uncommon malignancy of B-cell origin.Most patients are diagnosed between ages 15 and 30 years, followed by another peak in adults aged≥55 years. In 2025, an estimated 8720 people will be diagnosed with HL in the United States and 1150 people will die from the disease.1 The World Health Organization(WHO) classification divides HL into two main types: classic Hodgkin lymphoma(CHL) and nodular lymphocyte-predominant Hodgkin lymphoma(NLPHL).2 In Western countries, CHL accounts for 95% and NLPHL accounts for 5% of all HL.3 While the WHO has maintained the term NLPHL,2 the International Consensus Classification(ICC) has now replaced the term NLPHL with the term nodular lymphocyte predominant B-cell lymphoma(NLPBL)based on biological and clinical differences with CHL.4

CHL is divided into four subtypes: nodular sclerosis CHL; mixed cellularity CHL; lymphocyte-depleted CHL; and lymphocyte-rich CHL. CHL is characterized by the presence of Reed-Sternberg cells in an inflammatory background, whereas NLPHL lacks Reed-Sternberg cells but is characterized by the presence of lymphocytic-histiocytic cells, sometimes termed popcorn cells.

The past few decades have seen significant progress in the management of HL. The advent of more effective treatment options has improved the 5-year survival rates, which have been unmatched in any other cancer over the past 4 decades. HL is among the most curable of malignancies with modern treatments, and newly diagnosed HL has a very high likelihood of being cured with appropriate management. In fact, cure rates for HL have increased so markedly that overriding treatment considerations often relate to long-term toxicity. Clinical trials still emphasize improvement in cure rates for patients with both early and advanced disease, but the potential long-term effects of treatment remain an important consideration.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)for Hodgkin Lymphoma discuss the clinical management of CHL and NLPHL, focusing on adult patients ≥18 years who do not have serious intercurrent disease. For guidance on management of HL in pediatric patients, see the NCCN Guidelines® for Pediatric Hodgkin Lymphoma(available at www.NCCN.org). For guidance on management of HL in individuals with HIV, see the NCCN Guidelines for Cancer in People with HIV (available at www.NCCN.org).Individualized treatment may be necessary for patients >60 years and those with concomitant disease or poor performance status. Consistent with NCCN philosophy, participation in clinical trials is always encouraged.

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

Literature Search Criteria

Prior to the update of this version of the NCCN Guidelines for Hodgkin Lymphoma, an electronic search of the PubMed database was performed to obtain key literature in HL since the previous Guidelines update, using the following search terms: Hodgkin lymphoma, classic Hodgkin lymphoma, and nodular lymphocyte predominant. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.5 Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial,Phase III; Clinical Trial,Phase IV; Guideline; Practice Guideline;Randomized Controlled Trial; Meta-Analysis; 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 have been included in this version of the Discussion section.

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NCCN Guidelines Version 1.2026 Hodgkin Lymphoma

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.

Staging and Prognosis

Staging for HL is based on the Ann Arbor staging system.6,7 The system divides each stage into subcategories A and B, the latter for presence of B symptoms. “A” indicates that no systemic symptoms are present and“B” is assigned to patients with unexplained fevers>38°C, drenching night sweats, or unexplained weight loss of >10% of their body weight within 6 months of diagnosis.

Patients with HL are usually classified into three groups: early-stage favorable (stage I-II with no unfavorable factors); early-stage unfavorable(stage I-II with any of the unfavorable factors such as bulky mediastinal disease or>10 cm adenopathy, multiple involved nodal regions, B symptoms, extranodal involvement, or significantly elevated erythrocyte sedimentation rate [ESR]≥50 mm/hr); and advanced-stage disease(stage III-IV).

Mediastinal bulk, an unfavorable prognostic factor in patients with early-stage HL, is measured most commonly using the mediastinal mass ratio(MMR).8 The MMR is the ratio of the maximum width of the mass and the maximum intrathoracic diameter. Any mass with MMR>0.33 is defined as bulky disease. This is the definition most commonly used in North America and also by the German Hodgkin Study Group(GHSG). Another definition of bulk is any single node or nodal mass that is>10 cm in diameter. According to the Cotswolds modification of the Ann Arbor staging system, bulky disease is defined as the mediastinal thoracic ratio(MTR), which is the ratio of the maximum width of the mediastinal mass and the internal transverse diameter of the thorax at the T5-T6 interspace on a posteroanterior (PA) chest radiograph (CXR).9 In this context, any mass with MTR>0.35 is defined as bulky disease. This is the definition used by the European Organization for Research and Treatment of Cancer (EORTC). The definition of mediastinal bulk is best assessed with a standard CXR, as practice-changing studies utilized this staging modality. If a staging CXR is not obtained, disease bulk can also be assessed with CT. In this scenario, a single mass or nodal conglomerate chest in any direction, or any tumor mass or nodal conglomerate diameter of the also measured in any direction, should be considered "bulky."

The early-stage unfavorable factors are based largely on a composite of factors derived from the definition of unfavorable prognostic groups from

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the clinical trials conducted by the EORTC and the GHSG.10,11 Of note, the nodal regions as defined by the GHSG and EORTC are not the same as the Ann Arbor sites. Both research groups bundle the mediastinum and bilateral hila as a single region. In addition, the GHSG combines subpectoral with supraclavicular or cervical, while the EORTC combines subpectoral with axilla as one region. The EORTC unfavorable factors for stage I-II disease include bulky mediastinal disease (MMR>0.33 and MTR>0.35, respectively),B symptoms,ESR≥50 mm/h, and≥4 involved nodal regions. In contrast, the GHSG considers patients with≥3 nodal regions as having unfavorable disease.

An international collaborative effort evaluating >5000 patients with advanced CHL (stage III-IV) identified seven adverse prognostic factors,each of which reduced survival rates by 7% to 8% per year, 12 including:age ≥45 years; male gender; stage IV disease; albumin level <4 g/dL;hemoglobin level <10.5 g/dL; leukocytosis (white blood cell [WBC] count>15,000/mm3); and lymphocytopenia (lymphocyte count <8% of the WBC and/or lymphocyte count <600/mm3). The International Prognostic Score(IPS) is defined by the number of adverse prognostic factors present at diagnosis.12,13 The IPS helps to determine the clinical management and predict prognosis for patients with stage III-IV disease.12,13

The Role of FDG-PET Imaging in Management of CHL

Clinical management of CHL involves initial treatment with chemotherapy,chemoimmunotherapy, or combined modality therapy(CMT;chemoimmunotherapy or chemoimmunotherapy plus radiation therapy [RT]),followed by restaging at the completion of therapy to assess treatment response. Assessment of response to initial treatment is essential because the need for additional treatment is based on the treatment response.18F-fluorodeoxyglucose(FDG)-PET should not be used for routine surveillance following the completion of therapy due to risk for false positives.

FDG-PET imaging including integrated FDG-PET and CT (FDG-PET/CT)has become an important tool for initial staging and response assessment at the completion of treatment in patients with HL. ${ }^{14,15}$ In a meta-analysis,FDG-PET scans showed high positivity and specificity when used to stage and restage patients with lymphoma. ${ }^{16}$ FDG-PET positivity at the end of treatment has been shown to be a significant adverse risk factor in patients with early-stage as well as advanced-stage disease. ${ }^{17-19}$ In 2009,the Deauville criteria were defined for the interpretation of interim and end-of-treatment FDG-PET scans based on the visual assessment of FDG uptake in the involved sites. These criteria use a 5-point scale (5-PS) to determine the FDG uptake in the involved sites relative to that of the mediastinal blood pool and the liver. ${ }^{15,20,21}$ In the 5-PS (Deauville criteria),scores of 1 to 4 refer to initially involved sites and a score of 5 refers to an initially involved site and/or new lesions related to lymphoma. ${ }^{20,21}$ Interim or end-of-treatment FDG-PET scans with a score of 1, 2, or 3 are considered "negative" and FDG-PET scans with a score of 4 and 5 are considered "positive."22

A score of 4 can be difficult to assess when FDG uptake in mediastinal masses cannot clearly be differentiated from thymic uptake or inflammatory reactions, 15,23,24 and treatment decisions in these cases will require clinical judgment. In addition, Deauville 4 may represent just a single area of persistent disease or lack of response in any site. If disease is responding well to chemotherapy, but an interim FDG-PET/CT shows a Deauville 4 or 5 response, it may be appropriate to continue with the same chemotherapy regimen and repeat an FDG-PET/CT after 2 additional cycles. Similarly, if a post-chemotherapy FDG-PET/CT is only focally positive, consolidation RT may be appropriate, especially if a biopsy is not feasible. Additionally, in the era of checkpoint inhibitors(CPls), residual FDG uptake may be related to treatment and clinical judgment is necessary, as repeating a short-interval FDG-PET/CT may be preferred in

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such scenarios. At any point, if there is concern for refractory disease, a biopsy is appropriate to inform subsequent therapy.

The 5-PS (Deauville criteria) has been validated in international multicenter trials for FDG-PET-guided interim response assessment and risk-adapted therapy in patients with HL.25-29 The NCCN Hodgkin Lymphoma Panel encourages a second opinion of scans when there is a discrepancy between the clinical presentation and radiology report of a scan that was not originally interpreted by a qualified individual, and/or when no Deauville score is provided.

Interim FDG-PET Imaging

Interim FDG-PET scans can be prognostic and are increasingly being used to assess treatment response during therapy,30,31 as they can inform treatment adaptation, including treatment escalation and de-escalation.32,33 Early interim FDG-PET imaging after chemotherapy has been shown to be a sensitive prognostic indicator of treatment outcome in patients with advanced-stage disease(stage II disease with unfavorable risk factors[with or without bulky disease] or stage III-IV disease).34,35 Studies evaluating if interim FDG-PET imaging can identify patients with early-stage HL who have similar PFS with chemotherapy alone compared with CMT have been mixed.32,36,37 For advanced stage disease, studies have shown that interim FDG-PET scans identify patients with advanced disease with bulky tumors who do not derive benefit from consolidation RT.38,39 The NCCN Guidelines emphasize that the value of interim FDG-PET scans remains unclear for some clinical scenarios, and all measures of response should be considered in the context of management decisions. It is important that the Deauville score be incorporated into the nuclear medicine FDG-PET scan report, since subsequent management is often dependent on that score. Individual prospective trials that use interim FDG-PET imaging are discussed below in the treatment management section.

Principles of Radiation Therapy

RT can be delivered with photons, electrons, or protons, depending on clinical circumstances.40 Preliminary results from single-institution studies have shown that significant dose reduction to organs at risk (OARs; eg,lungs, heart, breasts, kidneys, spinal cord, esophagus, carotid artery, bone marrow, stomach, muscle, soft tissue, salivary glands) can be achieved with advanced RT planning and delivery techniques such as four-dimensional CT (4D-CT) simulation, intensity-modulated RT(IMRT)/volumetric modulated arc therapy (VMAT), image-guided RT(IGRT), respiratory gating, or deep inspiration breath hold (DIBH). 41.42 These techniques offer significant and clinically relevant advantages in specific instances to spare OARs and decrease the risk for both acute and long-term toxicity without compromising the primary goal of local tumor control.40.43.49 Achieving highly conformal dose distributions is especially important for patients who are being treated with curative intent or who have long life expectancies following therapy. Although advanced RT techniques emphasize tightly conformal doses and steep gradients between targets and OARs, the "low-dose bath" to normal structures is often increased. Particular attention to treatment technique and adherence to dose constraints is essential to minimize dose to high-risk OARs such as breast tissue in young premenopausal individuals. Target definition and treatment delivery verification require careful monitoring to avoid the risk of tumor geographic miss and subsequent decrease in tumor control. Initial diagnostic imaging with contrast-enhanced CT, MRI, FDG-PET, and other imaging modalities facilitate target definition. lmage guidance may be required to provide assurance of accurate daily delivery.

For optimal mediastinal treatment planning, organs or tissues to be contoured should include the lungs, heart, and the cardiac subunits,including the coronary arteries (the left main, circumflex, left anterior descending [LAD], and right coronary arteries, with priority placed on sparing the proximal over distal portions of the arteries), valves, and left

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ventricle. In mediastinal HL, use of gated treatment or DIBH at the time of simulation to deal with respiratory motion and minimize dose to OARs is essential. DIBH in particular has been shown to decrease incidental dose to the heart, lungs, and other OARs in many disease presentations.50 Further, IGRT during treatment delivery is essential to ensure accurate target localization. In certain circumstances, the use of protons for mediastinal lymphoma provides dosimetric advantages that may reduce long-term toxicity. Proton therapy is particularly advantageous in the setting of mediastinal disease to reduce dose to the heart and cardiac substructures and in young patients assigned female at birth to reduce dose to breast tissue.40,51,52

Randomized prospective studies to test these concepts are unlikely to be done since these techniques are primarily designed to decrease late effects, which usually develop ≥10 years after completion of treatment.Therefore, the Guidelines recommend that RT delivery techniques that are found to best reduce the doses to the OARs in a clinically meaningful manner without compromising target coverage should be considered in these patients, who are likely to enjoy long life expectancies following treatment.

Involved-site RT (ISRT) and involved-node RT (INRT) are being used as alternatives to involved-field RT (IFRT) in an effort to further restrict the size of the RT fields and to further minimize the radiation exposure to adjacent uninvolved organs and the potential long-term toxicities associated with radiation exposure. 53-56 ISRT targets the originally involved nodal sites and possible extranodal extensions, which generally defines a smaller field than the classical IFRT that encompassed entire lymph node regions, without a demonstrable attendant decrease in efficacy. 57

ISRT targets the initially involved nodal and extranodal sites as defined by the pre-treatment evaluation(physical examination, CT, and FDG-PET imaging). However, it is intended to spare the adjacent uninvolved organs

(such as lungs, bone, muscle, or kidney) when lymphadenopathy regresses following chemotherapy. Treatment planning for ISRT requires the use of CT-based simulation. The incorporation of additional imaging techniques such as FDG-PET and MRI often enhances treatment planning. The optimized treatment plan for ISRT is designed using three-dimensional conformal RT (3D-CRT), proton therapy, 40 or IMRT/VMAT techniques using clinical treatment planning considerations of coverage and dose reductions for OARs. For CHL, the gross tumor volume (GTV)defined by FDG-PET/CT imaging prior to chemotherapy or surgery provides the basis for determining the clinical target volume (CTV). For NLPHL treated with ISRT alone, the CTV should be expanded to include potential microscopic disease in the immediate region of the FDG-PET-positive disease. The planning target volume (PTV) is an additional expansion of the CTV to account for any setup variations and internal organ motion.58 PTV margins should be defined individually for each disease site.

In the setting of CMT, the Panel recommends an RT dose of 30 Gy when combined with ABVD(doxorubicin, bleomycin, vinblastine, dacarbazine[DTIC]) for most patients.59 In patients with stage I-II non-bulky disease,the recommended RT dose is 20 to 30 Gy following ABVD.60,61 For patients treated with RT alone(uncommon,except for NLPHL) the recommended dose is 30 to 36 Gy for the involved regions and 25 to 30 Gy for uninvolved regions. The Panel recommends that high cervical regions in all patients and axillae in patients assigned female at birth always be excluded from RT fields, if those regions are uninvolved.

Principles of RT Dose Constraints

Patients with hematologic malignancies typically receive far lower doses of RT than patients with epithelial or mesenchymal malignancies, while generally achieving more favorable long-term outcomes. More stringent dose constraints, often proportionally reduced from acceptable thresholds

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in other malignancies, are recommended. Doses to OARs should follow principles of ALARA (as low as reasonably achievable). In some scenarios, target coverage may require dose constraints to be exceeded if the OAR is within, or adjacent to, the PTV. For example, it may be difficult to meet thyroid constraints in the setting of bilateral supraclavicular lymphadenopathy.

A relatively rare but serious late complication of RT is the development of radiation-induced secondary cancers. Studies have reported that increasing RT dose without a safe threshold dose(linear no-threshold model) is associated with an increased risk for secondary cancers,although the pattern of risk is less well understood than for after low-dose exposure.62 Other contributing factors include age, environmental exposures, genetic risk factors, and radiation technique, among others.63

Select RT dose constraints recommended for OARs, including heart,lung,and breast, are described below. See RT Dose Constraint Guidelines for Lymphoma in the algorithm for further details.

Heart

Multiple cardiac complications can develop from mediastinal RT including pericarditis, arrhythmias, coronary artery disease (CAD), valvular heart disease (VHD), and cardiomyopathy/congestive heart failure.64,65 In addition to factors related to RT, the risk of cardiac events is also influenced by chemotherapy administration (eg, doxorubicin), pre-existing cardiovascular disease, age, and other cardiac risk factors (eg, diabetes,hypertension, hyperlipidemia).64,66-68 While global heart metrics such as mean heart dose (MHD) are most commonly used to assess risk, there is an increasing recognition that radiation dose-fractionation to cardiac substructures must be accounted for.

Mediastinal RT for lymphomas, relative to breast cancer and other thoracic malignancies, is characterized by radiation exposure to larger volumes of

the heart and substructures, albeit at lower doses (20-40 Gy). The MHD has been related to the risk of cardiac events, although the volume of the whole heart exposed to RT is variable.69,70 In a case-control study of HL survivors who were treated mainly with anteroposterior(AP)/PA fields,using MHD as a measure of cardiac toxicity risk, van Nimwegen et al demonstrated an excess relative risk (RR) of 7.4% per Gy MHD.70 A significantly increased risk of coronary heart disease was reported among patients who received an MHD as low as 5 to 14 Gy (RR, 2.31) compared to an MHD of 0 Gy.70 This risk was increased for an MHD of ≥15 Gy (RR,2.83 for 15-19 Gy,2.9 for 20-24 Gy, and 3.35 for 25-34 Gy).70

The number of studies evaluating specific dose constraints for cardiac substructures is limited.64,71-74 The prescribed mediastinal RT dose was the only independent risk factor for VHD in a pediatric cohort study, and increasing mediastinal RT dose(especially >30 Gy) has been associated with an elevated risk of valvular dysfunction.71,72 In a large Dutch cohort of adult patients treated with mediastinal RT, the 30-year cumulative risks of VHD increased with increasing mean valvular RT doses (3% for <30 Gy,6.4% for 31-35 Gy, 9.3% for 36-40 Gy, and 12.4% for >40 Gy) and there was no confounding effect of anthracycline chemotherapy on the risk of VHD.72 van Nimwegen et al demonstrated a relationship between heart failure and mean left ventricular(LV) dose.64 Chemotherapy was a clear confounder in regard to the risk of heart failure. Among patients treated with anthracyclines, the 25-year cumulative risk for heart failure was 11.2% for mean LV dose <15 Gy,15.9% for 16 to 20 Gy, and 32.9% for≥21 Gy. A retrospective study of patients treated in the Childhood Cancer Survivor Study found that mean doses of 5 to 9.9 Gy to the LV or right coronary artery were associated with an increased risk of CAD.73 Mean doses of 5 to 9.9 Gy to the tricuspid valve or right ventricle were associated with an increased risk of VHD.

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RT dose constraints for coronary arteries is a work in progress and only a few studies have evaluated the effect of coronary RT dose on the risk of CAD.73-78 In a large retrospective study of patients with non-small cell lung cancer (NSCLC) treated with thoracic RT, major adverse cardiac events were found to be associated with the volume of the LAD receiving 15 Gy(V15 Gy ≥ 10%).78 In a retrospective study utilizing the NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0617 data set,LAD V15 Gy ≥ 10% was also found to be associated with increased risk of all-cause mortality, with 2-year OS for patients with LAD V15 ≥ 10% Gy of 47% compared to 67% for patients with LAD V15 Gy < 10%(P = .04).74 Although there is no robust evidence to recommend specific guidance on dose constraints to specific coronary arteries in patients with lymphomas,limited available evidence supports the general notion of a dose-response effect in the clinical range of lymphoma RT prescriptions.

NCCN Recommendations

While the data regarding cardiac constraints for modern RT for lymphomas are imperfect, the Panel recommends that the MHD be kept as low as possible, ideally <8 Gy,although in some patients a higher dose will be necessary given lymphoma extent. Conversely, treatment plans for patients with superior mediastinal disease should achieve doses far less than 8 Gy. The Panel recognizes that nearly all patients with lymphoma receive anthracycline-based chemotherapy, although cumulative chemotherapy doses in modern practice tend to be lower than historical cohorts. Whole heart irradiation increases the risk of constrictive pericarditis, especially with whole heart RT doses >15 Gy79; therefore, it is recommended that MHD should rarely exceed 15 Gy.This may be reconsidered if patients are being treated in the second-line setting with curative intent where larger RT doses are necessary. Mean LV dose should not exceed 8 Gy, although in some circumstances up to 15 Gy may be necessary. LAD V15 Gy <10% is recommended. Aortic and mitral valve doses should be <25 Gy, although lower doses would be optimal. Given

that tricuspid and pulmonic valves may be less affected OARs, it is recommended that doses <30 Gy be administered, with a mean dose of<5 Gy to the tricuspid valve recommended. Constraints to coronary arteries are less well defined,80 but should be as low as possible in terms of dose, volume, and length. It is recognized that contouring the coronary arteries is challenging given anatomical variations and lung/heart motion.This may warrant designing a planning OAR volume in some patients.Furthermore, it is also important to preferentially spare high-dose overlap with the proximal coronary arteries. For dose recommendations for OARs,see Principles of RT- RT Dose Constraint Guidelines for Lymphoma in the algorithm.

Lungs

Mediastinal RT-related pulmonary toxicity is primarily radiation pneumonitis, although complications including symptomatic fibrosis or bronchopleural fistula have been encountered rarely. Radiation pneumonitis is a clinical diagnosis consisting of dry cough, dyspnea, and occasional low-grade fevers, and must be distinguished from other entities including drug-induced(especially bleomycin) pneumonitis, infectious pneumonia, acute bronchitis, and pulmonary embolism. Bleomycin pulmonary toxicity(BPT) does not preclude consolidation thoracic RT.81 Pulmonary complications can also arise from systemic therapies such as bentuximab vedotin(BV) and immunotherapy.

The most important risk factors for radiation pneumonitis are lung dose-volume metrics, including mean lung dose(MLD),V20 Gy,and V5 Gy. Such metrics have been associated with pneumonitis risk in both epithelial82 and hematologic malignancies.83 For epithelial malignancies such as NSCLC, it is generally recommended that MLD be<20 Gy and V20 Gy be<35%. In most circumstances, given the lower doses used in lymphoma management, much lower doses are generally achievable with careful planning.

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NCCN Recommendations

The Panel recommends limiting MLD to <13.5 Gy and V20 to Gy <20%,though higher incidental dose to the lungs may occasionally be necessary.Rarely should the lung V20 exceed 30%. In cases where IMRT or volumetric arc techniques are appropriate, limiting the V5 to <55% is recommended. DIBH can help meet MLD and V5 recommendations.84 Adherence to pulmonary constraints is particularly important in patients with heavily pretreated disease, particularly those who have received regimens with known lung toxicity.

Breast

Whole breast RT increases the risk of subsequent malignancies within the irradiated tissue. Therefore, the guidelines recommend a maximum mean breast dose of 4 Gy and a V4 of<10%.

Thyroid

The thyroid gland, in close proximity to the cervical lymph node chains and the mediastinum, is commonly affected by RT in patients with lymphomas.Functionally, hypothyroidism predominates and develops in up to 40% of long-term lymphoma survivors.85 The risk of developing hypothyroidism persists long after treatment has concluded, and lifetime screening is required.86 Both clinical and dosimetric factors are associated with an increased risk. White individuals, females, and those with a prior history of thyroid surgery seem to be at increased risk of hypothyroidism after RT.87 Dosimetrically, a variety of different metrics have been associated with a higher risk, all of which are closely related(V25>63.5%,88 mean dose>28 Gy,89 and V30>62.5%90).

As with other epithelial cancers, the risk of developing secondary thyroid cancer is approximately linear (higher exposures lead to higher risks).However, with doses above 20 to 30 Gy, the risk may begin to decline,presumably from cell death within the gland reducing the risk of malignant

degeneration. ${ }^{62}$ In addition to dose, younger age at exposure is another established risk factor. ${ }^{91}$ Papillary thyroid cancers predominate and behave similarly to sporadic thyroid carcinomas.

Thyroid nodules are common in the general population and also among lymphoma survivors.85 Given the ubiquitous nature of thyroid nodules,most screening guidelines recommend obtaining an ultrasound(US) only if a thyroid nodule is palpable on physical exam.

NCCN Recommendations

The Panel recommends limiting V25 Gy to <63.5% and minimizing V30 Gy.

Pancreas

Diabetes mellitus(DM) can develop after RT due to parenchymal structural damage of the pancreas. A dose of ≥10 Gy has been shown in a pediatric study to increase the risk of latent DM.92 A retrospective study of adults treated for gastric lymphoma showed that a median dose of ≥21 Gy was associated with an increased risk of DM.93 The 5-year cumulative incidence of DM was 9.6% compared to 1.6% for those who did not receive RT. It also demonstrated that a mean dose <21 Gy could be better achieved with IMRT compared with 3D-CRT.93 Data have shown that proton therapy can further reduce the dose compared to both 3D-CRT and IMRT.94

NCCN Recommendations

The Panel recommends limiting mean pancreatic dose to <21 Gy.

Kidneys

The kidneys are one of the most radiation-sensitive organs in the abdomen, necessitating careful planning to reduce the risk of long-term chronic renal insufficiency after treatment. In a study of 40 patients with gastric/duodenal mucosal-associated lymphoid tissue(MALT) lymphoma

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treated with 3D-CRT (median dose of 28 Gy), low-dose RT to both kidneys was most strongly associated with ≥ grade 2 chronic kidney disease (V5≥58%).9 The 5-year cumulative incidence rate of ≥ grade 2 chronic kidney disease was 15% and the median onset was 4.6 years. Half of the patients developed chronic kidney disease beyond 5 years after RT completion,which highlights the importance of longer follow-up.95

Another study included 38 patients with primary gastric diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy followed by 40 Gy of RT to the whole stomach and perigastric lymph nodes. ${ }^{96}$ V20 Gy ≥ 27% and a D30% (minimum dose covering 30% of the kidney volume) ≥ 19 Gy were associated with reduction of creatinine clearance and renal atrophy.

Taken together, these data support the consideration of more restrictive dose constraints/goals to the kidneys used during RT planning for lymphoma in the abdomen. The dose constraints used for gastrointestinal adenocarcinomas may not be applicable when the total RT dose is much higher and prognosis (eg, patients with pancreas cancer) affects the ability to fully capture late kidney toxicity. Dose constraints/goals in planning should include minimizing the low and intermediate doses (V5 Gy, V10 Gy) to the kidneys in addition to the commonly used constraints of V20 Gy and mean kidney dose.

NCCN Recommendations

The Panel recommends limiting mean dose to a single kidney to<5 Gy,though in certain circumstances higher doses to<8 Gy may be acceptable. For a single kidney, the Panel also recommends limiting V10 to<30% and V20 to<15%, though higher V20 doses to<25% are acceptable in certain circumstances.

For bilateral kidney RT, the Panel recommends limiting V5 to<58%.

Ovaries

Acute ovarian failure, defined as loss of ovarian function ≤5 years from diagnosis, and premature ovarian insufficiency (POI), defined as loss of ovarian function prior to age 40, are both associated with the mean RT dose to the least affected ovary and age of the patient at treatment. There are strong data to suggest that adolescents and young adults are at higher risk with lower doses of RT.97 The risk of acute ovarian failure also increases with cumulative dose of alkylating agent and use of HCT. In a systematic review, a dose of 2 Gy to the least affected ovary led to a 1%to 5% risk of acute ovarian failure without use of an alkylating agent, and increased to up to a maximum of 13% with increasing cumulative dose of an alkylating agent.98 Acute ovarian failure risk is predicted to be $\geq 50\%$ with 20 Gy to the least affected ovary in a 20-year-old patient and 13 Gy with higher alkylator doses. Similarly, a 20-year-old patient would have a 12% risk of POI with<10 Gy to the least affected ovary without alkylating chemotherapy and a 41% risk with alkylating chemotherapy while a 40-year-old demonstrates higher risk in both scenarios: 50% without alkylating chemotherapy and 94% with alkylating chemotherapy.

NCCN Recommendations

Testicles

Even scatter radiation doses as low as 0.2 to 2 Gy may cause temporary azoospermia that typically recovers within 2 years. ${ }^{99}$ Similarly,scatter radiation doses > 0.2 to 0.8 Gy and > 0.5 Gy can cause follicle-stimulating hormone (FSH) and luteinizing hormone (LH) elevations, respectively, with not all patients returning to baseline level at 2 years. In contrast, direct radiation to testicles is associated with significant Leydig cell dysfunction at even low doses of radiation. Testosterone levels can be abnormal after>0.2 Gy with doses > 12 Gy associated with abnormal testosterone in 40%of patients.

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Treatment Guidelines

Diagnosis and Workup

For evaluation and initial workup of HL the Panel recommends that an excisional lymph node biopsy generally be performed, although a core needle biopsy may be adequate if diagnostic. A diagnostic assessment based solely on fine-needle aspiration (FNA) biopsy is generally insufficient except in unusual circumstances when, in combination with immunohistochemistry (IHC), it is judged to be diagnostic of HL by an expert hematopathologist or cytopathologist. Immunostaining for CD3,CD15, CD20, CD30, CD45, CD79a, PAX5, and Epstein-Barr virus-encoded RNA in situ hybridization (EBER-ISH) is recommended for CHL.The Reed-Sternberg cells of CHL express CD30 in all patients, express CD15 in the majority of patients, and are usually negative for CD3 and CD45. CD20 may be detectable in <40% of patients. An extended panel of markers (ie, MUM-1, BOB-1, OCT-2) may be required, especially if there is an equivocal diagnosis. For NLPHL, the immunoarchitectural pattern should be specified as typical (subtypes A or B) or variant (subtypes C, D,E, or F).

Workup should include a thorough history and physical examination(H&P),including determination of B symptoms (unexplained fevers>38° C,renching night sweats, or unexplained weight loss of>10% of body weight within 6 months of diagnosis; other associated symptoms are alcohol intolerance, pruritus, fatigue, and poor performance status).Physical examination should include all lymphoid regions, spleen, and liver; standard laboratory tests (complete blood count [CBC], differential,ESR, serum lactate dehydrogenase [LDH], albumin, and liver and renal function tests); HIV testing (see the NCCN Guidelines for Cancer in People with HIV, available at www.NCCN.org); and FDG-PET/CT scan (skull base to mid-thigh or vertex to feet in selected cases).

The Panel recommends imaging be obtained in accordance with the American College of Radiology (ACR) guidelines. A diagnostic CT enhanced with oral and/or intravenous (IV) contrast may be useful in selected cases (neck, chest, abdomen, and pelvis). At minimum,diagnostic CT scans should include involved areas identified as abnormal on FDG-PET scan. PA and lateral CXRs are encouraged in selected cases for patients with large mediastinal masses.

The NCCN PET Task Force and the NCCN Guidelines consider FDG-PET scans essential for initial staging and treatment response assessment. ${ }^{100}$ An FDG-PET/CT is recommended for initial staging and should be obtained no longer than 1 month prior to the initiation of therapy. A separate contrast-enhanced diagnostic CT is not needed if it was part of the integrated FDG-PET/CT scan, though may be useful in certain circumstances. The Panel supports the ACR101 and Society of Nuclear Medicine and Molecular Imaging (SNMMI)102 recommendations for FDG-PET/CT interpretation (see Principles of FDG-PET/CT in the algorithm). ${ }^{103-106}$ However, it should be noted that FDG-PET scans may be positive in sites of infection or inflammation, even in the absence of HL. In patients with FDG-PET-positive sites outside of the disease already identified, or if the FDG-PET-positive sites are inconsistent with the usual presentation of HL, additional clinical or pathologic evaluation is recommended. Measures to reduce brown fat activation may also be considered. In patients with newly diagnosed HL undergoing pretreatment staging with FDG-PET/CT, routine bone marrow biopsy is not required if the FDG-PET scan is negative or displays a homogenous pattern of bone marrow uptake, which may be secondary to cytokine release. ${ }^{107,108}$ The bone marrow may be assumed to be involved if the FDG-PET scan displays multifocal (≥3) skeletal lesions. ${ }^{107,109}$ However, a bone marrow biopsy may be performed if the FDG-PET scan is negative, but unexplained cytopenias other than anemia are present. ln select cases,MRI with contrast to select sites may be considered, unless

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contraindicated. FDG-PET/MRI without contrast (skull base to mid-thigh)may also be considered for anatomical imaging.

Evaluation of ejection fraction (EF) is recommended if anthracycline-based therapy is indicated. Atvorstatin may be considered in patients receiving anthracycline-based therapy based on a randomized study that revealed less risk of a ≥10% reduction in LVEF with atorvastatin compared to placebo.110 Hepatitis B or C testing should be encouraged for patients with risk factors or unusual disease presentations. Pulmonary function tests,including diffusing capacity of the lungs for carbon monoxide (DLCO), are recommended for patients receiving bleomycin-based chemotherapy. In general, a DLCO threshold of at least 60% is acceptable for bleomycin use.111,112 A seasonal influenza vaccine is recommended.

A pregnancy test should be performed before patients of childbearing potential undergo treatment. Alkylating agent-based chemotherapy is associated with a higher risk of premature ovarian failure than chemotherapy with non-alkylating agent-based chemotherapy.113 All patients should be counseled on infertility risk. In select cases and if the patient is interested, the Guidelines recommend consideration of fertility preservation (ie, semen cryopreservation, ovarian tissue or oocyte cryopreservation) prior to the initiation of chemotherapy with alkylating agents or pelvic RT.114,115 While primary treatment for CHL may not have a significant effect on fertility in younger patients, a study of patients aged 18 to 45 years treated on the Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL) trial found that patients ≥35 years of age had significantly less recovery of ovarian function following completion of therapy compared to patients <35 years of age (P<.0001).116 At 1 year post-treatment, there was also less recovery of ovarian function for patients escalated to BEACOPPP (bleomycin, etoposide, doxorubicin,cyclophosphamide, vincristine, procarbazine, prednisone) following interim FDG-PET compared to patients who remained on ABVD or AVD.116

Similarly, in a study of patients aged <45 years treated on AHL2011, patients treated with 6 cycles of escalated BEACOPP had lower rates of ovarian function recovery and higher rates of premature ovarian insufficiency compared to patients treated with PET-driven de-escalation to ABVD.117 BrECADD (BV,etoposide, cyclophosphamide, doxorubicin,DTIC, dexamethasone) has similar effects on fertility as was found in the RATHL trial. ${}^{118}$ The risk of premature ovarian insufficiency and low ovarian reserve was also associated with more advanced age. ${}^{117}$

Consideration should be made for distress screening utilizing the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See the NCCN Guidelines for Distress Management, available at www.NCCN.org.

Management of Classic Hodgkin Lymphoma in Adults Aged 18-60 Years

Patients are divided into the following groups after initial diagnosis and workup:

● Stage I-II

● Stage III-IV

Patients with stage I-II are further classified into the following subgroups depending on the presence or absence of NCCN unfavorable factors:

● Stage I-II (unfavorable with non-bulky disease)

● Stage I-II (unfavorable with B symptoms, bulky mediastinal disease, or>10 cm adenopathy)

The standard treatment for early-stage CHL is with either CMT or chemotherapy alone. Selection of CMT or chemotherapy alone should be based on patient age, sex, family history of cancer or cardiac disease,comorbid conditions, and sites of involvement. CMT provides for a better

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progression-free survival (PFS)/freedom from progression (FFP).There was no difference in overall survival (OS) in prospective randomized trials,but these studies were not powered to detect an OS benefit. All patients will benefit from multidisciplinary team (including radiation oncology) input prior to final treatment decisions. Chemotherapy alone may be preferred for individuals assigned female at birth with intact breast tissue who are<30 years where recommended RT dose-volume histogram (DVH)constraints for breast tissue are exceeded, if cardiac constraints cannot be met, or in the presence of high-risk comorbidities, while CMT may be preferred if the doxorubicin dose would exceed 200 mg/m2 provided that breast and cardiac radiation constraints can be met.

Stage I-II

The HD10 trial from the GHSG investigated the reduction of the number of cycles of ABVD as well as the IFRT dose in patients with stage I-II disease with no risk factors.61 The definition of favorable disease implies the absence of unfavorable risk factors outlined in Unfavorable Risk Factors in the algorithm. It is worth noting that for purposes of stratification, the GHSG and EORTC do not define the lymph node regions strictly according to the Ann Arbor criteria. In this trial, patients were not eligible if they had≥3 involved lymph node regions, any E-lesions, bulky mediastinal adenopathy, ESR≥50 mm/h, or ESR≥30 mm/h in conjunction with B symptoms. In this trial, 1370 patients were randomized in a 2x2 design to 2 or 4 cycles of ABVD and 20 Gy or 30 Gy of IFRT.61 The final analysis of this trial showed that(with a median follow-up of 79-91 months) there were no significant differences between 4 and 2 cycles of ABVD in terms of 5-year OS (97.1% and 96.6%), freedom from treatment failure (FFTF) (93.0% vs. 91.1%), and PFS (93.5% vs. 91.2%). With respect to the dose of IFRT, the OS (97.7% vs. 97.5%), FFTF (93.4% vs.92.9%), and PFS (93.7% vs. 93.2%) were also not significantly different between 30 Gy and 20 Gy IFRT.61 More importantly, there were also no significant differences in OS, PFS, and FFTF among the four treatment

arms. The results of the HD10 study confirm that 2 cycles of ABVD with 20 Gy of IFRT is an effective primary treatment for patients with a very favorable presentation of early-stage disease with no risk factors, thereby minimizing the risk of late effects.

Subsequent studies have assessed the value of post-treatment and interim FDG-PET scans in defining the need for RT in patients with stage I-II disease. The UK RAPID trial showed that patients with stages IA-IIA disease with a negative FDG-PET scan after 3 cycles of ABVD have a somewhat inferior outcome without RT for PFS, albeit no difference in OS.29 In this study(n = 602; 426 patients had a negative FDG-PET scan after 3 cycles of ABVD), patients with stage IA-IIA favorable disease(no B symptoms or mediastinal bulky disease) and a Deauville score of 1-2 on interim FDG-PET scan after 3 cycles of ABVD were randomized to either IFRT (n = 209) or observation (n = 211). After a median follow-up of 60 months, in an intent-to-treat analysis, the estimated 3-year PFS rate was 94.6% for those treated with IFRT compared to 90.8% for those who received no further treatment(P=.16). The corresponding 3-year OS rates were 97.1% and 99.0%, respectively.29 In the "per protocol" (as treated) analysis, the 3-year PFS rates were 97.1% and 90.8%,respectively, favoring the use of CMT(P=.02). Of note, among patients with initial disease ≥5 cm, patients treated with CMT had a superior event-free survival (EFS) compared to patients treated with ABVD alone. 119

In the EORTC H10 trial, which included 754 patients in the favorable group(H10F),PET response after 2 cycles of ABVD was evaluated for whether it would allow treatment adaptation.120 In this study,mediastinal blood pool activity was used as the reference background activity for PET positivity of residual masses≥2 cm in greatest transverse diameter,regardless of location. A smaller residual mass or a normal-sized lymph node was considered positive if its activity was above that of the surrounding background. Patients with PET-negative response after

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receiving 2 cycles of ABVD received 1 additional cycle of ABVD(total of 3 cycles) followed by INRT in the standard arm, or 2 additional cycles of ABVD (total of 4 cycles) only in the experimental arm.120 After a median follow-up of 10 years, the intent-to-treat PFS rates were 98.8% and 85.4%in the ABVD + RT and ABVD only arms, respectively (P < .0001).32 If the interim PET was positive, patients in both the H10F and H10U(unfavorable group) were continued on ABVD for a total of 4 cycles on the standard arm or treatment was intensified to 2 cycles of escalated BEACOPP + INRT in the experimental arm.120

In the H10U group (n = 1196), patients were randomized into two treatment arms. ${}^{120}$ In the standard arm, patients were treated with 2 cycles of ABVD, underwent interim PET, and were treated with 2 additional cycles of ABVD + INRT (30-36 Gy). In the experimental arm, patients were treated with 2 cycles of ABVD, underwent interim PET scans, and if found to be PET negative, were treated with an additional 4 cycles of ABVD. For the patients with interim PET-negative response, the 10-year PFS was 91.4% following 4 cycles of ABVD + INRT versus 86.5%following 6 cycles of ABVD. ${}^{32}$ If patients were found to be PET positive after the initial 2 cycles of ABVD, chemotherapy was intensified with 2 cycles of escalated BEACOPP + INRT (30-36 Gy) as in the H10F group.Initial results of this trial demonstrated that in patients with stage I-II(favorable or unfavorable disease), a PET-positive response after 2 cycles of ABVD facilitates early treatment adaptation to 2 cycles of escalated BEACOPP + INRT, with improved 5-year PFS when compared to 2 additional cycles of ABVD and INRT (90.6% vs. 77.4%, respectively).120 Longer term follow-up, however, revealed that at 10 years, the difference in PFS between ABVD and escalated BEACOPP in patients with PET-positive response after 2 cycles of ABVD had lost its statistical significance (79.2% vs.85.1%, respectively; P=.1777).32

The GHSG HD16 trial(n= 1150) included patients with stage I-II favorable disease according to GHSG criteria. ${ }^{121}$ Patients randomized to the standard arm received 2 cycles of ABVD followed by an interim PET and IFRT(20 Gy), regardless of the PET result. On the experimental arm,following 2 cycles of ABVD, patients with a negative PET(Deauville score<3) received no further therapy, while those with a positive PET received IFRT(20 Gy). Among the 628 patients in the combined arms who had a negative interim PET, the 5-year PFS was 94.2% following CMT and 86.7% following ABVD alone (P=.14). ${ }^{122}$ Relapse analysis from this trial revealed a higher 5-year local recurrence rate in patients with PET-negative response with omission of IFRT, at 10.5$\%$ with chemotherapy alone compared to $2.4\%$ with CMT $(P=.54)$ . ${ }^{123}$

The CALGB 50604 trial examined the use of interim PET to guide treatment of patients with stage I-II HL (excluding only patients with bulky disease).37 Patients received 2 cycles of ABVD followed by PET. Patients with a PET-negative response (Deauville score of 1-3, which is different from the H10 and RAPID trials that used a score of 1-2) were given 2 more cycles of ABVD, whereas patients with a PET-positive response were treated with escalated BEACOPPP + IFRT.37 With a median follow-up time of 3.8 years, the estimated 3-year PFS for the PET-negative and PET-positive groups were 91% and 66%, respectively.37 The 3-year PFS was 94% for patients with Deauville 1-2 response on interim PET compared to only 77% for patients with Deauville 3 response.

The RATHL trial examined the use of interim PET to guide treatment for patients with advanced disease, which included 500 patients (41.6%) who had stage II disease with various risk factors (B symptoms, bulky disease, or $\geq 3$ involved sites). ${ }^{25,33}$ In the randomized trial, 1119 patients with stage II-IV disease received 2 cycles of ABVD and underwent interim PET scans. Patients with a Deauville score of 1-3 were assigned in a 1:1 ratio to continue treatment with 4 cycles of either ABVD or AVD. At a median of

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7.3 years, the 7-year PFS and OS rates between the ABVD and AVD groups did not differ significantly (81% vs. 79.2% and 93.2% vs. 93.5%,respectively). However, the omission of bleomycin from the ABVD regimen after negative PET results (ie, Deauville score of 1-3) led to a decrease in the incidence of pulmonary toxic effects when compared to continued ABVD.124 The potential value of added RT was not tested in this trial.

The phase II GHSG NIVAHL trial evaluated the safety and efficacy of nivolumab-AVD (doxorubicin, vinblastine, and DTIC) in patients (n = 109;age range: 18-60 years) with newly diagnosed, early-stage, unfavorable CHL by GHSG criteria (see Unfavorable Risk Factors in the algorithm).125 Patients were randomized to 4 cycles of concomitant nivolumab-AVD or sequential therapy with 4 cycles of nivolumab, 2 cycles of nivolumab-AVD,and 2 cycles of AVD. All patients received ISRT 30 Gy following completion of chemotherapy. At interim restaging after 2 cycles of nivolumab-AVD, 100% of patients in the concomitant arm achieved an objective response, with a complete response (CR) rate of 87%, compared to 96% and 51% in the sequential arm, respectively. Following completion of therapy, the CR rate for the concomitant arm was 90% and 94% in the sequential arm. With a median follow-up of 41 months, OS was 100% in both arms, with PFS of 100% in the concomitant arm and 98% in the sequential arm. With regard to immune-mediated adverse events (AEs),hypothyroidism requiring mediation support occurred in 15% of patients and there were no immune-mediated AEs necessitating corticosteroids.There were no secondary malignancies noted.

The phase II BREACH trial evaluated the safety and efficacy of BV-AVD in patients (n = 170; age range: 18-60 years) with newly diagnosed, supradiaphragmatic, early-stage, unfavorable CHL with ≥1 European Organization of Research and Treatment of Cancer (EORTC)/Lymphoma Study Association (LYSA) unfavorable criteria (see Unfavorable Risk Factors in the algorithm).126 Patients were randomized to 4 cycles of BV-

AVD or 4 cycles of ABVD. All patients received INRT 30 Gy following completion of chemotherapy. At interim restaging following 2 cycles of therapy,82.3% of patients in the BV-AVD arm achieved PET negativity,surpassing the study's primary endpoint (75%). Comparatively,75.4% of patients in the ABVD arm achieved PET negativity following 2 cycles of therapy. Two-year PFS favored the BV-AVD arm (97.3% [95% CI, 91.9% to 99.1%] vs. 92.6% [95% CI, 81.4% to 97.2%], respectively). Grade 3-4 AEs, the majority being hematologic, were more common in the BV-AVD arm(86% vs. 69%, respectively). Grade ≥3 peripheral neuropathy occurred in 3% of patients in the BV-AVD arm compared to 2% in the ABVD arm. Two secondary malignancies were noted in the ABVD arm compared to 1 in the BV-AVD arm.

The international phase III GHSG HD21 trial aimed to minimize treatment-related morbidity for adult patients ≤60 years of age with advanced-stage CHL by investigating a remodeled escalated BEACOPPP regimen referred to as BrECADD that eliminates bleomycin and procarbazine.118 Advanced-stage disease was defined as stage III/IV disease or stage II disease with B symptoms and large mediastinal mass and/or extranodal lesions, though the majority of patients who participated in the trial had stage III/IV disease, with<16% of patients with stage II unfavorable disease. Patients(n= 1500; 234 with stage II disease) were randomized to 4 to 6 cycles of PET-adapted BrECADD versus escalated BEACOPPP. BrECADD was associated with an improvement in 4-year PFS in all stages of disease, but most significantly in stage II disease(HR,0.35). BrECADD was also associated with significantly lower treatment-related morbidity than escalated BEACOPP in patients with stage II disease(HR,0.65).

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NCCN Recommendations for Stage IA-IIA Favorable Disease by GHSGE Criteria

The recommended primary treatment for stage I-IIA favorable disease by GHSG criteria (ESR <50 mm/h, no e-lesions, ≤2 nodal sites) is 2 cycles of ABVD (category 1), followed by restaging with FDG-PET/CT. For patients with a Deauville score of 1-3, CMT with ISRT (20 Gy) is preferred(adapted from GHSG HD16).61,121 Chemotherapy alone may be useful in certain circumstances, with options including additional ABVD x 2 cycles (adapted from the H10F and CALGB trials),32,37 or AVD x 4 cycles (for Deauville score 3 only; adapted from the CALGB and RATHL trials).33,37 Notably, outcomes with 4 cycles of ABVD were suboptimal in the CALGB 50604 trial when interim FDG-PET/CT showed a Deauville 3 response.37

NCCN Recommendations for Stage IA-IIA Favorable Disease by EORTC Criteria

For patients who do not meet GHSG favorable criteria but meet favorable criteria per EORTC (non-bulky, ≤3 nodal sites, or e-lesion[s]), 2 cycles of ABVD remains the primary treatment approach (category 1), followed by restaging with FDG-PET/CT. For patients with a Deauville score of 1-2,the recommended CMT approach is an additional cycle of ABVD (total 3)plus ISRT 30 Gy (adapted from RAPID29 and H10F32), while the recommended chemotherapy alone approach is an additional 2 cycles of ABVD (adapted from H10F32 and CALGB37). For patients with a Deauville score of 3, the recommended CMT approach is an additional 2 cycles of ABVD (total 4) plus ISRT 30 Gy (adapted from RAPID29), while the recommended chemotherapy alone approach is AVD x 4 cycles (adapted from CALGB and RATHL 37,124).

NCCN Recommendations for Stage IA-IIA Favorable CHL by GHSG or EORTC criteria with Deauville 4-5 After 2 Cycles of ABVD

Patients with stage IA-IIA favorable, non-bulky CHL with a Deauville 4-5 response following 2 cycles of ABVD, regardless of whether they meet GHSG or EORTC favorable criteria, should follow the same treatment

recommendations. For patients with a Deauville score of 4, if only focally positive on interim FDG-PET, patients may continue with 2 additional cycles of ABVD before repeat scan. Following restaging, a biopsy is recommended for all patients with a Deauville score of 4-5. The Panel recommends escalating therapy for patients with positive biopsies. ISRT(30 Gy) is recommended for patients with a Deauville score of 1-3, or 4-5 with a negative biopsy.29,32 For patients with a Deauville score of 5 after interim restaging, biopsy is recommended, with escalation of therapy for patients with a positive biopsy and treatment as per the Deauville score 4 pathway for those with a negative biopsy. If a post-chemotherapy FDG-PET/CT is only focally positive(Deauville 4 or 5), consolidation RT may be appropriate if a biopsy is not feasible. However, in certain circumstances when clinically disease appears to be responding, a Deauville 5 score may warrant the same treatment as a Deauville 4 score.

NCCN Recommendations for Stage I-II Unfavorable Disease with B Symptoms, Bulky Mediastinal Disease and/or >10 cm Adenopathy, ≥4 Nodal Sites, and/or ESR ≥50 mm/h

For stage I-II unfavorable CHL with B symptoms, bulky mediastinal disease and/or >10 cm adenopathy,≥4 nodal sites, and/or ESR ≥50 mm/h, one treatment option is ABVD for 2 cycles followed by restaging with FDG-PET/CT. If there is a preference to treat patients with CMT,patients with a Deauville score of 1-3 can be treated with 2 additional cycles of ABVD(total of 4) and ISRT 30 Gy (adapted from H10U).32 If there is a preference to treat with chemotherapy alone, patients with a Deauville score of 1 to 3 are recommended to receive 4 cycles of AVD(adapted from RATHL and H10U).32,124

Patients with a Deauville score of 4-5 may also be treated with an additional 2 cycles of ABVD or may have treatment escalated. The Panel now recommends treatment escalation to BrECADD plus granulocyte-colony stimulating factor(G-CSF) for 2 cycles rather than escalated BEACOPP despite a lack of data for BrECADD in this setting

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due to the significantly lower treatment-related morbidity shown with BrECADD in the GHSG HD21 trial.118 Following restaging, a Deauville score of 5 should prompt re-biopsy to inform subsequent therapy. For patients with a positive biopsy, or those in whom biopsy is not feasible,treatment is as described for primary refractory disease. Patients with a Deauville score of 1-4 following additional therapy may be treated with ISRT (30 Gy for Deauville 1-3; 36-40 Gy for Deauville 4).32 An additional option for patients with a Deauville score of 1-3 is an additional 2 cycles of BrECADD, if BrECADD was previously used. Of note, all BV-containing regimens should be utilized with caution in patients with neuropathy.Pneumocystis jirovec pneumonia (PJP) prophylaxis is also recommended for all BV-containing regimens.

Other treatment options include CMT with either nivolumab-AVD125 or BV-AVD,126 and BrECADD+ G-CSF for patients with stage IIB disease with large mediastinal mass and/or extranodal disease.118 Four cycles of either nivolumab-AVD or BV-AVD+ G-CSF are administered followed by restaging FDG-PET/CT. ISRT is recommended for patients with a Deauville score of 1-4, followed by appropriate follow-up and monitoring for relapse/late effects (see Follow-up After Completion of Treatment),while those with a Deauville score of 5 should undergo biopsy. If biopsy is negative, ISRT is recommended and thereafter patients can be followed as above. In those for whom biopsy is not feasible or for whom biopsy is positive, treatment is as described for primary refractory disease.

BrECADD+ G-CSF is administered for 2 cycles followed by restaging FDG-PET/CT. For patients with a Deauville score of 1-3, an additional 2 cycles of BrECADD+ G-CSF(total 4) is recommended, while an additional 4 cycles(total 6) is recommended for patients with a Deauville score of 4-5, followed by restaging. Following restaging, patients with a Deauville score of 1-3 can be followed, while biopsy is recommended for patients with a Deauville score of 4-5. For those with a negative biopsy, ISRT is

recommended prior to follow-up. For those with a positive biopsy,treatment is as described for primary refractory disease.

Stage III-IV

While chemotherapy is always used for patients with advanced-stage disease, CMT is an appropriate treatment approach in some instances,including for those who only experience a PR to chemotherapy. ${}^{127,128}$

The randomized phase III SWOG S1826 trial compared the safety and efficacy of 6 cycles of nivolumab-AVD to BV-AVD in patients ≥12 years of age (n = 970 in the intention-to-treat cohort; median age 27.6 years [range 12-83.7 years]) with stage III-IV HL.129 Use of growth factor was optional during the trial. Two-year PFS was significantly improved with nivolumab-AVD (92%) compared to BV-AVD (83%) (HR for disease progression or death, 0.45; 95% CI, 0.3-0.65). PFS benefit was noted among all age groups and IPS scores. Two-year EFS and OS rates were 90% and 99% with nivolumab-AVD compared to 81% and 98% with BV-AVD(EFS: HR for death, 0.50; 95% CI, 0.36-0.71; OS: HR for death,0.39; 95% CI, 0.15-1.03). RT was administered sparingly in both arms(0.6% with nivolumab-AVD compared to 0.8% with BV-AVD). The majority of AEs were more common with BV-AVD than nivolumab-AVD, including fatigue, nausea/vomiting, transaminitis, and peripheral neuropathy.Leukopenia and neutropenia were more common with nivolumab-AVD,however.

As previously discussed, the international phase III GHSG HD21 trial aimed to minimize treatment-related morbidity for adult patients≤60 years of age with advanced-stage CHL with BrECADD, a remodeled escalated BEACOPP regimen.118 Fifteen hundred patients were randomized to PET-2-adapted 4 to 6 cycles of BrECADD versus escalated BEACOPP. Sixty-four percent of patients in both the BrECADD and escalated BEACOPP arms had negative FDG-PET/CTs after cycle 2 and thus received only 4 cycles of treatment. With a median follow-up of 48 months, 4-year PFS for

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the entire cohort was superior with BrECADD compared to escalated BEACOPP (94.3% vs.90.9\%, respectively; P=.035; HR for stage III,0.65; HR for stage IV, 0.79). Hazard ratio (HR) for PFS favoring BrECADD was lower for patients with negative PET-2 scans who thus received 4 cycles compared to 6 cycles (0.51 vs. 0.72, respectively). Four-year OS rates were similar between the groups (98.6\% vs. 98.2\%, respectively).BrECADD was associated with significantly lower treatment-related morbidity than escalated BEACOPP (42% vs. 59\% of patients,respectively; P<.0001). Grade 2 or higher peripheral neuropathy (sensory and motor) occurred in $10\%$ of patients in the BrECADD arm and at 1 year following completion of treatment, peripheral sensory neuropathy had fully resolved in 88\% of patients. Similarly, other treatment-related toxicities fully resolved or improved to grade 1 in 96\% of patients in the BrECADD arm. Gonadal function recovery at 4 years was more common with BrECADD in both females (95.3\% vs. 72.5\%) and males (86\% vs.39.2\%). Based on these results, the GHSG has replaced escalated BEACOPP with BrECADD.

BV-AVD has emerged as a treatment option based on the results of the phase III ECHELON-1 trial.130-132 Initial results of the ECHELON-1 trial showed that BV-AVD had superior PFS compared to ABVD in first-line treatment of patients with stage III-IV disease.130,131 In this trial patients with previously untreated stage III or IV CHL were randomized to receive ABVD(n= 670) or BV-AVD(n= 664).130 Patients received 6 cycles of chemotherapy without treatment adaptation based on interim restaging.The 5-year follow-up data confirmed that PFS benefit for BV-AVD compared to ABVD was consistent in all patient subgroups independent of disease stage, age, and IPS.131 While the incidence of pulmonary toxicity was lower in the BV-AVD arm due to the elimination of bleomycin, there was a higher rate of peripheral neuropathy (19% compared to 9% for patients in the ABVD group) and febrile neutropenia (19% compared to 11% for patients in the ABVD group) mandating the use of growth factor

support with this regimen.130,131 Furthermore, the rate of pulmonary toxicity in the control group does not reflect that of modern management, as bleomycin may be omitted in the vast majority of patients after the first 2 cycles(see RATHL trial discussion above).

A more recent interim analysis revealed a significant OS benefit with BV-AVD compared to ABVD (HR, 0.59; P=.009).132 Estimated 6-year OS was 93.9% in the BV-AVD group versus 89.4% in the ABVD group. Consistent improvement in estimated 6-year OS was seen in both patients with positive PET scans following 2 cycles of treatment (95% vs. 77%; HR,0.16) and in patients with negative PET scans following 2 cycles of treatment (94.9% vs. 90.6%; HR, 0.54). In the prespecified subgroups,more favorable estimates of treatment effect with BV-AVD over ABVD were observed in patients with stage IV disease, patients <60 years (vs. patients ≥ 60 years), and in patients with an IPS ≥ 4 (vs. IPS of 0-1). In accordance with previous reports, PFS estimates at 6 years favored BV-AVD compared to ABVD, with estimates of 82.3% and 74.5%,respectively (HR, 0.68). Consistent 6-year PFS benefit was seen with BV-AVD over ABVD across multiple subgroups, including those with stage III or IV disease and those with negative or positive PET scans following two cycles of treatment. More patients had ongoing peripheral neuropathy in the BV-AVD group (18.9% compared to 9.0% in the ABVD group),though patients in both groups saw improvements (85.6% in the BV-AVD group had complete resolution or amelioration compared to 87.1% in the ABVD group). Subsequent therapy was used less frequently in the BV-AVD group compared to the ABVD group, including autologous and allogeneic HCT and immunotherapies, though the use of subsequent RT was similar between the two groups. There was a higher proportion of deaths due to a second cancer in the ABVD group compared to the BV-AVD group (4.9% vs. 3.5%).

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ABVD remains a treatment option based on several randomized clinical trials that did not show a survival benefit for more intensive regimens.128,133-135 The potential role for RT in stage III-IV disease has not been demonstrated in contemporary randomized clinical trials; however, it may be useful in selected clinical situations, such as described in the HD15 trial, below.

The results of the RATHL trial demonstrated that the omission of bleomycin from the ABVD regimen in patients with negative interim PET scan(Deauville score 1-3) after 2 cycles of ABVD resulted in a lower incidence of pulmonary toxicity than with continued ABVD, without impacting efficacy.124 In this trial, patients who had a positive interim PET (Deauville 4-5) had treatment intensified to escalated BEACOPPP.Seven-year PFS and OS for the entire cohort were 78.2% and 91.6%,respectively. Seven-year PFS and OS among patients with positive interim PET scans were 65.9% and 83.2%, respectively. Similar PET-adapted escalation has been evaluated in the U.S. Intergroup trial S0186136,137 and the Italian GITIL/FIL HD 0607 trial.138 For the U.S. Intergroup trial, the 5-year PFS and OS for patients who had a positive interim PET were 65%and 97%,respectively.136,137 Similar results were also seen in the 0607 trial for patients who had a positive interim PET, with a 3-year PFS and OS of 60% and 89%, respectively.138

NCCN Recommendations for Stage III-IV Disease

Based on data from the phase III SWOG S1826 trial,129 nivolumab-AVD is a category 1, preferred treatment option for stage III-IV CHL.

Nivolumab-AVD is initially administered for 6 cycles followed by restaging FDG-PET/CT. Patients with a Deauville score of 1-3 should be followed and monitored for relapse/late effects(see Follow-up After Completion of Treatment). For patients with a Deauville score of 4-5 there are two options: short-interval follow-up with repeat FDG-PET/CT at 12 weeks or biopsy. Clinical judgment is necessary, as residual FDG-uptake can be

seen in the setting of immunotherapy. If biopsy is pursued and positive,treatment is as described for primary refractory disease. If biopsy is negative, follow-up and monitoring for relapse/late effects is recommended. If repeat FDG-PET/CT at 12 weeks is obtained, those with a Deauville score of 1-3 can proceed to follow-up, while biopsy is recommended for patients with a Deauville score of 4-5. For patients in whom biopsy is obtained following repeat FDG-PET/CT at 12 weeks, if positive, treatment is as described for primary refractory disease. If biopsy is negative, follow-up and monitoring for relapse/late effects is recommended. Of note, some patients received ISRT 30 Gy on SWOG S1826. Criteria for RT included Deauville 4-5 (only 1-2 lesions), ≥30%reduction in transverse diameter, residual nodal mass ≥2.5 cm in axial diameter, or residual extranodal lesion >1 cm in axial diameter. Patients with≥3 Deauville 4-5 lesions and/or a lesion that that did not achieve≥30% reduction in transverse diameter were considered to have refractory disease. Patients with a Deauville score of 5 due to new PET-avid lesions were also considered to have refractory disease.

Based on data from the phase III GHSG HD21 trial, 118 BrECADD+ G-CSF is another category 1, preferred treatment option for stage III/IV CHL.BrECADD+ G-CSF is initially administered for 2 cycles followed by restaging FDG-PET/CT. Patients with a Deauville score of 1-3 are treated with 2 additional cycles of BrECADD+ G-CSF(total 4) followed by reassessment with FDG-PET/CT, while patients with a Deauville score of 4-5 are treated with 4 additional cycles of BrECADD(total 6) prior to repeat FDG-PET/CT. Patients with a Deauville score of 1-3 should be followed and monitored for relapse/late effects(see Follow-up After Completion of Treatment). For patients with a Deauville score of 4 after 4 or 6 cycles of BrECADD+ G-CSF, there are 3 options based on clinical judgment: 1) ISRT then follow-up; 2) short-interval follow-up with repeat FDG-PET/CT in 12 weeks; or 3) biopsy. Patients with a Deauville score of 1-3 on short-term follow-up imaging should be followed and monitored

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while ISRT is recommended for those with a Deauville score of 4-5. For patients with a Deauville score of 5 after 4 or 6 cycles of BrECADD, biopsy is recommended. If biopsy is negative, ISRT is recommended. For those with a positive biopsy, treatment is as described for primary refractory disease.

Based on data from the ECHELON-1 trial,132 BV-AVD + G-CSF is included as a category 1, useful in certain circumstances treatment option for stage III-IV CHL. BV-AVD + G-CSF is initially administered for 6 cycles followed by restaging FDG-PET/CT.132 If performing an FDG-PET/CT before completion of 6 cycles, a biopsy is recommended in patients with a Deauville score of 5. Therapy should be re-evaluated for positive biopsies.At the completion of therapy, patients with a Deauville score of 1-3 should be monitored for relapse/late effects(see Follow-up After Completion of Treatment). For patients with a Deauville score of 4-5, biopsy is recommended and, if positive, alternative therapy for primary refractory disease should be pursued. If biopsy is negative, patients can be followed.ISRT to initially bulky or remaining FDG-PET-positive sites at the end of therapy may also be considered.

It must be underscored that the ECHELON-1 trial design was not PET-adapted; consequently, patients treated with ABVD who could have benefited from dose escalation according to current practices or for whom bleomycin could have been omitted were continued on ABVD.Consequently, the superiority of BV-AVD+ G-CSF over PET-adapted ABVD according to the RATHL study has not been established.

ABVD is also included as a category 1, useful in certain circumstances treatment option for those for whom BV and CPI are not available or contraindicated. ABVD is initially administered for 2 cycles followed by restaging with FDG-PET/CT. Patients with a Deauville score of 1-3 are treated with 4 cycles of AVD based on results from the RATHL trial. ${}^{124}$ After 4 cycles of AVD, patients should be followed and monitored for

relapse/late effects (see Follow-up After Completion of Treatment). For patients with a Deauville score of 4-5, recommended treatment is 3 cycles of BrECADD plus G-CSF followed by reassessment of response with FDG-PET/CT. As previously noted, the Panel now recommends treatment escalation to BrECADD plus G-CSF rather than escalated BEACOPPP despite a lack of data for BrECADD in this setting due to the significantly lower treatment-related morbidity and superior efficacy shown with BrECADD in the GHSG HD21 trial.118 For patients with a Deauville score of 1-3 following 3 cycles of BrECADD plus G-CSF, the recommended options are to continue on therapy with 1 additional cycle of BrECADD,alone or combined with ISRT to initially bulky or remaining FDG-PET-positive sites at the end of therapy. A biopsy is recommended for patients with a Deauville score of 4-5. If the biopsy is negative, treatment is as described for patients with a Deauville score of 1-3. For patients with a positive biopsy, treatment is as described for primary refractory disease.

Management of Classic Hodgkin Lymphoma in Adults Aged >60 Years or Adults Unfit for Intensive Therapy

CHL in patients >60 years is associated with worse disease outcomes.B symptoms, poor performance status, mixed cellularity, histologic subtype,EBV-positive (EBV+) disease, and medical comorbidities are more frequent in this population.140 Standard chemotherapy regimens are associated with dose reductions, treatment toxicity, and transplant-related mortality (TRM) in patients who are older. 141-144 However, there are limited prospective data evaluating alternatives to standard therapies for patients who are older. Selection of standard versus alternate first-line regimens for patients who are older or for patients unfit for intensive therapy should be based on clinical judgment and patient's performance status, with the goal of minimizing toxicity while maximizing efficacy.

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In the HD10 and HD13 trials led by the GHSG, the impact of bleomycin in the ABVD regimen in patients $\geq 60$ years with stage I-II favorable HL was evaluated. Two hundred eighty-seven patients were randomized to receive: 2 cycles of ABVD or 2 cycles of AVD followed by 20 or 30 Gy IFRT (HD13 study) and 2 cycles of ABVD or 4 cycles of ABVD followed by 20 or 30 Gy IFRT (HD10 study). ${ }^{145}$ Overall grade III-IV toxicity and grade III-IV leukopenia and infection rates were higher in patients receiving 4 cycles of ABVD. The results of the study suggested limited benefit in patients $\geq 60$ years receiving $>2$ cycles of bleomycin.

Due to pulmonary toxicity, bleomycin should be used with caution, as it may not be tolerated in patients who are older. In a retrospective analysis,147 patients with stage I-IV HL aged≥60 years were treated with ABVD and evaluated for toxicity and survival. ${ }^{146}$ All patients received at least 1 full course of ABVD and 50 patients received additional RT (30-40 Gy).Bleomycin was removed or reduced in 53 patients due to pulmonary toxicity. CR was observed in 117 patients (80%) with a 5-year OS rate estimated at 67% (95% confidence interval [CI], 58-74). ${ }^{146}$ Other risk factors that may be associated with bleomycin-induced pulmonary toxicity (BPT) include a history of smoking and use of G-CSF during treatment. ${ }^{147,148}$

In a phase II multicenter study, the impact of sequential BV given before and after AVD was examined in patients ≥60 years with untreated stage II-IV HL (n=48).149 After two lead-in doses of BV, 37 of 48 patients (77%)completed 6 cycles of AVD, and 35 patients (73\%) received at least one BV consolidation. 149 Among 42 patients with evaluable response, the overall response and CR rates after 6 cycles of AVD were 95% and 90%,respectively.149 By intent-to-treat analysis, the 2-year EFS,PFS, and OS rates were 80%,84%, and 93%, respectively. 149

In a subset analysis of the randomized phase III S1826 trial, 6 cycles of nivolumab-AVD were compared to 6 cycles of BV-AVD in 103 patients ≥60

years with newly diagnosed stage III-IV CHL.150 ISRT was available to patients with residual disease on end-of-treatment FDG-PET. G-CSF was optional for nivolumab-AVD but required for the BV-AVD arm. Two-year PFS and EFS were superior in the nivolumab-AVD arm (PFS: 89% vs. 64%;P=.001;EFS: 89% vs. 58%;P<.001). There was also a significant improvement in 2-year OS with nivolumab-AVD compared to BV-AVD(96% vs.85%; P=.005). Nivolumab-AVD was also better tolerated in patients $\geq 60$ years, with treatment discontinuation due to toxicity more common with BV-AVD. While neutropenia was more common with nivolumab-AVD,BV-AVD was associated with more febrile neutropenia,infections, and sepsis, despite the required G-CSF in the BV-AVD arm.

A phase II study also investigated the safety and efficacy of nivolumab-AVD in 37 patients ≥60 years with newly diagnosed HL of any stage (78% of patients had stage III-IV disease). ${ }^{151}$ Overall response rates (ORRs)and CR rates were 100% and 97%, respectively, and 2-year PFS and OS rates were 86.2% and 96.4%, respectively. No grade 3 or higher immune-mediated AEs were noted.

A phase ll study evaluated the efficacy and safety of BV combined with nivolumab in 21 patients $\geq 60$ years with newly diagnosed advanced-stage HL. ${ }^{152}$ ORR was $86 \%$ , with $67 \%$ achieving a CR. With a median follow-up of 51.6 months, neither median PFS nor OS were reached. Nineteen percent of patients experienced sensory peripheral neuropathy and 19%experienced motor peripheral neuropathy.

The following regimens have also been used as front-line chemotherapy in patients who are older with HL:

● CHOP(cyclophosphamide, doxorubicin, vincristine, and prednisolone)153

● BV plus DTIC${}^{152,154,155}$

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● VEPEMB (vinblastine, cyclophosphamide, prednisolone,procarbazine, etoposide, mitoxantrone, and bleomycin)156,157

● BACOPPP (bleomycin, doxorubicin, cyclophosphamide, vincristine,procarbazine, and prednisone)144

● PVAG(prednisone, vinblastine, doxorubicin, and gemcitabine)158

NCCN Recommendations

The regimens listed below should be considered in patients >60 years or patients unfit for intensive therapy to lessen or minimize toxicity. These regimens have not been proven to overcome the poorer disease outcomes observed in patients who are older. Clinical trials are recommended when available. ISRT or extended-field RT (EFRT) alone are options when systemic therapy is not considered feasible or safe.

Candidate for Anthracycline

Stage I-II Favorable Disease by GHSG Criteria In this setting, 2 cycles of A(B)VD followed by ISRT 20 Gy is recommended.121,146,159 Bleomycin should be used with caution as it may not be tolerated in patients>60 years.

Stage I-II Favorable Disease by EORTC Criteria

In this setting, 3 cycles of A(B)VD with ISRT 30 Gy is recommended.121,146,159 As noted previously, bleomycin should be used with caution as it may not be tolerated in patients>60 years, and it should not be used beyond 2 cycles.

Stage I-II Unfavorable Disease

A(B)VD,BV-AVD+G-CSF,BV lead-in followed by AVD and BV, and nivolumab-AVD with ISRT are included as primary treatment options for patients>60 years or patients with poor performance status or substantial comorbidities with stage I-II unfavorable or stage III-IV disease.124-126,149 For the ABVD regimen, an FDG-PET scan follows treatment with 2 cycles

of ABVD. Bleomycin should not be used beyond 2 cycles if included in the regimen. If the FDG-PET scan is negative(Deauville score 1-3), patients can be treated with either an additional 4 cycles of AVD (total of 6 cycles)or two additional cycles of AVD (total of 4 cycles) followed by ISRT. If the FDG-PET scan is positive(Deauville score 4-5) after 2 cycles of ABVD,an individualized treatment plan should be developed. For patients without neuropathy, BV-AVD + G-CSF can be administered for 4 cycles or lead-in BV can be given for 2 cycles, followed by AVD x 6 cycles, conditionally followed by BV for an additional 2 cycles in patients achieving CR or PR.126,149 Nivolumab-AVD can be given for 4 cycles in combination with ISRT.125

Stage III-IV Disease

Nivolumab-AVD for 6 cycles is a category 1, preferred treatment option for stage III-IV disease.150,151 As described for stage l-II unfavorable disease,BV lead-in followed by AVD and BV can be administered for patients with stage III-IV disease and no neuropathy.149

Not a Candidate for Anthracycline

BV plus DTIC, BV-nivolumab, and nivolumab or pembrolizumab, all with or without ISRT, are included as primary treatment options for patients who are not candidates for anthracycline, regardless of stage.152,154,155

Management of Classic Hodgkin Lymphoma During Pregnancy

CHL is the most common hematologic malignancy diagnosed during pregnancy, as the peak incidence coincides with the reproductive years.160 CHL accounts for 6% of all cancers diagnosed during pregnancy$^{161}$ and as many as 3% of patients presenting with CHL present during pregnancy.$^{160}$

CHL in patients who are pregnant is enriched for the nodular sclerosis subtype and has a similar clinical presentation, natural history, and prognosis compared to patients who are not pregnant.160

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Management of CHL during pregnancy requires a multidisciplinary approach including medical oncology, high-risk obstetrics, and neonatology, with the goal of maximizing the cure rate for the patient as well as allowing for the delivery of a healthy child.160 Treatment of the patient who is pregnant should be individualized based on a multitude of factors, including the symptomatic burden and stage of disease,gestational age, and the beliefs and wishes of the patient.160

Complete radiologic staging of CHL is not required, given the need to minimize potential harm to the unborn fetus.160 Radiologic imaging should,however, help to estimate the stage of disease and should include a PA CXR with abdominal shielding and an abdominal US or MRI without gadolinium.160,161 FDG-PET and CT imaging should be avoided in order to minimize fetal radiation exposure. 160

As most patients diagnosed with CHL during pregnancy have early-stage disease and present with minimal or no symptoms, it is often safe to defer treatment until after delivery with close monitoring and follow-up.160,162-164 In a retrospective analysis by Evens and colleagues that examined treatment outcomes and complications for 90 patients with HL (n = 40)and non-Hodgkin lymphoma (NHL; n = 50) during pregnancy, there were no differences in maternal complications, median birth weight of infants, or perinatal events between those in whom therapy was deferred until the postpartum period and those who received antenatal treatment.165 Twenty-five percent of the patients with HL in this study had advanced-stage disease.

For patients requiring treatment during pregnancy due to severe symptoms or organ compromise,RT should also be avoided given potential risks of teratogenesis, prematurity,cognitive impairment,and childhood malignancy.166 Chemotherapy should be avoided during the first trimester given the high risk of congenital malformations or fetal demise.160,161 ABVD can be safely administered in the second and third

trimesters with excellent maternal and fetal outcomes, 165,167,168 while intensive regimens such as escalated BEACOPP, nivolumab-AVD and BV-AVD should be avoided during pregnancy given the paucity of data.For those receiving chemotherapy during pregnancy, consultation with pharmacy is recommended to ensure supportive medications are appropriate for use in pregnancy. G-CSF is category C in pregnancy.169 Ondansetron and metoclopramide are the preferred antiemetics for patients who are pregnant.170,171 Breastfeeding should be avoided in patients receiving chemotherapy in the postpartum period.160

In the previously discussed retrospective analysis by Evens and colleagues, 20 patients with HL received chemotherapy with either ABVD or AVD, with 13 patients starting chemotherapy in the second trimester and 7 patients starting in the third trimester. ${}^{165}$ An additional 4 patients received RT during the second or third trimester. The ORR for patients with HL who received antenatal therapy was 96%, with 83% of patients achieving CR. As previously noted, among all patients with HL with available obstetrical information, there were no differences in preterm or perinatal complications or median birth weight of infants between those who deferred therapy versus those who received antenatal chemotherapy or RT. There was, however, a trend towards patients who received antenatal therapy having infants who were small for gestational age (41% vs. 9% for patients in whom therapy was deferred,respectively; P=.09). Three-year PFS and OS rates for all patients with HL were 85% and 97%, respectively.

Another retrospective study examined maternal and fetal outcomes of 39 patients with lymphoma (31 with HL, 8 with NHL) during pregnancy.167 Three women electively terminated pregnancy. Of the remaining 36 patients, 12 (31%) deferred therapy until delivery while 24 (61%) received antenatal therapy. Two patients received chemotherapy during the first trimester, one with ABVD or an ABVD-like regimen and the other with a

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CHOP or CHOP-like regimen: Twenty-two patients received therapy during the second or third trimesters, with 4 receiving RT, 13 receiving ABVD or ABVD-like regimens, and 5 receiving CHOP or CHOP-like regimens. The ORR for those who received antenatal therapy was 91.7%,with 75% achieving CR. Among those who did not electively terminate pregnancy, there were no differences in PFS, OS, or rates of preterm delivery among those who received antenatal care and those who deferred antenatal care until delivery. Of the 31 patients with HL, 5-year PFS was 69.9% and 5-year OS was 80%.

In another retrospective study investigating 134 patients diagnosed with HL during pregnancy,56 patients (42%) deferred therapy,72 patients(54%) received antenatal chemotherapy, and 6 patients (4%) received antenatal RT.168 There were no differences in rates of neonates being small for gestational age or requiring neonatal intensive care unit(NICU)admission among those exposed to chemotherapy versus unexposed to chemotherapy, though those exposed to chemotherapy had lower birth weight percentiles (P=.035). In this study, patients who received antenatal therapy did have more obstetrical complications (P=.005),with the most common being preterm contractions and preterm rupture of membranes. A maternal survival analysis compared patients with HL who were pregnant (n = 77) versus not pregnant (n = 211) and found similar 5-year PFS and OS rates among those with early-stage HL (PFS, 82.6%vs.88.3%, respectively; P=.13; OS, 97.3% vs.98.4%, respectively; P=.534). Five-year PFS and OS rates were also similar among patients with HL who were pregnant versus not pregnant with advanced-stage disease(PFS,90.9% vs.74.0%,respectively;P=.334;OS,100% vs.96.2%,respectively; P=.146).

NCCN Recommendations for CHL During Pregnancy

For patients with CHL during pregnancy, the Panel recommends a referral to or consultation with a center with expertise at diagnosis. Referral or

consultation with a center of expertise is especially important in the setting of relapsed refractory CHL during pregnancy.

For patients with CHL in the first trimester of pregnancy who are asymptomatic or minimally symptomatic, the Panel recommends delaying treatment with close observation until the second or third trimester. For those in the first trimester of pregnancy with severe symptoms or organ compromise, referral to a center with expertise should be considered.Pregnancy termination or treatment with single-agent vinblastine followed by ABVD after the start of the second trimester may also be considered for those with severe symptoms or organ compromise.

For patients with CHL in the second or third trimester of pregnancy who are asymptomatic or minimally symptomatic, the Panel recommends delaying treatment with close observation until after delivery. For those in the second or third trimester of pregnancy with severe symptoms or organ compromise, the Panel recommends treatment with ABVD, with involvement of high-risk obstetrics to avoid delivery during the nadir period.

Nodular Lymphocyte-Predominant Hodgkin Lymphoma

NLPHL is characterized by an indolent course and occasional late relapse.It has a different natural history and response to therapy compared with CHL.172 The majority of patients present with early-stage disease and rarely with B symptoms, mediastinal or extranodal involvement, or bulky disease.173-175 Patients who present with bulky disease, subdiaphragmatic disease, or splenic involvement have a high risk for initial or later transformation to large cell lymphoma.3,176 Data suggest outcomes differ for typical immunoarchitectural patterns(A/B) versus variant patterns(C/D/E/F), with the variant patterns being associated with advanced-stage disease and a higher risk of relapse.3,177-179 In the retrospective analysis from the GHSG that included 394 patients with NLPHL, 63% had

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early-stage favorable, 16% had early-stage unfavorable, and 21% had advanced-stage disease. At a median follow-up of 50 months, FFTF (88%vs.82%) and OS (96% vs.92%) were better for NLPHL compared with CHL.174 Among patients with NLPHL,FFTF was better for early-stage favorable disease (93%) compared with early-stage unfavorable (87%)and advanced-stage disease (77%). The European Task Force on Lymphoma also reported favorable FFTF for early-stage disease (85% for stage I; 71% for stage II) compared with those with stage III (62%) or stage IV (24%) disease.173 Advanced stage at presentation, age (≥45 years), low hemoglobin, and the presence of B symptoms are associated with worse OS.174,175

Several retrospective studies have reported favorable clinical outcomes for patients with stage I to II disease treated with RT alone180-184 or in combination with chemotherapy.175,185,186 RT alone is an effective treatment option for patients with stage IA-IIIA disease.180,182,187 In a retrospective analysis, the Australasian Radiation Oncology Lymphoma Group reported follow-up of 202 patients with stage I-II NLPHL treated with RT alone, including mantle and total lymphoid irradiation(TLI). ${}^{182}$ At 15 years, FFP was 84% for patients with stage I disease and 73% for those with stage II disease. An additional retrospective analysis from the GHSG clinical trials reported favorable PFS and OS rates(91.9% and 99.0%, respectively) at 8 years in patients with stage IA disease treated with IFRT. ${}^{187}$ Among the studies that have evaluated the outcomes of patients treated with RT alone or CMT, the subgroup analysis of 64 patients with NLPHL included in the GHSG HD7 trial showed a non-significant trend toward better 7-year FFTF for the combined modality group(96%) compared with the EFRT group(83%; P=.07).186 However,other retrospective studies have shown no difference in outcome between patients treated with RT alone or in combination with chemotherapy.181,183,184 The GHSG retrospectively compared 3 treatment options, including EFRT, IFRT, and CMT in patients with stage IA

NLPHL. ${ }^{183}$ Median follow-up was 78 months for EFRT, 40 months for CMT, and 17 months for IFRT. CRs were observed in 98% after EFRT,95% after CMT, and 100% after IFRT, and no significant differences were seen in FFTF, suggesting that IFRT is equally as effective as EFRT and CMT.

A report from the French Adult Lymphoma Study Group that analyzed the long-term outcomes of 164 patients with NLPH (82% of patients had stage IA-IIA disease) included 58 patients who were observed following diagnosis and lymph node biopsy. ${ }^{188}$ The 10-year PFS rate for this group of patients was 41% compared to 66% for patients who received specific treatment. However, the 10-year OS rate was not different between the two groups (91% and 93%, respectively), and 50% of patients treated with a watch-and-wait approach had achieved a CR at a median follow-up of 3 years. Watchful waiting has also been shown to be an appropriate treatment option in pediatric patients with early-stage NLPH who are in CR following lymph node excision. ${ }^{189,190}$

Binkley et al reported an international retrospective review of 559 adult patients with stage I-II NLPHL treated with RT alone(n= 257), CMT(n=184), chemotherapy alone(n= 47), observation(n= 37), rituximab plus RT(n= 19), or rituximab monotherapy(n= 15). The 5-year PFS and OS rates for the entire cohort were 87.1% and 98.3%, respectively.191 The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after chemotherapy alone,73.5% after observation,80.8% after rituximab plus RT, and 38.5% after rituximab monotherapy.191 The variant immunoarchitectural pattern was associated with a worse PFS. Three point eight percent of patients developed large cell transformation.

In another retrospective study of 163 patients with NLPHL, including 26%with advanced disease, there was a 5-year PFS benefit among those who received active therapy compared to those who underwent active surveillance,(77% vs.87%;P=.017) but there was no significant

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difference in OS.192 Only 27% of patients who were observed eventually required treatment and median onset to treatment was 61 months.

Patients with advanced-stage NLPHL have a worse prognosis than those with early-stage favorable disease and can be treated with chemotherapy.In the European Task Force on Lymphoma study, the 8-year disease-specific survival and FFTF were 94% and 62%, respectively, for stage III disease and 41% and 24%, respectively, for stage IV disease.173 Most of these patients(80%-95%) were treated with chemotherapy(MOPP[mechlorethamine, vincristine, procarbazine, and prednisone]- or ABVD-like regimens), with or without RT.

In the absence of randomized trials comparing different chemotherapy regimens, no preferred chemotherapy regimens exists for NLPHL, although ABVD is often used based on the data for patients with CHL. Savage et al have reported that ABVD chemotherapy with (n = 89) or without (n = 11)RT was associated with superior outcomes compared to a historical cohort of patients treated with RT alone for stage IA, IB, or IIA NLPH.193 With a median follow-up of 6.4 years, patients treated with ABVD-like chemotherapy with or without RT had a superior 10-year time to progression (TTP) (98% vs. 76%), PFS (91% vs. 65%), and OS (93% vs.84%) compared to those treated with RT alone. However, an analysis of the combined data from the CALGB trials and Dana-Farber Cancer Institute trials that included patients with stage III-IV NLPHL treated with chemotherapy alone, showed that 75% of the 12 patients treated with ABVD or EVA (etoposide, vinblastine, and doxorubicin) and 32% of the 25 patients treated with alkylating agent-containing regimens (MOPPP or MOPP/ABVD) had inferior outcomes. 194 Some investigators have also reported good response rates with CHOP plus rituximab195-197 or CVbP(cyclophosphamide, vinblastine, and prednisolone) in patients with early-stage or advanced disease. 198

Because NLPHL cells consistently express CD20 antigen, several clinical studies have explored the efficacy of rituximab, an anti-CD20 antibody, for patients with newly diagnosed and relapsed or refractory NLPHL. ${ }^{199-203}$

In a prospective phase II trial conducted by the Stanford Group, patients with previously treated $(n=10)$ and untreated (n = 12) stage I-IV NLPHL received 4 weekly doses of rituximab at 375 mg/m2. The ORR was 100%(41% CR, 54% partial response [PR], and 5% CR unconfirmed [CRu]). At a median follow-up of 13 months, 9 patients experienced relapse and the estimated median FFP was 10.2 months.199 The estimated probability of disease progression at 10.2 months was 52%. Rituximab was well tolerated, with few adverse side effects.

In a GHSG phase II study that investigated rituximab in patients with newly diagnosed stage IA NLPH(l= 28), the ORR was 100% (CR and PR were achieved in 86% and 14% of patients, respectively). At a median follow-up of 43 months, the OS rate was 100%; the PFS rate at 12, 24,and 36 months was 96%, 85%, and 81%, respectively.201 However, the relapse rate was 25%. In the GHSG phase II study that evaluated rituximab in patients with relapsed or refractory CD20-positive NLPHL(n=15), the ORR was 94% (8 patients with CR and 6 patients with PR). At a median follow-up of 63 months, the median TTP was 33 months and the median OS was not reached.200

Rituximab followed by rituximab maintenance has also been evaluated in patients with newly diagnosed and relapsed or refractory NLPH. In a study conducted by the Stanford Group, patients with newly diagnosed or previously treated NLPHL(n= 39) were treated with rituximab(4 weekly doses of rituximab at 375 mg/m2) or rituximab followed by rituximab maintenance(once every 6 months for 2 years).203 The ORR was 100%(67% CR and 33% PR) at the end of initial therapy with rituximab alone.The median follow-up was 9.8 years for rituximab and 5 years for rituximab plus maintenance rituximab.The estimated 5-year PFS rate was

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39.1% and 58.9%, respectively, for patients treated with rituximab and rituximab followed by maintenance rituximab.The corresponding 5-year OS rates were 95.7% and 85.7%, respectively. Rituximab as initial treatment was also associated with a pattern of relapse with evidence of transformation to aggressive B-cell lymphoma, primarily in patients with intra-abdominal disease. This underscores the importance of biopsy of intra-abdominal sites of disease at initial presentation or relapse.Rituximab maintenance for 2 years was associated with a non-significant increase in median PFS compared to rituximab alone (5.6 years and 3 years, respectively; P=.26).

years, respectively; P=.26).

Collectively, the above data suggest that rituximab alone or in combination with chemotherapy has activity in the management of newly diagnosed and relapsed NLPHL..199,201,203

Binkley et al, representing the global nLPHL One Working Group (GLOW)evaluated treatment outcomes of 2243 patients with stage I-IV NLPH from 38 institutions and developed an LP-IPS.204 The score includes 1 point each for age $\geq$ 45 years, stage III-IV, hemoglobin $<10.5 g$ d/L, and splenic involvement. An increase in the LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31), as well as increased risk of lymphoma-specific death (HR, 2.63) and transformation(HR,1.41).

NCCN Recommendations for NLPHL

Available evidence from retrospective studies supports the use of ISRT alone as a treatment option for patients with early-stage disease.180-184

The Panel recommends that ISRT (30-36 Gy) be the preferred treatment for all patients with stage IA or contiguous stage IIA non-bulky disease.Observation may be an option for highly selected patients with stage IA disease with a completely excised solitary node. A brief course of chemotherapy plus ISRT with rituximab is recommended for patients with

stage IB or IIB disease and for very rare patients presenting with stage IA or IIA bulky disease. For patients with stage IIA non-contiguous disease, a brief course of chemotherapy with rituximab with or without ISRT is recommended. For select patients with stage IB or stage IIA non-contiguous disease, ISRT alone may be considered. Rituximab monotherapy can be used for palliation purposes only in select patients with stage IIA non-contiguous disease.

Chemotherapy and rituximab with or without ISRT is recommended for all patients with stage III-IV disease. Alternatively, patients can be observed if asymptomatic, or treated with rituximab or with local RT for palliation of locally symptomatic disease. Abdominal involvement, especially involvement of the spleen, has been associated with the risk of transformation to an aggressive B-cell lymphoma.203 Biopsy of persistent or new subdiaphragmatic sites should be considered to rule out transformation for patients with stage III or IV disease.

Restaging with FDG-PET should be done for all patients after completion of initial therapy. Observation is recommended for all patients who are asymptomatic with a clinical response. ISRT is recommended if not received previously. Biopsy is recommended for patients with stable or progressive disease, especially of subdiaphragmatic sites. Patients who are asymptomatic with a negative biopsy can be observed. For those with a positive biopsy, treatment is as described for relapsed or refractory disease.

Rituximab may be used in combination with chemotherapy regimens that are most commonly used at NCCN Member Institutions (ABVD,CHOP, or CVbP).193,194,196,198,205 Ongoing clinical trials may clarify the role of observation, rituximab, or combination chemotherapy options for patients with NLPHL. The results of two large randomized trials have demonstrated the non-inferiority of subcutaneous rituximab (rituximab and hyaluronidase human injection for subcutaneous use) compared to IV rituximab when

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used in combination with chemotherapy in patients with certain subtypes of NHL.206,207 Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by IV infusion.

Follow-up After Completion of Treatment

Recommendations included in the Guidelines are based largely on the clinical practices at NCCN Member Institutions and are not supported by high-level evidence, since there are very few data available on the follow-up and monitoring of late effects in patients with HL,after completion of treatment.208

The Panel overwhelmingly agrees that, given the long-term risks of the therapies for HL, patients should follow up with an oncologist who is aware of these risks and complications, and care should be coordinated with the primary care provider, especially during the first 5 years after treatment to detect recurrence and then annually due to the risk for late complications,including secondary cancers and cardiovascular disease.208 The follow-up schedule should be individualized, depending on clinical circumstances such as patient's age, stage of disease, and initial treatment modality.Patients should be encouraged to undergo counseling on issues regarding survivorship, long-term treatment effects(secondary cancers, cardiac disease, and reproduction), health habits, and psychosocial concerns(see the NCCN Guidelines for Survivorship, available at www.NCCN.org). It is recommended that the patient be provided with a treatment summary at the completion of therapy, including details of RT, the dose to the OARs,and cumulative anthracycline dosage given.

Follow-up physical examinations and blood tests (CBC, platelets,chemistry profile, and ESR if elevated at initial diagnosis) should be performed every 3 to 6 months for 1 to 2 years, then every 6 to 12 months for the next 3 years, and then annually. 209 Patients whose thyroid gland

was in the radiation field should have their thyroid function tested at least annually. Annual fasting glucose levels may also be monitored. An annual influenza vaccination and other vaccines as clinically indicated are recommended for all patients (see the NCCN Guidelines for Survivorship,available at www.NCCN.org).In addition, patients treated with splenic RT or splenectomy should receive pneumococcal, meningococcal, and H-flu type b revaccination after 5 to 7 years (according to the current Centers for Disease Control and Prevention [CDC] recommendations).

Once a patient has completed therapy and CR has been confirmed with FDG-PET/CT, surveillance imaging should only be obtained if there is significant clinical concern for relapse, or if mandated in an active protocol.210 Diagnostic CT imaging should be obtained no more frequently than at 3- to 6-month intervals for up to 2 years as clinically indicated, or after 2 years if relapse is suspected. However, PET scans are not recommended for routine surveillance due to the risk of false positives.103,104,106 FDG-PET/CT should only be done if evaluating for potential relapse.

Monitoring for Late Effects

Secondary cancers, cardiovascular disease, hypothyroidism, and fertility issues are the most significant late effects in long-term survivors of HL.The incidence of these late effects increases with longer follow-up time.The risk may be less with current treatment programs compared to those used>10 years ago.

Secondary Cancers

Solid tumors are the most common secondary cancers and most develop>10 years after the completion of treatment. The risk of developing secondary cancers is highest when RT, particularly extended field RT, was used as a component of first-line treatment. Meta-analysis by Franklin and colleagues showed that the risk of developing secondary cancers was

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lower with CMT than with RT alone as the initial treatment.211 The risk was marginally higher with CMT when compared with chemotherapy alone as initial treatment. No significant differences in the risk of developing secondary cancers were seen with IFRT versus EFRT, although the risk of developing breast cancer was substantially higher for EFRT and was likely related to the extent of mediastinal and axillary irradiation. Risks for secondary lung cancer, NHL, and leukemia were increased after treatment with chemotherapy alone, whereas CMT was associated with an increased risk for these and several other cancers. ${ }^{212}$ Lung cancer and breast cancer are the most common secondary cancers in patients treated for HL.

RT, and possibly some chemotherapy drugs such as alkylating agents,increase the risk of developing lung cancer, and the risk increases linearly with dose to the lung. ${}^{213,214}$ The increased risk is most apparent in people who smoke, particularly those who continue to use tobacco after diagnosis. ${}^{215}$

In fact, continuing to smoke after thoracic RT multiplies the risk of developing lung cancer. Therefore, a concerted effort should be made to help patients who currently smoke and require thoracic RT to stop smoking. Lung cancer screening with low-dose CT may also be appropriate depending upon clinical circumstances including age and pack-year tobacco exposure history. See the NCCN Guidelines for Lung Cancer Screening, available at www.NCCN.org.

Breast cancer is the most common malignancy in individuals assigned female at birth and the risk is increased with RT doses as low as 4 Gy.Annual breast screening(mammography and MRI) beginning 8 years after completion of therapy is recommended for individuals assigned female at birth treated with RT to the mediastinum or axilla before age 30. Standard screening is recommended for individuals assigned female at birth treated after age 30.210 They should also be encouraged to be familiar with their

breasts and any changes to them (breast awareness) and undergo breast examination by a health care professional 1 to 2 times per year. In a prospective study that evaluated the sensitivity and specificity of breast MRI with that of mammography in females who received chest irradiation for HL, the sensitivity of the combined MRI and mammography as a combined screening modality was higher than that of MRI or mammography alone (94% for combined MRI and mammography; 67%and 68%, respectively, for MRI and mammography).216 NCCN Guidelines recommend breast MRI in addition to mammography, often alternated every 6 months, for individuals assigned female at birth with intact breast tissue who received irradiation to the chest between ages 10 and 30 years, which is consistent with the recommendation of the American Cancer Society Guidelines.217 Neither MRI nor mammography should be pursued until a patient is at least 25 years of age. See the NCCN Guidelines for Breast Cancer Screening and Diagnosis (BSCR-3),available at www.NCCN.org.There are limited data on screening in individuals assigned male at birth at increased risk.

Recently, anthracycline use has been shown to be associated with an increased risk of breast cancer. Neppelenbroek et al identified a 1.5-fold increase in breast cancer risk for females exposed to >200 mg/m2 of doxorubicin compared to those treated without doxorubicin.218

Chemoprevention with selective estrogen receptor modulators and aromatase inhibitors have been shown to reduce the risk of breast cancer by 50% to 60% in populations at high risk for breast cancer. These trials,however, did not include individuals with prior breast RT for non-epithelial breast cancers. Patients should consider discussion of chemoprevention with their oncologist or breast specialist. See the NCCN Guidelines for Breast Cancer Risk Reduction, available at www.NCCN.org.

NCCN Guidelines recommend that routine surveillance tests for cervical,colorectal, endometrial, lung, and prostate cancer be performed as per the

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NCCN Guidelines for Detection, Prevention, and Risk Reduction (available at www.NCCN.org) and the American Cancer Society Guidelines.219

Cardiovascular Disease

Mediastinal irradiation and anthracycline-based chemotherapy are the highest risk factors for developing cardiac disease, which may be asymptomatic.220-222 RT-induced cardiotoxicity is usually observed >5 to 10 years after completion of treatment. However, cardiovascular symptoms may emerge at any age. Coronary CT angiography abnormalities have been detected in nearly 15% of patients within the first 5 years after treatment, and their incidence significantly increases 10 years after treatment.223 In a multivariate analysis, patient's age at treatment,hypercholesterolemia, hypertension, and RT dose to the coronary artery origins were identified as independent prognostic factors.

Based on data regarding increased long-term risk of cardiac disease,annual blood pressure monitoring(even in asymptomatic individuals) and aggressive management of cardiovascular risk factors is recommended.210 A baseline stress test, echocardiogram, or coronary artery calcium (CAC)score and carotid US (for patients treated with neck RT) should be considered at 10-year intervals after completion of treatment,210,224 or per institutional guidelines.

Hypothyroidism

Abnormal thyroid function, mostly hypothyroidism, is reported in approximately 50% of long-term survivors who received neck or upper mediastinal irradiation.208 A careful thyroid examination should be a part of the physical examination. Thyroid function tests should be done at least annually to rule out hypothyroidism in patients treated with RT to the neck or upper mediastinum if the thyroid was in the RT field.

Myelosuppression

Myelosuppression is the most common side effect of chemotherapy and is associated with increased risk of infections. It is uncommon for myelosuppression to continue for very long beyond completion of the primary treatment program. However, patients who undergo high-dose therapy(HDT)/autologous stem cell rescue (ASCR) or allogeneic hematopoietic cell transplant (HCT) may be at continued risk for infection.Pneumococcal, meningococcal, and H-flu revaccinations are recommended every 5 years for patients treated with splenic RT or splenectomy.225

Infertility

Certain chemotherapy combinations(eg, escalated BEACOPP) may cause immediate and permanent infertility.226,227 Other combinations(eg,ABVD) are only rarely associated with infertility.115,228 Since patients with ovaries who have received chemotherapy with alkylating agents and who maintain short-term fertility may experience premature menopause，113 this should be taken into consideration with respect to family planning.

Pulmonary Toxicity

BPT is well documented in patients with HL treated with bleomycin-containing chemotherapy regimens. Risk factors include older age, cumulative bleomycin dose, pulmonary irradiation, and prior history of lung disease. Some reports have suggested that the use of growth factors increases the incidence of pulmonary toxicity. Martin and colleagues reported that BPT significantly decreases the 5-year OS rate, especially in patients ≥40 years.229 They also showed that the use of growth factors with chemotherapy significantly increases the incidence of BPT(26% vs.9%).Two separate studies confirmed that ABVD chemotherapy can be safely administered at the full-dose intensity without any growth factor support.230,231 Five-year EFS (87.4% vs. 80%, respectively) and OS (94.1% vs. 91.3%, respectively) rates in patients who received ABVD with

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<BeginOfPara>no growth factors were comparable to those in patients who received prophylactic growth factor support with the ABVD regimen.231

Neutopenia is not a risk factor for reduction of dose intensity with ABVD.The NCCN Guidelines do not recommend the routine use of growth factors with ABVD regimens.

Relapsed or Refractory Disease

Classic Hodgkin Lymphoma

Two randomized phase III studies performed by the British National Lympha Investigation232 and the GHSG/European Group for Blood and Marrow Transplantation233 have compared HDT/ASCR with conventional chemotherapy in patients with relapsed or refractory HL. Both studies showed significant improvements in EFS, PFS, and FFTF (with no difference in OS) for patients with relapsed or refractory HL who underwent HDT/ASCR compared with conventional chemotherapy alone.

Studies have suggested that patients with a CR or with chemosensitive disease to second-line therapy have improved outcomes following HDT/ASCR compared to those with resistant disease.234,235 Moskowitz et al reported that the EFS,PFS, and OS were significantly better for patients with disease responding to second-line chemotherapy(60%,62%, and 66%, respectively) compared to those whose disease had a poor response (19%, 23%, and 17%, respectively) (P<.001).234 Sirohi et al also reported similar findings; the 5-year OS rate were 79%, 59%, and 17%, respectively, for patients who were in CR,PR, or those with resistant disease at the time of HDT/ASCR (P < .0001), and the 5-year PFS rates were 69%, 44%, and 14%, respectively (P < .001).235

Several investigators have developed prognostic models to predict the outcome in patients with relapsed or refractory disease undergoing HDT/ASCR. Brice and colleagues used end-of-treatment to relapse interval (≤12 months) and extranodal disease at relapse as adverse

prognostic factors to predict outcome of 280 patients undergoing HDT/ASCR.236 The PFS rates were 93%,59%, and 43%, respectively, for patients with 0 , 1 , or 2 of these risk factors. In a prospective study,Moskowitz and colleagues identified extranodal sites, CR duration of <1 year, primary refractory disease, and B symptoms as adverse prognostic factors associated with poor survival after HDT/ASCR.237 In patients with 0 to 1 risk factor, 5-year EFS and OS were 83% and 90%, respectively,which decreased to 10% and 25% if all factors were present. This prognostic model has been used for the risk-adapted augmentation of treatment for relapsed or refractory disease to improve EFS in patients with poor-risk disease.238 In a retrospective analysis of 422 patients with relapsed disease, Josting and colleagues from the GHSG identified time to relapse, clinical stage at relapse, and anemia at relapse as independent risk factors to develop a prognostic score that classified patients into four subgroups with significantly different freedom from second relapse and OS.239 Investigators of the GEL/TAMO group identified bulky disease at diagnosis, a short duration of first CR(<1 year), detectable disease at transplant, and the presence of >1 extranodal site as adverse factors for OS.240 Other groups have identified extent of prior chemotherapy, ${ }^{241}$ short time from diagnosis to transplant ${ }^{243}$ as significant prognostic factors for OS and PFS.Explant transplantation functional imaging status has also been identified as an independent predictor of outcome and it may be the most important factor in patients with recurrent/refractory HL。244-247 The main potential of these prognostic factor studies is to facilitate comparison of outcomes at different centers, where the preparatory regimens may vary.

Several studies have shown the importance of cytoreduction with second-line chemotherapy before HDT/ASCR.237,248-256 ICE (ifosfamide,carboplatin, and etoposide) and DHAP (dexamethasone, cisplatin, and high-dose cytarabine) are commonly used regimens. Gemcitabine-based combination regimens, such as GVD (gemcitabine, vinorelbine, and

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pegylated liposomal doxorubicin),257 IGEV(ifosfamide, gemcitabine, and vinorelbine),258 GCD(gemcitabine, cisplatin, and dexamethasone),259,260 and GEMOX(gemcitabine and oxaliplatin)261 have also been effective for relapsed or refractory HL. However, none of these regimens have been studied in randomized trials.

Bendamustine, lenalidomide, and everolimus as single agents have also shown activity in patients with relapsed or refractory HL, albeit in an era before the availability of BV or CPls.262-264 In a phase II trial, bendamustine was well tolerated and highly active in patients with heavily pretreated relapsed or refractory disease (including those with HL whose disease did not to respond to HDT/ASCR treatment), resulting in an ORR of 56%among patients with evaluable data (34 out of 36 patients enrolled).262 The ORR by intent-to-treat analysis was 53% (33% CR and 19% PR). The median response duration was 5 months. Lenalidomide and everolimus have also shown single-agent activity in a small cohort of patients with relapsed or refractory HL, resulting in ORRs of 19% and 47%,respectively.263,264 In a phase II study, bendamustine in combination with gemcitabine and vinorelbine (BeGEV) was used as induction therapy before HDT/ASCR in patients with relapsed or refractory HL, resulting in an ORR of 83% (73% CR and 10% PR).265 In a phase II/II study,bendamustine with carboplatin and etoposide also demonstrated 85%response rates (70% CR) in patients with relapsed or refractory HL.266

BV, a CD30-directed antibody-drug conjugate, has demonstrated activity in patients with relapsed or refractory CD30-positive lymphomas.267,268 In a pivotal phase II multicenter study of 102 patients with relapsed or refractory HL after HDT/ASCR, BV induced objective responses and CRs in 75% and 34% of patients, respectively, with a median follow-up of more than 1.5 years. The median PFS for all patients and the median duration of response for those in CR were 5.6 months and 20.5 months,respectively.267 Based on the results of this study, the FDA approved BV

for the treatment of patients with HL after failure of HDT/ASCR or at least two prior chemotherapy regimens in patients who are not candidates for HDT/ASCR. The 3-year follow-up data confirmed durable emissions in patients with disease responding to BV.268 After a median follow-up of approximately 3 years, the estimated median OS and PFS were 40.5 months and 9.3 months, respectively. In patients who achieved a CR on BV, the estimated 3-year OS and PFS rates were 73% and 58%,respectively.268 A systematic review and meta-analysis of effectiveness outcomes for BV revealed similar results to the pivotal phase ll trial, with pooled ORR estimates of 62.6% after 4 cycles, 66.7% after 4 to 6 cycles,and 72% after>6 cycles. Pooled CR rates were similar between all cycle subgroups, at 33.4% after>6 cycles.269

Several studies are investigating the utility of BV in combination with other regimens, as second-line therapy for relapsed or refractory disease prior to HDT/ASCR. Preliminary data from studies that have evaluated BV in combination with ICE or bendamustine have reported PET-negative responses ranging from approximately 75% to 90%.270-272 A trial from Memorial Sloan Kettering Cancer Center (MSKCC) used a PET-adapted design in which 45 patients received 2 cycles of BV followed by a PET scan.270 Patients who achieved a CR after BV (27%) proceeded directly to HDT/ASCR, while patients with residual disease received 2 cycles of augmented ICE. Overall, 76% of patients achieved a CR prior to HDT/ASCR using this PET-adapted approach.270 A similar approach was used by investigators at City of Hope National Medical Center in which 37 patients received 4 cycles of BV followed by a PET scan.273 Patients who achieved a CR after BV (35%) proceeded directly to HDT/ASCR, while those with residual disease received platinum-based chemotherapy.Overall, 65% of patients achieved a CR prior to HDT/ASCR using this approach.273

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The use of BV as consolidation therapy following HDT/ASCR was evaluated in the AETHERA trial.274 For patients with high-risk disease,defined as having primary refractory disease, duration of first CR<1 year,or relapse with extranodal or advanced-stage disease, the phase 3 AETHERA trial randomized patients to receive up to 16 cycles of BV consolidation or placebo post-HDT/ASCR. Patients were required to have obtained a CR, PR, or stable disease to second-line therapy prior to HDT/ASCR. At 5-year follow-up, there was a sustained PFS benefit with BV consolidation compared to placebo(5-year PFS, 59% vs. 41%; HR,0.52; 95% CI, 0.38-0.72) but no difference in OS. Peripheral sensory neuropathy was a common side effect of BV consolidation, but improved or resolved in the majority of patients after discontinuing therapy. 275

Attempts to increase the CR rate prior to HDT/ASCR have led to numerous trials incorporating novel agents into initial second-line therapy.CPIs, including programmed cell death protein 1(PD-1)-blocking monoclonal antibodies(eg, nivolumab or pembrolizumab), have also demonstrated activity in patients with relapsed or refractory PD-1-positive lymphomas(either as monotherapy or in combination regimens).276-289

In a phase II study (CheckMate 205 trial) of 80 patients with relapsed or refractory HL pretreated with both HDT/ASCR and BV, at a median follow-up of 8.9 months, nivolumab monotherapy induced an ORR of 66.3% (95% CI, 54.8-76.4) as determined by an independent radiologic review committee.277 Extended follow-up of the CheckMate 205 trial analyzed the safety and efficacy of nivolumab in patients with relapsed or refractory HL according to treatment history: BV-naive, BV received after HDT/ASCR, or BV received before and/or after HDT/ASCR.278 The ORR was 69% (95% CI, 63%-75%) overall and 65% to 73% in each cohort,with a median duration of response of 16.6 months (95% CI, 13.2-20 months). 278

In a phase III trial (KEYNOTE-204), pembrolizumab monotherapy versus BV was evaluated on the parameters of safety and efficacy in adults with relapsed or refractory CHL (patients who were ineligible for transplant or those with relapse after autologous HCT); 151 patients were randomly assigned to pembrolizumab and 153 patients to BV. ${}^{283}$ At second interim analysis, primary endpoint PFS (OS not analyzed in interim analysis) was 13.2 months for pembrolizumab and 8.3 months for BV (P = .0027). 283 Treatment-emergent AEs (TEAEs) were observed in 74% of patients receiving pembrolizumab and 77% of patients receiving BV. The most common grade 3-5 TEAEs were pneumonitis (4% in the pembrolizumab group vs.1\% in the BV group), neutropenia (2% vs. 7\%, respectively),decreased neutrophil count (1% vs. 5%, respectively), and peripheral neuropathy (1% vs. 3%, respectively).283 Serious TEAEs were observed in 16% of patients receiving pembrolizumab and 11% of patients receiving BV. ${}^{283}$

Nivolumab in combination with BV was evaluated as an option for relapsed or refractory HL prior to transplant. ${ }^{280}$ In a phase I/II study of 91 patients with relapsed or refractory CHL, the combination of nivolumab with BV resulted in an ORR of 85% (67% CR). At a median follow-up of 34 months, the estimated 3-year PFS and OS rates were 77% (91% for patients who underwent HDT/ASCR directly after study treatment with BV+ nivolumab) and 93%, respectively. ${ }^{280}$ Nivolumab alone or in combination with ICE as second-line therapy and bridge to autologous HCT was studied in a phase II trial in patients with relapsed or refractory CHL. ${ }^{285}$ In this study, patients received up to 6 cycles of nivolumab. Those in CR after cycle 6 went on to autologous HCT while those with progressive disease at any point or those not in CR after cycle 6 received 2 cycles of nivolumab plus ICE. Following nivolumab alone, ORRR and CR rates were 81% and 71%, respectively. Following nivolumab/nivolumab plus ICE,ORR and CR rates were 93% and 91%, respectively. Two-year PFS and OS were $72 \%$ and $95 \%$ , respectively, in all patients, with 2-year PFS of

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94% in those who bridged directly to autologous HCT.285 In a separate cohort, 35 patients with high-risk relapsed/refractory (R/R) CHL received non-PET-adapted, non-sequential nivolumab-ICE (NICE).290 Patients received 1 cycle of single-agent nivolumab followed by 2 cycles of NICE prior to FDG-PET/CT. A third cycle of NICE was optional. Patients achieving CR could proceed to autologous HCT, as could patients achieving a PR per physician discretion. With a median follow-up of 31.2 months, ORR was 100%, with a CR rate of 86%. Ninety-one percent of patients were successfully bridged to autologous HCT. Among all patients,2-year PFS and OS were 88% and 100%, respectively, while 2-year PFS and OS among patients who were bridged to autologous HCT were 94%and 100%, respectively. The majority of AEs, including immune-mediated AEs, were grade 1-2.

Pembrolizumab used in combination with GVD has also demonstrated activity as second-line treatment in transplant-eligible patients with relapsed or refractory CHL resulting in a CR rate of 95%.284 At a median follow-up of 13.5 months, all patients who had undergone transplant had achieved remission.

A phase II trial evaluated the combination of the PD-1 inhibitor camrelizumab with low-dose decitabine in 86 patients with relapsed or refractory CHL who had received ≥2 prior lines of therapy.286 Patients with prior PD-1 inhibitor exposure received combination therapy, while those without prior PD-1 inhibitor exposure were randomized to combination therapy or camrelizumab monotherapy. With a median follow-up of 14.9 months, CR rate was significantly higher in the combination arm(71% vs.32%;P=.003).Among patients with prior PD-1 inhibitor exposure, ORR was 52%, with 28% achieving CR. One hundred percent of patients treated on the combination arm maintained response at 6 months,compared to 76% with camrelizumab monotherapy. In a follow-up study evaluating responses to combination therapy among patients with prior

PD-1 inhibitor exposure in the original test cohort (n = 25) plus an expansion cohort (n = 26), ORR and CR rates were 52% and 36%,respectively,in the test cohort, and 68% and 24% in the expansion cohort.287 Median PFS was 20 months in the test cohort and 21.6 in the expansion cohort. An additional extended follow-up study of patients without prior PD-1 inhibitor exposure who were randomized to combination therapy versus monotherapy continued to show a significant CR benefit with combination therapy at 34.5 months (79% vs. 32%; P=.001).288 Median PFS was 35 months with combination therapy compared to 15.5 months with monotherapy(P=.02). Factors predicting durable remission with camrelizumab monotherapy included lower tumor burden, fewer prior therapies, and female gender.

A phase l/ll study compared PD-1 inhibitor pembrolizumab monotherapy with pembrolizumab combined with vorinostat in patients with relapsed or refractory CHL who had received ≥1 prior therapy and were not eligible for HDT/ASCR.289 Seventy-eight percent of patients had been exposed to PD-1 inhibitor therapy, with 56% having PD-1 refractory disease. ORR was 72%, with a CR rate of 34%. Among patients with PD-1 refractory disease,ORR and CR rates were 56% and 11%, respectively. Grade ≥3 AEs included cytopenias, hypertension, and hypoposphatemia.

The PD-1 inhibitor tisleizumab was studied in combination with GEMOX in a multicenter, single-arm phase II trial in 30 patients with R/R CHL in China.291 Patients received 6 to 8 cycles of tisleizumab with GEMOX,followed by tisleizumab maintenance for 2 years. ORR was 100%, with 96.7% of patients achieving a CR. One-year PFS was 96% without autologous HCT. The majority of AEs were grade 1-2, with the most common grade ≥3 AEs being hematologic.

The role of RT in the second-line therapy setting includes its use to cytoreduce prior to HDT/ASCR, its selective use to sites of relapse following HDT/ASCR, and occasionally its use as a primary component of

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second-line therapy. Moskowitz and colleagues have demonstrated the efficacy and feasibility of second-line RT with chemotherapy in patients with relapsed or refractory disease.237 At a median follow-up of 43 months,the response rate to ICE and IFRT was 88% and the EFS rate for patients who underwent HDT/ASCR was 68%. Thus, RT may improve the chance of transitioning to HDT/ASCR in relapsed or refractory disease.

Alternately, second-line RT may be effective in patients who are in good performance status with limited-stage late relapses and without B symptoms. It may be a very effective treatment for patients with initial favorable stage I-II disease who are treated with chemotherapy alone and relapse in initially involved sites. Josting and colleagues from the GHSG reported that second-line RT may be effective in a select subset of patients with relapsed or refractory disease.292 The 5-year FFTF and OS rates were 28% and 51%, respectively. B symptoms and stage at the time of disease progression or relapse were identified as significant prognostic factors for OS. A comprehensive review and recommendations for incorporation of RT into treatment regimens for relapsed or refractory disease are provided by the International Lymphoma Radiation Oncology Group consensus guidelines.293

NCCN Recommendations for Primary Refractory or Relapsed CHL Within 3 Months: Candidates for HDT/ASCR

Histologic confirmation with biopsy is recommended before initiating treatment for primary refractory or relapsed disease. For biopsy-proven refractory disease or relapsed disease, enrollment in a clinical trial is recommended, if available. Referral to or consultation with a center with expertise should be pursued. Although further cytoreduction and HDT/ASCR(with RT if not previously given) are often appropriate,occasional clinical circumstances may warrant the use of RT or systemic therapy with or without RT. RT should be strongly considered for selected sites of relapse that have not been previously irradiated.

Second-line systemic therapy followed by response assessment with FDG-PET/CT is recommended for all patients. CPI-based therapy is preferred for those who have not previously received a CPI and have no contraindications to a CPI. Patients with a Deauville score of 1-3 should proceed to HDT/ASCR with or without RT(category 1). HDT/ASCR with or without RT is also an option for those with a Deauville 4 response, though PET negativity prior to HDT/ASCR is preferred.247 Following HDT/ASCR,maintenance therapy with BV can be considered for patients with no prior BV exposure and high risk of relapse as defined by the AETHERA trial(defined as those having primary refractory disease, duration of first CR<1 year, or relapse with extranodal or advanced-stage disease). 274

An alternative systemic therapy regimen with or without RT or RT alone are additional recommended treatment options for patients with a Deauville score of 4 after second-line systemic therapy, and are also options for patients with a Deauville score of 5. For those achieving response to alternative systemic therapy, HDT/ASCR may be considered.HDT/ASCR would be followed by maintenance therapy with BV for patients with a high risk of relapse. 275 It is worth noting that the role of maintenance BV has not been well defined in patients who received BV earlier in the management of their disease. CPIs can be continued despite progression on imaging if patients are deriving clinical benefit, as imaging progression may be indicative of immune flare rather than true progression.294

CPI-based second-line and subsequent therapy options include:

● Nivolumab combined with ICE285,290 or BV280,295

● Pembrolizumab combined with GVD284 or ICE296

● Tislelizumab combined with GEMOX291

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Non-CPI second-line and subsequent therapy options include:

● BV alone267 or in combination with bendamustine272 or ICE297

● DHAP249,252

● Gemcitabine/bendamustine/vinorelbine265

● GVD257

● ICE 237,249,298

● IGEV258

Bendamustine, bendamustine/carpbloatin/etoposide,decitabine/pembrolizumab, GCD, GEMOX, ISRT, vinblastine, and vorinostat/pembrolizumab are included as therapy options for patients with disease refractory to at least 3 prior lines of therapy.259,261,262,266,287-289,299 Nivolumab and pembrolizumab can also be re-used in this setting.

NCCN Recommendations for Biopsy-Proven Relapsed CHL After≥3 Months: Candidates for HDT/ASCR

Suspected relapse at any point should be confirmed with biopsy. For patients with biopsy-proven relapse after ≥3 months, second-line systemic therapy is recommended followed by restaging with FDG-PET/CT. CPI-based therapy is preferred for those without prior CPI exposure and without contraindications to a CPI.

For patients with a Deauville score of 1-3 following restaging, HDT/ASCR with or without RT is recommended, with strong consideration for RT to selected sites that have not been previously irradiated. BV maintenance should be considered for patients undergoing HDT/ASCR who have not previously received BV and with high risk of disease relapse.275 For patients with initial stage l-IIA disease treated initially with abbreviated

chemotherapy alone (3-4 cycles) and relapsed only at initial sites of disease,RT alone may be appropriate.

For patients with a Deauville score of 4 after restaging, options include HDT/ASCR with or without RT, RT only, or subsequent systemic therapy with or without RT. For patients with a Deauville score of 5 after restaging,RT alone or subsequent systemic therapy with or without RT are options,and if there is response, HDT/ASCR can be considered. For those with a Deauville score of 4 or 5 proceeding to HDT/ASCR, BV maintenance should be considered for those at high risk of disease relapse who have not previously received BV. ${}^{275}$ For those receiving RT alone or subsequent therapy with or without RT, observation is recommended.

NCCN Recommendations for the Management of Relapsed or Refractory CHL in Adults Who Are Not Candidates for HDT/ASCR For individuals with relapsed or refractory disease who are not candidates for HDT/ASCR, clinical trials are recommended for appropriate patients.The Panel also notes the importance of referring to or consulting with a center with expertise and that individualized treatment is necessary.

Otherwise, a CPI-containing regimen for 4 cycles is recommended for those who have not received a CPI in the past, or for those who experienced progressive disease≥3 months following a CPI-based regimen. For those who have previously received a CPI or BV and have experienced progressive disease within 3 months of the regimen, either a CPI- or BV-based regimen for 4 cycles can be utilized. Restaging after 4 cycles is recommended for all instances. For those on CPI-containing regimens with a Deauville 1-4 response, or a Deauville 5 response with clinical benefit, continuation of the CPI-containing regimen is recommended, with or without ISRT, as long as there is continued clinical benefit. Repeat imaging is recommended no more than every 3 months unless there is clinical concern for progression. For patients on a CPI-containing regimen with a Deauville 5 response without clinical benefit, or

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with new symptomatic disease, subsequent therapy options, with or without RT, should be pursued. For patients on a BV-containing regimen with a Deauville 1-4 response, it is recommended to continue the BV-containing regimen until progression or unacceptable toxicity, with or without RT. For those on a BV-containing regimen with a Deauville 5 response or with new symptomatic disease, subsequent therapy options,with or without RT, are recommended.

Alternatively, for patients who initially received an abbreviated course of chemotherapy (3-4 cycles) without RT, second-line systemic therapy with ISRT is an option followed by restaging FDG-PET/CT. CPI-based therapy is preferred for those who have not previously received a CPI. Patients with a Deauville 1-3 response can be followed, while subsequent therapy options, with or without RT, should be pursued for patients with a Deauville 4-5 response.

Single-agent palliative options include nivolumab,277,278 pembrolizumab,282,283 bendamustine,262 BV,267 everolimus,264 gemcitabine,300 lenalidomide,263 or vinblastine.299 ISRT is also an option.

Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Relapsed or refractory NLPHL can be managed with second-line therapy as described below. However, some patients have chronic indolent disease and may not require aggressive treatment. Individualized treatment is recommended since there are no data available to support a superior outcome with any of the treatment modalities. Rituximab should be considered with all second-line chemotherapy regimens for patients with relapsed or refractory NLPHL.

NCCN Recommendations for Refractory or Suspected Relapsed NLPHL Late relapse or transformation to DLBCL has been reported in patients with NLPHL.301-303 In a study of 95 patients diagnosed with NLPHL, with a median follow-up of 6.5 years, transformation to aggressive lymphoma

was seen in 13 (14%) patients and the actuarial risk at 10 and 20 years was 7% and 30%, respectively.303

Re-biopsy should be considered to rule out transformation to aggressive lymphoma prior to initiation of treatment for refractory disease or suspected disease relapse. Patients with a negative biopsy can be observed with short-interval follow-up. For patients with biopsy-proven relapsed NLPHL who are asymptomatic or with low tumor burden,observation or treatment with rituximab or ISRT followed by restaging with FDG-PET/CT are options. For patients with biopsy-proven relapsed NLPHL who are symptomatic or with high tumor burden, second-line therapy(rituximab with or without chemotherapy) with or without ISRT without or without HDT/ASCR followed by restaging with FDG-PET/CT are options. For both patients with asymptomatic/low tumor burden disease and patients with symptomatic/high tumor burden disease with clinical response, observation is appropriate for patients who are asymptomatic.HDT/ASCR is an alternative option if not previously done. For patients with disease that has not responded or patients with progressive disease,biopsy should be considered to rule out transformation. At this stage,subsequent treatment options include any second-line chemotherapy that was not previously used, followed by re-evaluation with FDG-PET.Maintenance rituximab for 2 years may be considered for patients treated with rituximab alone.203 Disease transformation to DLBCL should be managed as discussed in the NCCN Guidelines for B-Cell Lymphomas(available at www.NCCN.org).

Summary

HL is an uncommon malignancy of B-cell origin. CHL and NLPHL are the two main types of HL. CHL is characterized by the presence of Reed-Sternberg cells in an inflammatory background, whereas NLPHL is characterized by the presence of lymphocytic and histiocytic (LP or“popcorn”) cells.

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Current management of CHL involves treatment with chemotherapy or CMT, followed by restaging with FDG-PET/CT to assess treatment response using the Deauville criteria (5-PS). Both CMT and chemotherapy alone are included as treatment options for patients with stage I or II CHL.Systemic therapy (nivolumab-AVD and BrECADD + G-CSF are included as preferred treatment options) followed by restaging with FDG-PET/CT to assess treatment response is recommended for patients with stage III-IV CHL.

Second-line systemic therapy, with CPI-based therapy preferred for those with no prior exposure to and no contraindications to a CPI, followed by HDT/ASCR with or without RT is recommended for the majority of patients with relapsed or refractory CHL. Maintenance therapy with BV following HDT/ASCR can be considered for patients at high risk of relapsed disease. BV (as monotherapy or in combination regimens) is also included as a second-line therapy option for relapsed or refractory disease in appropriate patients.

ISRT is the preferred treatment for patients with stage IA or IIA non-bulky NLPHL. Observation may be an option for highly selected patients with stage IA disease with a completely excised solitary node. A brief course of chemotherapy plus ISRT with rituximab is recommended for patients with stage IB or IIB disease and for very rare patients presenting with stage IA or IIA bulky or non-contiguous disease. Palliative rituximab can be considered for palliation in select patients with stage IA or IIA bulky or non-contiguous disease or stage IB or IIB disease. Chemotherapy with rituximab and with or without ISRT is recommended for all patients with stage III-IV disease. Alternatively, selected patients with stage III-IV disease can either be observed(if asymptomatic) or treated with local palliative RT or rituximab.

Late relapse or transformation to DLBCL has been reported in patients with NLPHL. In patients with suspected relapse, re-biopsy should be

considered to rule out transformation to DLBCL. Relapsed or refractory NLPHL can be treated with second-line therapy. However, some patients have chronic indolent disease and may not require aggressive treatment,unless they are symptomatic.

Long-term follow-up with careful monitoring for late treatment-related side effects and counseling about issues of survivorship should be an integral part of management of HL. Consistent with NCCN philosophy,participation in clinical trials is always encouraged.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hodgkin Lymphoma

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203. Advani RH, Horning SJ, Hoppe RT, et al. Mature results of a phase II study of rituximab therapy for nodular lymphocyte-predominant Hodgkin lymphoma. J Clin Oncol 2014;32:912-918. Available at:http://www.ncbi.nlm.nih.gov/pubmed/24516013.

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230. Boleti E, Mead GM. ABVD for Hodgkin's lymphoma: full-dose chemotherapy without dose reductions or growth factors. Ann Oncol 2007;18:376-380. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17071938.

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232. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet 1993;341:1051-1054. Available at:http://www.ncbi.nlm.nih.gov/pubmed/8096958.

233. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet 2002;359:2065-2071.

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237. Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood 2001;97:616-623. Available at:http://www.ncbi.nlm.nih.gov/pubmed/11157476.

238. Moskowitz CH, Yahalom J, Zelenetz AD, et al. High-dose chemo-radio therapy for relapsed or refractory Hodgkin lymphoma and the significance of pre-transplant functional imaging. Br J Haematol 2010;148:890-897. Available at:http://www.ncbi.nlm.nih.gov/pubmed/20085577.

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243. Horning SJ, Chao NJ, Negrin RS, et al. High-dose therapy and autologous hematopoetic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results and prognostic indices. Blood 1997;89:801-813. Available at:http://www.ncbi.nlm.nih.gov/pubmed/9028311.

244. Jabbour E, Hosing C, Ayers G,et al. Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer 2007;109:2481-2489. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17497648.

245. Mocikova H, Pytlik R, Markova J, et al. Pre-transplant positron emission tomography in patients with relapsed Hodgkin lymphoma. Leuk Lymphoma 2011;52:1668-1674. Available at:http://www.ncbi.nlm.nih.gov/pubmed/21699377.

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257. Bartlett NL, Niedzwiecki D, Johnson JL, et al. Gemcitabine,vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvageae regimen in relapsed Hodgkin's lymphoma: CALGB 59804. Ann Oncol 2007;18:1071-1079. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17426059.

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表 1
Excisional biopsy Core needle biopsy	Essential: -38℃; drenching night sweats; or weight loss >10% of body weight within 6 mo of diagnosis), alcohol intolerance, pruritus, fatigue, performance status, and examination of lymphoid regions, spleen, and liver	Classic Hodgkin lymphoma (CHL)k HODG-2
Excisional biopsy Core needle biopsy	●Complete blood count (CBC), differential ●Erythrocyte sedimentation rate (ESR) ●Comprehensive metabolic panel, lactate dehydrogenase (LDH), and liver function test (LFT) ●Human immunodeficiency virus (HIV) testing (See NCCN Guidelines for Cancer in People with HIV) ●Pregnancy test for those of childbearing potential prior to cytotoxic chemotherapy or radiation therapy (RT)	Classic Hodgkin lymphoma (CHL)k HODG-2
Excisional biopsy (recommended)	-Pregnancy test for those of childbearing potential prior to cytotoxic chemotherapy) or radiation therapy (RT)
Core needle biopsy	-FDG-PET/CT scan (skull base to mid-thigh or vertex to feet in selected cases)	-S-counsl: Fertility/psychosocial $^{e}$ and smoking cessation (See NCCN Guidelines for Smoking Cessation)
Immunohistochemistry evaluationb	●Counseling: Fertility/psychosocial $^{e}$ and smoking cessation (See NCCN Guidelines for Smoking Cessation)
Useful in selected cases:	-		Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) per WHO 5th edition1
-Fertility preservation $^{e}$
-Pulmonary function tests ([PFTs] including diffusing capacity of the lung for carbon monoxide [DLCO])$^{h}$ if ABVD is being used			HODG-11
-Pulmonary B/C testing (encouraged)			Hodgkin lymphoma (NLPHL) per WHO 5th edition1
-Diagnostic CTi (contrast-enhanced)
-Chest x-ray (encouraged, especially if large mediastinal mass)
●Adequate bone marrow biopsy if there are unexplained cytopenias other than anemia and negative FDG-PETj
●Echocardiogram or multigated acquisition (MUGA) scan if anthracycline-based chemotherapy is indicated
●MRI of select sites, with contrast unless contraindicated ●FDG-PET/MRI (skull base to mid-thigh) without contrast

表 2
Stage	Bulky Mediastinal Diseaseem or>10 cm Adenopathy	# of Nodal Regions	ESR ≥50 mm/hr	E-lesion(s)	Type	Guidelines Page
IA/IIA	No	≤2	No	No	Favorable Disease by GHSG Criteria	HODG-5
IA/IIA	No	≤3	No	Yes/No	Favorable Disease by EORTC Criteria	HODG-5A
IA/IIA	Yes	Any	Yes/No	Yes/No	Unfavorable Disease	HODG-6
IB/IIB	Yes/No	Any	Yes/No	Yes/No	Unfavorable Disease	HODG-6
III-IV	Yes/No	Any	N/A	Yes/No	Advanced Disease	HODG-7

表 3
Risk Factor	GHSG	EORTC	NCCN
Age			≥50 mm/hr
ESR and B symptoms	≥50 mm/hr if A;≥30 mm/hr if B	≥50 mm/hr if A;≥30 mm/hr if B	≥50 mm/hr or any B symptoms
Mediastinal massn	MMR >0.33	MTR >0.35	MMR >0.33
# Nodal regions	≥3^{*}	≥4^{*}	≥4
E lesion	any
Bulkyn

表 4
		Ann Arbor Nodal Sites	EORTC Nodal Regions	GHSG Nodal Regions
Supradiaphragmatic	R Cervical/Supraclavicular
Supradiaphragmatic	R ICL/Subpectoral
Supradiaphragmatic	R Axilla
Supradiaphragmatic	L Cervical/Supraclavicular
Supradiaphragmatic	L Infraclavicular/Subpectoral
Supradiaphragmatic	L Axilla
Supradiaphragmatic	Mediastinum
Supradiaphragmatic	R Hilum
Supradiaphragmatic	L Hilum
Infradiaphragmatic	Celiac/Spleen hilar
Infradiaphragmatic	Para-aortic
Infradiaphragmatic	Mesenteric
Infradiaphragmatic	R Iliac
Infradiaphragmatic	L Iliac
Infradiaphragmatic	R Inguinal/Femoral
Infradiaphragmatic	L Inguinal/Femoral

表 5
	Follow-up After Completion of Treatment Up to 5 Years
Interim H&P	●Every 3-6 months for 1-2 years, then every 6-12 months until year 3, then annually.
Vaccines	●Annual influenza vaccine and other vaccines as clinically indicated (see NCCN Guidelines for Survivorship).
Laboratory studies2:	CBC,ESR (if elevated at time of initial diagnosis), chemistry profile as clinically indicated. Thyroid function tests (TFTs) at least annually if thyroid gland was in the RT field.
Counseling	Reproduction, health habits, psychosocial, cardiovascular, breast awareness, skin cancer risk, end-of-treatment discussion (see NCCN Guidelines for Survivorship).
Cardiovascular Toxicity Screening	●ECHO at 1 year after completion of anthracycline therapy. ●Imaging should only be obtained if significant clinical concern for relapse or as mandated if enrolled in an active protocol. ●If imaging is necessary, it may include diagnostic CT at 3- to 6-month intervals for up to 2 years as clinically indicated, or after 2 years if relapse is suspected. FDG-PET/CT should only be done if last FDG-PET/CT was Deauville 4-5, to confirm CR at the end of all prescribed therapy including RT. Once negative, repeat FDG-PET/CT should not be done unless evaluating suspicious findings on H&P or CT.
	●Surveillance FDG-PET/CT should not be done routinely due to risk for false positives. Management decisions should not be based on FDG-PET scan alone; clinical or pathologic correlation is needed.

表 6
Score	Score	PET/CT Scan Result
Negative	1	No uptake
Negative	2	Uptake ≤ mediastinum
Negative	3	Uptake > mediastinum but ≤ liver
Positive	4	Uptake moderately higher than liver and visually above adjacent background activity
Positive	5	Uptake markedly higher than liver and/or new lesions
Positive	xa	New areas of uptake unlikely to be related to lymphoma

表 7
Primary Systemic Therapy Regimens	Primary Systemic Therapy Regimens (Listed in Alphabetical Order)
Stage I-II Favorable Disease by GHSG Criteria	●A(B)VDC,d,e,m (2 cycles)+ISRT 20 Gyf,1,11,12	IsRT 20 Gyf,1,11,12
Stage I-II Favorable Disease by EORTC Criteria	●A(B)VDC,d,e,m (3 cycles)+ISRT 30 Gyf,1,11,12
Stage I-II Unfavorable	●A(B)VDC,d,e,m (2 cycles) followed by AVD (4 cycles), if FDG-PET scan is negative after 2 cycles of ABVD.133 patients with a positive FDG-FET scan after 2 cycles of ABVD need individualized treatment. ●A(B)VDC,d,e,m x 4 cycles+ISRTf,14 ●BV x 2 cycles followed by AVD x 6 cycles, conditionally followed by BVX 2 cycles in patients with CR or PR and no neuropathy-I,j,k,15	Any Age and Not a Candidate for Anthracycline
Stage III-IV Disease	●Nivolumab-AVD x 6 cyclesd,I,16,17 (category 1, preferred) ●If contraindications to CPI: BV x 2 cycles followed by AVD x 6 cycles, conditionally followed by BVX (4 cycles) in AVD x 6 cycles, conditionally followed by CVR and no neuropathy-I,j,15	●BV-Nivolumab± ISRTf,i,j,20 ●Nivolumab or Pembrolizumab± ISRTf (if contraindications to BV)

表 8
Primary Systemic Therapy Regimens (Listed in Alphabetical Order)
	Any Age and Not a Candidate for Anthracycline
Stage I-IV	●BV-DTIC (Dacarbazine) ± ISRTf,i,j,18,19 ●BV-Nivolumab ± ISRTf,i,j,20
	●Nivolumab or Pembrolizumab ± ISRTf (if contraindications to BV)

表 9
Primary Refractory Disease or Relapse(within any time frame)(Candidate for or Not a Candidate for HDT/ASCR)	Additional Considerations for Relapsed/ Refractory CHL (Not a Candidate for HDT/ ASCR)
Second-Line and Subsequent Therapyq,r(in alphabetical order)	Therapy for Disease Refractory to at Least 3 Prior Lines of Subsequent Therapy(in alphabetical order)	●Individualized treatment is necessary. ● For localized relapse, consolidative ISRT should be strongly considered.f ● Refer to or consult a center with expertise. ●Single-agent palliative therapy options include: CPI: □Nivolumab24,25 Non-CPI-containing regimens: □Bendamustum82,27 Non-CPI containing regimen: ▶▶Voinostat-Pembrolizumab28 Everolimus29 √ISRTf
CPI-containing regimens ●BV-Nivolumab1,1	● Bendamustine17	●Individualized treatment is necessary. ● For localized relapse, consolidative ISRT should be strongly considered.f ● Refer to or consult a center with expertise. ●Single-agent palliative therapy options include: CPI: □Nivolumab24,25 Non-CPI-containing regimens: □Bendamustum82,27 Non-CPI containing regimen: ▶▶Voinostat-Pembrolizumab28 Everolimus29 √ISRTf
CPI-containing regimens ●BV-Nivolumab1,1	● Bendamustine/carbolopatin/etoposide18 ● GEMOC-tislelizumab-jsgr2 ●GVD-Pembrolizumab3 ●ICE-Nivolumab4,5 ●ICE-Pembrolizumab6	● Single-agent palliative therapy options include: □Nivolumab24,25 口Pembrolizumab26,27 Non-CPI containing regimen: ▶▶Bendamustine17 Bendamustum82,27 Non-CPI containing regimens: ▶▶ISRTd,17 Everolimus29 √ISRTf
Non-CPI-containing regimens ●BV-Bendamustine1,1,8	● Nivolumab24,25 ●Pembrolizumab26,27	For 1,39,30
●BV-Bendamustine1,1,8	● Vorinostat-Pembrolizumab28	For 1,49
●DHAP(Dexamethasone/Cisplatin/High-Dose Cytarabine)9,10	Consider referral for allogeneic HCT in appropriate patients	◆ Gemcitabine30 √Lenalidomide31
●GVD (Gemcitabine/Vinorelbine/Liposomal Doxorubicin)12	appropriate patients	◆ Vinblastine32

表 10
OAR	OAR	Dose Recommendation (1.5-2 Gyfraction)	Toxicity
Head and Neck	Pituitary gland	Mean<30 Gy	Hormone deficiencies15
Head and Neck	Optic nerves and chiasm	Dmax<45 Gyrd	Optic neuropathy16
Head and Neck	Retina	Dmax<35 Gyrd	Retinopathy16
Head and Neck	Lacrimal glands		Dry eye syndrome17
Head and Neck	Parotid glandsc	Ipsilateral:Mean<11 Gy(recommended);<24 Gy (acceptable) Contralateral: as low as reasonably achievable (ALARA)	Xerostomia18,19
Head and Neck	Submandibular glandsc	Ipsilateral:Mean<11 Gy(recommended);<24 Gy (acceptable) Contralateral: ALARA	Xerostomia20
Head and Neck	Oral cavity (surrogate for minor salivary glands)	Mean<11 Gy	Xerostomia, dysgeusia, oral mucositis20
Head and Neck	Thyroid	V25 Gy<63.5% Minimize V30 Gy	Hypothyroidism21
Head and Neck	Larynx/Pharyngeal constrictors	Mean<25 Gy	Laryngeal edema, dysphagia22
Head and Neck	Carotids	Ipsilateral: Avoid hotspots Contralateral: ALARA	Carotid artery atherosclerosis

表 11
OAR	OAR	Dose Recommendation (1.5-2 Gy/fraction)	Toxicity
	The most important cardiac constraints are mean heart dose and dose to the left anterior descending artery and left ventricle
Thorax	Hearte	Mean <8 Gy (recommended) Mean <15 Gy (acceptable); ALARA given increased risk with even lower doses	Major adverse cardiac events23-26
Thorax	Left ventricle	Mean <8 Gy (recommended) Mean <15 Gy (acceptable)	Heart failure24, 27 Coronary artery disease28
Thorax	Left anterior descending (LAD) artery	V15 Gy <10%e	Major adverse cardiac events29, 30
Thorax	Limiting dose to the following cardiac substructures is also recommended
Thorax	Aortic and mitral valves	Dmax <25 Gy	Valvular heart disease24, 31, 32
Thorax	Pulmonic valve	Dmax <30 Gy	Valvular heart disease24, 31, 32
Thorax	Tricuspid valve	Mean <5 Gy (recommended); Dmax <30 Gy	Valvular heart disease28
Thorax	Right ventricle	Mean <5 Gy (Nonimize the maximum dose to individual coronary arteries	Valvular heart disease28
Thorax	Left circumflex artery	V15 Gy <14%	Major adverse cardiac events
Thorax	Right coronary artery	Mean <5 Gy	Coronary artery disease28
Thorax	Lungs	Mean <13.5 Gy V20 <20%(recommended); <30 Gy (acceptable)	Pneumonitis33- 35
Thorax
Thorax

表 12
OAR	OAR	Dose Recommendation (1.5-2 Gy fraction)	Toxicity
Abdomen	Liver	Mean <15 Gy V20 <30% V30 <20%	Hepatic toxicity39.40
Abdomen	Liver	Dmax <45 Gy	Dmax <45 Gy	Ulceration41
Abdomen	Spleen	Mean <10 Gy V5 ≤30% V15 ≤20%	Late infections42 Lymphopenia43
Abdomen	Pancreas	Mean <21 Gy	Mean <21 Gy	Diabetes44-47
Abdomen	Small bowel	V15 <120 cc Dmax <45 Gy	Diarrhea37 Obstruction,ulceration,fistula37
Abdomen	Kidney	Single organ Mean <5 Gy (recommended);<8 Gy (acceptable); (available) V10 <103% (recommended);<15% (recommended);<25% (acceptable)	Renal ins /58 %
Abdomen	Pelvis/ Other	Ovaries	Mean <2 Gy (recommended);<10 Gy (acceptable); <10 Gy (acceptable)	Acute ovarian failure51, 52
Testes	Pelvis/ Other	Mean <2 Gy (recommended);<12 Gy (acceptable)	Azoospermia53
Bone marrow f	Pelvis/ Other	V5: ALARA V10 <50% V25 <25%	Acute cytopenias 54, 55 Chronic cytopenias 56
Long bone	Pelvis/ Other	V40 <64%	V40 <64%	Fracture57

表 13
OAR	Dose Recommendation (1.8-2 Gy/fraction)	Secondary Malignancy
Breast	Minimize volume >4 Gy (ideally <10%)	Breast cancer (adenocarcinoma $)^{61}$
Colon	Minimize volume >10 Gy	Colon cancer $62
Lung	Minimize volume >5 Gy	Lung cancer $63
Esophagus	Minimize volume >30 Gy	Esophageal cancer $64
Stomach	Minimize volume >25 Gy	Gastric cancer $65
Pancreas	Minimize volume >5 Gy	Pancreatic cancer $66

表 14
4D-CT	four-dimensional computed tomography	EFRT
ACGME	Accreditation Council for Graduate Medical Education	ERORT
ACS	American Cancer Society	ESR
ALARA	as low as reasonably achievable	FDG
AMAB	assigned male at birth	FNA
AP	anteroposterior	FSH
ASCR	autologous stem cell rescue	G-CSF
AYA	adolescent and young adult	GHSG
CAD	coronary artery disease	GTV
CBC	complete blood count	H&P
CCSS	Childhood Cancer Survivor Study	HCT
CHL	classic Hodgkin lymphoma	HDT
CME	continuing medical education	HIV
CMT	combined modality therapy	HL
CPI	checkpoint inhibitors	ICL
CR	complete response	ICRU
CTV	clinical target volume
CXR	chest radiograph	IGRT
DIBH	deep-inspiratory breath hold	IMRT
DLBCL	diffuse large B-cell lymphoma	IPS
DLCO	diffusing capacity of the lung for	ISRT
carbon monoxide	TVF	internal target volume
DM	diabetes mellitus	IVF
DVH	dose-volume histogram	LAD
EANM	European Association of Nuclear Medicine	LCx
EBER-	Epstein-Barr encoding region in situ hybridization	LDH
ISH	hybridization	LDHL
EBV	Epstein-Barr virus	LFT
ECHO	echocardiogram

表 15
ABBREVIATIONS	ABBREVIATIONS	ABBREVIATIONS	ABBREVIATIONS
4D-CT	four-dimensional computed tomography	EFRT	extended-field radiation therapy
ACGME	Accreditation Council for Graduate Medical Education	EORTC	European Organisation for Research and Treatment of Cancer
ACGME	Accreditation Council for Graduate Medical Education	ESR	erythrocyte sedimentation rate
ACS	American Cancer Society	FDG	fluorodeoxyglucose
ACS	American Cancer Society	FPF	freedom from progression
AMAB	assigned male at birth	FNA	fine-needle aspiration
AMAB	assigned male at birth	FSH	follicle-stimulating hormone
ASCR	autologous stem cell rescue	G-CSF	granulocyte colony-stimulating factor
ASCR	AAYA	adolescent and young adult	GHSG
CAD	coronary artery disease	GTV	gross tumor volume
CAD	coronary artery disease	H&P	history and physical
CCSS	Childhood Cancer Survivor Study	HCT	hematopoietic cell transplant
CCSS	Childhood Cancer Survivor Study	HDT	high-dose therapy
CME	continuing medical education	HIV	human immunodeficiency virus
CME	continuing medical education	HL	Hodgkin lymphoma
CPI	checkpoint inhibitors	ICL	infraclavicular
CPI	CR	CR	CR
CTV	complete response	complete response	complete response
CTV	clinical target volume
CXR	chest radiograph	IGRT	image-guided radiation therapy
DIBH	deep-inspiratory breath hold
DIBH	IMRT intensity-modulated radiation therapy
DLBCL	diffuse large B-cell lymphoma
DLBCL	diffusing capacity of the lung for
DLCO	diffusing capacity of the lung for
DLCO	carbon monoxide	carbon monoxide	carbon monoxide
DM	diabetes mellitus		invitro fertilization
DVH	dose-volume histogram	LAD
DVH	LAD	LAD	LAD
EANM	European Association of Nuclear
EANM	Medicine	Medicine	Medicine
EBER-ISH	Epstein-Barr encoding region in situ hybridization
EBER-ISH	LDHL	LDHL	LDHL
EBV	Epstein-Barr virus	Epstein-Barr virus	Epstein-Barr virus
EBV	LFT	LFT	LFT

表 16
LH	luteinizing hormone
LRHL	lymphocyte-rich Hodgkin lymphoma
MALT	mucosal-associated lymphoid tissue
MCHL	mixed cellularity Hodgkin lymphoma
MLD	mean lung dose
MMR	mediastinal mass ratio
MTR	mediastinal thoracic ratio
MUGA	multigated acquisition
NLPBL	nodular lymphocyte-predominant B-Cell lymphoma
NLPHL	nodular lymphocyte-predominant Hodgkin lymphoma
NLPHL	nodular lymphocyte-predominant Hodgkin lymphoma
NSHL	nodular sclerosis Hodgkin lymphoma
OAR	organ at risk
PA	posteroanterior
PCP	primary care physician
PFS	progression-free survival
PFT	pulmonary function test
PJP	nneumocystis jiroveci pneumonia
POI	premature ovarian insufficiency
PR	partial response
PTV	planning target volume
RATHL	risk-adapted therapy in Hodgkin lymphoma
RCA	right coronary artery
RR	relative risk
SNMMI	Society of Nuclear Medicine and Molecular lmaging
SUV	standardized uptake value
TFT	thyroid function test
TLLI	total lymphoid irradiation
VHD	valvular heart disease
VMAT	volumetric modulated arc therapy

表 17
	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 18
NCCN Categories of Preference
Preferred	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended	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：Deauville AbeV's 1-39 Preferred combined modality therapy: ISRT 20 Gyr' (adapted from GHSG HD16)1 Useful in Certain Circumstances Chemotherapy alone (see important considerations on HODG-4): ABVD x 2 cycles (total 4) (adapted from H10F, CALGB)^{s,2,3} or ADPU6-1 8 Top to 2 2 cycles with FDG-(category 1)^p FDG- REastage FDG- with FDG- category 1)^p PET/CT^c Deauville 4-5° HODG-5 HODG-5

图示：PRIMARY TREATMENT Deauville 1-29 Combined modality therapy ABVD x 1 cycle (total 3) + ISRT 30 Gyr'(adapted from RAPID, H10F) = 2.5\,Chemotherapy alone ABVD x 2 cycles (total 4) ABVD x 2 cycles (total 4) 2,3,3,4 Combined modality therapy ABVD x 2 ISRT 30 Gy' (adaptated from favorable disease (category 1) \rightarrow 2 cycles with FDG-84 yprC 39 J Chemotherapy alone AVD x 4 cycles (adapted from CALGB, RATHL)3,4 Deauville Deauville 3.4 and CADG constraints Follow-up(HODG-12) Stage I/IA/IA favorable disease by EORTC criteria 2 cycles (category 1) 0 Deauville 2 - 9 Thallow FET/CTC Restage with FDG-1 copy (1) PET/CT°C Deauville 39 ALDvoiles play a better potential to recover the detection and detection H10F) 2.5 Chemotherapy alone AVD x 1 cycle (total 3) + ISRT 30 Gy' (adaptated from CALGB, RATHL)3,4 Combined modality therapy ABVD x 2 cycles (total 4) ISRT 30 Gy' (adaptated from RAPID) 3.4 Deauville 4-59 - HODG-5B

图示：Stage IA/IIA favorable CHL by GSHG or EORTC GHSG or RORTC criteriaV with deauville 4-5 after 2 Deauville 5q,u ABVD 4q,u Decuille 4-5 Reageville 1-3q ISRT 30 Gyr (adaptated from RAPID, H10)2,5 Novelet 4-59u Deauville 5q,u ABVD 4-5q,u Reagelet 5 Deauville 6-5 u Regelikeva Positive of Primary Refractory Disease (HODG-13)

图示：PRIMARY TREATMENT(see Important Considerations) on HODG-4) ABVD x 2 cyclesP ADFD PET/CT Deauville 4-5q,u ADneophary(EG-6A Other Regimens ADG-6A Restage with FDG-PET/CT°C ABVD cyclesp ADuville ADneopharyosis ·24 Nodal sites ASR ESR ≥50 mm/hr ABVD ABVD 4-7c Restage ABE Restage with FDG-PET/CT°C ADuville ADneopathy ●24 Nodal sites · AD/or ESR ≥50 mm/hr

图示：ABVD x 2 cycles (total 4)s ABCD A 399(1-3q Disauville) or BrECADD + 496(r) 44 BrECADD previously used)*x ADauville (1-3q Disauville) 449(1) 5q, u A C B A Dueville (1-3q Biopsy ReGECADD previously used)*x Combined modality therapy ISRT 36-40 Gyr (adapted from H10U) 2 From H10U) 2 A Dueville (1-4q, u A Duev-259(94) 44 Deauville 59, u A Dueville (1-3q) 449(1) 5q, u A Duev-259(104) 2 Annoine therapy Refractory Disease (HODG-13)

图示：Stage I/II unfavorable CHL: •or •B Symptoms or BV-AVD+G-CSF\t5 cycles,p,y (adapted from BREACH)^7 Restage with FDG-PET/CT Disauvalville:4,9 →Biopsy Negative Negative →ISRT°→ →Deauville 1-4,9 →Biopsy Positive →Primary Refractory Disease(HODG-13) Positive Primary Refractory Disease(HODG-13)

图示：BrECADD+G-CSF x 2 cycles 1-39 Deauville+G-CSF with FDG-PET/CTC BrECADD+G-CSF x 2 cycles 4-c5-u Deauville→G-CSF x 4 cycles 4-5 q,u Reastage FDG-PET/CTC BrECADD+G-CSF x 4 cycles 4-6 u Deauville→G-CSF x 4 cycles 4-6 u FDG-PET/CTC Biopsy Deauville→G-CSF x 49 q-u Deauville→HCHUCAN Redstage 494-1-3 Reustage FDG-PET-CTC Deauville→HCHUCAN ISRT r Deauville→HCHUCN Biopsy Diauville Biopsy (+) Negative→ISRT'→ Follow-up(HODG-12) Positive→ISRT'→ Primary Refractory Disease (HODG-13)

图示：Preferred: Nivolumab-AVD^{p} (category 1) → HODG-7A or BrECADD + G-CSFP^{p} (category 1) → HODG-7B Useful in Certain Circumstances: BV-AVD + G-CSFP^{p} (category 1) → HODG-7C or ABVDP^{p} (category 1) → HODG-7D

图示：Nivolumab-706°C/cyclesp,z,aa (category)from SWOG from SWOG S1826)9 Reastage FDG-PET/CTC Deauville 1-39 Deauville 4-59,u,bb Repeat FDG-PET/CT at 12 weeks' 0 Negative Deauville 1-39 +Deauville 4-59,u,bb Negative Deauville 3-9 Negative Deauville 1-39 +Deauville 4-59,u,bb Negative Deauville 2-4 Negative Positive Primary Refractory Disease (HODG-13) HODG-12)

图示：Preferred: BrECADD + G-CSF 1-3^9 Deauville + G-CSF with FDG-FET/total 4)xY Restage (category 1) with (adapted from HD21)^8 /FDG-PET/CTC Deauville 4-5^9,u BrECADD + G-CSF x 4 cycles (total 6)xY Deauville 59,u Biopsy - Diauville - Di abopey (i) Positive for reference of the following experimental or for reference for inflation or reference for subsequent therapy Deauville 1-3^9 Re板ADD + G-CSF 4-5^9,u ,Chen (total 6)xY Deauville 1-3^9 Deauville → Di abope y (total 4) Y Reastage with FDG-FET/CTC Endage (1-4) 2 Deauville 1-3^9 FDG-FET/CTC Endage (1-5,1) Disauville 1-3^9 Re板ADD + G-CSF x 4 cycles (total 6)xY Disauville 1-3^9 Deauville → Di abope y (total 6)xY

图示：BV-AVD + G-CSF x 6 cycles (category 1)b,x,y,cc (adapted from ECHELON-1)10

图示：ABVD x 2 cyclesp Restage with FDG-PET/CT cct,ee Deauville $\to$ AVD x 4 cyclesdd 1-39 Adapted from RATHL $4^{4} Deauville $\to$ BRECADD $+5^{9} Deauville $\to$ BRECADD $+6\text { CSF }x 3 \to \to PET / CT^c dycle $+5^{9},u u\end{aligned}$$ Deauville $\to$ Angeville by $\to$ Angeville by $\to$ Angeville Follow-up (HODG-C 12) HODG-12) AVD ble BrECADD $+1-3^9 Deauville $\to$ Angeville by $\to$ Angeville by $\to$ Angeville $4-5^9,u u\end{aligned}$$ Addageleft $HODG-C-2$ Japanese, which should be a significant following of the following is a significant change is $\to$ 9 CnN, which should be a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a significant result is a sign

图示：Stage IA, IIA (non-bulky) IsRT^{r} (preferred for stage IA or contiguous stage IIA) or (non-bulky) Oserve\ii{\,}\\\end{array} Stage\text{Stage IB,},{hh} IIB,or Stage\text{IA-IIA}(\text{bulky}) O\text{~\text{~\text{~\text{~\text{~}}}}}\text{Stage IB,},{h}\text{~\text{~\text{~\text{~}}}\text{~\text{I}}}\text{Stage IIA}(\text{non-contiguous})\text{~\text{Observe}\text{~\text{I}}\text{~\text{I}}\text{SRT}^{\text{r}}(\text{non-}\text{~\text{I}}\text{I})\text{~\text{I}}\text{SRT}^{\text{r}}(\text{non-}\text{I}}\text{~\text{I}}\text{S}\text{S}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\text{r}\

图示：PRIMARY REFRACTORY CHL49 OR RELAPSE WITHIN 3 MONTHS: CANDIDATE FOR HIGH-DOSE THERAPY AND AUTOLOGOUS STEM CELL RESCUE (HDT/ASCR) ACSR) Second-LINE THERAPYtt Reception HDT/ASCR ±RT/r3,tt(category 1) Observe Consider BV maintenance for patients with high risk of relapse or and no prior BV exposure$x,y,vv,ww $DHT/ASCR$ Be $$\pm RT,tt$$\pm R^{T,r}$$ HDT/ASCR Observe or Consider BV maintenance for patients with high risk of relapse Follow-up(HODG-12) Observe Consider BV maintenance for patients with high risk of relapse (HTDG-12) HDT/ASCR or Consider BV assessment who is subsequent and no prior BV exposure$x,y,vv,ww $D7,tt$$\pm RT,tt$$ VTP$ Reception OR Consider BV maintenance for patients with high risk of relapse HDT/ASCR or Consider BV assessment who is subsequent and no prior BV exposure$x,y,vv,ww $D7,tt$$\pm RT,tt$$ VTP$ Ab HDT/ASCR Reception RRT$ ▲ Observe or Consider BV maintenance for patients with high risk of relapse HDT/ASCR + no prior BV exposure$x,y,vv,ww $D7,tt$$\pm RT,tt$$ Observe or Consider BV assessment for patients who underwent HDT/ risk of relapse exposurex,y,vv,ww VTR,tt VTP$ ▲ Observe or Consider BV assessment for patients with high risk of relapse HDT/ASCR Subsequent systemic therapy SDequent → HDT/ASCR → EXU4 → Observe or Consider BV assessment for patients with high risk of relapse VTR,tt VTP$\alpha$

图示：CHL BIPSY PROVEN RELAPSE AFTER ≥23 MONTHS: CANDIDATE FOR HDT/ASCR SECOND-LINE THERAPYY ADDITIONAL THERAPYY HDT/ASCR Deauville 1-39 HDT/ASCR Useful in Certain Circumstances ISRT (localized relapse & limited prior treatment only)× 1-39 Addutional THERAPYY HDT/ASCR ± ISRT,ss,tt Observe or Consider BV maintenance for patients with high risk of relapse and no prior BV exposure x,y,vv,ww HDT/ASCRY Observe HDT/ASCRY Observe BV maintenance for patients with high risk of relapse and no prior BV exposure x,y,vv,ww HDT/ASCRY Observe BVaintenance HDT/G-12 Observe Vtreatment for patients with high risk of relapse ChL BIopsy-reformance by 23 months: Deauville 1-39 HDT/ASCR± ISRT,ss,tt Observe BVt maintenance for patients with high risk of relapse and no prior BV exposure x,y,vv,ww HDT/ASCRY Observe BVtreatment for patients with high risk of relapse ChL BIopsy-reformance by 23 months: Observe Vtreatment for patients with high maintenance behavior and no prior BV exposure x,y,vv,ww ObODU-12 HODG-12

图示：RELAPSED/ REFRACTORY CHL: NOT A CANDIDATE FOR HDT/ASCR NCCIN National Comprehensive Neural Guidelines 2022.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2023.2024.2

图示：Refractory and disease or transected cyclIsCT$\longrightarrow$ Biopsy by Biopsy negative 口 observe with short-interval follow-up (HODG-12) Refractory or Disuspected $\boldsymbol{\in}$ Suspected $\boldsymbol{\in}$ CTc$\longrightarrow$ 信息系统 Refractory Disease) NCCN Guidelines for B-Cell Lymphomas for B-Cell Lymphomas for B-Cell Lymphomas for Reractory Disease) Aggressive B-cell lymphoma + Diuse large B-cell lymphoma - Relapsed/Refractory Disease) See NCCN Guidelines for B-Cell Lymphomas for B-Cell Lymphomas for Reractory Disease)

图示：NLPHL Asymptomatic and non-bulky Observe or Rituximabccc or ISRT^{\dagger} Second-line therapy(HODG-B 6 of 8) Iakouge Ristage with FDG-PET/CT after treatmentc ± HDT/ASCR Progressive disease dded Observe if asymptomatic (HODG-12) or HDT/ASCR(if not done previously) Symptomatic or bulky ISRT^{\dagger} Standard-line therapy Progressive disease HodG-B 6 of 8) Subsequent therapy${}^{eee}$ （HODG-B 6 of 8） Subsequent therapy${}^{eee}$ （HODG-B 6 of 8）

引用 / 出处

（2026.V1）NCCN临床实践指南：霍奇金淋巴瘤. 2026.