（2026.V1）NCCN临床实践指南：造血生长因子

指南综合与多学科· 未分类与其他 · 2026

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

*Elizabeth A. Griffiths, MD/Chair † $\ddagger$ Roswell Park Comprehensive Cancer Center

Mark Geyer, MD/Vice-Chair ‡ $\ddagger$ p Memorial Memorial Sloan Kettering Cancer Center

Samia if, MBBS P $\pm $ BD \& Pamela Buffett Cancer Center

Kimo Bachiashvili, MD $\ddagger$ O'Neal Comprehensive Cancer Center at UAB

John Baird, MD †$\varepsilon$China of Hope National Medical Center

Shivani Bakhshi, DO $\ddagger$ Abramson Cancer Center at the University of Pennsylvania

Emily Cheng,PharmD,BCOP∑$\_$Case Comprehensive Cancer Center/University Hospitals Saidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

Rita Cool, PharmD, BCOP $\Sigma $ The University of Texas MD Anderson Cancer Center

Tyler Dickerson, PharmD, BCOP$\Sigma$\nNccner Center-James Cancer Hospital and Solove Research Institute

Shira Dinner,MD+\#Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Michael Fallon, PharmD $\Sigma $$\ast $University of Wisconsin Carbone Cancer Center

NCCN Guidelines Panel Disclosures

John Glaspy, MD, MPH $\dagger$ UCLA Jonsson Comprehensive Cancer Center

Ivana Gojo, MD $\ddagger$

Johns Hopkins Kimmelancer Center

Khushali Jhaveri, MD‡

Indiana University Melvin and Bren Simon Comprehensive Cancer

Wajih Zaheer Kidwai, MD $†

Yale Cancer Center/Smilow Cancer Hospital

Yuchen Liu, MD t$\ddagger$

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Jordan Lundberg, PharmD∑

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

Gary H. Lyman, MD, MPH#

Fred Hutchinson Cancer Center

Anjlee Mahajan, MD ††

UC Davis Comprehensive Cancer Center

Ginny Mason,BSN,RN¥

Inflammatory Breast Cancer Research Foundation

Foundation

Victoria Nachar, PharmD, BCOP ∑$\sharp

University of Michigan Rogel Cancer Center

Anthony Nguyen, MD

UC San Diego Mooresc Cancer Center

Thomas Odeny, MD, PhD, MPH P+

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Sukhmani Padda, MD †Fox Chase Cancer Center

Hetalkumari Patel, PharmD, BCOP ∑❸UT Southwestern Simmons Comprehensive Cancer Center

Shiven Patel, MD, MBA $\ddagger$ Huntsman Cancer Institute at the University of Utah

Lia E.Perez,MD#ξ

Moffitt Cancer Center

Fauzia Riaz,MD†

Stanford Cancer Institute

Kelley Rone,DNP,APRN #+Mayo Clinic Comprehensive Cancer Center

Rachel Rosovsky, MD, MPH$\ddagger$

Martha Wadleigh, MD $+$ Dana-Farber/Brigham and Women's Cancer Center

Kelly Westbrook, MD †Duke Cancer Institute

Bradley Yelvington, PharmD, BCOP $\Sigma \dagger$ "Vanderbilt-Ingram Cancer Center

Benjamin Yoder, PharmD,BCOP∑+

University of Colorado Cancer Center

NCCN

Frankie Jones Swathi Ramakrishnan, PhD

$\xi$ Bone marrow

Nursing

transplantation

$\Sigma$ Pharmacology

Hematology oncology

B Internal medicine

* Discussion writing committee member

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

Version 1.2026, 11/07/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

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

NCCN Guidelines Index Table of Contents Discussion

Find an NCCN Member Institution: https://www.nccn.org/home/memberinstitutions.

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

indicated.

See NCCN Categories of Evidence and Consensus.

NCCN Categories of Preference: All recommendations are considered appropriate.

See NCCN Categories of Preference.

NCCN Hematopoietic Growth Factors Panel Members

Summary of the Guidelines Updates

Management of Neutropenia

• Evaluation, Risk Assessment, and Prophylactic Use of Myeloid Growth Factors (MGF-1)

• Additional Evaluation of Patient Risk Factors for Prophylactic Use of MGFs (MGF-2)

• Secondary Prophylaxis with MGFs (MGF-3)

• Therapeutic Use of MGFs (MGF-4)

• Examples of Disease Settings and Chemotherapy Regimens with a High/Intermediate Risk for Febrile Neutropenia (MGF-A)

• G-CSFs for Prophylaxis of Febrile Neutropenia and Maintenance of Scheduled Dose Delivery(MGF-B)

• Toxicity Risks with MGFs (MGF-C)

Management of Thrombocytopenia

• Use of Thrombopoietin Receptor Agonists (TPO-RA) in Patients with Cancer (TGF-1)

• Use of TPO-RA in Patients Post-Hematopoietic Cell Transplant (TGF-2)

Management of Immune Effector Cell-Associated Hematologic Toxicity

• Pre-treatment Evaluation of Patient Risk factors for Immune Effector Cell-Associated Hematologic Toxicity (ICAHT) and Indications for Prophylactic Intervention (ICAHT-1)

• Post-treatment Assessment of Suspected ICAHT (ICAHT-2)

Management of Cancer- and Chemotherapy-Induced Anemia

• Evaluation of Anemia (ANEM-1)

• Risk Assessment and Indications for Initial Transfusion in Acute Setting (ANEM-2)

• Special Categories in Considering Erythropoiesis-Stimulating Agent (ESA) Use (ANEM-3)

• Evaluation of Iron Deficiency (ANEM-4)

• Erythropoietic Therapy - Dosing, Titration, and Adverse Effects (ANEM-A)

• Parenteral Iron Preparations (ANEM-B)

• Management of Cancer- and Chemotherapy-Induced Anemia for Patients Who Refuse Blood

Transfusions (ANEM-C)

Abbreviations (ABBR-1)

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

Updates in Version 1.2026 of the NCCN Guidelines for Hematopoietic Growth Factors from Version 1.2025 include:MGF-1

• Prophylactic Use of G-CSFs for Febrile Neutropenia; Curative/Adjuvant or Palliative Setting

Footnote i added: It should be noted that antibody-drug conjugates (ADCs) have a significantly longer half-life than the naked chemotherapy drug. The

cycle day for administration of MGFs to optimize safety and efficacy has not been systematically determined. (Also for MGF-2 and MG-3)

Footnote j added: MGFs should not be withheld for neutropenia/cytopenia associated with bispecific T-cell engagers and monoclonal antibodies

regardless of timing during the cycle of administration. (Also for MGF-2 and MG-3)

MGF-A 1 of 10

• This section has been extensively reformatted.

Bullets added:

◊ G-CSF prophylaxis is routinely used in modern clinical trials testing new regimens, and febrile neutropenia rates may not be accurately captured in these studies. Therefore, patients who are being treated with such regimens, not as part of the trials but during standard clinical care, should

receive G-CSF per guidance in the original study.

◊ It should be noted that ADCs have a significantly longer half-life than the naked chemotherapy drug. The cycle day for administration of MGFs to optimize safety and efficacy has not been systematically determined.

◊ MGFs should not be withheld for neutropenia/cytopenia associated with bispecific T-cell engagers and monoclonal antibodies regardless of timing during the cycle of administration.

MGF-A 2 of 10

• Examples with High Risk for Febrile Neutropenia (>20%)

Breast Cancer, example added:

◊ Sacituzumab govitecan-hziy moved from intermediate to high risk

MGF-A 3 of 10

• Examples with High Risk for Febrile Neutropenia (>20%)

Melanoma, example added:

◊ Melphalan percutaneous hepatic perfusion (PHP)

Multiple Myeloma, examples added:

◊ DCEP (Dexamethasone/Cyclophosphamide/Etoposide/Cisplatin)◊ High-Dose Cyclophosphamide

MGF-A 4 of 10

• Examples with Intermediate Risk for Febrile Neutropenia (10%–20%)Esophageal and Gastric Cancers, example added:

◊ FLOT (Docetaxel/Fluorouracil/Leucovorin/Oxaliplatin)

MGF-A 5 of 10

• Examples with Intermediate Risk for Febrile Neutropenia (10%–20%)Prostate Cancer, example added:

◊ Docetaxel

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UPDATES

MGF-A 7 of 10 through MGF-A 10 of 10

• References have been updated.

MGF-B 1 of 2

• Efbemalenograstim alfa-vuxw

Footnote h added: Efbemalenograstim alfa-vuxw is a non-pegylated long-acting formulation.

MGF-C

• Sargramostim

Bullet 2, sub-bullet 2 modified: Autologous hematopoietic cell transplant or with peripheral blood progenitor cell transplant...

Bullet 2, sub-bullet 3 modified: Allogeneic hematopoietic cell transplant or peripheral blood progenitor cell transplant...... high glucose, low albumin

high blood urea nitrogen (BUN), high cholesterol

TGF-1

• This section has been revised.

Assessment

◊ Bullet 2, sub-bullet 6 modified: Heparin-induced thrombocytopenia (HIT) or other medication-induced thrombocytopenia

◊ Bullet 2, sub-bullet 11 modified: Consumption of platelets Dilutional thrombocytopenia secondary to blood loss

◊ Bullet 2, sub-bullet 15 modified: Thrombotic microangiopathies (TMAs) such as drug-associated TMA, thrombotic microangiopathic anemia,thrombotic thrombocytopenic purpura (TTP), etc. and hemolytic uremic syndrome (HUS)

TGF-2

• Title revised and moved to separate page: Use of TPO-RA in Patients Post-Hematopoietic Cell Transplant

TGF-3

• Footnote c revised: Insufficient data are available to support use of TPO-RAs other than romiplostim for CIT outside of a clinical trial. Retrospective

Studies have evaluated other TPO-RA agonists, including avatrombopag, but there are insufficient data from these studies to recommend these agents.

Additional prospective studies are needed to determine safety, efficacy, and benefits of TPO-RA agonists.

TGF-4

• References have been updated.

ICAHT-1 through ICAHT-3

• New section added which covers pre-treatment and post-treatment evaluation and management of suspected immune effector cell-associated hematologic toxicity (ICAHT)

ANEM-1

• Evaluation of Anemia

Text modified: Evaluate anemia for possible cause as indicated: (Discussion)

◊ Footnote b modified: This is a basic evaluation for possible causes of anemia. See Discussion for more details.

Bullet 2, sub-bullet 6 revised: Treatment-induced myelosuppression Cancer treatment or other drug-induced myelosuppression/anemia

Bullet 2, sub-bullet 9 added: Secondary myeloid disorders including clonal cytopenia of undetermined significance (CCUS)

• Footnote f revised: The ferritin value indicating iron deficiency is laboratory-specific. In general, the lower the level of ferritin, the higher the probability that the patient has true iron deficiency anemia.... (Also forANEM-4)

Updates in Version 1.2026 of the NCCN Guidelines for Hematopoietic Growth Factors from Version 1.2025 include:

Continued

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NCCN Guidelines Index Table of Contents Discussion

UPDATES

ANEM-3

• Text modified: There is not enough evidence to support ESA use in these patient populations; therefore, ESAs are not recommended at this time (in the absence of other indications, eg, advanced chronic kidney disease)

ANEM-A 5 of 5

• Reference updated: Overgaard J, Hoff C, Sand Hansen H, et al. Randomized study of the importance of novel erythropoiesis stimulating protein

(Aranesp) for the effect of radiotherapy in patients with primary squamous cell carcinoma of head and neck (HNSCC): The Danish Head and Neck Cancer Group DAHANCA 10 randomized trial [abstract]. Eur J Cancer Suppl 2007;5:7:Abstract 6LB. Overgaard J, Hoff CM, Hansen HS, et al.

DAHANCA 10 - Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, openlabel, randomized, phase 3 trial by the Danish head and neck cancer group. Radiother Oncol 2018;127:12-19.

ANEM-B 1 of 2

• Parenteral Iron Preparations

List of iron preparations have been reordered alphabetically

◊ Header modified: Recommendations for Administering Parenteral Iron Products (listed in alphabetical order)

Low-Molecular-Weight Iron Dextran

◊ Test dose removed/revised: Test dose per institutional practices required: 25 mg slow IV push over 1–2 min If tolerated, follow with 75 mg IV bolus for total dose of 100 mg

◊ Dosage removed/revised: Refer to prescribing information 100 mg IV over 5 min Repeated dosing once weekly for 10 doses to total of 1000 mg or Total dose infusion given over several hours, Calculated total iron dextran dose in 500 mL of 0.9% NaCl solution administered at 175 mL/h

Footnote b modified: .....Ferric carboxymaltose has been associated with severe phosphate deficiency. Monitoring phosphorus 5–10 days after

administration is recommended.

Footnote f removed: Dose (mL) = 0.0442 (desired Hb - observed Hb) x LBW + (0.26 x LBW). Dose (mg) = Dose (mL) x 50 mg/mL; LBW = lean body

weight (kg); Hb = hemoglobin (g/dL). If dose exceeds 1000 mg, remaining dose may be given after 4 weeks if inadequate Hb response.

ANEM-B 2 of 2

• Reference removed: Gilreath JA, Stenehjem DD, Rodgers GM. Total dose iron dextran infusion in cancer patients: is it SaFe2+? J Natl Compr Canc Netw 2012;10:669-676.

Updates in Version 1.2026 of the NCCN Guidelines for Hematopoietic Growth Factors from Version 1.2025 include:

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

EVALUATION PRIOR TO FIRST CHEMOTHERAPY CYCLEa,b

RISK ASSESSMENTd FOR FEBRILE NEUTROPENIAe

OVERALL FEBRILE NEUTROPENIA RISK

PROPHYLACTIC USE OF G-CSFs FOR FEBRILE NEUTROPENIA CURATIVE/ADJUVANT OR PALLIATIVE SETTING9

![Evaluation of risk for febrile neutropenia following chemotherapy therapy High-dose therapy Dose-dense therapy f chemical therapy in adult patients with solid tumors and non-myeloid malignancies c - Treatment intent (curative vs. palliative) Low(<10%)\rightarrow Granulocyte colony-MGF-3) / 666266cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS9\n](2/aj0YEe4oUhYkBdfpda0fYP/figuref1c0bc6c19ff4cf2a6e8771b090f1a6c_0_8.png) a The NCCN Guidelines for Hematopoietic Growth Factors were formulated in reference to adult patients.

b Patients receiving cytotoxic chemotherapy as part of a clinical trial may be evaluated for prophylaxis with myeloid growth factors (MGFs) as clinically indicated, unless precluded by trial specifications.

cFor use of growth factors in myelodysplastic syndromes(MDS), see the NCCN Guidelines for Myelodysplastic Syndromes; in acute myeloid leukemia(AML), see the NCCN Guidelines for Acute Myeloid Leukemia; in chronic myeloid leukemia(CML), see the NCCN Guidelines for Chronic Myeloid Leukemia; in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), see the NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.For use of growth factors in other cancer types, refer to the appropriate Guidelines.

d There are many factors that need to be evaluated to determine a patient's risk categorization; these include type of chemotherapy regimen(MGF-A) and patient risk factors(MGF-2).

e Febrile neutropenia is defined as single temperature:≥38.3°C orally or≥38.0°C over 1 hour; and neutropenia:<500 neutrophils/mcL or<1000 neutrophils/mCL and a predicted decline to ≤500 neutrophils/mcL over the next 48 hours. See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

f In general, dose-dense regimens require MGF support to maintain dose intensity and schedule.

9 Toxicity Risks with MGFs(MGF-C).

h G-CSFs for Prophylaxis of Febrile Neutropenia and Maintenance of Scheduled Dose Delivery (MGF-B).

it should be noted that antibody-drug conjugates(ADCs) have a significantly longer half-life than the naked chemotherapy drug. The cycle day for administration of MGFs to optimize safety and efficacy has not been systematically determined.

j MGFs should not be withheld for neutropenia/cytopenia associated with bispecific T-cell engages and monoclonal antibodies regardless of timing during the cycle of administration.

${}^{k}$ G-CSFs may be considered for patients receiving low-risk regimens who have${}^{2}$ patient-related risk factors (MGF-2). Use of G-CSF in this setting is based on clinical judgment.

NCCN

National Comprehensive Cancer Network®

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NCCN Guidelines Index Table of Contents Discussion

OVERALL FEBRILE NEUTROPENIA® RISK

PATIENT RISK FACTORS ASSESSMENT

PROPHYLACTIC USE OF G-CSFs FOR FEBRILE NEUTROPENIA

![Intermediate (10%-20%)\nX\nY\nY\nPersistent neutropenia\nBone marrow involvement by tumor\nPossible tests of error\nNo risk factors $\rightarrow$ Observe\nInverse\nNask factors \n $\ge 1$ risk factor\nNo risk factors $\rightarrow$ Observe\nEvaluation Prior to Second and Subsequent Chemotherapy\nCycles (MG F-3)\n $\begin{array}{l}\text{Evaluation Prior to Second and Subsequent Chemotherapy\nCycles (MG F-3)\n $\text{Dox}\in \mathcal{L}N\ge 1.5\pi\end{array}$\n\begin{array}{l}\text{Evaluation Prior to Second and Subsequent Chemotherapy\nCycles (MG F-3)\n $\text{Dox}\in \mathcal{L}N\ge 1.5\pi\eta\end{array}$\n](2/aj0YEe4oUhYkBdfpda0fYP/figure3bd4a384b64d49f08f51878f99fff32e_0_8.png) e~ Febrile neutropenia is defined as single temperature:≥38.3°C orally or≥38.0°C over 1 hour; and neutropenia:<500 neutrophils/mcL or<1000 neutrophils/mcL and a predicted decline to ≤500 neutrophils/mcL over the next 48 hours. See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

h G-CSFs for Prophylaxis of Febrile Neutropenia and Maintenance of Scheduled Dose Delivery (MGF-B).

It should be noted that ADCs have a significantly longer half-life than the naked chemotherapy drug. The cycle day for administration of MGFs to optimize safety and efficacy has not been systematically determined.

jMGFs should not be withheld for neutropenia/cytopenia associated with bispecific T-cell engagers and monoclonal antibodies regardless of timing during the cycle of administration.

k G-CSFs may be considered for patients receiving low-risk regimens who have ≥2 patient-related risk factors. Use of G-CSF in this setting is based on clinical judgment.

Other possible patient risk factors for febrile neutropenia may include poor performance status or human immunodeficiency virus(HIV) infection (in particular, patients with low CD4 counts). The listed patient risk factors are based on a multivariable risk model using a prospective cohort study of several thousand ambulatory patients with cancer receiving chemotherapy. This cohort did not include patients with HIV, acute leukemia, or hematopoietic cell transplant (Lyman GH, et al. Crit Rev Oncol Hematol 2014;90:190-199).

m Other factors may warrant the use of G-CSFs(eg, chronic immunosuppression in the post-transplant setting, including organ transplant).

National Comprehensive Cancer Network®

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NCCN Guidelines Index Table of Contents Discussion

EVALUATION PRIOR TO SECOND AND SUBSEQUENT CHEMOTHERAPY CYCLES

SECONDARY PROPHYLAXIS

![Evaluate patient prior to second and subsequent chemotherapy cycles\n\nNo febrile neutropenia or dose-limiting neutropenic event\n\nPrior use of G-CSFsh,i,j\n\n\n\n\n\n\n\n| No febrile neutropenia or dose-limiting neutropenic event\n\n\n\n\n\n| 双 subsequent cycle\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figured430d18934f14530a65d09415879a8c8_0_6.png) e~ Febrile neutropenia is defined as single temperature:≥38.3°C orally or≥38.0°C over 1 hour; and neutropenia:<500 neutrophils/mcL or<1000 neutrophils/mcL and a predicted decline to ≤500 neutrophils/mcL over the next 48 hours. See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

h G-CSFs for Prophylaxis of Febrile Neutropenia and Maintenance of Scheduled Dose Delivery (MGF-B).

${}^{i}$ It should be noted that ADCs have a significantly longer half-life than the naked chemotherapy drug. The cycle day for administration of MGFs to optimize safety and efficacy has not been systematically determined.

j MGFs should not be withheld for neutropenia/cytopenia associated with bispecific T-cell engages and monoclonal antibodies regardless of timing during the cycle of administration.

nDose-limiting neutropenic event could be a nadir count or day of treatment count that could otherwise impact planned dose of chemotherapy.

National Comprehensive Cancer Network®

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THERAPEUTIC USE OF MGFs$e,0,p,q

![PRESENTATION\nG-CSFs USE DURING CURRENT CHEMOTHERAPY CYCLE\nPatients receiving daily prophylactic filgrastim or tbo-filgrastim\nPatients receiving or those who received prophylactic G-CSFs\nPresent with febrile neutropenia\nPresent with febrile neutropenia\nPatients patients receiving or those who received prophylactic filgrastim\nPatienting receiving or those who received prophylactic P-CSFs\nPatients who have received long-lasting prophylactic pegfilgrastim or elpegraftrim-xnst or efbemalenograst imfa-vuxw\nPresent with febrile neutropeniae\nPresent with febrile neutropenia\nPatient who did not receive prophylactic G-CSFs\nPresent with did not receive prophylactic G-CSFs\nRisk factors not present for an infection-associated complication\nRisk factors present for an infection-associated complication\nConsider therapeutic MGFst,u\ncomplication\\n](2/aj0YEe4oUhYkBdfpda0fYP/figure99076ad8f988499e868c761161ec7a68_0_5.png) Patients with radiation-induced myelosuppression following a radiologic/nuclear Theraitic MGFsv,w incident(hematopoietic acute radiation syndrome [H-ARS])

e~Febriable neutropenia is defined as single temperature:≥38.3°C orally or≥38.0°C over 1 hour; and neutropenia:<500 neutrophils/mcL or<1000 neutrophils/mcL and a predicted decline to ≤500 neutrophils/mcL over the next 48 hours.See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

°For antibiotic therapy recommendations for fever and neutropenia, see the NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

P The decision to use MGFs in the therapeutic setting is controversial. See Discussion for further details.

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

rRisk factors/possible indications for therapeutic MGFs include sepsis syndrome, age>65 years, absolute neutrophil count[ANC]<100/mcL,neutropenia expected to be>10 days in duration, pneumonia or other clinically documented infections, invasive fungal infection, hospitalization at the time of fever, and prior episode of febrile neutropenia.

${}^{a}$ There are no studies that have addressed therapeutic use of filgrastim for febrile neutropenia in patients who have already received prophylactic pegflragstim. However, pharmacokinetic data of pegfilgrastim demonstrated high levels during neutropenia and suggest that additional G-CSFs may not be beneficial; however,in patients with prolonged neutropenia additional G-CSFs may be considered.

See Discussion for further details. Pegfilgrastim(or biosimilars), eflapegrastim-xnst, and efbemalenograstim alfa-vuxw have only been studied for prophylactic use. Filgrastim(or biosimilars),tbo-filgrastim, or sargramostim may be used therapeutically with initial dosing and discontinued time at of neutrophil recovery.

uFilgrastim(or biosimilars) or tob-filgrastim: daily dose of 5 mcg/kg; sargramostim:used in clinical trials at a dose of 250 mcg/m2 per day. Continue therapeutic MGFs until post-nadir ANC recovery to normal or near-normal levels by laboratory standards.

V Therapeutic options include filgrastim(or biosimilars),tbo-filgrastim(or biosimilars),sargramostim,eflectragrastim-xnst, and efbemalenograstim alfa-vuxw.

wFarese AM,et al. Drugs Today(Barc)2015;51:537-548.

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

MGF-A 1 OF 10

FEBRILE NEUTROPENIA RISK

DISEASE SETTINGS AND CHEMOTHERAPY REGIMENS

• The following pages include examples of chemotherapy regimens with a high risk (>20%) or intermediate risk (10%–20%) of febrile

neutropenia within specific disease settings.

• THESE LISTS ARE NOT COMPREHENSIVE. There are other agents/regimens that have a high risk or intermediate risk for the development of febrile neutropenia.

• Regimens recommended in the NCCN Guidelines for Treatment by Cancer Type are considered when updating these lists of examples.

The type of chemotherapy regimen is only one component of the risk assessment (Patient Risk Factors for Developing Febrile Neutropenia,

MGF-2).

The exact risk includes agent, dose, and the treatment setting (ie, treatment naïve vs. heavily pretreated patients) (MGF-1).

clinical care, should receive G-CSF per guidance in the original study.

In general, dose-dense regimens require MGF support to maintain dose intensity and schedule.

• It should be noted that ADCs have a significantly longer half-life than the naked chemotherapy drug. The cycle day for administration of

MGFs to optimize safety and efficacy has not been systematically determined.

• MGFs should not be withheld for neutropenia/cytopenia associated with bispecific T-cell engagers and monoclonal antibodies regardless of timing during the cycle of administration.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

EXAMPLES OF DISEASE SETTINGS AND CHEMOTHERAPY REGIMENS WITH A HIGH RISK FOR FEBRILE NEUTROPENIA(>20%) ${}^{a}$

*This list is not comprehensive. There are other agents/regimens that have a high risk or intermediate risk for the development of febrile neutropenia.*

|EXAMPLES WITH HIGH RISK FOR FEBRILE NEUTROPENIA(>20%)|| |---|---| |Acute Lymphoblastic Leukemia (ALL)|● Select ALL regimens as directed by treatment protocol (NCCN Guidelines for ALL)| |Bladder Cancer|●DDMVAC (Dose-Dense Methotrexate/Vinblastine/Doxorubicin/Cisplatin) ${}^{1}$| |Bone Cancer|●VAIA (Vincristine/Doxorubicin [alternating with Dactinomycin]/lfosfamide)2 ●VDC-IE (Vincristine/Doxorubicin [or Dactinomycin]/Cyclophosphamide-lfosfamide/Etoposide)3 ●Cisplatin/Doxorubicin4 ●VDC (Vincristine/Doxorubicin [or Dactinomycin]/Cyclophosphamide)5 ●VIDE (Vincristine/lfosfamide/Doxorubicin [or Dactinomycin]/Etoposide)6| |Breast Cancer|●Dose-Dense AC (Doxorubicin/Cyclophosphamide) followed by Dose-Dense Paclitaxel7,b ●TAC (Docetaxel/Doxorubicin/Cyclophosphamide)8 ●TCa,c (Docetaxel/Cyclophosphamide)9 ●TCHa (Docetaxel/Carboplatin) + Trastuzumab10 ●Sacituzumab govetc-nziy11,12| |Head and Neck Squamous Cell Carcinoma|●Cisplatin/Docetaxel/Fluorouracil13-15| |Hodgkin Lymphoma|●AVD (Doxorubicin/Vinblastine/Dacarbazine) + Brentximitabine/Dacarbazine) + Brentximitabine/Dacarbazine) - Escalated BEACOPd4 (Bleomycin/Etoposide/Doxorubicin/Cyclophosphamide/Incortwine/Procarbazine/ Prednisone)17 ●BrECADD (Brentuximab vedotin/Etoposide/Cyclophosphamide/Doxorubicin/Dacarbazine) + BrECADD (Brentuximab vedotin/Etoposide/Cyclophosphamide/Doxorubicin/Dexamethasone)18| |Kidney Cancer|●Doxorubicin/Gemcitabine19| |Non-Hodgkin Lymphomas|●CHP (Cyclophosphamide/Doxorubicin/Prednisone) + Brentuximab vedotin Dose-Adjusted EPOCHa (Etoposide/Prednisone)/Vincristine/Cyclophosphamide/Doxorubicin)20 ●ICE (Ifosfamide/Carboplatin/Etoposide)a,21,22 ●Dose-dense CHOP-14a (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone)23,24 ●MINEa(Mesna/lfosfamide/Mitoxantrone/Etoposide)25 ●DHAPa(Dexamethasone/Cytarabine/Cisplatin)26 ●ESHAPa(Etoposide/Methylprednisolone/Cytarabine/Cisplatin)27 ●HyperCVADa(Cyclophosphamide/Vincristine/Doxorubicin/Dexamethasone)28,29 ●Pola-R-CHP (Polatuzumab vedotin-piq/Cyclophosphamide/Doxorubicin/Prednisone) + Rituximab30|

NCCN

National Comprehensive Cancer Network®

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Table of Contents Discussion

EXAMPLES OF DISEASE SETTINGS AND CHEMOTHERAPY REGIMENS WITH A HIGH RISK FOR FEBRILE NEUTROPENIA (>20\%)

*This list is not comprehensive. There are other agents/regimens that have a high risk or intermediate risk for the development of febrile neutropenia.*

|EXAMPLES WITH HIGH RISK FOR FEBRILE NEUTROPENIA(>20%)|| |---|---| |Melanoma|●CVD (Cisplatin/Vinblastine/Dacarbazine)31 ●Melphalan percutaneous hepatic perfusion(PHP)32| |Multiple Myeloma|●DTPACE (Dexamethasone/Thalidomide/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide)33 ± Bortezomib (VTD-PACE)34 ●DCEP (Dexamethasone/Cyclophosphamide/Etoposide/Cisplatin)35 ●High-Dose Cyclophosphamide36| |Ovarian Cancer|●Topotecana,37 ● Docetaxel38 ●Carboplatin/Docetaxel39| |Soft Tissue Sarcoma|●MAID (Mesna/Doxorubicin/lfosamide/Dacarbazine)40 ●Doxorubicin,a41 ●Doxorubicin/lfosamide42| |Small Cell Lung Cancere|●Topotecan 43| |Testicular Cancer|●VelP (Vinblastine/lfosamide/Cisplatin)44 ●VIP (Etoposide/lfosfamide/Cisplatin)44 ●TIP (Paclitaxel/|fosfamide/Cisplatin)45|

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

EXAMPLES OF DISEASE SETTINGS AND CHEMOTHERAPY REGIMENS WITH AN INTERMEDIATE RISK FOR FEBRILE NEUTROPENIA (10%-20%)a

*This list is not comprehensive. There are other agents/regimens that have a high risk or intermediate risk for the development of febrile neutropenia.*

|EXAMPLES WITH INTERMEDIATE RISK FOR FEBRILE NEUTROPENIA (10%-20%)|| |---|---| |Occult Primary- Adenocarcinoma|●Docetaxel/Gemcitabine46| |Breast Cancer|●Docetaxel,a47,48 ●AC (Doxorubicin/Cyclophosphamide) + sequential Docetaxel(taxane portion only)a,49 ●Paclitaxel every 21 daysa,50| |Cervical Cancer|●Cisplatin/Topotecan51,52 ●Cisplatin/Paclitaxela,61,51 ●Topotecan53 ●Irinotecan54| |Colorectal Cancer|●FOLFIRINOX(Leucovorin/Fluorouracil/Irinotecan/Oxaliplatin)f,55-57| |Esophageal and Gastric Cancers|●Cisplatin/Irinotecan,58 ●FLOT(Docetaxel/Fluorouracil/Leucovorin/Oxaliplatin)59| |Non-Hodgkin Lymphomas|●GDP (Gemcitabine/Dexamethasone/Cisplatin [or Carboplatin])^a,60 ●CHOPa(Cyclophosphamide/Doxorubicin/Vincristine/Prednisone)^61,62 including regimens with pegylated liposomal Doxorubicin(CDOP)63,64 ●Bendamustinea| |Non-Small Cell Lung Cancer|●Cisplatin/Pacitaxel65 ●Cisplatin/Vinorelbine66 ●Cisplatin/Docetaxel65,67 ●Cisplatin/Docetaxel65,67 ●Carboplatin/Paclitaxel^a,69 & 69 ●Docetaxel67| |Pancreatic Cancer|●FOLFIRINOXh,70,71 (Leucovorin/Fluorouracil/lrinotecan/Oxaliplatin)|

Intermediate risk continued

Footnotes References

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

Table of Contents Discussion

EXAMPLES OF DISEASE SETTINGS AND CHEMOTHERAPY REGIMENS WITH AN INTERMEDIATE RISK FOR FEBRILE NEUTROPENIA (10%-20%)a

*This list is not comprehensive. There are other agents/regimens that have a high risk or intermediate risk for the development of febrile neutropenia.*

|EXAMPLES WITH INTERMEDIATE RISK FOR FEBRILE NEUTROPENIA (10%-20%)|| |---|---| |Prostate Cancer|●Cabazitaxel,72 ● Docetaxel,73,74| |Small Cell Lung Cancere|●Carboplatin/Etoposide75| |Testicular Cancer|●BEPd (Bleomycin/Etoposide/Cisplatin)76-78 ●Cisplatin/Etoposide79| |Uterine Sarcoma|●Docetaxel80|

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

MGF-A 6 OF 10

INTERMEDIATE OR HIGH RISK FOR FEBRILE NEUTROPENIA EXAMPLES FOOTNOTES

References

a Guidelines apply to chemotherapy regimens with or without monoclonal antibodies (eg, trastuzumab, rituximab). There is the potential for increased neutropenia risk

with the addition of monoclonal antibodies. Rituximab has been associated with prolonged neutropenia with or without chemotherapy. For details on when monoclonal antibodies are recommended with the regimens listed above in clinical practice, see NCCN Guidelines for Treatment by Cancer Type.

b Growth factor support may not be needed during the paclitaxel portion and can be safely avoided in a large percentage of patients.c Risk for febrile neutropenia has been reported variably as intermediate risk or high risk depending on the study.d Risk of bleomycin-induced pulmonary toxicity may be increased in patients treated with G-CSFs. See Toxicity Risks with MGFs (MGF-C). e Trilaciclib may be used as a prophylactic option to decrease the incidence of chemotherapy-induced myelosuppression when administered before (prophylactic G-CSF may be administered after cycle 1) platinum/etoposide ± immune checkpoint inhibitor-containing regimens or a topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC).

f There are many factors that need to be evaluated to determine a patient’s risk categorization; these include type of chemotherapy regimen (MGF-A) and patient risk

factors (MGF-2).

g If carboplatin dose is area under the curve ≥6 and/or patient is of Japanese ancestry.h A small retrospective trial had a 17% risk of febrile neutropenia in the neoadjuvant setting70 and a randomized trial had a 5.4% risk in the metastatic setting (G-CSFs

were administered to 42.5% of patients who received FOLFIRINOX).71 While G-CSF was not recommended as primary prophylaxis, it may be considered in patients with high-risk clinical features.

i The published results for cabazitaxel have an 8% rate of febrile neutropenia but neutropenic deaths were reported. Primary prophylaxis with G-CSFs is recommended in patients with high-risk clinical features, and should be considered in all patients receiving a dose of 25 mg/m2.

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CHEMOTHERAPY REGIMEN REFERENCES

Note: The references listed for each regimen are limited by the specific populations studied, methods, and collection of data for febrile neutropenia in the clinical trial.

1Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin(MVAC)chemotherapy and recombinant human granulocyte colony stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001;19:2638-2646.

2Paulussen M, Craft AW, Lewis I, et al. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 2008;26:4385-4393.

3 Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive nectodermal tumor of bone. N Engl J Med 2003;348:694-701.

4 Lewis IJ, Noooij MA, Whelan J, et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy:a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 2007;99:112-128.

5 Miser JS, Krailo MD, Tarbell NJ, et al. Treatment of metastatic Ewing's sarcoma or primitive neuroectdermal tumor of bone: evaluation of combination ifosamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study.J Clin Oncol 2004;22:2873-2876.

${}^{6}$ Juergens C, Weston C, Lewis I, et al. Safety assessment of intensive induction with vincristine, ofosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 2006;47:22-29.

7 Citron ML,Berry DA,Cirrincione C,et al.Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741.J Clin Oncol 2003;21:1431-1439.

8 Martin M, Lluch A, Segui MA, et al. Prophylactic growth factor(GF) support with adjuvant docetaxel, doxorubicin, and cyclophosphamide(TAC) for node-negative breast cancer(BC): An interim safety analysis of the GEICAM 9805 study[abstract]. J Clin Oncol 2004;22(Suppl):Abstract 620.

9 Kosaka Y, Rai Y, Masuda N, et al. Phase III placebo-controlled, double-blind,randomized trial of pegfilgrastim to reduce the risk of febrile neutropenia in breast cancer patients receiving docetaxel/cyclophosphamide chemotherapy.Support Care Cancer 2015;23:1137-1143.

10 Gilbar P, McPherson I, Sorour N, Sanmugarajah J. High incidence of febrile neutropenia following adjuvant breast chemotherapy with docetaxel with captedolin and trastuzumab. Breast Cancer Manag 2014;3:327-333.

11 Rugo HS, Tolaney SM, Loirat D,et al. Safety analyses from the phase 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast cancer. NPJ Breast Cancer 2022;8:98.

12Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 2021;384:1529-1541.

13 Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-1715.

14 Pointreau Y, Garahaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009;101:498-506.

15 Vermorken JB, Remenar E, van Herpen C,et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer.N Engl J Med 2007;357:1695-1704.

16 Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med 2018;378:331-344.

17 Diehl V,Franklin J,Pfreundschuh M,et al. Standard and increased-dose BEACOPM chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 2003;348:2386-2395.

18 Borchmann P, Moccia AA, Greil R,et al. BreECADD Is non-inferior to eBEACOPP in patients with advanced stage classical Hodgkin lymphoma:Efficacy results of the GHSG Phase III HD21 trial. Hematol Oncol 2023;41:881-882.

19 Nanus DM,Garino A,Milowsky Ml,et al.Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 2004;101:1545-1551.

20 Gutierrez M,Chabner B, Pearson D,et al.Role of a doxorubicin-containing regimen in relapsed and resistant lymphomas: An 8-year follow-up study of EPOCH.J Clin Oncol 2000;18:3633-3642.

21 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;Suppl 4:iv25-30.

22 Kewalramani T,Zelenetz AD,Nimer SD,et al.Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 2004;103:3684-3688.

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CHEMOTHERAPY REGIMEN REFERENCES

Note: The references listed for each regimen are limited by the specific populations studied, methods, and collection of data for febrile neutropenia in the clinical trial.

23 Blayney DW,LeBlanc ML,Grogan T,et al. Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group(SWOG 9349). J Clin Oncol 2003;21:2466-2473.

35 Griffin PT, Ho VQ, Fulp W, et al. A comparison of salvage infusional chemotherapy regimens for recurrent/refactory multiple myeloma. Cancer 2015;121:3622-3630.

36 Rivell GL, Brunson CY, Milligan L, et al. Effectiveness and safety of high-dose cyclophosphamide as salvage therapy for high-risk multiple myeloma and plasma cell leukemia refractory to new biological agents. Am J Hematol 2011;86:699-701.

24 Watanabe T, Tobinai K, Shibata T, et al. Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial. J Clin Oncol 2011;29:3990-3998.

37 Swisher EM, Mutch DG, Rader J, et al. Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol 1997;66:480-486.

25 Rodriguez MA,Cabanillas FC, Hagemeister FB,et al. A phase II trial of mesna/ ifosfamide, mitoxantrone and etoposide for refractory lymphomas. Ann Oncol 1995;6:609-611.

38 Verschraegen CF, Sittisomwong T, Kudelka AP, et al. Docetaxel for patients with paclitaxel-resistant Mullerian carcinoma. J Clin Oncol 2000;18:2733-2739.

39 Vasey,PA,Jayson GC,Gordon,A et al.Phase III randomized trial of docetaxel-carboplatin versus pacitxel-carboplatin as first line chemotherapy for ovarian carcinoma.J Nat Can Inst 2004;96:1682-1691.

26 Velasquez WS, Cabanillas F, Salvador P,et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone(DHAP). Blood 198:711-117-122.

40 Antman K, Crowley J, Balcerzak SP, et al. A Southwest Oncology Group and Cancer and Leukemia Group B phase II study of doxorubicin, dacarbazine,ifosfamide, and mesa in adults with advanced osteosarcoma, Ewing's sarcoma,and rhabdomyosarcoma. Cancer 1998;82:1288-1295.

27 Velasquez WS,McLaughlin P, Tucker S,et al. ESHAP--an effective chemotherapy regimen in refractory and relapsing lymphoma: A 4-year follow-up study.J Clin Oncol 1994;12:1169-1176.

28 Thomas DA, Faderl S, O'Brien S, et al. Chemocommunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 2006;106:1569-1580.

41 Nielsen OS, Dombernowsky P. Mourridsen K, et al. High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC UT soft tissue and bone sarcoma group. Br J Cancer 1998;78:1634-1639.

29Raugemaue J,Fayad L,Rodriguez MA,et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol 2005;23:7013-7023.

42 Patel SR, Vadhan-Raj S, Burgess MA, et al. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and of fisplamide in patients with sarcomas.Am J Clin Oncol 1998;21:317-321.

30 Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumabodetin in previously untreated diffuse large B-cell lymphoma. N Engl J Med 2022;386:351-363.

43 Von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;17:658-667.

31 Eton O, Legha S, Bedikian A, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: Results from a phase III randomized trial. J Clin Oncol 2002;20:2045-2052.

44 Miller KD, Loehr PJ, Gonin R, Einhorn LH. Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma. J Clin Oncol 1997;15:1427-1431.

32 Zager JS, Orloff M, Ferrucci PF, et al. Efficacy and safety of the melphalan/hepatic delivery system in patients with unresectable metastatic uveal melanoma:results from an open-label, single-arm, multicenter phase 3 study. Ann Surg Oncol 2024;31:5340-5351.

45 Kondagunta GV,Bacik J, Donadio A,et al. Combination of paclitaxel, ifosfamide,and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 2005;23:6549-6555.

33 Lee CK, Barlogie B, Munshi N, et al. DTPACE: An effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol 2003;21:2732-2739.

46 Pouessel D, Culine S, Becht C, et al. Gemcitabine and docetaxel as front line chemotherapy in patients with carcinoma of an unknown primary site. Cancer 2004;10:1257-1261.

34 Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol 2007;138:176-185.

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CHEMOTHERAPY REGIMEN REFERENCES

Note: The references listed for each regimen are limited by the specific populations studied, methods, and collection of data for febrile neutropenia in the clinical trial.

47 Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005;23:4265-4274.

57 Bennouna J,Andre T,Campion L,et al. Rationale and design of the IROCAS study: multicenter, international, randomized phase 3 trial comparing adjuvant modified (m) FOLFIRINOX to mFOLFOX6 in patients with high-risk stage III(pT4 and/or N2) colon cancer-A UNICANCER GI-PRODIGE Trial. Clin Colorectal Cancer 2019;18:e69-e73.

48 Burris HA 3rd. Single-agent docetaxel(Taxotere) in randomized phase III trials.Semin Oncol 1999;26:1-6.

58 lson DH. Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. Oncology(Williston Park) 2004;18(14 Suppl 14):22-25.

49 Sparano JA, Wang M, Martino S, et al. Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in operable breast cancer: Results of Intergroup Trial E1199[abstract]. J Clin Oncol 2007;25(Suppl):Abstract 516.

59 Al-Batran SE, Homann N, Pauligk C,et al.Perioperative chemotherapy with fluorouracil plus leucovorin, oxalipatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma(FLOT4): a randomised, phase 2/3 trial. Lancet 2019;393:1948-1957.

50 Seidman AD, Tiersten A, Hudis C, et al. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol 1995;13:2575-2581.

60 Crump M, Baetz T, Couban S, et al. Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or refractory aggressive histology B-cell non-hodgkin lymphoma: a Phase II study by the National Cancer Institute of Canada Clinical Trials Group(NICC-CTG).Cancer 2001;101:1835-1842.

51 Long III HJ, Bundy BN, Grends Jr EC, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cvix: A Gynecologic Oncology Group Study. J Clin Oncol 2005;23:4626-4633.

61 Coiffer B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242.

52 Monk B, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2009;7:4649-4655.

62 Lyman G, Delgado DJ. Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin's lymphoma receiving CHOP chemotherapy.Leuk Lymphoma 2003;44:2069-2076.

53 Muderspach LI, Blessing JA, Levenback C,et al. A phase II study of topotecan in patients with squamous cell carcinoma of the cervix: a gynecologic oncology group study. Gynecol Oncol 2001;81:213-215.

63 Martino R, Perea G, Caballero MD,et al. Cyclophosphamide, pegylated liposomal doxorubicin(Caelyx), vincristine and prednisone(CCOP) in elderly patients with diffuse large B-cell lymphoma: results from a prospective phase II study.Haematologica 2002;87:822-827.

54 Verschraegen CF, Levy T, Kudelka AP, et al. Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol 1997;15:625-631.

55 Falcone A,Ricci S, Brunetti I,et al. Phase III trial of infusional fluorouracil,leucovorin,oxaliplatin, and irinotecan(FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan(FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007;25:1670-1676.

64 Zaja F, Tomadini V, Zaccaria A, et al. CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma 2006;47:2174-2180.

65 Schiller JH, Harrington D, Belani CP,et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002;346:92-98.

56 Conroy T, Bosset JF, Etienne PL,et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer(UNICANCER-PRODIGE 23): a multicentre, randomised,open-label, phase 3 trial. Lancet Oncol 2021;22:702-715.

66 Pujol J-L, Breton J-L, Gervais R, et al. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing for cisplatin. Ann Oncol 2005;16:602-610.

67 Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: The TAX 326 study group. J Clin Oncol 2003;21:3016-3024.

Continued

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CHEMOTHERAPY REGIMEN REFERENCES

Note: The references listed for each regimen are limited by the specific populations studied, methods, and collection of data for febrile neutropenia in the clinical trial.

68 Cardenal F, Lopez-Cabrero P, Anton A, et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 1999;17:12-18.

69 Ohe Y,Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinocetamine versus carplatin plus acpitaliet, cisplatin plus gemcitabine, and cisplatin plus vinorebine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317-323.

79 Motzer RJ, Sheinfeld J, Mazumdar M, et al. Etoposide and cisplatin adjuvant therapy for patients with pathologic stage ll germ cell tumors. J Clin Oncol 1995;13:2700-2704.

80 van Hoesel Q, Verweij J, Catimel G, et al. Phase II study with docetaxel(Toxotere) in advanced soft tissue sarcomas of the adult. Ann Oncol 1994;5:539-542.

70Hosein PJ, Macintyre J, Kawamura C,et al. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer 2012;12:199.

71 Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-1825.

72 de Bono JS, Ourdard S, Ozguroglu M, et al. Prednisone plus azabitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376:1147-1154.

73 Peltekian S, Sajwani S, Wang X, et al. Incidence, predictors, and outcomes of febrile neutropenia and neutropenia in patients with metastatic castrate-resistant prostate cancer receiving docetaxel. Support Care Cancer 2023;31:311.

74 Weycker D, Li X, Edelsberg J, et al. Risk and consequences of chemotherapy-induced febrile neutropenia in patients with metastatic solid tumors. J Oncol Pract 2015;11:47-54.

75 Kosmidis PA, Samantas E, Fountzlas G, et al. Cisplatin/etoposide versus carbotplatin/etoposide chemotherapy and irradiation in small cell lung cancer randomized phase II study. Hellenic Cooperative Oncology Group for Lung Cancer Trials. Semin Oncol 1994;21(3 Suppl 6):23-30.

76 Garcia del Muro X, Maroto P, Guma J, et al. Chemotherapy as an alternative to radiotherapy in the treatment of stage IIA and IIB testicular seminoma: a Spanish Germ Cell Cancer Group Study. J Clin Oncol 2008;26:5416-5421.

77 Fizazi K, Pagliaro L, Laplanche A, et al. Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours(GETUG 13): a phase 3,multicentre,randomised trial. Lancet Oncol 2014;15:1442-1450.

78 de Wit R, Skoneczna I, Daugaard G, et al. Randomized phase III study comparing paclitaxel-bleomycin,etoposide, and cisplatin(BEP) to standard BEP in intermediate-prognosis germ-cell cancer: intergroup study EORTC 30983.J Clin Oncol 2012;30:792-799.

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

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G-CSFs FOR PROPHYLAXIS OF FEBRILE NEUTROPENIA AND MAINTENANCE OF SCHEDULE DOSE DELIVERYa

●Filgrastim(category 1) or tbo-filgrastim ${}^{b}$ (category 1)

▶There are phase ll studies that demonstrate efficacy for chemotherapy regimens given every 2 weeks.

Daily dose of 5 mcg/kg(rounding to the nearest vital size by institution-defined weight limits) until post-nadir absolute neutrophil count(ANC) recovery to normal or near-normal levels by laboratory standards.

There are insufficient data to support use for cytotoxic chemotherapy regimens administered every week; therefore, pegfilgrastim should not be used.

Start the next day c or up to 3-4 days after completion of myelosuppressive chemotherapy and treat through post-nadir recovery.d,e,1

●Eflapegrastim-xnst17,18

Administer 13.2 mg subcutaneously once per chemotherapy cycle.

Administer approximately 24 hours after cytotoxic chemotherapy. Do not administer within the period from 14 days before to 24 hours after administration of cytotoxic chemotherapy.

●Pegfilgrastimf,2(category 1)

One dose of 6 mg

▷Based on clinical trial data, pegfilgrastim can be administered the day after myelosuppressive chemotherapy(category 1).3 There are data for and against same-day dosing,c but the U.S.Food and Drug Administration(FDA)-approved dosing schedule is still recommended.4-9

●Efbemalenograstim alfa-vuxwh,19

Administer 20 mg subcutaneously once per chemotherapy cycle.

Administer approximately 24 hoursc after cytotoxic chemotherapy.Do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

□There should be at least 12 days between the dose of pegfilgrastim and the next cycle of chemotherapy.

●Caution should be exercised when administering prophylactic G-CSF in patients given concurrent chemotherapy and radiation.20 Randomized data have indicated a detrimental effect on toxic deaths with the use of granulocyte-macrophage colony-stimulating factor (GM-CSF) during concurrent chemoradiotherapy. This was not observed in a more recent secondary analysis of the CONVERT trial, in which prophylactic G-CSF was allowed. The risks and benefits of G-CSF versus dose reduction or delay during modern chemoradiotherapy are uncertain at this time.21

If the treatment cycle includes chemotherapy administration on Days 1 and 15, pegfilgrastim may be given after each chemotherapy treatment.

For patients who cannot return to the clinic for next-day administration, there is an FDA-approved delivery device available that can be applied the same day as chemotherapy in order to deliver the full dose of pegfilgrastim the following day(approximately 27 hours after application).9,10-16

●Subcutaneous route is preferred for all G-CSFs listed above.

●For information regarding prophylactic anti-infectives (le, viral, fungal,bacterial), see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

There is evidence to support use for chemotherapy regimens given every 3 weeks(category 1).

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

bTbo-filgrastim is a human G-CSF approved by the FDA through an original biologic license application. All of these G-CSFs are indicated for reducing the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy.

c Non-cytotoxic targeted therapeutics should be excluded from 24-hour recommendation.

d Studies suggest that shorter durations of G-CSFs may be less efficacious.

e Neutrophil counts should be monitored, as indicated, appropriate to the setting.

f Pegfilgrastim administration increases bone marrow and spleen fluorodeoxyglucose(FDG) uptake, which may impact PET/CT assessment and interpretation.

9 Rarely(1.7%-6.9%), there is a failure to inject that requires further medical attention. Individuals with on-body injectors should avoid MRIs.

h Efbemalenograstim alfa-vuxw is a non-pegylated long-acting formulation.

National NCCN Comprehensive NCCN Guidelines Version 1.2026 Cancer Cancer Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

REFERENCES

1 Weycker D, Li X, Tziveleis K, et al. Burden of chemotherapy-induced febrile neutropenia hospitalizations in US clinical practice, by use and patterns of prophylaxis with colony-stimulating factor. Support Care Cancer 2017;25:439-447.

13 Townley C, Porter C, McMullen N. Comparing grade 4 neutropenia associated with pegfilgrastim administered via the Onpro device versus manual injection with a prefilled syringe. J Hematol Oncol Pharm 2018;8:3397.

2 Minamimoto R, Barato L, lagaru A. Association between time since administration of pegylatedG-CSF(pegfilgrastim) and bone marrow uptake on FDG PET/CT:Determination of a minimum interval. AJR Am J Roentgenol 2022;21:3851:358.

14 Yang BB, Morrow PK, Wu X, et al. Comparison of pharmacokinetics and safety of pegfilgrastim administered by two delivery methods: on-body injector and manual injection with a prefilled syringe. Cancer Chemother Pharmacol 2015;75:1199-1206.

3Lyman GH,Allcott K, Garcia J,et al.The effectiveness and safety of same-day versus next-day administration of long-acting granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced neutropenia: a systematic review.Support Cancer Care 2017;25:2619-2629.

15 McBride A, Krendyukov A, Mathieson N,et al. Febrile neutropenia hospitalization due to pegfilgrastim on-body injector failure compared to single-injection pegfilgrastim and daily injections with reference and biosimilar figrastim: US cost simulation for lung cancer and non-Hodgkin lymphoma. J Med Econ 2020;23:28-36.

4 Eckstrom J, Bartels T, Abraham I, et al. Incidence of febrile neutropenia using same-day versus next-day pegfiligrastim in patients with gastrointestinal cancers.Support Care Cancer 2019;27:873-878.

16 Long Zur, Kurup AN, Jensen NM, et al. Initial testing of pegfilgrastim(Neulasta Onpro) on-body injector in multiple radiological imaging environments. J Appl Clin Med Phys 2021;22:343-349.

5 Matera RM, Relias V, Saif MW. Safety and efficacy of same-day administration of pegfilgrastim in patients receiving chemotherapy for gastrointestinal malignancies.Cancer Med J 2021;4:6-11.

17 Schwartzberg LS, Bhat G, Peguero J, et al. Elfapegrastim, a Long-acting granulocyte-colony stimulating factor for the management of chemotherapy-induced neutropenia: Results of a phase III trial. Oncologist 2020;25:e1233-e1241.

6Cbride A, Alrawshad N, Bartels T, et al. Same-day versus next-day pegfilgrastim or pegfilgrastim- in patients with lymphoma receiving CHOP-like chemotherapy. Future Oncol 2021;17:3485-3497.

7 Kitchen K, Mosier MC. Real-world comparison of febrile neutropenia rates with same-day versus next-day administration of pegfilgrastim. J Clin Oncol 2021;39:299-299.

18 Cobb PW, Moon YW, Mezei K, et al. A comparison of effelagrastim to pegfilgrastim in the management of chemotherapy-induced neutropenia in patients with early-stage breast cancer undergoing cytotoxic chemotherapy(RECOVER):A Phase 3 study. Cancer Med 2020;9:6234-6243.

8 Burris HA, Belani CP, Kaufman PA, et al. Pegfilgrastim on the same day versus next day of chemotherapy in patients with breast cancer, non-small-cell lung cancer, ovarian cancer, and non-Hodgkin's lymphoma: Results of four multicenter,double-blind, randomized phase II studies. J Oncol Pract 2010;6:133-140.

19 Glaspy J, Daley W, Bondarenko I, et al. A phase III, randomized, multi-center,open-label, fixed dose, Neulasta active-controlled clinical trial of F-627, a novel G-CSF, in women with breast cancer receiving myelotoxic chemotherapy [abstract]. Blood 2021;138(Suppl):4290.

9 Lyman GH, Balaban E, Diaz M, et al. American Society of Clinical Oncology statement: Biosimilars in oncology. J Clin Oncol 2018;36:1260-1265.

${}^{20}$ Gomes F,Faivre-Finn C,Mistry H,et al.Safety of G-CSF with concurrent chemo-radiotherapy in limited-stage small cell lung cancer- Secondary analysis of the randomised phase 3 CONVERT trial. Lung Cancer 2021;153:165-170.

10 Joshi RS,Egbuna Ol,Cairns AS,et al.Performance of the pegfilgrastim on-body injector as studied with placebo buffer in healthy volunteers. Curr Med Res Opin 2017;33:379-384.

11Stuessy P, Sanchez FA, Schober M. Retrospective review of pegfilgrastim on-body injector delivery rates in a large health system[abstract]. J Clin Oncol 2017;35(Suppl): Abstract e18273.

21Bunn PA,Crowley J,Kelly K,et al.Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632-1641.

12 Mahler LJ, DiBlasi R, Perez A, et al. On-body injector: an administration device for pegfilgrastim. Clin J Oncol Nurs 2017;21:121-122.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

TOXICITY RISKS WITH MGFsa

Filgrastim, Pegfilgrastim, and Tbo-filgrastim ${}^{b,c,d,e}$

●Warnings:

Allergic reactions

◆ Skin: rash, urticaria, facial edema

◆Respiratory: wheezing, dyspnea

□Cardiovascular:hypotension,tachycardia,aphanylaxis

Bleomycin-containing regimens: pulmonary toxicity

Splenic rupture

Acute respiratory distress syndrome

Alveolar hemorrhage and hemoptysis

Sickle cell crises (only in patients with sickle cell disease)

Myelodysplastic syndrome(MDS) and acute myeloid leukemia(AML)

●Precautions

Rare: vasculitis, Sweet syndrome

●Immunogenicity

●Adverse reactions

Bone painh

Eflapegrastim-xnst and Efbemalenograstim alfa-vuxwb,e

●Warnings:

●Splenic rupture

Acute respiratory distress syndrome

Serious allergic reactions, including anaphylaxis

Sickle cell crisis (only in patients with sickle cell disease)

Glomerulonephritis

Leukocytosis

Thrombocytopenia

MDS and AML in patients with breast and lung cancer

Capillary leak syndrome

Aortitis

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

b Full prescribing information for specific product information.

c Not all of the toxicities listed have been seen with each preparation, but similar toxicities are expected with filgrastim,tbo-filgrastim,pefilgrastim,and biosimilars.

d The toxicities listed are from the prescribing information and are based on studies from different patient populations. For filgrastim, tbo-filgrastim, and biosimilars, the toxicities are based on non-myeloid malignancies. For sargramostim, the toxicities are based primarily on studies from leukemia and transplant patients, and the listed toxicities may reflect IV route of administration and may differ from those of subcutaneous administration.

e G-CSFs are not recommended for use within 14 days after receipt of chimeric antigen receptor(CAR)-modified T cells due to concern for exacerbation of cytokine release syndrome. Use after that time period can be considered for treatment of neutropenia.

f See Discussion for details.

9 Lyman et al reported an increase in absolute and relative risk of AML/MDS of 0.41% and 1.92, respectively, related to G-CSFs. Overall mortality was decreased. See Discussion for details and references.

h Available data support use of naproxen and other nonsteroidal anti-inflammatory drugs (NSAIDs) or loratadine. See Discussion for more details.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

USE OF THROMBOPOIETIN RECEPTOR AGONISTS (TPO-RA) IN PATIENTS WITH CANCER

PRESENTATION

ASSESSMENT

MANAGEMENT

![USE OF THROMBOPOIETIN RECEPTOR AGONISTS (TPO-RA) IN PATIENTS WITH CANCER MANAGEMENT ASSESSMENT\nPERESENTATION\n$LNCC\nSUSpected chemotherapy- induced thrombocytopenia (CIT)$\{{}^{a, 1, 2}\$\nEvaluate for other potential causes of thrombocytopenia as indicated\nComplete blood count (CBC) with differential, including evaluation for other cytopenias\nBlood smear or morphology, including evaluation for platelet clumping\nNCCN 6954444444\nNCCN 75644444\nButronic polyoPIETIN RECEPTOR AGONISTS (TPO-RA) IN PATIENTS WITH CANCER MANAGEMENT ASSESSMENT\nPERESENTATION\nL96200-2053020050302005\nUSE OF THROMBOPOIETIN RECEPTOR ARTificial hemogliene (PNH) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633,\n](2/aj0YEe4oUhYkBdfpda0fYP/figure8e44d1b37b914ec8b3009ac2ae248a5e_0_9.png) Known MDS

NCCN Guidelines for Myelodysplastic Syndromes

Known myeloid malignancy or ALL

Treat underlying disease per NCCN Guidelines

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

TGF-2

Thrombocytopenia

post-hematopoietic cell transplanta,g,1,2,10,11

• Evaluate for other potential causes

of thrombocytopenia as indicated,

including examples above, as well as

primary or secondary graft failure, graftversus-host disease (GVHD), relapse of hematologic malignancy, and transplantassociated TMA (TA-TMA)

Treat underlying cause(s) as indicated

Primary or secondary

failure of platelet recovery

without other clear

underlying causes

Consider:

• Platelet transfusion per AABB guidelines

• Clinical trial of TPO-RAb

• Eltrombopagh,12-17

References

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

Footnotes

USE OF TPO-RA IN PATIENTS POST-HEMATOPOIETIC CELL TRANSPLANT

PRESENTATION

ASSESSMENT

MANAGEMENT

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

TGF-3

USE OF TPO-RA – FOOTNOTES

a Definitions used in several studies include thrombocytopenia (platelets <100,000/mcL) for ≥3 to 4 weeks following last chemotherapy administration and/or following

delays in chemotherapy initiation related to thrombocytopenia.

b In patients for whom a TPO-RA is being considered for management of CIT, participation in clinical trials is strongly encouraged whenever possible. c Studies have evaluated other TPO-RA agonists, including avatrombopag, but there are insufficient data from these studies to recommend these agents. Additional

prospective studies are needed to determine safety, efficacy, and benefits of TPO-RA agonists.

d The primary purpose of TPO-RAs for CIT is to maintain dose schedule and intensity of chemotherapy when such benefit is thought to outweigh potential risks.

Romiplostim dosing strategies include weekly dosing beginning at 2–4 mcg/kg, increased no more than 1–2 mcg/kg per week to target platelet count 100,000–150,000/mcL. Maximum dose is 10 mcg/kg weekly per prescribing information.

e It is uncertain whether use of TPO-RAs for CIT increases the risk of venous thromboembolism (VTE) in patients with cancer. Caution is warranted.f Insufficient data are available to support routine use of TPO-RAs for CIT in pediatric patients.g Several reports have separately examined use of TPO-RA in patients with prolonged thrombocytopenia following hematopoietic cell transplantation, including patients with secondary failure of platelet recovery. Clinical trial participation is encouraged whenever possible for such patients.

h Eltrombopag has been evaluated with efficacy in patients with prolonged thrombocytopenia post-allogeneic transplant and poor graft function.

References

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

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

USE OF TPO-RA-REFERENCES

1Soff GA,Miao Y,Bendheim G,et al.Romiplostim treatment of chemotherapy-induced thrombocytopenia. J Clin Oncol 2019;37:2892-2898.

2Al-Samkari H, Parnes AD, Goodarzi K, et al. A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies. Haematologica 2021;106:1148-1157.

3 Al-Samkari H, Kolb-Sielecki J, Safina SZ, et al. Avatrombopag for chemotherapy-induced thrombocytopenia in patients with non-haematological malignancies: an international, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol 2022;9:e179-e189.

4 Roumier M, Le Burel S, Audia S, et al. High dose rompilostim as a rescue therapy for adults with severe bleeding and refractory immune thrombocytopenia.Am J Hematol 2021;96:E43-E46.

5 Miao J, Leblejbian H, Scullion B, Parnes A. A single center experience with romiptimost for the management of chemotherapy-induced thrombocytopenia.Am J Hematol 2018;93:E68-E88.

${}^{6}$ Parameswaran R, Lunning M, Manhattan S, et al. Romiplostim for management of chemotherapy-induced thrombocytopenia. Support Care Cancer 2014;22:1217-1222.

7 de Latour RP, Chevret S, Ruggeri AL, et al. Romiplostim in patients undergoing hematopoietic stem cell transplantation: results of a phase 1/2 multicenter trial.Blood 2020;135:227-229.

${ }^{8}$ Christakopoulos GE,DeForTE,Hage S,et al.Phase I dose-finding,safety,and tolerability trial of romiplostim to improve platelet recovery after UCB transplantation.Transplant.Transplant Cell Ther 2021:27:497.e1-497.e6.

9 Scordo M, Gilbert LJ, Hanley DM, et al. Open-label pilot study of romiplostim for thrombocytopenia after autologous hematopoietic cell transplantation. Blood Adv 2023;7:1536-1544.

10 Mahat U, Rotz SJ, Hanna R. Use of thrombopoietin receptor agonists in prolonged thrombocytopenia after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2020;26:e65-e73.

11 Gao F,Zhou X,Shi J,et al.Eltrombopag treatment promotes platelet recovery and reduces platelet transfusion for patients with post-transplantation thrombocytopenia.Ann Hematol 2020;99:2679-2687.

12 Marotta S, Marano L, Ricci P, et al. Elstrombopag for post-transplant cytopenias due to poor graft function. Bone Marrow Transplant 2019;54:1346-1353.

13 Yuan C, Boyd AM, Nelson J, et al. Elstrombopag for treating thrombocytopenia after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2019;25:1320-1324.

14 Halahleh K, Gale RP, Da'na W, et al. Therapy of posttransplant poor graft function with etlrombopag. Bone Marrow Transplant 2021;56:4-6.

15 Aydin S, Dellacasa C, Manetta S, et al. Rescue treatment with eltrombopag in refractory cytopenias after allogeneic stem cell transplantation. Ther Adv Hematol 2020;11:2040620720961910.

16 Shahzad M, Iqbal Q, Munir F, et al. Outcomes with eltrombopag for poor graft function following allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis. Blood 2022;140:12846-12847.

17 Ahmed S, Bashir Q, Bassett R, et al. Elstrombopag for post-transplantation thrombocytopenia: Results of phase II randomized, double-blind, placebo-controlled trial. Transplant Cell Ther 2021;27:430.e1-430.e7.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

PRE-TREATMENT EVALUATION OF PATIENT RISK FACTORS FOR IMMUNE EFFECTOR CELL-ASSOCIATED HEMATOLOGIC TOXICITY(ICAHT) AND INDICATIONS FOR PROPHYLACTIC INTERVENTION

RISK ASSESSMENT FOR ICAHT OVERALL ICAHT RISK PROPHYLACTIC USE OF G-CSFs FOR FEBRILE NEUTROPENIA

![Risk evaluation for ICAHT prior to immune effector cell (IEC)therapies\n Risk factors for ICAHT include1. Bone marrow involvement by tumor\n>High tumor burdena > Preexisting inflammatory stateb Active infection\n> Prexisting inflammatory cell transplant\nReceipt of bridging therapy's 22-4\nHigh of herematotoieic cell High (21 risk factors) High (21 risk factors) High (21 kri 6nN) S SFCS 2021 ▶\nIn factive infection \n Current netropenia (see below) beyond 30 days post- infusion. \n High (21 risk factors) High (21 risk factors) 00000-9000-9000-1-7 III(ICA) 00000-1-8 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III\n](2/aj0YEe4oUhYkBdfpda0fYP/figure8c8d5ab860b14b0fa2ea96f5e8986818_0_6.png) ● Consider hematopoietic cell boost ${ }^{d,7-9}$

a Represented by elevated serum lactate dehydrogenase (LDH), or bulky disease by disease-specific staging criteria.

b Represented by elevated C-reactive protein(CRP) or ferritin.

c Defined as cancer-directed therapy received between leukapheresis and lymphodepletion chemotherapy.

d If cryopreserved autologous stem cells are available.

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

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

POST-TREATMENT ASSESSMENT OF SUSPECTED ICAHT

|PRESENTATION|ASSESSMENT|MANAGEMENT| |---|---|---|

![######Suspected CICAHT in patients$\underline{Re}\text{propto}\text{Hepatopio}\text{Cytosis}$\underline{ar}\text{the}\text{Hepatopoio}\text{C}(t)\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\te\n](2/aj0YEe4oUhYkBdfpda0fYP/figure6a7c2a32c7d743dda19fe0673b6fe216_0_6.png) a Represented by elevated serum LDH, or bulky disease by disease-specific staging criteria.

b Represented by elevated CRP or ferritin.

c Defined as cancer-directed therapy received between leukapheresis and lymphodepletion chemotherapy.

d If cryopreserved autologous stem cells are available.

e Defined per European Hematology Association/European Society for Blood and Marrow Transplantation (EHA-EBMT) consensus criteria as grade 4 thrombocytopenia(platelets <25,000/mcL) persistent for >7 days, or that requires transfusion or growth factor dependence.

f Eltrombopag has been evaluated with efficacy in patients with prolonged thrombocytopenia post-allogeneic transplant and poor graft function, as well as in patients with prolonged thrombocytopenia post-IEC/CAR T-cell therapy.

References

National NCCN Comprehensive NCCN Guidelines Version 1.2026 Cancer Cancer Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

PRE-TREATMENT/POST-TREATMENT EVALUATION AND ASSESSMENT OF SUSPECTED ICAHT REFERENCES

${}^{1}$ Rejeski K, Subklewe M, Aljurf M, et al. Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations. Blood 2023;142:865-877.

2Rejeski K, Perez A, Sesques P,et al. CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma.Blood 2021;138:2499-2513.

3Rejeski K,Wang Y,Albanyan O,et al.The CAR-Hematotox Score identifies patients at high risk for hematological toxicity, infections and poor clinical outcomes following breuxabtagene autoleucel in relapsed/refractory mantle cell lymphoma. Blood 2022;140:651-653.

4Rejeski K, Hansen DK, Bansal R,et al.The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma. J Hematol Oncol 2023;16:88.

5Beyar-Katz O,Rejeski K, Shouval R. Immune effector cell-associated hematotoxicity: mechanisms, clinical manifestations, and management strategies.Haematologica 2025;110:1254-1268.

${}^{6}$ Rejeski K, Jain MD, Shah NN, et al. Immune effector cell-associated haematoxicity after CAR T-cell therapy: from mechanism to management.Lancet Haematol 2024;11:e459:e470.

7Rejeski K, Burchert A, lacoboni G, et al. Safety and feasibility of stem cell boost as a salvage therapy for severe hematotoxicity after CD19 CAR T-cell therapy.Blood Adv 2022;6:4719-4725.

8 Mullanfiroze K, Lazareva A, Chu J, et al. CD34+-selected stem cell boost can safely improve cytopenias following CAR T-cell therapy. Blood Adv 2022;6:4715-4718.

9 Gagelmann N, Wulf GG, Duell J,et al. Hematopoietic stem cell boost for persistent neutropenia after CAR T-cell therapy: a GLA/DRST study. Blood Adv 2023;7:555-559.

10 Marotta S, Marano L, Ricci P, et al. Elstrombopag for post-transplant cypenias due to poor graft function. Bone Marrow Transplant 2019;54:1346-1353.

11 Yuan C, Boyd AM, Nelson J,et al. Eltrombopag for treating thrombocytopenia after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2019;25:1320-1324.

12 Halahleh K, Gale RP, Da'na W, et al. Therapy of posttransplant poor graft function with etlrombopag. Bone Marrow Transplant 2021;56:4-6.

13 Aydin S, Dellacasa C, Manetta S, et al. Rescue treatment with eltrombopag in refractory cytopenias after allogeneic stem cell transplantation. Ther Adv Hematol 2020;11:2040620720961910.

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

14 Shahzad M, Iqbal Q, Munir F, et al. Outcomes with etlrombopag for poor graft function following allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis. Blood 2022;140:12846-12847.

15 Ahmed S, Bashir Q, Bassett R, et al. Eltrombopag for post-transplantation thrombocytopenia: Results of phase II randomized, double-blind, placebo-controlled trial. Transplant Cell Ther 2021;27:430.e1-430.e7.

16 Wesson W, Ahmed N, Rashid A, et al. Safety and efficacy of etrombopag in patients with post-CAR T cytopenias. Eur J Haematol 2024;112:538-546.

17 Mingot-Castellano ME, Reguera-Ortega JL, Torres DZ, et al. Use of eltrombopag to improve thrombocytopenia and transfusion requirement in anti-CD19 CAR-T Cell-Treated Patients. J Clin Med 2024;13:5117.

18 Beyar-Katz O, Perry C, On YB, et al. Thrombopoietin receptor agonist for treating bone marrow aplasia following anti-CD19 CAR-T cells-single-center experience. Ann Hematol 2022;101:1769-1776.

19 Drillet G, Lhomme F, De Guibert S, et al. Prolonged thrombocytopenia after CAR T-cell therapy: the role of thrombopoietin receptor agonists. Blood Adv 2023;7:537-540.

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

HEMOGLOBIN CONCENTRATION TO PROMPT AN EVALUATION OF ANEMIA

EVALUATION OF ANEMIAa,b,c

Evaluate anemia for possible cause as indicatedb:

● First check

Reticulocyte count and mean corpuscular volume(MCV)

·Then consider

Hemorrhage(consider upper and lower endoscopic evaluation)

Hemolysis (ie, direct antiglobulin test, DIC panel, haptoglobin, indirect bilirubin, lactate dehydrogenase[LDH])

Nutritional(ie, iron, total iron-binding capacity, ferritin,B_{12}, folate)f^{B_{12}, folate)f^{f}

Inherited (ie, prior history, family history)

Renal dysfunction(glomerular filtration rate[GFR]<60 mL/min/1.73 m2)

● Cancer treatment or other drug-induced myelosuppression/anemia

▶Hormone dysfunction(ie, hypogonadism, adrenal dysfunction, hyper/hypothyroidism)

Anemia of chronic inflammation (ie, C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR])

Secondary myeloid disorders including clonal cytopenia of undetermined significance (CCUS)

Treat as indicated

![Treat as indicated\nNo cause identified\nRisk Assessment and Indications for Transfusion(ANEM-2)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure4b7ea3ba9c9d4cafba16ba97d9637ac5_0_20.png)

MDS

Myeloid malignancies or ALL

NCCN Guidelines for Myelodysplastic Syndromes

Treat underlying disease per NCCN Guidelines for Treatment by Cancer Type

d Consideration of gender in evaluation of anemia is relevant since women have a lower baseline Hb than men. See Discussion for more details.

a The NCCN Guidelines for Hematopoietic Growth Factors were formulated in reference to adult patients.

bThis is a basic evaluation for possible causes of anemia. See Discussion for more details.

cTrilaciciib may be used as a prophylactic option to decrease the incidence of anemia and red blood cell (RBC) transfusions when administered before platinum/etoposide $\pm$ immune checkpoint inhibitor-containing regimens or a topotecan-containing regimen for ES-SCLC. Use of trilaciciib in this setting is a category 2B recommendation.

e Correct reticulocyte count for degree of anemia. See Discussion.

f In general, the lower the level of ferritin, the higher the probability that the patient has true iron deficiency anemia. However, in the cancer setting, be aware of a chronic inflammatory state, which may falsely elevate the serum ferritin.Additionally, if serum iron studies are not performed while the patient is fasting or if the patient has taken a recent oral iron tablet, serum iron levels may be falsely elevated, and thus also falsely elevate the percent transferrin saturation(TSAT).Fasting is preferred when testing for serum iron and total iron-binding capacity.

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

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

RISK ASSESSMENT AND INDICATIONS FOR INITIAL TRANSFUSION IN ACUTE SETTING9

![\nAsymptomatic without significant comorbidities$h\longrightarrow$ Observe\nPeriodic re-evaluation\n\nSymomatic\n(physiologic):● Sustained tachycardia● Tachypnea● Chest pain\n\nInader of excitative growth for Hb with hematopoietic Growth Factors\n\nConsider red blood cell (RBC) transfusion per AABB Guidelines9 Consider red blood cell (RBC) transfusion per AABB Guidelines9\n\nSymomatic (physiologic):● Sustained tachycardia● Tachypnea● Chest pain\n\nInader of excitative growth for Hb with hematopoietic Growth(a)\ng Bacterlives\n\n\n\n\nAsymptomatic without significant comorbidities!● Chronic pulmonary disease\nAsymptomatic\n\n\n\nAsymptomatic:● Sustained tachycardia● Tachypnea● Chest pain\n\nAsymptomatic with chemical therapy\nH\nCardiac disease\n·Chronic pulmonary disease\nCerebral vascular disease\nSymptomatic (physiologic):● Sustained tachycardia● Tachypnea● Chest pain\n\n\n\n\n\n\nasimptomatic:9\nSymptomatic (physiologic):● Sustained tachycardia● Tachypnea● Chest pain\n\n\nAsymptomatic with significant good differential eigenvalue of high-quality and electrical\nRBC transfusion per AABB Guidelines9\n\n\n\n\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figurec8894e4e42f2481b8dfaca85c9621bfc_0_5.png) See Discussion for comparison of risks and benefits of ESA use versus RBC transfusion

See Special Categories in Considering ESA Use(ANEM-3)

9 The AABB has made recommendations regarding appropriate indications for RBC transfusion. See Discussion for details.

h Degree of severity of comorbidities in combination with the degree of severity of anemia should be taken into consideration when initiating RBC transfusion.

iFatigue(FACT-F)and Anemia(FACT-An) subscales of the Functional Assessment of Cancer Therapy(FACT) and Brief Fatigue Inventory(BFI) are examples of standardized measures for assessing patient-reported fatigue.

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

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

SPECIAL CATEGORIES IN CONSIDERING ERYTHROPOIESIS-STIMULATING AGENT(ESA) USE

![Cancer and chronic kidney disease(moderate to severe)\nConsider ESAs by FDA dosing/dosing\nconsider based on patient preferences:\n●ESAs by FDA dosing/dosing adjustmentsj,m,nor\nlyelos suppressive chemotherapy without other identifiable cause of anemia\n● Clinical trial\nConsider an patient preferences:\n● 283.85 of cancer and Dosing.dosing adjustmentsj,m,n\nManagement of Cancer and Chemotherapy-Induced Anemia for\n● Patients Who Refuse Blood Transfusions(ANEM-C)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure3624af28c2bd45189f707dd650bd6443_0_5.png) •Patients with cancer not receiving therapy

•Patients receiving non-myosuppressive therapy

●Patients receiving myelosuppressive chemotherapy with curative intent!(Examples of cancers for which there is therapy with curative intent:Early-stage breast cancer, Hodgkin lymphoma, non-Hodgkin lymphomas,testicular cancer, early-stage non-small cell lung cancer, and small cell lung cancer)

There is not enough evidence to support ESA use in these patient populations; therefore, ESAs are not recommended at this time(in the absence of other indications, eg, advanced chronic kidney disease)

Optimal response to ESAs depends on adequate iron storage and availability.

k For comparison of risks and benefits of ESA use versus RBC transfusion, see Discussion.

A few studies suggest that patients with small cell lung cancer on myeloppressive chemotherapy may not have an increase in mortality when receiving ESAs(Nagel S,et al.Clin Lung Cancer 2011;12:62-69).

m Erythropoietic Therapy- Dosing. Titration, and Adverse Effects (ANEM-A).

${}^{n}$ Patients with previous risk factors for thrombosis are at higher risk for thrombosis with the use of ESAs. If considering use of ESAs, evaluate and counsel patients regarding the risk factors for thrombosis: history of thromboembolism, known heritable mutation, hypercoagulability, elevated pre-chemotherapy platelet counts,hypertension,steroids,prolonged immobilization,recent surgery,certain therapies for multiple myeloma,horonal agents,etc.(Nagel S,et al.Clin Lung Cancer 2011;12:62-69; Gergal Gopalkrishna Rao SR,et al. Cureus 2021;13:e17835)(NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease).

°The Hb threshold for treatment and dosing with ESAs is different for chemotherapy-induced anemia and chronic kidney disease. For more details on the use of ESAs in patients with cancer and chronic kidney disease, see Discussion.

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

![National Comprehensive Cancer Network®\n](2/aj0YEe4oUhYkBdfpda0fYP/figure2cfc8aaa061843c5bc6053e7b698dd51_0_1.png)

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

![EVALUATION OF IRON DEFICIENCY\nIron panel (serum iron, total iron-binding capacity, serum ferritin)ferritin 450 mg/L AND (ferritin >500-800 ng/mL AND TSAT<20%)\nAbsolute iron deficiency(ferritin <30 ng/mL AND transferrin saturation [TSAT] <20%)\nNonider IV or oral iron supplementationu\nNo Hb increase after 4 wks\nSection paper below for functional iron deficiency See Discussion for clinical examples of iron status\nIron panel (serum iron panel (serum iron, total iron-binding capacity, serum ferritin)ferritin 450-800 ng/mL AND TSAT<50%)\nPossible functional iron deficiency(ferritin >500-800 ng/mL AND TSAT<50%)\nNo iron suppression for select patients\nFerritin >800 ng/mL\nI\nNo iron deficiency(ferritin >800 ng/mL\nI\nNo iron deficiency(ferritin >800 ng)/l\nIn general, the lower the level of ferritin, the higher the probability that the patient has true iron deficiency anemia. However, in the cancer setting, be aware of a chronic iron studies are not performed while the patient is fasting or if the patient has taken a recent oral iron tablet, serum iron levels may be falsely elevated, and thus also falsely elevate the percent TSAT. Fasting is preferred when testing for serum iron and total iron-binding capacity.\n](2/aj0YEe4oUhYkBdfpda0fYP/figure9e92a727a33346cfa3a900a4caf1d136_0_4.png)

Parenteral Iron Preparations (ANEM-B)

In general, the lower the level of ferritin, the higher the probability that the patient has true iron deficiency anemia. However, in the cancer setting, be aware of a chronic inflammatory state, which may falsely elevate the serum ferritin. Additionally, if serum iron studies are not performed while the patient is fasting or if the patient has taken a recent oral iron tablet, serum iron levels may be falsely elevated, and thus also falsely elevate the percent TSAT. Fasting is preferred when testing for serum iron and total iron-binding capacity.

P ESAs work optimally in patients who have adequate iron stores; thus, determination of iron stores and management of iron storage status is necessary.

9If the ferritin and TSAT are discordant, the low ferritin value should take precedence in determining whether IV iron will be of benefit.

$^{'}$ In clinical trials using IV iron plus an ESA, a higher response rate is seen when iron is used for patients with a TSAT<20%. For patients who received IV iron that had baseline TSATs>20%, the response rate to IV iron is both diminished and prolonged as the TSAT increased from 20% to 50%. Therefore, the decision to offer IV iron to this subset of patients should be reserved for those in whom benefits are likely to outweigh risks.

s Only one of six studies(Henry DH, et al. Oncologist 2007;12:231-242) of IV iron therapy in patients with cancer provided a TSAT guideline for monitoring.

${}^{t}$ Although patients with ferritin levels of>500-800 ng/mL may have functional iron deficiency, as evidenced by clinical trials in patients with cancer, there are insufficient data to support the routine use of IV iron in this setting. Administration of IV iron to such patients should be individualized with the goal of avoiding allogeneic transfusion.

uIV iron has superior efficacy and should be considered for supplementation. Oral iron has been more commonly used but is less effective. See Parenteral Iron Preparations(ANEM-B).

vAlthough all combinations of serum ferritin and TSAT could be found in at least one of six randomized controlled trials evaluating the use of IV iron with an ESA,eligibility criteria testing for serum ferritin and TSAT generally ranged from >10 to <900 ng/mL and >15% to <60%, respectively.

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

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

ANEM-A

1 OF 5

ERYTHROPOIETIC THERAPY - DOSING AND TITRATION (1 of 5)a-f

INITIAL DOSING

TITRATION FOR NO RESPONSE*

TITRATION FOR RESPONSE

• The dose should be adjusted for each patient to maintain the

lowest Hb level sufficient to

avoid RBC transfusion.

• If Hb reaches a level needed to avoid transfusion or increases>1 g/dL in any 2-week period,

reduce dose by 25% for epoetin alfa or epoetin alfa-epbxc,1 and by 40% for darbepoetin alfa.

• For Hb target limits, refer to

ANEM-A 3 of 5.

Footnotes and References

(ANEM-A 2 of 5)

Erythropoietic Therapy - Adverse

Effects (ANEM-A 3 of 5)

* No response is defined as Hb increase <1 g/dL and remains below 10 g/dL after the initial 4 weeks of epoetin, or 6 weeks of darbepoetin. Discontinue therapy after 8 weeks if no response.

** Data indicate that darbepoetin alfa 300 mcg is equivalent in terms of efficacy to darbepoetin alfa 500 mcg for initial dosing.4

PACKAGE INSERT DOSING SCHEDULE

Epoetin alfa 150 units/kg 3 times per wk by subcutaneous injection

Increase dose of epoetin alfa to 300 units/kg 3 times per wk by subcutaneous injection

Epoetin alfa 40,000 units every wk by subcutaneous injection

Increase dose of epoetin alfa to 60,000 units every wk by subcutaneous injection

Darbepoetin alfa 2.25 mcg/kg every wk by subcutaneous injection

Increase darbepoetin alfa to up to 4.5 mcg/kg every wk by subcutaneous injection

Darbepoetin alfa 500 mcg** every 3 wks by subcutaneous injection ALTERNATIVE REGIMENSg

Darbepoetin alfa 100 mcg fixed dose

every wk by subcutaneous injection

Increase darbepoetin alfa to up to 150–200 mcg fixed

dose every wk by subcutaneous injection2

Darbepoetin alfa 200 mcg fixed dose

every 2 wks by subcutaneous injection3

Increase darbepoetin alfa to up to 300 mcg fixed dose

every 2 wks by subcutaneous injection3

Darbepoetin alfa 300 mcg* fixed dose

every 3 wks by subcutaneous injection4

Increase darbepoetin alfa to up to 500 mcg fixed dose

every 3 wks by subcutaneous injection5

Epoetin alfa 80,000 units every 2 wks by subcutaneous injection6 or

Epoetin alfa 120,000 units every 3 wks by subcutaneous injection7

Erythropoietic Therapy -Dosing and Titration (ANEM-A 1 of 5) Erythropoietic Therapy-Adverse Effects (ANEM-A 3 of 5)

NCCN Guidelines Index Table of Contents Discussion

Abstract

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

Abstract

Footnotes a The head-to-head comparisons of epoetin alfa versus darbepoetin alfa are inconclusive with regard to superiority of one drug over another. Schwartzberg LS, Yee LK, Senecal FM, et al. A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. Oncologist 2004;9:696-707; Waltzman R, Croot C, Justice GR, et al. Randomized comparison of epoetin alfa (40,000 U weekly) and darbepoetin alfa (200 mcg every 2 weeks) in anemic patients with cancer receiving chemotherapy. Oncologist 2005;10:642-650; Grant MD, Piper M, Bohlius J, et al. AHRQ Comparative Effectiveness Reviews. Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013. b Less-frequent dosing regimens of darbepoetin or epoetin alfa could be considered as an alternative to dose reduction. c The epoetin alfa and darbepoetin alfa dosages and regimens included in this table have been evaluated in patients with cancer receiving chemotherapy. Epoetin alfaepbx has been studied in patients with chronic kidney disease; there are limited data in patients with cancer. d IV iron has superior efficacy and should be considered for supplementation. Oral iron has been more commonly used but is less effective (see Discussion for details). See Parenteral Iron Preparations (ANEM-B). e See prescribing information for perioperative deep vein thrombosis (DVT) prophylaxis. f An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. g There are no data on alternative dosing schedules for epoetin alfa-epbx.

References

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

Survival of Patients with Cancer

• Studies have reported possible decreased survival in patients with cancer receiving erythropoietic drugs for correction of anemia. Analyses of eight studies in patients with cancer found decreased survival in patients receiving erythropoietic drugs for correction of anemia and

target Hb levels of >12 g/dL.1-8 One analysis in patients with cancer not receiving active therapy found decreased survival in patients treated with ESAs.6 Please refer to the FDA website for additional information: https://www.fda.gov/drugs/drug-safety-and-availability/postmarketdrug-safety-information-patients-and-providers. Unless new evidence demonstrates a change in benefit:risk estimates, physicians should

be advised not to administer ESAs (darbepoetin alfa, epoetin alfa, or epoetin alfa-epbx) to patients outside of the treatment period of cancerrelated chemotherapy. A treatment period is defined as anemia following initiation of therapy and continuing approximately 6 weeks after the completion of treatment.

• While three meta-analysis updates on survival have indicated an increased mortality risk with the use of ESAs,8-11 two meta-analyses have indicated that ESA use did not significantly affect mortality or disease progression.12,13

• Recent pharmacovigilance trials have reported no adverse effects on survival in patients with cancer with chemotherapy-induced anemia

receiving ESAs.14-16

• The risks of shortened survival and tumor progression have not been excluded when ESAs have been dosed to a target Hb of <12 g/dL.

• Additional prospective clinical trials designed and powered to measure survival of patients with cancer are ongoing to provide clinicians

with data to guide optimal use of erythropoietic agents.

• Because of the above issues, providers should inform patients of risks and benefits of ESA therapy versus RBC transfusion (see Discussion for comparison of risks and benefits of ESA use versus RBC transfusion).

• Recent studies suggest that use of ESAs may be deleterious when used in patients with metastatic breast cancer. See Discussion.

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

ANEM-A

3 OF 5

ERYTHROPOIETIC THERAPY - ADVERSE EFFECTS (3 of 5)

Erythropoietic Therapy - Adverse

Effects continued (ANEM-A 4 of 5)

References

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

Thrombosis

• Early trials of recombinant human erythropoietin reported that a high-target hematocrit (42 ± 3%) was found to have an increased number of vascular events (arterial and venous).

• EPO has a thrombogenic potential independent of Hb levels.17 Patients with previous risk factors for thrombosis may be at higher risk for

thrombosis with the use of ESAs. If considering use of ESAs, evaluate the risk factors for thrombosis: history of thromboembolism, heritable mutation, hypercoagulability, elevated pre-chemotherapy platelet counts, hypertension, steroids, prolonged immobilization, recent surgery,certain therapies for multiple myeloma, hormonal agents, etc.

(NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease)

• Five meta-analyses reported an increase in relative risk of thrombotic events ranging from 48% to 69% with ESA use.9,11-13,18

The absolute risk of venous thromboembolism (VTE) was 7.5% in patients treated with ESAs compared to 4.9% in control patients.9

• A clinical trial in chronic kidney disease demonstrated a 92% increase in the relative risk of stroke (absolute risk 5.0% vs. 2.6%) with

darbepoetin alfa.19

Hypertension

• Blood pressure should be controlled in all patients prior to initiating therapy with erythropoietic drugs and must be monitored regularly in

treated patients.

• Hb level should be monitored to decrease the risk of hypertension (Titration for Response ANEM-A 1 of 5).

ESA-Neutralizing Antibodies (pure red cell aplasia, PRCA)

• Given that cases of PRCA related to anti-EPO antibodies have been reported rarely but with increased incidence with some preparations of recombinant EPOs (rEPOs), PRCA should be suspected whenever a response to rEPO is lost. It is important to report these cases to the FDA along with information on which biosimilar or innovator molecule is involved.20-22

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

ANEM-A

4 OF 5

ERYTHROPOIETIC THERAPY - ADVERSE EFFECTS (4 of 5)

References

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

ERYTHROPIETIC THERAPY- ADVERSE EFFECTS(5 of 5)ADVERSE EFFECTS

1Leyland-Jones B, BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 2003;4:459-460.

2Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 2003;362:1255-1260.

3Wright JR, Ung YC, Julian JA,et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 2007;25:1027-1032.

4 Hedenus M, Adriansson M, San Miguel J, et al. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: A randomized,double-blind, placebo-controlled study. Br J Haematol 2003;122:394-403.

5Overgaard J, Hoff CM, Hansen HS,et al. DAHANCA 10-Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck.A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group. Radiother Oncol 2018;127:12-19.

6 Smith R, Aapro MS, Ludwig H, et al. Darboepetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol 2008;26:1040-1050.

7 Thomas G, Ali S, Hoebers FJ, et al. Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin inemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol 2008;108:317-325.

8 Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: A meta-analysis of randomised trials. Lancet 2009;373:1532-1542.

9 Bennett CL,Silver SM,Djulbegovic B,et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008;299:914-924.

10 Bennett CL, Henke M, Lai SY. Erythropoisies-stimulating agents in the treatment of cancer-associated anemia reply. JAMA 2008;300:2855-2857.

11 Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: A meta-analysis. CMAJ 2009;180:E62-E71.

12 Glaspy J, Crawford J, Vansteenkiste J,et al.Erythropoiesis-stimulating agents in oncology: A study-level meta-analysis of survival and other safety outcomes. Br J Cancer 2010;102:301-315.

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

13 Ludwig H, Crawford J, Osterborg A et al. Pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa in the treatment of patients with chemotherapy-induced anemia. J Clin Oncol 2009;27:2838-2847.

14 Engert A, Josting A, Haverkamp H, et al. Epoetin alfa in patients with advanced-stage Hodgkin's lymphoma: results of the randomized placebo-controlled GHSG HD15EPO trial.J Clin Oncol 2010;28:2239-2245.

15 Moebus V, Jackisch C, Lueck H, et al. Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: Mature results of an AGO phase III study. J Clin Oncol 2010;28:2874-2880.

16 Untch M, von Minckwitz G, Konecny GE, et al. PREPARE trial: A randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer-outcome on prognosis. Ann Oncol 2011;22:1999-2006.

17 Singh A, Szczech L, Tang K, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-2098.

18 Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 2012;12:CD003407.

19 Pfeffer MA, Burdmann EA, Chen C,et al.A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-2032.

20 Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Eng J Med 2004;351:1403-1408.

21 Bennett CL,Couroyer D,Carson KR,et al.Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: A follow-up report from the Research on Adverse Drug Events and Reports(RADAR) Project. Blood 2005;106:3343-3347.

22 McKoy J,Stonecash R,Cournoyer D,et al.Epoetin-associated pure red cell aplasia:past, present, and future considerations.Transfusion 2008;48:1754-1762.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

PARENTERAL IRON PREPARATIONS $^{1-6, a}$

RECOMMENDATIONS FOR ADMINISTERING PARENTERAL IRON PRODUCTS(listed in alphabetical order)

||Ferric Carboxymaltose7-10,b|Ferric Derisomaltoseb|Ferric Gluconate12,b|Ferumoxyto14-17,b,c (in select cases)|Iron Sucrose21,b|Low-Molecular-Weight Iron Dextran24,b| |---|---|---|---|---|---|---| |Test dosed|Test dose not required|Test dose not required|Test dose not required|Test dose not required|Test dose not required|Test dose per institutional practices| |Dosage11,e|750 mg IV for patients weighing $\>50 kg$ (110 lb) ● Repeat dose once at least 7 days later ● Total treatment course = 1500 mg or 15 mg/kg body weight IV for patients <50 kg (110 lb) ● Repeat dose once at least 7 days later ● Total treatment course not to exceed 1500 mg|1000 mg IV over 20 min for patients weighing 50 kg (110 lb) ● Repeat dose once at least 7 ● Single dose ● Total treatment course not to exceed 1000 mg|125 mg IV over 60 min for patients weighing 250 kg (110 lb) ● Total dosing given once weekly for 8 doses ● Individual doses ●125 mg kg are not recommended based on published trial results $^{13}$ ● Total treatment course = 1000 mg|510 mg IV dose over 15 min ● Repeat 510 mg dose 3-8 days later ● Total treatment course = 1020 mg|Total treatment recommended = 1000 mg ● Various dosing schedules have been tested. For additional details about dosing, see prescribing information22,23|Refer to prescribing information| |Routes|IV|IV|IV|IV|IV|IV; intramuscular (IM) (not recommended)|

a Five2-6 of six13 studies suggest that parenteral iron products improve Hb response rates in treating absolute or functional iron deficiency in patients with cancer who are receiving ESAs.

b Examples of adverse events associated with FDA-approved doses of parenteral iron preparations include: hypotension, hypertension, nausea, vomiting, diarrhea, pain, fever,dyspnea, pruritus, headaches, and dizziness. Adverse effects associated with low-molecular-weight iron dextran may be delayed 24-48 hours. Ferric carboxymtaltose has been associated with severe phosphate deficiency. Monitoring phosphorus 5-10 days after administration is recommended.

c Ferumoxytol is indicated for the treatment of iron deficiency anemia in adult patients who have intolerance to oral iron or have had unsatisfactory response to oral iron, or those with chronic kidney disease. Ferumoxytol has not been prospectively evaluated in patients with cancer- or chemotherapy-induced anemia. Ferumoxytol may cause interference with MRI scans causing potential false interpretation of organ iron overload.

d Premedications prior to IV iron should not be routinely used unless there is a history of allergy to more than one drug, an allergic diathesis or asthma, and a history of inflammatory arthritis, wherein both parenteral and oral iron have been shown to exacerbate symptoms. If warranted, premedications should be given before any test doses.

e For additional details about iron dosing, see prescribing information.

References

National NCCN Comprehensive NCCN Guidelines Version 1.2026 Cancer Cancer Hematopoietic Growth Factors

NCCN Guidelines Index Table of Contents Discussion

PARENTERAL IRON PREPARATIONS

1 Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol 2004;76:74-78.

12 National Institutes of Health. Ferric gluicate package insert. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1fe028ff-42ac-4329-b1a5-dai9adfcb79f6.Accessed March 8,2019.

2Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferruc gluconate significantly improves response to epoetina alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist 2007;12:231-242.

13 Steensma DP, Sloan JA, Dakhil SR, et al. Phase III, randomized study of the effects of parenteral iron, oral iron, or iron on supplementation on the erythropoietic response to darbeepoetin alfa for patients with chemotherapy-associated anemia. J Clin Oncol 2011;29:97-105.

3 Auerbach B. Ballard B, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: A multicenter, open-label, randomized trial. J Clin Oncol 2004;22:1301-1307.

14 Vadhan-Raj S, Dahl NV, Bernard K, et al. Efficacy and safety of IV ferumoxytol for iron deficiency anemia in patients with cancer. J Blood Med 2017;8:199-209.

4 Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbeepetino alpha J. Clin Oncol 2008;26:1619-1625.

15 Vadhan-Raj S, Strauss W, Ford W, D et al. Efficacy and safety of IV ferumoxytol for adults with iron deficiency anemia previously unresponsive to or unable to tolerate oral iron. Am J Hematol 2014;89:7-12.

5Hedenus M, Birgegard G, Nasman P, et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia 2007;21:627-632.

16 U.S. Food& Drug Administration. Ferumoxytol package insert. Available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.Accessed November 15,2019.

17 Schieda N. Parenteral ferumoxytol interaction with magnetic resonance imaging:a case report, review of the literature and advisory warning. Insights Imaging 2013;4:509-512.

${}^{6}$ Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepetoin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol 2008;26:1611-1618.

18 Auerbach M, Strauss W, Auerbach S, et al. Safety and efficacy of total dose infusion of 1,020 mg of ferumoxytol administered over 15 min. Am J Hematol 2013;88:944-947.

7Makharadze T, Boccia R, Krupa A, et al. Efficacy and safety of ferric carboxymaltose infusion in reducing anemia in patients receiving chemotherapy for nonmyeloid malignancies: A randomized, placebo-controlled study(IRON-CLAD).Am J Hematol 2021;96:1639-1646.

19 Karki NR, Auerbach M. Single total dose infusion of ferumoxytol (1020 mg in 30 minutes) is an improved method of administration of intravenous iron. Am J Hematol 2019;94:E229-E231.

20 Khan H, May P, Kuo E,et al. Safety and efficacy of a single total dose infusion(1020 mg) of ferromoxytol. Ther Adv Hematol 2021;12:20406207211006022.

21 National Institutes of Health. Iron sucrose package insert. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=626dc9e5-c6b4-4f9c-9bf4-774fd3ae619a.Accessed March 8,2019.

8 National Institutes of Health. Ferric carboxymaltose package insert. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=517b4a19-45b3-4286-9f6a-ced4e10447de.Accessed March 8,2019.

9 Toledano A, Luporsi E, Morere JF,et al. Clinical use of ferric carboxymaltose in patients with solid tumours or haematological malignancies in France. Support Care Cancer 2016;24:67-75.

22Macdougall IC, Comin-Colet J, Breymann C,et al. Iron sucrose: A wealth of experience in treating iron deficiency. Adv Ther 2020;37:1960-2002.

10Keeler BD, Simpson JA, Ng O,et al.Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer. Br J Surg 2017;104:214-221.

23 Hollands JM, Foote EF, Rodriguez A, et al. Safety of high-dose iron sucrose infusion in hospitalized patients with chronic kidney disease. Am J Health Syst Pharm 2006;63:731-734.

11 Gilreath JA, Sageser DS, Jorgenson JA, Rodgers GM. Establishing an anemia clinic for optimal erythropoietic-stimulating agent use in hematology-oncology patients.J Natl Compr Canc Netw 2008;6:577-584.

24 National Institutes of Health. Iron dextran package insert. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=abacb7fa-2fc2-471e-9200-944eeac8ca2a.Accessed March 8,2019.

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

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MANAGEMENT OF CANCER- AND CHEMOTHERAPY-INDUCED ANEMIA

FOR PATIENTS WHO REFUSE BLOOD TRANSFUSIONS1-8

• There are limited available data on the best management of cancer- and chemotherapy-induced anemia for patients who refuse blood

transfusions.

• In extreme cases of severe, life-threatening anemia, pure oxygen (400 mmHg, SaO2 = 1.0) by mechanical ventilation has been used to

increase blood oxygenation.

• To reduce blood loss, minimize phlebotomy, use pediatric tubes, return discard in closed system, and batch test.

• Prior to initiation of myelosuppressive chemotherapy:

Consider anemia risk when making treatment decisions.

Consider daily folic acid and B12 supplementation.

Evaluate and correct baseline coagulation abnormalities.

In patients with high clinical suspicion of folate and vitamin B12 deficiency, nutritional deficiency should be ruled out and iron deficiency should be corrected using IV iron.

• Consider use of ESAs for select patients by FDA dosing/dosing adjustments, given there is no option for transfusion.

ESAs are NOT recommended for:

◊ Patients with cancer not receiving chemotherapy

◊ Patients receiving non-myelosuppressive therapy

Therefore, if ESAs are prescribed off-label for the indications listed immediately above, patients should be made aware of the potential

increased risks of thrombosis and tumor progression, and should know that under these circumstances the ESAs are being used off-label.

• Blood substitutes

A clinician may obtain access to investigational blood substitute products for a single patient by submitting an Expanded Access -

Investigational New Drug Application (IND) through the FDA.4

References

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REFERENCES

1 Heh-Foster AM, Naber M, Pai MP, Lesar TS. Epoetin in the 'untransfusable' anaemic patient: a retrospective case series and systematic analysis of literature case

reports. Transfus Med 2014;24:204-208.

2 Resar LM, Frank SM. Bloodless medicine: what to do when you can't transfuse. Hematology Am Soc Hematol Educ Program 2014;2014:553-558.3 Resar LM, Wick EC, Almasri TN, et al. Bloodless medicine: current strategies and emerging treatment paradigms. Transfusion 2016;56:2637-2647. 4 Panico ML, Jenq GY, Brewster UC. When a patient refuses life-saving care: issues raised when treating a Jehovah's Witness. Am J Kidney Dis 2011;58:647-653. 5 Scharman CD, Burger D, Shatzel JJ, et al. Treatment of individuals who cannot receive blood products for religious or other reasons. Am J Hematol 2017;92:1370-1381.

6 McConachie SM, Almadrahi Z, Wahby KA, Wilhelm SM. Pharmacotherapy in acutely anemic Jehovah's Witnesses: an evidence-based review. Ann Pharmacother

2018;52:910-919.

7 McConachie S, Wahby K, Almadrahi Z, Wilhelm S. Early experiences with PEGylated carboxyhemoglobin bovine in anemic Jehovah’s Witnesses: A case series and review of the literature. J Pharm Pract 2020;33:372-377.

8 Joseph NS, Kaufman JL, Boise LH, et al. Safety and survival outcomes for bloodless transplantation in patients with myeloma. Cancer 2019;125:185-193.

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NCCN Guidelines Index

Discussion

AABB Association for the Advancement of Blood & Biotherapies

ALL acute lymphoblastic leukemia

AML acute myeloid leukemia

ANC absolute neutrophil count

APS antiphospholipid syndrome

BFI Brief Fatigue Inventory

CAR chimeric antigen receptor

CBC complete blood count

CCUS clonal cytopenia of undetermined significance

CIT chemotherapy-induced thrombocytopenia

CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma

CML chronic myeloid leukemia

CRP C-reactive protein

DIC disseminated intravascular coagulation

DVT deep vein thrombosis

ESA erythropoiesis-stimulating agent

ESR erythrocyte sedimentation rate IND ES-SCLC extensive-stage small cell lung cancer

ABBREVIATIONS

FACT

FACT-An

FACT-F Functional Assessment of Cancer Therapy-Fatigue

FDG

G-CSF granulocyte colony-stimulating factor

GFR

GI gastrointestinal

GM-CSF granulocyte-macrophage colony- stimulating factor

GVHD graft-versus-host disease

H-ARS hematopoietic acute radiation syndrome

Hb hemoglobin

HIT heparin-induced thrombocytopenia

HIV human immunodeficiency virus

ICAHT immune effector cell-associated hematotoxicity

IEC effector effector cell

IEC-HS

IEC-effector cell-associated hemophagocytic lymphotic styptosis-like syndrome

IND Investigational New Drug Application

LBW

LDH

LBW lean body weight LDH lactate dehydrogenase

MAS macrophage activation syndrome

MCV mean corpuscular volume

MDS myelodysplastic syndrome

MGF myeloid growth factor

NSAID nonsteroidal anti-inflammatory drug

PHP percutaneous hepatic perfusion

PNH paroxysmal nocturnal hemoglobinuria

PRCA pure red cell aplasia

RBC red blood cell rEPO recombinant EPO

TA-TMA transplant-associated thrombotic microangiography

TMA thrombotic microangiography

TPO-RA thrombopoietin receptor agonists

TSAT transferrin saturation

TTP thrombotic thrombocytopenic purpura

VTE venous thromboembolism

Version 1.2026,11/07/25©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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Discussion

This discussion corresponds to the NCCN Guidelines for Hematopoietic Growth Factors.Last updated: October 11,2024

Overview $\ldots$ 2

Guidelines Update Methodology $\ldots$ 3

Literature Search Criteria.

Sensitive/Inclusive Language Usage $\ldots$ 4

Biosimilars $\longdots$ 4

Filgrastim Biosimilars $\longdots$ 5

Pegfilgrastim Biosimilars $\longdots$ 6

Epoetin Alfa Biosimilars $\ldots$ 6

Management of Neutropenia.

Benefits of MGFs $\ldots$ 7

Risks of MGFs $\ldots$ 8

Prophylactic Use of MGFs $\ldots$ 10

Risk Assessment.10

Chemotherapy Regimens and Risk for FN.

Patient Risk Factors for Developing FN 10

Evaluation Prior to Subsequent Chemotherapy Cycles 12

Dosing and Administration.12

Therapeutic Use of MGFs $\ldots$ 14

Dosing and Administration.14

Severe Chronic Neutropenia 15

Management of Thrombocytopenia $\ldots$ 15

Use of Thrombopoietin Receptor Agonists in Patients with Cancer$\longdots$15

Management of Cancer- and Chemotherapy-Induced Anemia.17

Etiology of Anemia Associated with Cancer and Myelosuppressive Chemotherapy...17

Initial Evaluation of Anemia 17

Red Blood Cell Transfusion $\ldots$ 19

Benefits and Risks of Red Blood Cell Transfusion $\ldots$ 20

Red Blood Cell Transfusion Goals and Basic Principles ..20

Patients with CIA Who Refuse Blood Transfusions $\ldots$ 21

Erythropoietic Therapy.22

Benefits of ESA Therapy $\ldots$ 22

Risks of ESA Therapy $\ldots$ 23

Considerations for the Use of ESAs.24

Dosing Schedules..25

Response Assessment and Dose Titration $\ldots$ 25

Iron Monitoring and Supplementation..26

Iron Deficiency Evaluation and Definitions of Iron Status $\ldots$ 26

Intravenous Versus Oral Iron.27

Clinical Examples of Iron Status $\ldots$ 30

References.32

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Overview

Hematopoietic growth factors are defined by their ability to promote proliferation and differentiation of hematopoietic progenitors into mature blood cells.1 Colony-stimulating factors (CSFs) are hematopoietic growth factors that regulate the growth and differentiation of progenitor cells towards different myeloid lineages (granulocytes, red blood cells [RBCs],or platelets). Myeloid growth factors (MGFs), such as granulocyte colony-stimulating factors (G-CSF), are primarily used to reduce the incidence of febrile neutropenia (FN) in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. Erythropoiesis-stimulating agents (ESAs), including epoetin alfa and darbepoetin alfa, are primarily used to manage cancer- and chemotherapy-induced anemia (CIA).Thrombopoietin receptor agonists (TPO-RAs), including rompiestim, are a class of platelet growth factors that can be used to manage chemotherapy-induced thrombocytopenia (CIT).2 Management and chemotherapy-induced thrombocytopenia (CIT).2 Management and prevention of FN, CIA, and CIT are integral parts of supportive care for many patients undergoing cancer treatment.

FN is defined as an absolute neutrophil count(ANC) of <500 neutrophils/mcL, or <1000 neutrophils/mcL with an anticipated decline to s<500 within the next 48 hours, accompanied by a single oral temperature of ≥38.3℃ or ≥38.0℃ for a duration of over 1 hour.3 FN is a major dose-limiting toxicity of many chemotherapy regimens. Patients who develop FN often require prolonged hospitalization and treatment with broad-spectrum antibiotics.4 Development of FN increases treatment costs and can prompt dose reductions or treatment delays, which may compromise clinical outcome.5 Additionally, a study found correlations between changes in neutrophil counts and quality of life, as measured by physical functioning,vitality, and mental health.6

These guidelines focus on the two primary MGFs that have the most clinical applicability: G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF). For simplicity, the term "MGF" will be used

when data support both G-CSF and GM-CSF. Pharmacologic G-CSFs,currently approved by the U.S. Food and Drug Administration (FDA) to decrease the incidence of FN in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy are: filgrastim, filgrastim-sndz,tbo-filgrastim, filgrastim-aafi, pegfilgrastim, pegfilgrastim-jmdb, pegfilgrastim-bmez, pegfilgrastim-fpgk, eflagestrim-sndz,xnst, and non-PEGylated efbemalenograstim alfa-vuxw.7 Filgrastim-sndz,filgrastim-aafi, pegfilgrastim-jmdb, pegfilgrastim-cbqv, pegfilgrastim-fpgk,and pegfilgrastim-bmez were approved as biosimilars which allows their use for the same indications as the originator products. Tbo-filgrastim was approved by the FDA in an original biologic license application and therefore has a more restricted indication.7 Several studies have demonstrated similar outcomes with the use of tbo-filgrastim compared to filgrastim for FN prevention. One trial randomized 348 patients with breast cancer receiving docetaxel/doxorubicin therapy to tbo-filgrastim, filgrastim,or placebo.8 Tbo-filgrastim was equivalent to filgrastim and superior to placebo in reducing the duration of severe neutropenia and FN incidence.Two other randomized studies in patients with lung cancer and non-Hodgkin lymphoma (NHL) receiving chemotherapy reported similar efficacy and toxicity for tbo-filgrastim and filgrastim.9,10 A meta-analysis of these three trials concluded that tbo-filgrastim and filgrastim are similarly efficacious in reducing FN incidence.11 Pharmacokinetic and pharmacodynamic profiles are alike in studies performed in healthy volunteers. 12,13 Tbo-filgrastim has demonstrated low immunogenicity in patients with cancer who are receiving chemotherapy, with no evidence for the development of neutralizing antibodies or immunogenic adverse events. 14

The only FDA-approved GM-CSF is saragramostim, although some clinical trials have used the GM-CSF molgramostim. Molgramostim is not currently FDA approved; it is not recommended by the Panel due to increased adverse events compared to sargramostim. ${ }^{15}$ Sargramostim is

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primarily used for FN treatment; prophylactic use is not recommended.MGFs are also indicated for patients with radiation-induced myelosuppression following a radiologic/nuclear incident(hematopoietic acute radiation syndrome[H-ARS; any available product would be acceptable in this context])16,17 and those with severe chronic neutropenia.

chemotherapy initiation related to thrombocytopenia. CIT occurs in 15% to 25% of patients with cancer and can disrupt treatment.20-22 TPO-RAs, such as romiptimost, activate the TPO receptor and increase platelet production.20 Romiplostim and other TPO-RAs are widely used to treat immune thrombocytopenia; at present there are no FDA-approved treatments for CIT.

Anemia is characterized by a decrease in hemoglobin (Hb) concentration,RBC count, and/or hematocrit (Hct) to subnormal levels. The pathophysiologic origins of anemia can be grouped into three categories:1) decreased production of functional RBCs; 2) increased destruction of RBCs; and 3) blood loss. The degree of anemia can be graded according to the anemia scale provided by the National Cancer Institute. Refer to the most recent updated version of the Common Terminology Criteria for Adverse Events (CTCAE) for the cut-offs for anemia grades. CIA occurs in 30% to 90% of patients with cancer. ${}^{18,19}$ CIA can be improved by transfusion with packed red blood cells (PRBCs) or ESAs administration,with or without iron supplementation, in select patients receiving myelosuppressive chemotherapy. Epeto infa, a recombinant human erythropoietin (rhEpo), was the first FDA-approved ESA for anemia treatment in patients receiving myelosuppressive chemotherapy.7 A second-generation rhEpo, darbecoetin alfa, with a longer half-life than epoetin alfa, is also FDA-approved for this indication.7 In 2018, the FDA approved epoetin alfa-epbax as the first epoetin alfa biosimilar, which allows its use for the same indications as the originator product.7

The NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines®)for Hematopoietic Growth Factors are divided into three sections outlining the evaluation, prevention, and management of FN, CIT, and CIA. The purpose of these guidelines is two-fold: 1) to operationalize the evaluation,prevention, and treatment of FN, CIT, and CIA in adult patients with cancer, especially those who are receiving chemotherapy; and 2) to enable the patient and clinician to assess management options for FN,CIT, and CIA in the context of an individual patient condition.

These guidelines focus on adult patients with solid tumors and lymphoid malignancies. Use of hematopoietic growth factors in the treatment of myeloid disorders or leukemias is discussed in the NCCN Guidelines for Myelodysplastic Syndromes, NCCN Guidelines for Chronic Myeloid Leukemia, NCCN Guidelines for Acute Myeloid Leukemia, NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, and NCCN Guidelines for Hairy Cell Leukemia. Use of hematopoietic growth factors in the context of hematopoietic cell transplantation(HCT) is addressed separately in the NCCN Guidelines for Hematopoietic Cell Transplantation.

Guidelines Update Methodology

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

Thrombocytopenia is characterized by a low blood platelet count resulting in decreased blood clotting capability. Mild thrombocytopenia does not require treatment or intervention. Moderate thrombocytopenia(platelet counts<50,000/mcL) increases the risk of bleeding in patients on systemic anticoagulation and severe thrombocytopenia(platelet counts<10,000/mcL) increases the risk for spontaneous bleeding events. CIT is defined as platelet count<100,000/mcL for≥3 to 4 weeks following the last chemotherapy administration and/or resulting in delays in

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Literature Search Criteria

Prior to this update of the NCCN Guidelines® for Hematopoietic Growth Factors, an electronic search of the PubMed database was performed to obtain key literature using the following search terms: myeloid growth factors and cancer; febrile neutropenia and cancer; filgrastim and cancer;pegfilgrastim and cancer; anemia and cancer; erythropoiesis stimulating agents and cancer; thrombocytopenia and cancer; and romiplostim and cancer. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.23

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following types: Clinical Trial,Phase II; Clinical Trial,Phase III; Clinical Trial,Phase IV; Guideline;Practice Guideline; Meta-Analysis; Randomized Controlled Trial;Systematic Reviews; Validation Studies; Multicenter Study; and Controlled Clinical Trials. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the Panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel's review of lower-level evidence and expert opinion.

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity,inclusion, and representation.24 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.

Biosimilars

The cost of biologics such as filgrastim, pegfilgrastim, and epoetin alfa has limited their accessibility for many patients. In 2009, the Biologics Price Competition and Innovation Act established an abbreviated licensure pathway for biosimilars with the goal of reducing expenses for costly biologic drugs.25,26 In 2015, the FDA approved the first biosimilar,filgrastim-sndz.27 The increased need for cost-effective hematopoietic growth factors has led to the rapid approval of additional biosimilars.

A biosimilar is a biological product that is highly similar to the FDA-approved originator product with the exception of minor differences in clinically inactive components and no clinically meaningful differences in efficacy, safety, and purity.28 FDA-approved biosimilars have the same amino acid sequence as the originator product; however, differences may be seen in the three-dimensional structure, glycosylation sites, isoform profiles, and level of protein aggregation.28 Therefore, pharmacokinetic and pharmacodynamic studies are essential in evaluating biological activity, efficacy, and safety.26,29 Since biosimilars are supported by limited clinical data at the time of approval, data must be extrapolated to support the use of biosimilars for additional indications of the originator product.Scientific justification is required for extrapolation, including mechanism-of-

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action studies in each indication as well as pharmacokinetic,immunogenicity, and toxicity assessments in different patient populations.30 If overall safety and efficacy are equivalent, biosimilars may be approved for the same indications and can be substituted for the originator product.

Switching between the biosimilar and the originator product without the intervention of a health care provider is permitted if a biosimilar is designated as interchangeable.28 Concerns regarding interchangeability include enhanced immunogenicity, compromised safety, and diminished efficacy. Although the FDA has not designated any biosimilars as interchangeable, limited data suggest that patients can alternate between the biosimilar and the originator biologic without any clinically meaningful differences regarding efficacy or safety.31 Another concern is the potential for product drift that may arise during the manufacturing process of biologics and biosimilars that could result in differences in efficacy and safety over time. Continued post-marketing surveillance of all biologic products is necessary for long-term monitoring. To maintain pharmacovigilance of specific products, health care providers should be aware of the FDA's nomenclature for biosimilars(originator biologic name followed by a random four-letter suffix). It should be noted that bto-filgrastim was approved as an original biologic in the United States, and therefore has a more restricted indication than filgrastim biosimilars.

The FDA's approval of biosimilars is based on review of evidence including structural and functional characterization, animal study data,human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data.Based on the review, the NCCN Guidelines recommend FDA-approved biosimilars as appropriate substitutes for originator filgrastim,pegfilgrastim, and epoetin alfa.

Filgrastim Biosimilars

In March 2015, the FDA approved the first biosimilar, filgrastim-sndz, for all indications of the originator filgrastim. The approval of filgrastim-sndz was based on data demonstrating highly similar protein structure to filgrastim with near-identical pharmacokinetics, pharmacodynamics, and immunogenicity in healthy volunteers and patients with cancer.32-34 Filgrastim-sndz has an identical mass, size, charge, and hydrophobicity as the originator product.32 Pharmacokinetic and pharmacodynamic modeling have further confirmed the same mechanism of action (ie, G-CSF receptor binding).33 A potential concern regarding immunogenicity exists with biosimilars based on the originator filgrastim biologics and the nature of filgrastim as an unglycosylated protein; however, immunogenicity is anticipated to be low to nonexistent with filgrastim biosimilars. A limited clinical study of healthy volunteers 0at patients with those patients showed no evidence of neutralizing antibodies, suggesting that there is no increased risk of immunogenic adverse events or reduction in efficacy.34 Phase III trials in patients with breast cancer receiving myelosuppressive chemotherapy(TAC; docetaxel, doxorubicin, and cyclophosphamide) showed no clinically meaningful differences in efficacy, safety, or immunogenicity between filgrastim and filgrastim-sndz, even when the two biologics were alternated in subsequent chemotherapy cycles.31,36 Several retrospective studies report similar efficacy between prophylactic use of filgrastim-sndz and filgrastim during chemotherapy-induced neutropenia.37-40

In July 2018, the FDA approved a second biosimilar, filgrastim-aafi, for the same indications as filgrastim. A phase III randomized equivalence study in 279 patients receiving docetaxel/doxorubicin chemotherapy for breast cancer found that filgrastim-aafi is bioequivalent to filgrastim in terms of efficacy and safety and with similar incidence of FN, treatment-related bone pain, and mean time to neutrophil recovery.41 The prospective, non-

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interventional, longitudinal VENICE study observed the tolerability, safety,and efficacy of filgrastim-aafi in 386 patients with cancer receiving chemotherapy.42 The study concluded that filgrastim-aafi was effective and well-tolerated in both primary and secondary prophylactic settings.42 The majority of patients(95.6%) experienced no change in chemotherapy dose or schedule due to FN and less than one-third(29.8%) of patients experienced one or more treatment-related adverse events. Two other non-interventional studies reached similar conclusions regarding the bioequivalence of filgrastim-aafi in to reference filgrastim in both the prophylactic and therapeutic settings.43,44

Pegfilgrastim Biosimars

In 2018, the FDA approved biosimilars, pegfilgrastim-jmdb and pegfilgrastim-cbqv, for the same indications as pegfilgrastim based on data showing highly similar pharmacokinetics, pharmacodynamics, and safety in healthy volunteers.45-47 Pegfilgrastim-jmdb is analytically and functionally analogous to pegfilgrastim, with similar structure, molecular mass, physicochemical characteristics, and G-CSF receptor binding affinity.48,49 A phase I randomized equivalence trial in healthy volunteers concluded that compared to pegfilgrastim, pegfilgrastim-jmdb had similar pharmacokinetics, pharmacodynamics, and safety profiles.45 In a multicenter, randomized, phase III efficacy and safety trial, compared to patients with breast cancer receiving myelosuppressive chemotherapy with reference pegfilgrastim, patients receiving pegfilgrastim-jmdb showed no difference in the duration of severe neutropenia, time to ANC nadir,pedution of post-nadir recovery, or treatment-related adverse events.50 Pegfilgrastim-jmdb shows low immunogenic potential in healthy volunteers and in patients with cancer receiving myelosuppressive chemotherapy.51 There are limited comparative studies of pegfilgrastim-cbqv. A multicenter randomized crossover study with 122 healthy volunteers showed that compared to pegfilgrastim, pegfilgrastim-cbqv has a similar safety profile and bioequivalent pharmacokinetics and pharmacodynamics.46,47 No

serious treatment-related adverse events were observed with pegfilgrastim-cbqv use.

In late 2019, the FDA approved the third biosimilar, pegfilgrastim-bmez, for the same indications as pegfilgrastim. In healthy volunteers, pegfilgrastim-bmez showed similar pharmacokinetics and pharmacodynamics to pegfilgrastim with no clinically meaningful differences in safety, tolerability,or immunogenicity.52 Two randomized phase III trials(PROTECT-1 and PROTECT-2) demonstrated equivalent efficacy and safety between pegfilgrastim-bmez and pegfilgrastim in patients with breast cancer receiving myelosuppressive chemotherapy.53,54 In PROTECT-1, patients with breast cancer who were randomized to receive pegfilgrastim-bmez or pegfilgrastim had equivalent duration of severe neutropenia during cycle 1 of chemotherapy(difference=.07 days; 95% CI,-0.12-0.26).54 This was confirmed in PROTECT-2, which reported a difference of 0.16 days in the duration of severe neutropenia between patients receiving pegfilgrastim-bmez or pegfilgrastim(95% CI,-0.40-0.08).53 Compared to pegfilgrastim,pegfilgrastim-bmez had similar safety and tolerability across both trials,with no significant difference in reported adverse events.55

In September 2022, the FDA approved pegfilgrastim-fpgk. Pegfilgrastim-fpgk showed bioequivalent pharmacokinetics and pharmacodynamics to pegfilgrastim in healthy volunteers, with no clinically meaningful differences in safety,tolerability,or immunogenicity.56,57

Epoetin Alfa Biosimilars

In May 2018, the FDA approved the first epoetin alfa biosimilar, epoetin alfa-epbx, for anemia associated with administration of myelosuppressive chemotherapy, chronic kidney disease(CKD), or HIV treatment, or to prevent the need for RBC transfusions in patients undergoing surgery.Analytical studies and clinical pharmacology data from healthy volunteers show that epoetin alfa and epoetin alfa-epbx have similar protein structure,stability, pharmacokinetics, and pharmacodynamics.58 In two randomized

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phase III clinical trials in patients with anemia secondary to CKD, epoetin alfa and epoetin alfa-epbx showed similar efficacy, safety, and mechanism of action.58 Additionally, the results of three independent studies in patients with CKD and healthy volunteers showed similar rates and titers of anti-drug antibodies for both products, indicating that there is no clinically meaningful difference in immunogenicity risk for epoetin alfa-epbx as compared to epoetin alfa. Although there are limited data on the efficacy of epoetin alfa-epbx in treating CIA, two studies concluded that there were no clinically meaningful differences in efficacy or safety between epoetin alfa-epbx and epoetin alfa in the treatment of anemia in patients with CKD.59,60 Therefore, the FDA approved extrapolation of epoetin alfa-epbx for the treatment of anemia in patients undergoing treatment with myelosuppressive chemotherapy, as well as all other indications for the originator product.

Management of Neutropenia

Benefits of MGFs

The NCCN Guidelines recommend MGF use based on therapeutic efficacy and clinical benefit. Prophylactic use of MGFs is known to reduce FN incidence, duration, and severity, decrease the subsequent rates of infection and hospitalization, and improve the delivery of full dose-intensity chemotherapy on schedule in patients with various cancers.61-89 In a meta-analysis of 13 studies (1518 patients) by Clark et al, the prophylactic use of MGFs resulted in a clear reduction in infection-related mortality (odds ratio [OR],0.51;95\% CI,0.26-1.00; P=.05), length of hospitalization(hazard ratio [HR],0.63;95\% CI,0.49-0.82;P=.0006), and time to neutrophil recovery (HR, 0.32; 95\% CI, 0.23-0.46; P<.0001).86 In a systematic review of 17 randomized trials including 3493 patients with solid tumors and lymphoma, primary prophylaxis with G-CSF (defined as G-CSF administration within 5 days of beginning chemotherapy) reduced the risk of FN (relative risk [RR], 0.54; 95\% CI, 0.43-0.67; P<.001).88 The review showed a significant improvement with an average difference in the

relative dose intensity(RDI) of chemotherapy of 8.4$\%$ between patients treated with G-CSF(mean RDI= 85.1$\%$ ) and patients who did not receive G-CSF(mean RDI= 86.7$\%$ )(P=.001).${}^{88}$ This analysis also reported a substantial reduction in the risk of infection-related mortality (RR, 0.55;$95\%$ CI, $0.33-0.90$ ; $P=.018$ ) and early death during chemotherapy (RR,0.60; $95\%$ CI, $0.43-0.83$ ; $P=.002$ ) with G-CSF use. This survival advantage was confirmed in a systematic review of 25 randomized controlled trials that involved $>12,000$ patients undergoing chemotherapy with or without G-CSF support. ${}^{89}$ With an average follow-up of 5 years, G-CSF support was associated with a 3.4% reduction in absolute risk of mortality and an RR of 0.9 for all-cause mortality. Notably, the degree of survival benefit correlated with the chemotherapy dose intensity.

An increasing number of studies have assessed the financial implications of MGF use. Based on data analyzed in 2004, the rising cost of inpatient hospitalization resulted in a reduction of FN risk threshold from 40% to~20% for prophylactic G-CSF use.90 For example, if the risk of FN is>20%in a given patient, the overall costs of treatment are substantially reduced with prophylactic G-CSF. While the MGF addition to treatment regimens inevitably raises drug costs, it may equate to substantial savings in comparison to the costs of hospitalization and subsequent FN treatment.Pharmacoeconomic models of MGF use have reflected these clinical observations by simulating sequential chemotherapy regimens to account for FN risk on a per-cycle basis, and by accounting for chemotherapy dose reductions and consequent survival losses.91 Economic analyses of MGFs have yielded mixed results depending on the usage context.92-96 Selective use of MGFs in patients at an increased risk for neutropenic complications may also enhance cost-effectiveness.90,97 Additionally, the use of biosimilars represent a new opportunity for cost containment in oncology care, as biosimilars are typically more affordable than their originator products.26,98-101

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Risks of MGFs

The risks and benefits of G-CSF vs. dose reduction or delay during modern chemoradiotherapy are uncertain at this time. While MGFs may result in improved outcomes, they are also associated with toxicities. The listed toxicities are from the FDA package inserts (see the full inserts for specific products), which are based on studies from different patient populations. For filgrastim, tob-filgrastim, and filgrastim biosimilars, the toxicities are based on studies in patients with non-myeloid malignancies.For sargramostim, the toxicities are based on studies in patients with leukemia or who are undergoing transplant. The listed toxicities may reflect the IV route of administration, which may differ from those of subcutaneous administration. Not all the toxicities are seen with each preparation, but similar toxicities are expected with filgrastim, tbo-filgrastim, pegfilgrastim, and biosimilars.

Bone Pain

The adverse event consistently associated with prophylactic G-CSF is mild to moderate bone pain, which occurs in 10% to 30% of patients.79,102-105 Data for G-CSF-related bone pain treatment is limited to case series,reviews, and small randomized trials. These studies support the use of naproxen 500 mg, two times per day (BID) or other similar nonsteroidal anti-inflammatory drugs (NSAIDs) for 5 to 7 days after G-CSF administration. 103,106 However, NSAID use may not be appropriate for all patients with ongoing chemotherapy receiving G-CSF support due to comorbidities, side effects, drug-drug interactions, and drug-disease interactions.106 Additionally, some patients may experience bone pain that is unresponsive to NSAIDs.103 As an alternative, loratadine 10 mg daily or a similar anti-histamine can be used for 5 to 7 days after G-CSF administration. 107-110 Some studies have suggested that reducing the pegfilgrastim dose may be effective in managing G-CSF-related bone pain without increasing FN risk.111-113 However, this strategy may not be feasible since pegfilgrastim comes in a pre-filled, non-graduated syringe

designed and FDA-labeled for single-patient use. Therefore, use of reduced-dose pegfilgrastim is not currently recommended by the Panel for management of G-CSF-related bone pain.

Splenic Rupture

Rare cases of splenic rupture have been reported with G-CSF use, some of which are fatal.114-120 These cases occurred in patients with underlying hematopoietic disorders, patients with solid tumors, and healthy donors of peripheral blood progenitor cells(PBPCs). The exact mechanism of G-CSF-induced splenic rupture is unknown but is thought to involve intrasplenic accumulation of circulating granulocytes and myeloid precursors.62 Physicians should monitor patients closely for signs of splenic rupture, including abdominal pain(especially in the upper left quadrant), nausea, vomiting, and progressively worsening anemia.Prospective studies on health status, baseline spleen size, and complete blood count (CBC) may be required to identify risk factors for rupture.

Bleomycin-Induced Pulmonary Toxicity

The risk of bleomycin-induced pulmonary toxicity may be higher in patients treated with G-CSF. In a retrospective study of 141 patients with Hodgkin lymphoma receiving ABVD(doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, bleomycin-induced pulmonary toxicity was observed in 26% of patients receiving G-CSF compared with 9% of patients who did not receive it(P=.014). 121 Two studies have shown that ABVD can be safely administered at full dose without G-CSF support. 122,123 Due to the risk of pulmonary complications, G-CSF use in conjunction with the most common chemotherapy regimens, ABVD and Stanford V, is not recommended in patients with classical Hodgkin lymphoma. The toxicity potential for patients following BEACOPP(bleomycin, etoposide,doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) is less clear, although bleomycin is given every 3 weeks in this regimen as opposed to every 2 weeks in ABVD. G-CSF support is

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recommended for patients with Hodgkin lymphoma receiving the escalated BEACOPP regimen due to the high incidence of toxicity and treatment delays.

AML and MDS

Epidemiologic studies suggest an increased risk for development of acute myeloid leukemia(AML) and myelodysplastic syndrome(MDS) following MGF administration; however, this has not been observed in individual randomized trials.114,124-126 A meta-analysis by Lyman et al reported a 0.41% increase in absolute risk (95% CI, 0.10%-0.72%; P=.009) and an estimated RR of 1.92 (95% CI, 1.19-3.07; P=.007) of G-CSF-related AML/MDS development.89 Although this meta-analysis could not determine whether the risk for AML/MDS is secondary to G-CSF or related to higher total doses of chemotherapy, overall mortality decreased with the addition of G-CSF support. An updated meta-analysis and systematic literature review by Lyman et al largely reached the same conclusions,reporting an increased risk for the development of secondary malignancies, including AML/MDS (RR, 1.85; 95% CI, 1.19-2.88; P<.01),and improved survival (mortality RR, 0.86; 95% CI, 0.80-0.92; P<.0001)in patients receiving primary G-CSF support. 127 Analyses of the SEER database also show a slightly elevated risk of developing AML/MDS in patients receiving G-CSF support.126,128 However, these studies should be interpreted with caution since they cannot exclude the possibility that G-CSFs were used in cases that were more likely to progress into AML/MDS, regardless of adjuvant therapy use.

Other Toxicities

Some patients may develop allergic reactions to G-CSF that involves the skin, respiratory system, or cardiovascular system. Other potential toxicities include acute respiratory distress syndrome, alveolar hemorrhage, and hemoptysis.129 Sickle cell crisis, sometimes fatal, has been reported in patients with sickle cell disease receiving G-CSF, but not

<BeginOfPara>in patients with sickle cell trait.130-132 Two case reports also found significant toxicity following G-CSF administration in patients with amyloidosis.133,134

Adverse events have also been reported with GM-CSF use. Adverse reactions, including mild myalgias, facial flushing, low-grade fever,headache, nausea, and dyspnea, were seen in 65% of patients with advanced malignancy following GM-CSF administration, although they were not severe and were reversible. ${ }^{135}$ A side-effect study of GM-CSF,completed several years later, reported mild-to-moderate adverse events in 20% to 30% of patients, and attributed this decline to improved dosing and delivery. ${ }^{136}$ Although uncommon, severe side effects have also been reported with GM-CSF use; $<1\%$ of patients develop blood clots, which may lead to pulmonary embolism or stroke in rare cases. ${ }^{7,137,138}$ There have also been reports of capillary leak syndrome, a condition in which fluids move from the vascular system into the interstitial space, resulting in hypotension and reduced blood flow to internal organs. ${ }^{7,139-141}$ While this is more common with GM-CSF use, it has also been reported to occur with G-CSF use. ${ }^{142,143}$

Data regarding the safety of MGF administration following infusion of chimeric antigen receptor (CAR)-modified T cells are limited and institutional practices vary widely.144-146 The FDA label for siagenlecleucel recommends avoiding MGFs, particularly GM-CSF, during the first 3 weeks after cell infusion or until cytokine release syndrome (CRS) has resolved.7 Although data are not provided to support this recommendation,it is likely based on the potential of GM-CSF to promote antigen-presenting cell function that may exacerbate CRS severity or incidence. 144,147 More studies are needed to determine the safety of MGFs in patients undergoing CAR T-cell therapies due to the high rates of neutropenic complications and the potential for promotion of CRS with MGF use.

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Prophylactic Use of MGFs

Risk Assessment

The risk of developing FN is related to the treatment regimen, delivered dose intensity, and patient-specific risk factors. FN risk should be evaluated prior to the first and each subsequent cycle of chemotherapy.Risk assessment should include disease type, chemotherapy regimen(high-dose, dose-dense, or standard-dose), patient-specific risk factors,and treatment intent (curative/adjuvant vs. palliative). Based on the chemotherapy regimen, the patient is assigned to an overall high-risk group (>20% risk of FN), intermediate-risk group (10%-20% risk), or low-risk group (<10% risk). Patients in the high-risk group should receive prophylactic G-CSF(category 1). Prophylactic G-CSF should also be considered for those in the intermediate-risk group based on patient-specific risk factors. Patients in the low-risk group should generally not receive prophylactic G-CSF.

There is currently no consensus nomogram for FN risk assessment. While the NCCN Panel outlines criteria to aid FN risk assessment, independent clinical judgment should be exercised based on the individual patient's situation. The NCCN Panel recommends that patients receiving cytotoxic chemotherapy as part of a clinical trial be evaluated for prophylactic use of G-CSF based on both regimen-specific and patient-specific risk factors,unless precluded by trial specifications.

Chemotherapy Regimens and Risk for FN

The Panel considers chemotherapy regimens for which clinical trial data show an incidence of FN>20% in patients who have not received prior chemotherapy as high risk. The addition of monoclonal antibodies to chemotherapy regimens has the potential to increase FN risk. Of particular concern is rituximab, an anti-CD20 monoclonal antibody mainly used in the treatment of CD20+ hematologic malignancies, with known independent potential to cause severe neutropenia. Rituximab is

associated with prolonged, delayed-onset neutropenia with and without chemotherapy.148

The algorithm lists common chemotherapy regimens associated with high or intermediate risk of developing FN based on published data. These lists are not comprehensive and are meant to serve as examples only. Other agents/regimens may also have a high or intermediate risk for FN. In general, dose-dense regimens require MGF support to maintain dose intensity and schedule. The Panel emphasizes that chemotherapy regimen is only one component of risk assessment and needs to be combined with patient-specific risk factors to estimate the overall risk of FN.

Patient Risk Factors for Developing FN

Patient-specific risk factors are important in estimating the overall risk of FN, particularly when chemotherapy regimens are considered an intermediate risk.149 For example, many regimens for breast and lung cancers are associated with an intermediate risk of neutropenic complications. The presence of patient-specific risk factors may elevate the overall risk to a high-risk category, where prophylactic G-CSFs are more routinely recommended. Even a low-risk regimen may warrant G-CSF use in a patient with one or more clinical risk factors.

An important patient-specific risk factor for FN development is age(>65 years; see NCCN Guidelines for Older Adult Oncology).150-155 Other identified risk factors that might prompt the use of prophylactic G-CSF include prior exposure to chemotherapy or radiation therapy (RT),persistent neutropenia, tumor involving the bone marrow, poor performance status, recent surgery and/or open wounds, renal or liver dysfunction, and HIV infection.156 Chronic immunosuppression in the post-transplant setting (including organ transplant) may also warrant G-CSF use. Most of these have been confirmed as independent risk factors for the development of neutropenic complications in a risk model developed

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by Lyman et al in 3760 patients with cancer beginning chemotherapy.157 This model and its associated risk factors have been retrospectively validated both internally and externally in an independent patient population.158 In the future, external validation of other proposed FN risk assessment models and novel patient-specific risk factors may improve identification of individuals at high risk of developing FN.97,159-162

The Panel recognizes that different circumstances exist in which patients treated with relatively non-myelosuppressive chemotherapy regimens are at a high risk for FN due to bone marrow compromise, comorbidities, or other patient-specific risk factors. Prophylactic G-CSF is recommended for any patient considered to have high-risk features, regardless of the treatment regimen or intent.

Patients at High Risk for FN

The Panel recommends prophylactic G-CSF use if a patient's risk of developing FN is>20% (category 1). The American Society of Clinical Oncology (ASCO) and European Organization for Research and Treatment of Cancer (EORTC) guidelines have also adopted the 20%threshold for considering routine prophylactic MGF support. 163.164 This consistent recommendation is based on several large randomized trials that show primary G-CSF prophylaxis, when the risk of FN without prophylaxis is >20%, results in a significant reduction in FN incidence. 88.165 A phase III, randomized, placebo-controlled trial in patients with breast cancer receiving docetaxel and cyclophosphamide found that FN incidence was significantly lower in patients who received prophylactic G-CSF compared to those who received placebo (1.2% vs. 68.8%,respectively; P < 001). 165 Patients in the G-CSF group also had lower rates of hospitalization and antibiotic use. In individuals with diffuse large B-cell lymphoma (DLBCL), 13.8% and 8% of patients who received Pola-R-CHP (polatuzumab vedotin-piiq, rituximab,cyclophosphamide,doxorubicin, and prednisone) or R-CHOP (rituximab, cyclophosphamide,doxorubicin, vincristine, and prednisone), respectively, had grade 3 or 4 febrile neutropenia.166 In these studies, 90.1% and 93.2% of patients treated with Pola-R-CHP and R-CHOP, respectively, also received prophylactic G-CSF.166 Prophylactic G-CSF use was associated with a 46% reduction in the RR of developing FN in a systematic review of 17 randomized controlled trials involving 3493 patients with solid tumors or malignant lymphoma receiving systemic chemotherapy.88

Patients at Intermediate Risk for FN

The NCCN Panel defines intermediate risk as a 10% to 20% probability of developing FN or a neutropenic event that would compromise treatment.For patients receiving intermediate-risk chemotherapy regimens, the Panel recommends individualized consideration of prophylactic G-CSF use based on the presence of patient-specific risk factors. Patients with one or more risk factors should be considered for prophylactic G-CSF, while patients with no risk factors should be observed. The Panel also recommends physician-patient discussion of the risk-benefit ratio of G-CSF use with respect to the likelihood of developing FN, the potential consequences of a neutropenic event, and the implications of reduced chemotherapy dose delivery.

When the intent of chemotherapy is palliative, G-CSF use is a difficult decision and requires careful discussion between the physician and patient. If the increased risk for FN is due to patient-specific risk factors,G-CSF use is reasonable. However, if the risk is due to the chemotherapy regimen, alternatives such as dose reduction or the use of less myelosuppressive chemotherapy, of comparable benefit, should be explored.

Patients at Low Risk for FN

For patients receiving low-risk chemotherapy regimens, as defined by an FN risk of $<10$%, routine use of G-CSF prophylaxis is not recommended. ${}^{90,167,168}$ However, prophylactic G-CSF use may be

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appropriate if the individual is receiving therapy with curative intent and is at significant patient-specific risk of developing FN.

prophylactic G-CSF was allowed.170 For information regarding prophylactic anti-infectives(ie, viral, fungal, bacterial), see the NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

Evaluation Prior to Subsequent Chemotherapy Cycles

After the first cycle of chemotherapy, the patient should be evaluated prior to each subsequent cycle to determine FN risk category. If the patient experienced an episode of FN or a dose-limiting neutropenic event (a nadir count or a day-of-treatment count impacting the planned dose of chemotherapy) during the previous treatment cycle with the same dose and schedule as planned for the current cycle, this patient is now considered to be at high risk for FN. Prophylactic G-CSF support should be considered for such patients who have not received prior G-CSF. In patients who received prior G-CSF, the Panel recommends a chemotherapy dose reduction or a change in treatment regimen unless there is an impact on patient survival. If the patient did not develop FN or a dose-limiting neutropenic event in the first cycle and is thought to be benefiting from chemotherapy, the assessment of patient-specific risk factors should be repeated prior to each subsequent chemotherapy cycle before a decision is made regarding prophylactic G-CSF use.

Filgrastim and Filgrastim Biosimilars

Subcutaneous administration of filgrastim, tbo-filgrastim, or filgrastim biosimilars is a category 1 recommendation for FN prevention. Initial doses are administered the next day or up to 3 to 4 days after completion of myelosuppressive chemotherapy. A daily dose of 5 mcg/kg is administered until post-nadir ANC recovery to normal or near-normal levels by laboratory standards. The dose may be rounded to the nearest vial size by institution-defined weight limits. Neutrophil counts should be monitored as indicated and appropriate to the setting. The NCCN Panel recommends treatment of patients through post-nadir recovery since studies show shorter durations of G-CSF treatment to be less efficacious.171

Pegfilgrastim and Pegfilgrastim Biosimilars

Pegfilgrastim and pegfilgrastim biosimilars are pegylated versions of filgrastim designed to have a longer half-life and allow for a single administration of 6 mg. Based on clinical trial data, pegfilgrastim or pegfilgrastim biosimilars can be administered the day after myelosuppressive chemotherapy(category 1).172,173 Administration up to 3 to 4 days after myelosuppressive chemotherapy is also reasonable based on trials of filgrastim. The rationale for not giving same-day pegfilgrastim is the potential neutropenic exacerbation caused by hematopoietic progenitor stimulation(by active cytotoxic chemotherapy) in dividing cells,which can cause progenitor loss.174,175 A systematic literature review evaluating the relative merits of next-day versus same-day pegfilgrastim found that delivery at least 24 hours after myelosuppressive chemotherapy improved patient outcomes across a variety of tumor types.172 A retrospective analysis found that administration of pegfilgrastim 24 to 72

Dosing and Administration

Prophylactic G-CSFs are given the next day or 3 to 4 days after chemotherapy. The Panel clarified that non-cytotoxic targeted therapies are excluded from this 24-hour recommendation. Filgrastim, tbo-filgrastim,pegfilgrastim, and biosimilars are FDA-approved options for FN prophylaxis in patients with solid tumors receiving myelosuppressive chemotherapy. Sargramostim is not recommended in this setting. Caution should be exercised when administering prophylactic G-CSF in patients receiving concurrent chemotherapy and radiation.169 Randomized data have indicated a detrimental effect on toxic deaths with the use of GM-CSF during concurrent chemoradiotherapy. This was not observed in a more recent secondary analysis of the CONVERT trial, in which

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hours after chemotherapy was significantly associated with maintenance of chemotherapy dose intensity in patients with various cancers.176 Another retrospective study found that 50% of all FN episodes requiring hospitalization occurred among patients with cancer who either did not receive or received pegfilgrastim on the same day as chemotherapy.171 An observational study in Korea found that administration of secondary prophylactic pegfilgrastim 24 hours after chemotherapy in patients with breast cancer reduced FN incidence from 11.8% to 1.6%.177 A large-scale retrospective analysis in 53,814 patients receiving intermediate- or high-risk chemotherapy found significantly higher FN incidence in patients administered prophylactic pegfilgrastim either the same day or 4 to 5 days after chemotherapy compared to those receiving pegfilgrastim on days 1 to 3 following chemotherapy.178 In a direct comparative study, Kaufman et al showed that in individuals with breast cancer with ongoing TAC treatment, 33% of patients who received same-day pegfilgrastim had FN events compared to only 11% of patients who received pegfilgrastim the next day.179 A similar trend was seen in a prospective, randomized trial in patients receiving CHOP(cyclophosphamide, doxorubicin, vincristine,prednisone) or CHOP-like therapy for NHL, where same-day pegfilgrastim was associated with enhanced myelosuppression. 180

In contrast, some retrospective analyses found no statistically significant difference in FN rates among patients administered pegfilgrastim the next day versus the same day as chemotherapy.181-184 In a retrospective analysis of 297 patients (64% had breast cancer and 24% had lymphoma)treated with dose-dense chemotherapy, 6% of patients in the same-day pegfilgrastim group and 6.7% in the next-day group experienced one or more episode of FN in cycle 1(P=.814).184,185 Across all cycles, 9.3% in the same-day group and 8.9% in the next-day group experienced one or more episode of FN(P=.910). In a single-institution retrospective review of 69 patients who received pegfilgrastim the same day as chemotherapy, there were no reported FN cases.182 A retrospective review of 93 patients

concluded that pegfilgrastim can be safely administered the same day as chemotherapy in patients with lymphoma receiving CHOP-like chemotherapy.183 Although there are data for and against same-day pegfilgrastim administration, the FDA-approved dosing schedule of next-day administration is recommended.

The NCCN Panel recognizes that some institutions have administered pegfilgrastim on the same day as chemotherapy for logistical reasons and to minimize travel burdens on patients traveling long distances. Travel burden in addition to patients' prior knowledge and prescribing practices can impact G-CSF administration.186-188 An alternative for patients who cannot return to the clinic for next-day administration is an FDA-approved delivery device that can be applied the same day as chemotherapy and set to deliver the full dose of pegfilgrastim the following day(approximately 27 hours after application).189 However, this on-body delivery device is currently only available for use with originator pegfilgrastim and not pegfilgrastim biosimilars. Failure to inject, which requires further medical attention, is rare (1.7%-6.9%).189-192 The Panel suggests that physicians be aware that on-body injectors may not be acceptable or safe for patients who require an MRI study during the period of wear.193

The Panel has also discussed the use of pegfilgrastim in chemotherapy regimens of different cycle lengths. In general, there should be at least 12 days between pegfilgrastim administration and the next chemotherapy cycle. If the treatment cycle includes chemotherapy administration on days 1 and 15, pegfilgrastim may be given after each chemotherapy treatment.Pegfilgrastim use, during chemotherapy given every 3 weeks in phase III clinical trials, is a category 1 recommendation.65,194 Pegfilgrastim use is a category 2A recommendation, based on phase II studies, for chemotherapy regimens given every 2 weeks.195-200 There are insufficient data to support pegfilgrastim use for weekly regimens; therefore,pegfilgrastim should not be used. The Panel extends these recommendations to pegfilgrastim biosimilars. The Panel notes that pegfilgrastim can increase fluorodeoxyglucose(FDG) uptake in bone

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marrow/spleen and therefore advises careful assessment and interpretation of PET/CT scans after pegfilgrastim administration.201

Therapeutic Use of MGFs

There is less evidence supporting the therapeutic use of MGFs for FN.While there are clinical benefits to G-CSF therapy for FN, such as shorter time to neutrophil recovery and shorter length of hospitalization, it remains unclear whether these benefits translate into a survival advantage.86,202 The NCCN Panel recommends that patients presenting with FN who are receiving or have previously received prophylactic filgrastim, tbo-filgrastim,or filgrastim biosilromars should continue G-CSF. No studies address the therapeutic use of filgratim for FN in patients who have already received prophylactic pegfilgrastim or a pegfilgrastim biosimilar. However, since pegfilgrastim and pegfilgrastim biosimilars are long-acting,203 those who have received these agents prophylactically should not be treated with additional G-CSF. Pharmacokinetic data following treatment with pegfilgrastim demonstrate high levels during neutropenia and suggest that additional G-CSF use may not be beneficial.204 However, additional G-CSF support may be considered in patients with prolonged neutropenia(beyond 12-14 days) as the pegylated products are unlikely to endure beyond this window.

The NCCN Panel recommends an evaluation of risk factors for infection-related complications or poor clinical outcome for patients presenting with FN who have not received prophylactic G-CSF. Features associated with poor outcome include age>65 years; sepsis syndrome; ANC < 100 neutrophils/mcL; anticipated prolonged (>10 days) neutropenia;pneumonia or other clinically documented infection; invasive fungal infections; hospitalization at the time of fever; and prior FN episode(s).Therapeutic MGF use should be considered if risk factors are present. Filgrastim, tbo-filgrastim, filgrastim biosimilars, or sargramostim may be administered in the therapeutic setting. Pegfilgrastim, pegfilgrastim biosimilars, eflapegrastim-xnst, and efbemalenograstim alfa-vuxw have

<EndOfPara>only been studied prophylactically and are not recommended for therapeutic use at this time.205,206

Filgrastim, pegfilgrastim, and sargramostim are also FDA-approved for the treatment of patients with radiation-induced myelosuppression following a radiologic/nuclear incident (H-ARS). ${ }^{16,207}$ The Panel also recommends use of tbo-filgrastim, eflapegrastim-xnst, efbemalenograstim alfa-vuxw, or filgrastim/pegfilgrastim biosimars as appropriate options in this setting. The goals of using MGFs to treat radiation-induced myelosuppression are to shorten the duration of severe neutropenia, minimize the severity of neutropenia-associated complications, and increase survival.208 According to U.S. Department of Health and Human Services Radiation Emergency Medical Management guidance, MGF initiation should be strongly considered for patients who received $\geq$ 2 Gy whole body exposure or significant partial body exposure and have an ANC $\leq 500$ cells $/ mm^{3}$ and will likely have prolonged periods of significant neutropenia. ${ }^{208}$ Patients who have trauma and/or burns have worse clinical outcomes compared to radiation exposure alone, which can impact cytokine administration. ${ }^{208}$ Most of the data that support MGF use in this setting are derived from animal studies and case reports concerning patients involved in radiation accidents. ${ }^{209-218}$

Dosing and Administration

Filgrastim,tbo-filgrastim,filgrastim biosimilars, and sargramostim are the recommended MGFs for FN treatment in select patients who are high risk as outlined above who have not received prophylactic G-CSF. Filgrastim,tbo-filgrastim, and filgrastim biosimilars should be given at a daily dose of 5 mcg/kg and sargramostim should be given at a daily dose of 250 mcg/m2. Treatment should continue through post-nadir recovery. For patients presenting with H-ARS, filgrastim, tbo-filgrastim, or filgrastim biosimilars should be given at a daily dose of 10 mcg/kg; pegfilgrastim and pegfilgrastim biosimilars should be given as a single dose of 6 mg; and sargramostim should be given at a daily dose of 250 mcg/m2.208 MGFs

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should be administered as soon as possible after acute radiation exposure.

Severe Chronic Neutropenia

These guidelines focus on the management of neutropenia in the cancer setting; therefore, severe chronic neutropenia is only briefly discussed below. G-CSF is established as an effective treatment for cyclic,congenital, and idiopathic neutropenia based on a randomized controlled trial involving 123 patients.219 In this study, daily treatment with subcutaneously administered G-CSF normalized neutrophils in most patients and prevented fever, mouth ulcers, and infections. Subsequent observational studies showed that patients with idiopathic and cyclic neutropenia generally responded to low-dose daily, alternate-day, or thrice-per-week subcutaneous G-CSF administration (1-3 mcg/kg per day). Patients with congenital neutropenia generally require higher doses(3-10 mcg/kg per day). All patients should have doses adjusted to maintain a blood neutrophil level in the normal or low-normal range. Acute adverse effects include bone pain, arthralgias, and myalgias, which usually diminish in the first few weeks of treatment. The greatest concern is that patients with severe congenital neutropenia are at risk for myelodysplasia and leukemia, with or without G-CSF treatment. More severely affected patients, who require higher G-CSF doses, appear to be at greater risk. These considerations emphasize the importance of making a correct diagnosis and following these patients carefully. Currently, the only alternative therapy for severe chronic neutropenia is HCT. For further reading on severe chronic neutropenia, refer to the website developed by The Severe Chronic Neutropenia International Registry:http://depts.washington.edu/registry/index.html.

Management of Thrombocytopenia

Use of Thrombopoietin Receptor Agonists in Patients with Cancer Thrombocytopenia is common in patients with cancer and can lead to chemotherapy delays or dose reductions that disrupt treatment.20-22 Platelet transfusion only offers temporary improvement in platelet count and is often unreliable and impractical to continue for extended periods.21 TPO is the main growth factor responsible for the stimulation of platelet production. TPO-RAs, such as romiplostim, bind to and activate the TPO receptor, thereby increasing platelet production.20 Romiplostim is FDA-approved to treat immune thrombocytopenia.Although romiplostim is widely used to treat CIT; there are no FDA-approved agents for treating CIT. Retrospective studies have evaluated other TPO-RA agonists, including avatrombopag; however, the Panel emphasizes that there are insufficient data from these studies to recommend any of these agents.220 No overall survival (OS) or progression-free survival (PFS) benefits have been demonstrated with these agents and thus far no randomized trials have been conducted to address survival benefits. Additional prospective studies are needed to determine safety, efficacy, and benefits of TPO-RA agonists. Whenever possible, participation in clinical trials is strongly encouraged. The subcommittee on Hemostasis and Malignancy from the International Society on Thrombosis and Haemostasis (ISTH) has similar recommendations and emphasizes the need to optimize study design including selection criteria in managing CIT.221

Patients with suspected CIT should be evaluated for other potential etiologies such as nutritional deficiencies, medications/supplements that suppress platelet production, infections(including viral reactivation),immune thrombocytopenia, heparin-induced thrombocytopenia(HIT),radiation-or chemotherapy-induced myelosuppression, hematologic malignancy, consumption of platelets secondary to blood loss, and thrombotic microangiopathies, among others and treated accordingly. A

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CBC with differential and blood smear for morphologic evaluation,including evaluation for platelet clumping and other cytopenias, should be performed. If CIT is diagnosed, consider platelet transfusion per Association for the Advancement of Blood& Biotherapies(AABB)guidelines, chemotherapy dose reduction or change in regimen,enrollment in a clinical trial of TPO-RAs, or treatment with rompiestim.The primary purpose of using TPO-RAs for CIT is to maintain chemotherapy dose schedule and intensity. In patients for whom a TPO-RA is being considered for CIT management, participation in clinical trials is encouraged whenever possible. Romiplostim dosing strategies include weekly dosing beginning at 2 to 4 mcg/kg, increased by no more than 1 to 2 mcg/kg per week to target platelet count 100,000 to 150,000/mcL.20,21 Maximum dose is 10 mcg/kg weekly per prescribing information.

Studies of romiplostim to manage CIT have been limited to case series and small single-center studies that have shown that romiplostim is effective in increasing platelet counts in patients with solid tumors.21,222,223 Romiplostim use in non-myeloid hematologic malignancies has not been evaluated. In a multicenter retrospective analysis (N = 173), 71% of patients with solid tumors had response to romiplostim. *21 A case series of 20 patients with solid tumors and CIT reported that romiplostim treatment improved platelet counts in all patients, which allowed chemotherapy resumption.223 In a phase II randomized trial in patients with solid tumors and CIT, 93% of patients treated with romiplostim experienced correction of their platelet count and thus CIT within 3 weeks compared with 12.5% of patients who did not receive romiplostim(P $<.001$). $^{20}$ However, data suggest that TPO-RAs used for CIT may increase the risk of venous thromboembolism(VTE) in patients with cancer.20,21,222,223 Therefore, caution is warranted.

Several reports have examined the efficacy of TPO-RAs in patients with prolonged thrombocytopenia following HCT, including those patients with

secondary failure of platelet recovery.224,225 Patients with thrombocytopenia post-HCT should be evaluated for other potential causes of thrombocytopenia mentioned above as well as primary or secondary graft failure, graft-versus-host disease (GVHD), relapse of hematologic malignancy, and transplant-associated thrombotic microangiopathy (TA-TMA). Patients with primary or secondary failure of platelet recovery without another clear underlying cause should be considered for platelet transfusion per AABB guidelines. Clinical trial participation is encouraged whenever possible.

Eltrombopag has been shown to be efficacious in patients with prolonged thrombocytopenia post-allogeneic transplant and poor graft function. ${}^{226}$ - ${}^{231}$ Eltrombopag is FDA-approved for patients with chronic immune thrombocytopenia or severe aplastic anemia. In a phase II randomized trial in 60 patients with post-HCT thrombocytopenia, a significantly higher proportion of patients in the eltrombopag arm achieved a platelet count of $\geq 50,000/\mu$L compared with the placebo arm (21% vs. 0%; P=.046). However, OS, PFS, relapse rate, and non-relapse mortality were similar in the two arms.

TPO-RA lusutrombopag has been suggested to have activity for thrombocytopenia in patients with cancer or thrombocytopenia post-HCT.Lusutrombopag is currently FDA-approved for thrombocytopenia management in patients with chronic liver disease who are scheduled to undergo a medical or dental procedure. The efficacy oflusutrombopag was assessed in an integrated analysis of data from two phase III trials that comparedlusrombopag to placebo in 270 patients with chronic liver disease and hepatocellular carcinoma (HCC). Treatment withlusutrombopag reduced the need for platelet transfusions, increased platelet counts for 3 weeks, and reduced the number of bleeding events compared with placebo in patients with HCC secondary to chronic liver disease.232 Although these reports are promising, outside of a clinical

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trial setting, insufficient data are available to support use of TPO-RA other than romiplostim and etlrombopag for treatment of CIT.

During the pandemic, when many institutions decided to limit platelet transfusions to patients with active bleeding or a numerical value<10 K/mcL, the Panel convened a voluntary subcommittee to provide guidance for more optimal use of growth factors.233 Prophylactic antifibrinolytics (tranexamic acid or epsilon aminocaproic acid) can be used for those with platelet counts <10 K/mcL when platelets are unavailable due to blood supply shortage, or in patients who are alloimmunized who do not have suitable human leukocyte antigen-matched units available. The Panel recommends holding antifibrinolytics when endogenous platelet counts are >30 K/mcL and in patients with embolic strokes, active thromboembolism, and urinary tract bleeding.

Management of Cancer- and Chemotherapy-Induced Anemia

Etiology of Anemia Associated with Cancer and Myelosuppressive Chemotherapy

Causes of anemia in patients with cancer are often multifactorial.234 Anemia may be attributed to underlying comorbidities such as bleeding,hemolysis,nutritional deficiencies, hereditary disease, renal insufficiency,hormone dysfunction, chronic inflammation, or a combination of these factors.235,236 The malignancy itself can lead to or exacerbate anemia in a number of ways.237 Cancer cells may directly suppress hematopoiesis through bone marrow infiltration. They may also produce cytokines that lead to iron sequestration, which decreases RBC production and may shorten RBC survival. Chronic blood loss at tumor sites from blood vessels or organ damage can also exacerbate anemia in patients with cancer. Additional indirect effects may include nutritional deficiencies caused by loss of appetite, hemolysis by immune-mediated antibodies, or changes in coagulation parameters. For this myriad of reasons, anemia is

highly prevalent among patients with cancer at initial presentation,especially in patients with lung cancer.19,238-240

Many chemotherapy agents cause myelosuppression, which contribute to anemia.240 Chemotherapeutic agents induce anemia by directly impairing hematopoiesis in the bone marrow, including disruption of RBC precursor production.237 Additionally, the nephrotoxic effects of some cytotoxic agents(eg, platinum-containing agents) can result in decreased erythropoietin production by the kidneys.237 RT to the skeleton has also been associated with hematologic toxicity. In a retrospective analysis of 210 patients with primary central nervous system tumors receiving craniospinal RT, approximately one-third of patients developed grade 3/4 hematologic toxicities including anemia.241 Newer modalities such as immunotherapies may also produce anemia, although data are limited.242-245 Clinicians should become familiar with the adverse effects of immunotherapy drugs, including hematologic toxicities, and be watchful for other less-documented clinical conditions as these therapies become more prevalent in cancer care.

The myelosuppressive effects of certain cytotoxic agents are likely to accumulate over the course of repeated cycles of therapy, resulting in a steady increase in the rate and severity of anemia with additional chemotherapy cycles. In the European Cancer Anaemia Survey(ECAS),the rate of anemia(Hb level<12 g/dL) increased from 19.5% in cycle 1 to 46.7% by cycle 5.239 An increase in the fraction of grade 2 to 3 anemia was also associated with a greater number of chemotherapy cycles. Other factors to consider when evaluating CIA risk include nadir Hb level, the time to nadir Hb level (roughly estimated at 2 weeks, but time can vary),and whether an Hb measurement is considered to be pre- or post-nadir.237

Initial Evaluation of Anemia

Given the wide variation in Hb levels among healthy subjects, a universal“normal” value is difficult to define. The NCCN Panel recommends that an

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Hb level ≤11 g/dL should prompt an evaluation of anemia in patients with cancer. A decrease by ≥2 g/dL below baseline is also cause for concern and assessment. Importantly, clinicians should consider gender differences in Hb as part of the initial evaluation of anemia, since women typically have a lower baseline Hb level than men.246 As discussed above,a patient with cancer may suffer from anemia as the result of a combination of causes, some of which may not be directly related to the cancer(reviewed by Gilreath et al234). The overall goals of evaluation are to characterize the anemia and identify any underlying comorbidities that can be potentially modified prior to initiating treatment.

Initial characterization of anemia involves a CBC with indices to determine if other cytopenias are present. A visual review of the peripheral blood smear morphology is critical to confirm the size, shape, and Hb content of RBCs. A detailed history and physical examination must also be taken.The history should include the onset and duration of symptoms,comorbidities, family history, and whether there has been any exposure to antineoplastic drugs or radiation. Common complaints are syncope,exercise dyspnea, headache,vertigo, chest pain, fatigue that is disruptive to work and daily activities, and abnormal menstruation. Pallor may also be apparent. A key characteristic distinguishing fatigue related to cancer from fatigue in healthy individuals is that cancer-related fatigue is less likely to be ameliorated by rest.247 The above clinical manifestations are not sensitive or specific to the type of anemia. Clinicians should watch for signs of underlying etiologies such as jaundice, splenic enlargement,neurologic symptoms, blood in the stool, petechiae, and heart murmur,among others.

from fatigue in healthy individuals is that cancer-related fatigue is less likely to be ameliorated by rest. ${}^{247}$ The above clinical manifestations are not sensitive or specific to the type of anemia. Clinicians should watch for signs of underlying etiologies such as jaundice, splenic enlargement,neurologic symptoms, blood in the stool, petechiae, and heart murmur,among others.

Approaches to Evaluation

There are two common approaches to anemia evaluation: morphologic and kinetic. A complete evaluation should use both. The morphologic approach is a characterization of anemia by the mean corpuscular volume

(MCV), or average RBC size, reported in the initial CBC and classified as follows:

● Microcytic(<80 fL)-most commonly caused by iron deficiency;other etiologies include thalassemia, anemia of chronic disease,and sideroblastic anemia.

● Macrocytic(>100 fL)-most commonly caused by medications248 and alcoholism, both of which are forms of non-megaloblastic anemia. MDS also causes mild macrocytosis. Macrocytosis seen in megaloblastic anemia is most frequently caused by vitamin deficiency resulting from inadequate intake(folic acid or B12) or inadequate absorption of B12 from lack of intrinsic factor or antibodies to parietal cells. Macrocytosis accompanies increased reticulocyte counts following brisk hemorrhage or hemolysis.

Normocytic (80-100 fL)-may be due to hemorrhage, hemolysis,bone marrow failure, anemia of chronic inflammation, or renal insufficiency.

The kinetic approach focuses on the underlying mechanism of anemia,distinguishing among the production, destruction, and loss of RBCs. The most basic RBC index is the reticulocyte index(RI) that corrects the reticulocyte count against the degree of anemia as measured by Hct. The reticulocyte count, often represented as a percentage, reflects the number of reticulocytes(immature RBCs) per number of total RBCs. The RI is calculated based on the reticulocyte count and is an indicator of the RBC production capacity by the bone marrow. The normal RI ranges from 1.0 to 2.0.

● RI = Reticulocyte count(%) x [(observed Hct)/(expected Hct)],where the expected Hct is equal to 45%.

Reticulocytes normally persist in circulation for 24 hours before becoming erythrocytes. However, as anemia increases younger reticulocytes are

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released from the marrow, thus remaining in circulation for 2 to 3 days before becoming erythrocyte. This results in false high RI values. The reticulocyte production index (RPI) is an adjusted index that takes this into account and is calculated by the following formula: RPI= RI x (1/RMT),where RMT is the reticulocyte maturation time (RMT) constant determined by the observed Hct (see Table 1).

● Low RI/RPI ratio(<1) indicates decreased RBC production,suggesting iron deficiency, B12/folate deficiency, aplastic anemia,or bone marrow dysfunction due to cancer or cancer-related therapy(eg, radiation, myelosuppressive chemotherapy).

•High RI/RPI ratio(>1) indicates normal RBC production,suggesting blood loss or hemolysis in the patient with anemia.

Additional signs and symptoms of common underlying ailments and/or informative diagnostic tests are as follows:

● Nutritional deficiency-low iron and elevated total iron-binding capacity (TIBC) and/or low vitamin B12 or red cell folate levels(commonly tested together with iron studies). Ferritin values are also useful in evaluating iron stores. Fasting values are preferred for serum iron and TIBC studies.

● Hemorrhage-consider upper and lower endoscopic evaluation.

● Hemolysis-direct antiglobulin test positive, disseminated intravascular coagulation panel positive, low haptoglobin levels,elevated indirect bilirubin, and elevated lactate dehydrogenase(LDH).

● Renal dysfunction-glomerular filtration rate<60 mL/min/1.73 m2 for ≥3 consecutive months.

● Inherited anemia-personal and/or family history.

● Sideroblastic anemia-sideroblasts present in bone marrow biopsy.

● Hormone dysfunction-hypogonadism,adrenal dysfunction, and hyper/hypothyroidism.

● Chronic inflammation-increased C-reactive protein level and/or erythrocyte sedimentation rate.249

● Treatment-induced myelosuppression

Any cause of anemia that is independent of cancer or chemotherapy should be treated as indicated. When no such etiology is identified, the effects of cancer-related inflammation and/or myelosuppressive chemotherapy (if applicable) should be considered the cause of anemia. If this is the case, a risk assessment of the patient with anemia is necessary to determine the initial intervention plan. The decision regarding the best treatment option is dependent on many factors. While PRBC transfusion is best for symptomatic patients requiring an immediate boost in Hb levels,consideration of ESA therapy with or without iron supplementation may be warranted for long-term anemia management in patients with high risk or in patients with no symptoms but with comorbidities.

Red Blood Cell Transfusion

The decision to offer PRBC transfusion should not be made based on whether the Hb level of the patient has reached a certain threshold or"trigger." Instead, the NCCN Panel outlines three general recommendations: 1) observation and periodic re-evaluation are appropriate for patients who are asymptomatic without significant comorbidities; 2) transfusion can be considered for patients with high risk(ie, progressive decline in Hb with recent intensive chemotherapy or radiation) or patients who are asymptomatic with comorbidities(eg,cardiac disease, chronic pulmonary disease, cerebral vascular disease);and 3) transfusion should be performed for patients with symptoms(physiologic). Physiologic symptoms warranting PRBC transfusion include sustained tachycardia, tachypnea, chest pain, dyspnea on exertion,

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lightheadedness, syncope, or severe fatigue preventing work and usual activities.

The clinical manifestations are associated with anemia onset, severity,and duration, as well as other factors influencing tissue demands for oxygen. Symptoms are likely to be more pronounced when anemia onset is acute; whereas physiologic adjustments that compensate for lower oxygen-carrying capacity of blood can occur with gradual anemia onset.These adaptive measures include heightened cardiac output, increased coronary flow, altered blood viscosity, and changes in oxygen consumption and extraction. The presence of preexisting cardiovascular,pulmonary, or cerebral vascular disease may compromise the ability of a patient to tolerate anemia. Hence, decisions related to whether immediate correction of anemia is needed must be based on an assessment of individual patient characteristics, severity of anemia, presence and severity of comorbidities, and clinical judgment of the physician. For example, even when a patient with anemia has no physiologic symptoms or significant comorbidities, transfusion may be appropriate if there is an anticipated progressive decline in Hb level following anti-cancer treatment.

PRBCs are the blood product of choice for transfusion to correct anemia.These are concentrated from centrifuged whole blood donations or collected by apheresis. They are anticoagulated and may contain added preservatives. Further enhancements include leukoreduction, y-irradiation, freezing, and washing. Patients who are immunocompromised may need PRBCs that are cytomegalovirus (CMV) negative. Leukoreduction is often sufficient to reduce the risk of CMV transmission. For example, patients who are candidates for or undergoing autologous or allogeneic HCT require blood products that have undergone leukocyte reduction and y-irradiation to reduce the risks of transfusion-associated GVHD, viral transmission, and alloimmunization. One unit of PRBCs (~300 cc) can have an Hct ranging from 50% to 80%, and typically contains 42.5 to 80 g of Hb (with 147-278 mg of iron) and 128 to 240 mL of pure RBCs.250

Benefits and Risks of Red Blood Cell Transfusion

Benefits of Red Blood Cell Transfusion

The major benefit of PRBC transfusion, offered by no other anemia treatment, is the quick increase in Hb and Hct levels and thus a rapid improvement in anemia-related symptoms. Hence, PRBC transfusion is the best option for patients who require immediate correction of anemia.Transfusion of 1 unit (~300 cc) of PRBCs has been estimated to an average increase in Hb level by 1 g/dL or in Hct level by 3% in an adult who is not experiencing simultaneous blood loss.250,251 It should be noted that patients receiving concomitant fluid resuscitation may not experience an Hb increase of 1 g/dL per unit of blood transfused.

Risks of Red Blood Cell Transfusion

Risks associated with PRBC transfusion include transfusion-related reactions (eg, hemolytic, non-hemolytic, febrile, lung injury), transfusion-associated circulatory overload (TACO), and bacterial contamination. The introduction of numerous safety interventions to screen the U.S. blood supply for infectious organisms has dramatically decreased the risk of transfusion-transmitted infections. 252,253 Bacterial infection was the most common form, and occurred as frequently as 1 in 3000 random-donor samples before the mandate of bacterial screening in 2004.253 Since the screening implementation, fewer than 10 deaths from bacterial sepsis per year have been reported in patients receiving PRBC transfusion.Additionally, pre-storage leukoreduction has been shown to decrease the incidence of febrile non-hemolytic transfusion reactions, the most common adverse event.254,255

Red Blood Cell Transfusion Goals and Basic Principles

The overall goal of PRBC transfusion is to treat or prevent deficiencies in the blood oxygen-carrying capacity and improve oxygen delivery to tissues. In 2016, based on a systematic review of randomized controlled trials, the AABB published clinical practice guidelines evaluating Hb

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thresholds for RBC transfusion.256 AABB recommendations include: 1)using an Hb level of 7 g/dL as a threshold for adult patients who are hospitalized and hemodynamically stable; 2) using an Hb level of 8 g/dL as a threshold for patients undergoing orthopedic surgery, cardiac surgery,or those with pre-existing cardiovascular disease; and 3) using RBC units selected at any point within their licensed dating period rather than limiting patients to transfusion of only fresh RBC units. However, there is lack of evidence to provide specific recommendations for individuals with cancer. The NCCN Panel agrees that no single target Hb level is appropriate for all cases and that the balance between transfusion risks and benefits should be evaluated on an individual basis. Clinicians are urged to exercise their clinical judgment based on symptoms, cancer course and treatment, comorbidities, and patient preference.

Prior to transfusion, PRBCs must be crossmatched to confirm compatibility with ABO and other antibodies with the recipient. There is no evidence to support routine premedication with acetaminophen or an antihistamine to prevent allergic and febrile non-hemolytic transfusion reactions.257,258 However, if repeated transfusions are required, leukocyte-reduced blood and the use of premedication may minimize adverse transfusion reactions.In most instances, PRBCs should be transfused by the unit and reassessed after each transfusion. When considering PRBC transfusion,refer to the 2016 AABB clinical practice guidelines. ${ }^{259}$

Patients with CIA Who Refuse Blood Transfusions

Patients with CIA who refuse blood transfusions are occasionally seen in clinical practice. Religious beliefs or personal preferences may prohibit

patients from using blood products. For these patients, clinicians should consider the risk of anemia when making treatment decisions. Although there are limited available data on the best management of CIA in patients who refuse blood transfusions, several strategies can be used to reduce anemia, including minimizing blood loss,260-264 ESA use,263,265,266 or substitute blood products.260,263,265-268 Strategies to reduce blood loss

include batching routine laboratory testing, using pediatric blood collection tubes,minimizing phlebotomy, and returning discard in a closed system.260-264 Additionally, daily folic acid and vitamin B12 supplementation should be considered prior to initiating myelosuppressive chemotherapy.Nutritional sufficiency for iron, folate, and vitamin B12 should be evaluated and deficiencies corrected. Iron deficiency should be corrected using IV iron. Baseline coagulation abnormalities should also be fully evaluated and corrected prior to myelosuppressive treatment.

Most data regarding the use of ESAs in patients who refuse blood transfusions are from published case reports and small cohort series involving individuals who are Jehovah's Witnesses. These types of reports carry inherent bias and vary significantly in reporting outcomes, regimens,and dosing. 265 Overall there is scarcity of data regarding individuals who are Jehovah's Witnesses with CIA. A 2008 analysis of 14 case reports of individuals who are Jehovah's Witnesses receiving ESA therapy in a variety of clinical situations concluded that while administration of ESAs enhanced Hb levels in each situation, time to the start of treatment,dosage, route of administration, and duration varied widely among included studies.269 Additional case reports on individuals who are Jehovah's Witnesses, including three involving patients with cancer, have shown similar results on ESAs effectiveness in increasing Hb levels.270-276 In one case report, a 57-year-old Jehovah's Witness diagnosed with CIA,secondary to aggressive NHL, was administered darbepoetin alfa once per week, which increased Hb levels from 7.5 to 11.5 g/dL within 1 month and enabled completion of intensive chemotherapy.270 Although there is a lack of prospective data, ESAs should be considered given that there is no option for transfusion.263,265 However, ESAs are not recommended for patients with cancer who are not receiving therapy, patients receiving non-myelosuppressive chemotherapy, and patients receiving myelosuppressive chemotherapy with curative intent. If ESAs are prescribed off-label for these indications, patients should be made aware

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of the off-label use along with potential increased risks of thrombosis and tumor progression. It should be noted that ESA therapy impact on Hb level may not be evident for several days after administration. Therefore, in cases of severe, life-threatening anemia, pure oxygen(400 mmHg,SAO2=1.0) by mechanical ventilation can be used to increase blood oxygenation.277

Although not FDA-approved, clinicians may access investigational blood substitute products,also known as Hb-based oxygen carriers (HBOCs),for single-patient compassionate use under the FDA's Expanded Access program.260,263,265-268,278 HBOCs are cell-free Hb molecules typically derived from animals that offer advantages over transfusions, including transportability, the lack of need for refrigeration or crossmatching, and reduced risks of infectious and allergic complications.265 Despite these benefits, few products have advanced to phase III trials and none have produced a significant decrease in the need for transfusions (in patients who accept transfusion support). HBOCs have been associated with serious adverse reactions.268 A 2008 meta-analysis by Natson et al concluded that patients treated with an HBOC had a 1.3- and 2.7-fold increased risk of mortality and myocardial infarction, respectively, when compared with patients who had undergone conventional treatment with or without blood products.279 However, with compassionate use in emergent settings, HBOCs have successfully treated individuals with severe anemia who are Jehovah's Witnesses. 267,280-284 A case series evaluation has suggested that delay in receipt of HBOCs is independently associated with mortality in patients who refuse blood transfusions. Therefore, clinicians should consider starting the regulatory process for HBOC procurement early in the treatment course.285 While HBOCs may represent a lifesaving modality in severe anemia in patients who refuse blood transfusions,further evaluation of these products in clinical trials is needed.

Erythropoietic Therapy

ESAs stimulate erythropoiesis in patients with low RBC levels, although not all patients have diseases that respond to ESA therapy. In a study involving 2192 patients with cancer receiving ESA therapy, 65% of patients showed an Hb increase of $\ge 1$ g/dL. ${}^{286}$ Unlike transfusion, which immediately boosts Hb level; ESAs can take weeks to elicit an Hb response, but they are effective at maintaining a target Hb level with repeated administration. Iron studies (serum iron, TIBC, and serum ferritin) should accompany ESA therapy to monitor the development of iron deficiency.

Benefits of ESA Therapy

The main goals of ESA therapy are gradual improvement in anemia-related symptoms and avoidance of transfusion. In a randomized,placebo-controlled study, epoetin alfa increased Hb levels (2.2 vs. 0.5 g/dL;P<.001) and reduced transfusion requirements (24.7% vs. 39.5%;P=.0057) in patients with anemia receiving chemotherapy.287 In a randomized phase III study, patients with lung cancer with Hb ≤11 g/dL receiving chemotherapy and darpeboepetin alfa required fewer transfusions(27% vs. 52%; 95% CI, 14%-36%; P<.001) than patients receiving chemotherapy and darpeboepetin alfa required fewer transfusions at 288. The ability of ESAs to reduce transfusions was one endpoint used in a Cochrane review that analyzed 20,102 patients undergoing treatment for cancer with concomitant ESA therapy.289 A decreased RR for transfusion was observed in patients receiving ESAs(RR, 0.65; 95% CI, 0.62-0.68).289 Of the patients treated with ESAs, 25 out of 100 subsequently received a transfusion versus 39 out of 100 patients in the untreated group. This equated to a one-unit reduction of transfusion in patients treated with ESA. The first meta-analysis found that more patients with CIA who received darpeboetin alfa than placebo achieved an Hb increase of ≥1 g/dL (fixed-effects HR, 2.07; 95% CI, 1.62-2.63) or ≥2 g/dL (HR, 2.91; 95% CI, 2.09-4.06) when treatment was

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initiated at Hb ≤10 g/dL. ${ }^{290}$ Transfusions were also less common in patients receiving darbepoetin alfa (HR, 0.58; 95% CI, 0.44-0.77).

Risks of ESA Therapy

ESA-associated toxicities include increased thrombotic events, possible decreased survival, and shortened time to tumor progression. When considering ESAs, the risks of ESA therapy including the potential for tumor growth, increased mortality, blood clots, and hypertension should be discussed with patients.

Possible Increased Mortality and Tumor Progression

The FDA has made substantial revisions to the label information and regulations regarding epoetin alfa and darbeproeto alfa, including the addition of black-box warnings, since their approval in 2007. These strengthened FDA restrictions were based on the results of eight randomized studies that individually showed a decrease in OS and/or locoregional disease control with ESA usage in breast, cervical, head and neck, lymphoid, non-myeloid, and non-small cell lung cancers(NSCLCs).291-298 Of the eight studies, four investigated ESAs in patients who received chemotherapy, two studies involved patients receiving RT alone, and two studies involved patients receiving neither chemotherapy nor RT. All eight trials had an off-label target Hb level >12 g/dL. Additional meta-analyses of randomized controlled trials have confirmed worsened health outcomes associated with ESA use when targeting Hb levels $>12$ g/dL.289,299-302 Data from the Cochrane Database also reported increased mortality associated with ESA use in patients when targeting Hb levels >12 g/dL.289 It should be noted that the risks of shortened survival and tumor progression have not been excluded when ESAs have been dosed to a target Hb of [12 g/dL]. Data from a systematic review by the Agency for Healthcare Research and Quality (AHRQ) showed that delaying ESA treatment until Hb <10 g/dL resulted in fewer thromboembolic events and reduced mortality.302

The association between increased mortality and ESA therapy has been debated in other meta-analyses, including two studies reporting no statistically significant effect of ESAs on mortality or disease progression.303,304 Pharmacovigilance trials have also reported no adverse effects on survival in patients with CIA receiving ESAs.305,306 Several prospective trials have reported similar outcomes. The phase III WSG-ARA trial that included 1234 patients with early-stage breast cancer receiving adjuvant ESA therapy evaluated survival as the primary endpoint.307 In this study, no impact on event-free survival (EFS)(darbepoetin alfa, 89.3% vs. no darbepoetin alfa, 87.5%; $P_{\text {log-rank }}=0.55$ ) or OS (darbepoetin alfa, 95.5% vs. no darbepoetin alfa, 95.4%; $P_{\text {log-rank }}=$ 0.77) was observed with ESA use. In the AGO-ETC trial, which included 1284 patients with high-risk breast cancer, epoetin alfa resulted in improved Hb levels and decreased transfusions without an impact on relapse-free survival or OS.308 Additionally, data from randomized studies showed no increase in mortality in patients receiving chemotherapy for small cell lung cancer when ESAs were given as indicated in the prescribing label.309-311 A systematic review also showed no major change in OS with ESA therapy in patients with cancer.312 While these data suggest that although ESA use may not be associated with decreased survival or increased disease progression as previously thought, data from additional prospective trials designed and powered to measure survival of patients with cancer are needed to guide clinicians on optimal ESA use.

Thromboembolism

Increased thromboembolic events, including VTE, are associated with ESA therapy in patients with cancer.289,299,301-304,312 The cause of VTE in patients with cancer is complex with increased baseline risk related to both the malignancy itself and to the chemotherapy regimen used(see NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease).313-316 Risk factors for VTE in patients with cancer include but are not limited to prior history of VTE, inherited or acquired mutations, hypercoagulability,

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elevated pre-chemotherapy platelet counts, recent surgery, hormonal agents, prolonged immobility, steroid use, and comorbidities such as hypertension.317 Patients with risk factors may be more susceptible to thrombosis with ESA use. Therefore, risk factors should be evaluated individually before administrating ESA therapy. The NCCN Panel recommends physicians to be on alert for signs and symptoms of thromboembolism in patients with cancer receiving ESAs.

In an analysis of phase III trials comparing ESAs with placebo for CIA treatment, the absolute risk of VTE was 7.5% in patients treated with ESAs compared with 4.9% in patients in the control group.299 Additionally,an increased risk of stroke was associated with darbepoetin alfa in a clinical trial of patients with CKD (RR, 1.92; 95% CI, 1.38-2.68; absolute risk, 5% vs. 2.6% in the placebo group).318 ESA use was also associated with a significantly increased risk of stroke (OR, 1.83; 95% CI, 1.26-2.65)in a retrospective case-controlled study of patients with all three conditions: anemia, CKD and cancer.319 It is important to note that the thrombotic potential of ESAs is independent of Hb levels.320

Hypertension

A Cochrane review reported an increased risk for hypertension with ESA use in patients with cancer(RR, 1.30; 95% CI, 1.08-1.56).289 A systematic review also reported increased hypertension risk in patients with cancer receiving ESAs.312 Blood pressure should be controlled in all patients prior to initiating ESA therapy and must be monitored regularly throughout treatment. Hb levels should be monitored before and during ESA use to decrease the risk of hypertension.

Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) related to anti-EPO antibodies have been reported rarely but with increased incidence in specific preparations of recombinant EPOs (rEPOs); PRCA should be suspected whenever a response to rEPO is lost. It is important to report these cases to the FDA

along with information on which biosimilar or innovator molecules are involved.7,321,322

Considerations for the Use of ESAs

In 2017, the FDA determined that the ESA Risk Evaluation and Mitigation Strategy (REMS) program is no longer necessary to ensure that the benefits of ESA therapy outweigh its risks.7 The FDA made this determination based on the results of REMS assessments and additional FDA analyses. For patients with cancer, the black box warning on the revised FDA label states that ESAs should only be used to treat CIA and be discontinued once the chemotherapy course is complete. As discussed previously, randomized trial data suggest that ESAs may promote tumor growth in an off-target manner. For this reason, the FDA states that these agents should not be used when the treatment intent is curative. This includes primary and adjuvant chemotherapy for malignancies such as early-stage breast cancer, NSCLC, lymphomas, and testicular cancer,among others. An exception to this may be small cell lung cancer, for which there are trials demonstrating no negative impact on survival or disease progression with ESA use.309-311 Additionally, ESAs are not recommended for use in patients with cancer who are not receiving therapy or in patients receiving non-myelosuppressive therapy. Patients undergoing palliative treatment may be considered for ESA therapy,PRBC transfusion, or participation in a clinical trial, depending on their preferences and personal values. The NCCN Panel recognizes that it is not always clear whether a chemotherapy regimen is considered curative.Under these circumstances, if no other cause of anemia has been identified, physicians should first consider PRBC transfusion or clinical trial enrollment, if available, for anemia management. If ESAs are utilized,physicians are advised to use the lowest dose necessary to eliminate symptoms and avoid transfusion.

CKD is an independent indication for ESA therapy. Increased risks of mortality and adverse cardiovascular outcomes are associated with ESA

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use in patients with CKD and Hb levels >11 g/dL in controlled clinical trials. ${ }^{318-320,323-325}$ Hence, the FDA label mandates individualized dosing to reduce the need for PRBC transfusions. Since almost one-third of patients with end-stage renal disease are also diagnosed with cancer, they represent a unique subgroup who require personalized ESA administration based on careful risks and benefits evaluation(reviewed by Bennett et al}^{326} . In a study comparing darbepoetin alfa to placebo, a significant increase in cancer-related death occurred in patients with CKD, pre-existing cancer at baseline and who were treated with ESA therapy (P=.002). ${ }^{318}$ Additionally, data from Seliger et al indicated that ESA treatment in patients with CKD was not associated with an overall increased risk for stroke, except in the subpopulation diagnosed with cancer.319 ESAs should be tried to be avoided in patients with CKD not receiving active therapy for a malignancy, while those receiving palliative chemotherapy can receive carefully dosed ESAs to treat severe anemia over transfusion. If the patient with CKD has a curable solid tumor, ESAs should not be administered during chemotherapy. However, they may be used with caution after chemotherapy is complete, keeping in mind the possibility of recurring disease.

Dosing Schedules

The NCCN Panel recommends epoetin alfa, epoetin alfa-epbx, or darbepoetin alfa. Head-to-head comparisons for superiority between epoetin alfa versus darbepoetin alfa have been inconclusive.302,327,328

Recommended dosing schedules for patients receiving chemotherapy are summarized in the algorithm. The Panel recommends two initial dosing schedules for epoetin alfa and epoetin alfa-epbx: 150 units/kg 3 times weekly287,329 or 40,000 units once weekly294,297,298,330 administered by subcutaneous injection. Other dosing ranges and schedules of epoetin alfa may be considered, including an extended dose of 80,000 units administered every 2 weeks331 and a dose of 120,000 units administered once every 3 weeks.332

Although darbepoetin alfa doses were initially administered at 2.25 mcg/kg every week,288,292,333 studies have tested fixed doses or higher doses at decreased frequency. A randomized trial comparing weekly dosing at 2.25 mcg/kg versus fixed dosing at 500 mcg every 3 weeks in 705 patients with anemia and non-myeloid malignancies showed that the percentage of patients achieving the target Hb level(≥11 g/dL) was higher in the weekly arm compared to those receiving darbepoetin alfa every 3 weeks(84% vs.77%).333 Dosing once every 3 weeks was further refined in two studies that reduced the dose to 300 mcg. Initially, a multicenter study of 1493 patients showed that 79% of patients receiving the lower dose achieved a target Hb level≥11 g/dL,334 which was confirmed in a phase II randomized trial of head-to-head comparison with 500 mcg. In this study, the proportion of patients who achieved target Hb levels(≥11 g/dL) was similar between those receiving 300 mcg versus 500 mcg darbepoetin alfa(75% vs.78%,respectively).335 Alternative dosing schedules for darbepoetin alfa include a fixed weekly dose of 100 mcg288 and a fixed dose of 200 mcg every 2 weeks.336 The NCCN Panel recommends these alternative regimens to support the delivery of the lowest ESA dose possible while maintaining maximum efficacy.

Response Assessment and Dose Titration

To determine whether the initial dose should be reduced, escalated, or withheld, response to ESA therapy should be assessed. Decisions related to ESA dose adjustment are based on the goal of maintaining the lowest Hb level sufficient to avoid transfusion. ESAs require at least 2 weeks of treatment for increasing RBC numbers. Hb levels should be measured weekly until stabilized. Dose reduction(generally 25% for epoetin alfa or epoetin alfa-epbx and 40% for darbepoetin alfa) should be implemented once Hb reaches a level sufficient to avoid transfusion or if the Hb level increases by ≥1 g/dL during a 2-week period.

Conversely, ESA dose should be increased according to the algorithm for patients receiving chemotherapy who show no response(defined as Hb

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increase <1 g/dL that remains $<10$ $g/dL$) following 4 weeks of epoetin alfa or epoetin alfa-epbxt treatment or following 6 weeks of darbepoetin alfa treatment. A subsequent response at 8 weeks may necessitate a dose escalation to avoid transfusion. Iron supplementation should be considered to improve response to ESA therapy. A Cochrane Database review concluded that adding iron to ESA therapy offers superior hematopoietic response, reduces the risk of transfusions, improves Hb levels, and appears to be well tolerated.337 A meta-analysis of randomized controlled trials also showed that the addition of parenteral iron reduces the risk of transfusions by 23% and increases the chance of hematopoietic response by 29% compared to ESAs alone. ${ }^{338}$ ESA therapy should be discontinued and PRBC transfusion should be considered in patients showing no response despite iron supplementation after 8 weeks of therapy. ESAs should also be discontinued when chemotherapy is completed or withdrawn.

Iron Monitoring and Supplementation

Iron Deficiency Evaluation and Definitions of Iron Status

Iron deficiency is reported in 32% to 60% of patients with cancer, most of whom also have anemia.339 Iron studies, including serum iron, TIBC, and serum ferritin, should be performed prior to ESA treatment to rule out absolute iron deficiency that may respond to oral or IV iron monotherapy.Serum iron and TIBC levels may be falsely elevated by diet(reviewed in Collings et al340); therefore, fasting is recommended to provide more accurate measurements. Transferrin saturation(TSAT) should be calculated from these values using the following formula:

● TSAT = (serum iron level x 100)/TIBC

Treatment for iron deficiency is guided by iron status, defined in these guidelines as absolute iron deficiency, functional iron deficiency, possible functional iron deficiency, or no iron deficiency. In the absence of a universal numerical definition of iron deficiency in relevant studies, the

NCCN Panel recognizes that ferritin and TSAT values defining absolute and functional iron deficiencies represent moving targets. ${ }^{234}$ However, as general guidance, definitions and characteristics of each iron status group are discussed below.

Absolute Iron Deficiency

Absolute iron deficiency refers to the depletion of total body iron stores. It is characterized by low Hb, low serum iron, and high TIBC that result in a TSAT level <20% and a ferritin level <30 ng/mL. If the TSAT and ferritin parameters are discordant, a low ferritin value should take precedence in determining whether iron supplementation is beneficial. The reference interval for serum ferritin depends on laboratories, but in general, the lower the level, the more probable that true iron deficiency is present. However,in the cancer setting, clinicians should be aware of chronic inflammatory states, which may falsely elevate serum ferritin levels.

Although IV iron is preferred, either IV or oral iron products alone (without an ESA) are recommended for patients with cancer who develop absolute iron deficiency. A meta-analysis showed that treatment with both ESA and iron showed a greater increase in Hb, Hct, RBC count, and hematopoietic response rate in patients with CIA and treated with both ESA and oral iron compared to oral iron alone.341 Hb levels should increase after 4 weeks of treatment. Periodic evaluation of ferritin and TSAT levels is required as some patients, especially those with continued internal bleeding, may suffer a relapse. If the patient initially receives oral iron and the anticipated response is not seen after 4 weeks, a trial of IV iron should be considered.If Hb is not improved after 4 weeks following IV iron supplementation, the patient should be evaluated for functional iron deficiency. Although data are conflicting in the literature, concerns exist regarding the possibility of IV iron promoting inflammation and bacterial growth. ${}^{342}$ Hence, IV iron supplementation is not recommended for patients with an active infection.For further discussion of absolute iron deficiency, see Clinical Examples of Iron Status, case scenarios 1 and 2.

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Functional Iron Deficiency

Functional iron deficiency is a condition in which stored iron is sufficient but bioavailable iron necessary for erythroblast production is deficient.

This may occur when infection or inflammation blocks iron transport to the bone marrow, as seen in anemia of chronic inflammation. Functional iron deficiency is defined in these guidelines as ferritin levels between 30 and 500 ng/mL and TSAT levels<50%. IV iron supplementation with erythropoietic therapy should be considered for these patients. Although oral iron has been used more commonly, IV iron has superior efficacy and should be considered for supplementation in this setting (see Intravenous Versus Oral Iron below). Functional iron deficiency often arises following continued ESA use, resulting in a blunted erythropoietic response to anemia. Hence, iron supplementation will eventually be required in most patients to maintain optimal erythropoiesis. ${ }^{343,344}$ For further discussion of functional iron deficiency, see Clinical Examples of Iron Status, case scenario 3.

Possible Functional Iron Deficiency

Possible functional Iron deficiency is a condition in which stored iron is sufficient but bioavailable iron necessary for erythroblast production may be deficient. These patients are defined by TSAT levels<50% and a ferritin level of 500 to 800 ng/mL. Although clinical trials suggest that these patients have functional iron deficiency, there are insufficient data to support the routine use of IV iron in this setting. The Panel recommends no iron supplementation or the consideration of IV iron supplementation for patients with possible functional iron deficiency. Administration of IV iron to these patients should be individualized with the goal of avoiding transfusion. ESA therapy is not recommended in this setting. For further discussion of possible functional iron deficiency, see Clinical Examples of Iron Status, case scenarios 4 and 5.

No Iron Deficiency

Patients with ferritin values>800 ng/mL or a TSAT≥50% are not iron deficient. These patients do not require iron supplementation or ESA therapy.

Intravenous Versus Oral Iron

Iron can be administered orally or intravenously. Although oral iron is appropriate for most patients with iron-deficient anemia, there are situations in which IV iron therapy is a valuable option: 1) CIA in many patients may not respond to oral iron; 2) oral iron cannot be given due to intolerance; and 3) patients may require higher iron doses than achievable with oral iron.345 Evidence from several published studies utilizing iron in conjunction with an ESA suggest that IV iron is superior to oral iron in improving Hb response rates in patients with CIA.346-351 In 2011, a trial published by Steensma et al challenged these results.352 In this study,patients with CIA(n= 502) were randomized to receive IV iron, oral iron,or oral placebo in combination with ESA therapy. Initial analysis of the data led the authors to conclude that IV iron did not confer any benefit in terms of Hb response, transfusion requirement, or quality of life compared to oral iron or placebo. However, the lack of response to IV iron may have been attributable to problems with the study design, including a suboptimal IV iron dosing regimen and a high proportion of participant dropouts.353 Indeed, reanalysis of study data indicated that trial participants who received at least 80% of the planned IV iron dosage had Hb response rates similar to participants in other IV iron trials.354 It should be noted that patients with a baseline TSAT level <20% have a higher response rate to IV iron supplementation when given with an ESA. As the TSAT level increases from 20% to 50%, the response rate to IV iron is diminished and the time to response is prolonged. Hence, for patients with TSAT levels between 20% to 50%, the decision to offer IV iron should be reserved for those in whom the benefits are likely to outweigh the risks. Studies on

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parameters that make patients more or less likely to benefit from IV iron and alternative IV iron dosing schedules are needed.

None of the studies on iron supplementation in conjunction with ESAs provide instruction on how or when to re-dose iron after the initial cumulative dose has been given. Generally, repeating iron studies is not recommended within 3 to 4 weeks of administration. Clinicians may consider repeating iron studies when the MCV declines, or hypochromic RBCs are seen on the peripheral blood smear. Additionally, repeating iron studies can be considered for anemia that does not respond to iron supplementation 4 to 6 weeks after administration of the total intended dose. 348,352 If evidence of iron overload exists, do not administer IV iron.Subsequent doses of iron should be withheld if the serum ferritin exceeds 800 ng/mL or if the TSAT exceeds 50%.347-349

Subsequent doses of iron should be withheld if the serum ferritin exceeds 800 ng/mL or if the TSAT exceeds 50%.347-349

Since most studies show that IV iron is superior to oral iron, the Panel recommends that IV iron supplementation be used in most clinical circumstances. Low-molecular-weight iron dextran, ferric gluconate, iron sucrose, ferric carboxymaltose, ferumoxytol, and ferric derisomaltose are the recommended IV iron preparations. Common adverse events following FDA-approved doses of IV iron include hypotension, hypertension, nausea, vomiting, diarrhea, pain, fever, dyspnea, pruritus, headaches, and dizziness. 355-357 Dosage details for administering IV iron therapy are listed in the algorithm.

Low-Molecular-Weight Iron Dextran

A prospective, multicenter trial randomized 157 patients with CIA on epoetin alfa to receive: 1) no iron; 2) oral iron; 3) iron dextran IV bolus; or 4) iron dextran total dose infusion(TDI).346 Increases in Hb concentration were greater with IV iron dextran(groups 3 and 4) compared to oral iron or no iron(P<.02). Importantly, there was no difference between the oral and no iron groups(P=.21). Additionally, there was no statistically

<BeginOfPara> no iron(P<.02). Importantly, there was no difference between the oral and no iron groups(P=.21). Additionally, there was no statistically significant difference between groups 3 and 4 (P=.53), suggesting that

lower, intermittent doses of IV iron dextran are equally as efficacious as TDI. Most adverse events including headaches, dizziness, nausea, vomiting, and diarrhea occurred with high-molecular-weight iron dextran.358 Therefore, low-molecular-weight iron dextran is the recommended iron dextran preparation.359 Test doses are required for iron dextran(25 mg slow IV push over 1-2 minutes; if tolerated, followed by 75 mg IV bolus for a total dose of 100 mg).346 Premedication should occur prior to test dose administration since reactions to the IV iron dextran test dose may be severe. Anaphylaxis-like reactions occur within minutes of the test dose but respond readily to IV epinephrine, diphenhydramine, and corticosteroids. It should be noted that patients may develop a reaction to IV iron dextran with later doses, and clinicians should be prepared to administer appropriate treatment. Delayed reactions to iron dextran may result in adverse events up to 24 to 48 hours following injection.

Ferric Gluconate

In a multicenter trial, 187 patients with CIA on chemotherapy and epoetin alfa were randomized to receive no iron, oral ferrous sulfate three times daily, or weekly IV ferric gluconate. ${ }^{349}$ The Hb response rate (≥2 g/dL increase) was higher in the IV ferric gluconate arm (73%; P=.0099 vs. oral iron; P=.0029 vs. no iron) compared to the oral (45%; P=.6687 vs.no iron) or no iron (41%) arms. ln another study, 149 patients with solid tumors and CIA were randomly assigned to receive weekly darbepoetin alfa with or without IV ferric gluconate. ${ }^{350}$ The IV ferric gluconate group showed a higher hematopoietic response rate compared to the no iron group (93% vs. 70%, respectively; P=.0033). In a study evaluating 396 patients with non-myeloid malignancies and CIA undergoing chemotherapy, patients were treated with darbepoetin alfa with or without IV ferric gluconate every 3 weeks for 16 weeks. ${ }^{347}$ Erythropoietic responses were improved in the IV ferric gluconate arm. Significantly, this was the first study to show IV iron associated with fewer RBC transfusions in patients with cancer (9% vs. 20%; P=.005).

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Iron Sucrose

A randomized controlled trial involving 64 patients with gynecologic cancers compared the efficacy of IV iron sucrose to oral ferrous fumarate for primary anemia prevention(ie, patients did not present with anemia).^{360}In this study, patients received a single dose of 200 mg iron sucrose after each chemotherapy infusion course for 6 cycles. The number of patients requiring blood transfusion was double in the oral iron group compared to the IV iron sucrose group (56.3% vs. 28.1%; P=.02). Even when patients required transfusion in the IV iron sucrose group, they received a lower median number of PRBC units (0 vs. 0.5 units; P=.05). Another study randomized 67 patients with lymphoproliferative malignancies not undergoing chemotherapy to receive weekly ESA therapy with or without IV iron sucrose. ${ }^{348}$ Although an oral iron arm was not included, IV iron sucrose resulted in a higher mean change in Hb level from baseline (2.76 vs. 1.56 g/dL; P=.0002) and a higher Hb level response rate (≥2 g/dL increase; 87% vs. 53%; P=.0014) compared to the no IV iron group.

Ferric Carboxymaltose

An observational study by Steinmetz et al^{361} evaluated the use of ferric carboxymtaltose with and without an ESA in patients with cancer. In 233 patients treated with ferric carboxymaltose alone, a median Hb increase of 1.4 g/dL(range, 1.3-1.5 g/dL) was observed with an overall increase in>11 g/dL median Hb levels within 5 weeks of treatment.361 Similar results were seen in patients receiving concomitant treatment with ferric carboxymtose and an ESA(1.6 g/dL increase; range, 0.7-2.4 g/dL; n=46). Another observational study of 367 patients with solid tumors or hematologic malignancies also demonstrated improved median Hb levels following administration of ferric carboxymaltose alone or in combination with an ESA(1.3 vs. 1.4 g/dL, respectively) over a 3-month period.362 A retrospective analysis of 303 patients with gastrointestinal cancers and anemia found that IV administration of ferric carboxymaltose resulted in a significant increase in Hb levels, with a median change between baseline

and follow-up Hb of 0.5 g/dL(interquartile range [IQR]:-0.1-1.6).363 In the randomized clinical IVICA trial, including 116 patients with anemia and colorectal cancer, preoperative administration of ferric carboxymaltose showed higher Hb levels after surgery compared to oral ferrous sulfate(11.9 vs.11.0 g/dL;P=.002).364 A follow-up study indicated that patients who received ferric carboxymaltose had significantly improved quality-of-life scores, as measured by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) subscale, compared to patients who received oral iron.365 In patients with colon cancer and anemia, preoperative treatment with ferric carboxymaltose was shown to significantly reduce RBC transfusion requirements (9.9% vs. 38.7%; P<.001) and length of hospital stay (8.4±6.8 vs.10.9±12.4 days to discharge; P<.001)compared to those not receiving IV iron.366

Ferric carboxymaltose is associated with severe phosphate deficiency that is often asymptomatic.367-371 Lack of awareness of this complication causes delayed time to diagnosis and results in significant morbidity.367 Therefore, patients receiving ferric carboxymaltose should be closely monitored for hypophosphatemia.

Ferumoxytol

Ferumoxytol is colloidal iron oxide indicated for the treatment of iron-deficiency anemia in patients with CKD or intolerance or poor response to oral iron.322,372,373 However, ferumoxytol has not been prospectively evaluated in patients with CIA.321 In a phase III trial involving patients with anemia due to various causes, 81.1% of patients treated with ferumoxytol had an Hb increase ≥2.0 g/dL at week 5 compared to only 5.5% of patients given placebo(P<.0001).322 Only a small percentage of patients in this study had cancer(n= 39).322 A positive trend, not significant, was observed in ferumoxytol in patients with cancer compared with placebo(ferumoxytol, 51.7% vs. placebo, 30.0%;P<.2478).322 In a randomized phase III study of patients with iron-deficiency anemia that did not responded to oral iron, a similar percentage of patients had a ≥2 g/dL

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increase in Hb from baseline to week 5 in the ferumoxytol and iron sucrose groups (84% with ferumoxytol vs. 81.4% with iron sucrose). ${ }^{373}$ However, these results were not observed in the cancer subgroup (n=31), potentially due to the small sample size. A post-hoc analysis of pooled data, in a subgroup of 98 patients with cancer, from these two trials found that ferumoxytol and iron sucrose administration resulted in a significant increase in Hb from baseline compared to placebo (1.8 g/dL, P < .0001 and 1.9 g/dL, P = .002, respectively). ${ }^{321}$

It should be noted that ferumoxytol may cause interference with MRI,causing potential false interpretation of organ iron overload.374 This is especially pertinent for populations at risk for serious organ-threatening iron deposition and should be a consideration when selecting the agent for iron supplementation.

Ferric Derisomaltose

Ferric derisomaltose is indicated for the treatment of iron-deficiency anemia in patients with CKD or an intolerance or poor response to oral iron. Ferric derisomaltose increased Hb levels similar to iron sucrose in two randomized phase III trials in patients with iron-deficiency anemia.375,376 The FERWON-IDA trial demonstrated that a single 1000-mg dose of IV ferric derisomaltose resulted in a significant rapid hematologic response in the first 2 weeks, swift reduction in fatigue, and a similar safety profile compared to repeated doses of iron sucrose.375 The FERWON-NEPHRO trial in patients with iron-deficiency anemia and CKD demonstrated that compared to iron sucrose, ferric derisomaltose induced a similar 8-week hematologic response, lower rates of hypersensitivity reactions, and a significantly lower incidence of cardiovascular adverse events.376 Additionally, the PHOSPHARE trials demonstrated that the incidence of hypophosphatemia was significantly lower following ferric derisomaltose treatment compared to ferric carboxymaltose.377 The phase III PROFOUND trial analyzed the safety and efficacy of ferric derisomaltose for the treatment of iron-deficiency anemia in 350 patients

with cancer. ${ }^{378}$ Results showed that ferric derisomaltose was equivalent to oral iron sulfate in increasing Hb concentration from baseline to week 4.Ferric derisomaltose resulted in a faster onset of Hb response and a higher proportion of patients treated with oral iron experienced adverse drug reactions. Hypophosphatemia was reported at similar but low frequencies in the two groups.

Clinical Examples of Iron Status

The following clinical scenarios illustrate how iron studies may guide iron supplementation and ESA treatment of patients with CIA.

Patient Case

A 59-year-old female with no significant medical history presented to her primary care provider after acute onset of bloody stools in addition to a 2-month history of early satiety and 9 kg weight loss. Abdominal imaging revealed a colonic mass and mesenteric lesions. She was referred to an oncologist. Biopsy of the mass demonstrated a poorly differentiated adenocarcinoma. Her oncologist has begun palliative treatment with FOLFOX plus bevacizumab, a myelosuppressive regimen. After 2 cycles of chemotherapy, her CBC results are as follows: Hb 8.8 g/dL, Hct 26.7%,MCV 73 fL, reticulocytes 0.8%,mean corpuscular Hb 25 pg, red cell distribution width 18.2%, and platelets 398,000/μL. She does not have CKD. Serum folate, vitamin B12 levels, indirect bilirubin, and serum LDH are within normal limits. Bleeding has ceased, but given her baseline anemia and red cell indices, iron studies have been ordered. Five different scenarios are provided below to illustrate the potential management of this patient depending on various ferritin and TSAT combinations.

Scenario 1: Serum Ferritin 5 ng/mL& TSAT 4%

With a ferritin level<30 ng/mL and a TSAT level<20%, this patient has absolute iron deficiency and would benefit from iron repletion. Reducing transfusion requirements remains the goal of therapy. With a baseline Hb

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of 8.8 g/dL, imminent chemotherapy initiation, and very low iron stores, IV iron repletion is preferred. Oral iron may not supply bioavailable iron rapidly enough in certain patients.346

Scenario 2: Serum Ferritin 10 ng/mL & TSAT 22%

With low ferritin and normal TSAT levels, we can postulate that iron stores are becoming depleted. Iron is being mobilized, but signs of iron-restricted erythropoiesis are beginning to emerge. If the ferritin and TSAT levels are discordant, the low ferritin level should take precedence to determine if IV iron therapy would be helpful. Iron would be beneficial in this patient as these laboratory values reflect a transition from an iron-replete to an iron-deficient state. For the same reasons as discussed in scenario 1, IV iron is preferred over oral iron. It is also possible for TIBC to be low secondary to malnutrition, resulting in a normal TSAT level despite definitive absolute iron deficiency. ESA use should be considered only after iron repletion.

Scenario 3: Serum Ferritin 580 ng/mL & TSAT 12%

With normal or elevated ferritin and low TSAT levels, we can assume that iron is either not bioavailable or that the ferritin level reflects an acute-phase response, potentially secondary to cancer-related inflammation(functional iron deficiency). Functional iron deficiency may cause iron-restricted erythropoiesis, and there is no ferritin threshold at which we can assume iron supply is adequate for erythropoiesis if the TSAT level is low.Thus, patients with ferritin levels>100 ng/mL could be treated with IV iron.However, as the ferritin level moves across the spectrum from absolute iron deficiency to iron overload, the response to either an ESA or IV iron will diminish and therefore an ESA should be considered first.Concomitant IV iron can be considered as it may increase the percentage of patients whose anemia responds to the ESA as well as reduce the time to response.

Scenario 4: Serum Ferritin 100 ng/mL & TSAT 30%As the TSAT level increases from 20% to 50%, the percentage of patients with anemia that responds to iron decreases; therefore, this patient may not necessarily require IV iron until the TSAT level trends downward as a result of ESA use. If the anticipated response to ESA therapy is not realized by 4 to 6 weeks, consider repeating iron studies. If TSAT and/or ferritin levels decrease, consider giving IV iron. If iron studies remain unchanged, continue the ESA for a total of 8 weeks. Discontinue thereafter if lack of response persists and consider RBC transfusion.

Scenario 5: Serum Ferritin 500 ng/mL & TSAT 40%

These ferritin and TSAT parameters suggest that functional iron deficiency is unlikely. Therefore, this patient is iron replete and unlikely to benefit from iron therapy. In this scenario, an ESA may be considered. ESA use induces functional iron deficiency by increasing iron utilization without the compensatory ability to mobilize stored iron in a timely manner. Therefore,iron repletion can be initiated if response to ESA therapy is not seen and the patient remains transfusion-dependent. Of note, improved response is generally expected as the TSAT level decreases from 50% to 20%.Ultimately, clinical judgment must be used to determine whether the potential benefits of iron administration are likely to outweigh the risks.

Tables

Table 1. Correction Factor for RPI Calculation

|Hematocrit %|Reticulocyte maturation time (RMT) in days| |---|---| |40-45|1.0| |35-39|1.5| |25-34|2.0| |15-24|2.5| |<15|3.0|

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113. Kim E, Jin R, Choi K, et al. Safety and efficacy of low-dose pegfilgrastim(pegfil) in maintaining chemotherapy (CT) dose density in patients (pts) receiving docetaxel/doxorubicin/cyclophosphamide (TAC) or

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122.Evens AM, Gilley 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. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17459049.

115. Akyol G, Pala C, Yildirim A, et al. A rare but severe complication of filgrastim in a healthy donor: splenic rupture. Transfus Apher Sci 2014;50:53-55. Available at:

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116. Funes C, Garcia-Candel F, Majado MJ, et al. Splenic rupture in a plasma cell leukemia, mobilized with G-CSF for autologous stem cell transplant. J Clin Apher 2010;25:223-225. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20818717.

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124. Relling MV,Boytt JM,Blanco JG,et al. Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment. Blood 2003;101:3862-3867. Available at:http://www.ncbi.nlm.nih.gov/pubmed/12531808.

117. O'Malley DP, Whalen M, Banks PM. Spontaneous splenic rupture with fatal outcome following G-CSF administration for myelodyplastic syndrome. Am J Hematol 2003;73:294-295. Available at:https://www.ncbi.nlm.nih.gov/pubmed/12879437.

125. Smith RE, Bryant J, DeCillis A, et al. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol 2003;21:1195-1204. Available at:http://www.ncbi.nlm.nih.gov/pubmed/12663705.

118.Veerappan R, Morrison M, Williams S, Variakojis D. Splenic rupture in a patient with plasma cell myeloma following G-CSF/GM-CSF administration for stem cell transplantation and review of the literature.Bone Marrow Transplant 2007;40:361-364. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17563733.

119. Watring NJ, Wagner TW, Stark JJ. Spontaneous splenic rupture secondary to pegfilgrastim to prevent neutropenia in a patient with non-small-cell lung carcinoma. Am J Emerg Med 2007;25:247-248. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17276841.

126. Hershman D, Neugut Al, Jacobson JS, et al. Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 2007;99:196-205. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17284714.

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128. Calip GS, Moran KM, Sweiss Kl,et al. Myelodysplastic syndrome and acute myeloid leukemia after receipt of granulocyte colony-stimulating factors in older patients with non-Hodgkin lymphoma. Cancer 2019;125:1143-1154. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30548485.

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134. Bashir Q, Langford LA, Parmar S, et al. Primary systemic amyloid light chain amyloidosis decompensating after filgrastim-induced mobilization and stem-cell collection. J Clin Oncol 2011;29:e79-80.Available at: http://www.ncbi.nlm.nih.gov/pubmed/21060030.

135. Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocyte-macrophage colony-stimulating factor in cancer patients: a phase lb clinical study. Behring Inst Mitt 1988:107-118. Available at:http://www.ncbi.nlm.nih.gov/pubmed/2467645.

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138. Winer ES, Miller KB, Chan GW. GM-CSF and low-dose cytosine arabinoside in high-risk, elderly patients with AML or MDS. Oncology(Williston Park) 2005;19:11-14. Available at:http://www.ncbi.nlm.nih.gov/pubmed/15934494.

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143. Vial T, Descotes J. Clinical toxicity of cytokines used as haemopoietic growth factors. Drug Saf 1995;13:371-406. Available at:http://www.ncbi.nlm.nih.gov/pubmed/8652081.

144. Mahmoudjafari Z, Hawks KG, Hsieh AA, et al. American Society for Blood and Marrow Transplant Pharmacy Special Interest Group survey on chimeric antigen receptor T cell therapy administrative, logistic,and toxicity management practices in the United States. Biol Blood Marrow Transplant 2019;25:26-33. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30266675.

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146. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy- assessment and management of toxicities. Nat Rev Clin Oncol 2018;15:47-62. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28925994.

147. Mehta HM, Malandra M, Corey SJ. G-CSF and GM-CSF in neutropenia. J Immunol 2015;195:1341-1349. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26254266.

148. Moore DC. Drug-induced neutropenia: a focus on rituximab-induced late-onset neutropenia. P T 2016;41:765-768. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27990078.

149. Lyman GH, Lyman CH, Agboola O. Risk models for predicting chemotherapy-induced neutropenia. Oncologist 2005;10:427-437.Available at: http://www.ncbi.nlm.nih.gov/pubmed/15967836.

150. Aslani A, Smith RC, Allen BJ, et al. The predictive value of body protein for chemotherapy-induced toxicity. Cancer 2000;88:796-803.Available at: http://www.ncbi.nlm.nih.gov/pubmed/10679649.

151. Chrischilles E, Delgado DJ, Stolshek BS, et al. Impact of age and colony-stimulating factor use on hospital length of stay for febrile neutropenia in CHOP-treated non-Hodgkin's lymphoma. Cancer Control 2002;9:203-211. Available at:

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152. Lyman GH, Dale DC, Friedberg J, et al. Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin's lymphoma:a nationwide study. J Clin Oncol 2004;22:4302-4311. Available at:http://www.ncbi.nlm.nih.gov/pubmed/15381684.

153. Lyman GH, Delgado DJ. Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma. Cancer 2003;98:2402-2409. Available at:http://www.ncbi.nlm.nih.gov/pubmed/14635075.

154. Lyman GH, Morrison VA, Dale DC, et al. Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin's lymphoma receiving CHOP chemotherapy. Leuk Lymphoma 2003;44:2069-2076.Available at: http://www.ncbi.nlm.nih.gov/pubmed/14959849.

155. Morrison VA, Picozzi V, Scott S, et al. The impact of age on delivered dose intensity and hospitalizations for febrile neutropenia in patients with intermediate-grade non-Hodgkin's lymphoma receiving initial CHOP chemotherapy: a risk factor analysis. Clin Lymphoma 2001;2:47-56.

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156. Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review. Crit Rev Oncol Hematol 2014;90:190-199. Available at:http://www.ncbi.nlm.nih.gov/pubmed/24434034.

157. Lyman GH, Kuderer NM, Crawford J, et al. Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy.Cancer 2011;117:1917-1927. Available at:http://www.ncbi.nlm.nih.gov/pubmed/21509769.

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158. Lyman GH, Poniewiersi MS. A patient risk model of chemotherapy-induced febrile neutropenia: lessons learned from the ANC study group. J Natl Compr Canc Netw 2017;15:1543-1550. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29223991.

159. Razzaghdoust A, Mofid B, Moghadam M. Development of a simplified multivariable model to predict neutropenic complications in cancer patients undergoing chemotherapy. Support Care Cancer 2018;26:3691-3699.

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160. Aagaard T, Roen A, Reekie J, et al. Development and validation of a risk score for febrile neutropenia after chemotherapy in patients with cancer: the FENCE score. JNCI Cancer Spectr 2018;2;pky053. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31360873.

161. Aagaard T, Reekie J, Roen A, et al. Development and validation of a cycle-specific risk score for febrile neutropenia during chemotherapy cycles 2-6 in patients with solid cancers: the (CSR) FENCE score. Int J Cancer 2019;146:321-328. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30839100.

162. Family L, Li Y, Chen LH, et al. A study of novel febrile neutropenia risk factors related to bone marrow or immune suppression, barrier function, and bacterial flora. J Natl Compr Canc Netw 2018;16:1201-1208. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30323090.

163. Smith TJ, Bohlke G, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2015;33:3199-3212. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26169616.

164. Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 2011;47:8-32. Available at:

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165. Kosaka Y, Rai Y, Masuda N, et al. Phase III placebo-controlled,double-blind, randomized trial of pegfilgrastim to reduce the risk of febrile neutropenia in breast cancer patients receiving docetaxel/cyclophosphamide chemotherapy. Support Care Cancer 2015;23:1137-1143. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25576433.

166. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med 2021;386:351-363. Available at:https://www.nejm.org/doi/full/10.1056/NEJMoa2115304.

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167. Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management.Cancer 2004;100:228-237. Available at:http://www.ncbi.nlm.nih.gov/pubmed/14716755.

168. Lyman GH. Risk assessment in oncology clinical practice. From risk factors to risk models. Oncology (Williston Park) 2003;17:8-13. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14682113.

169. Gomes F, Faivre-Finn C, Mistry H, et al. Safety of G-CSF with concurrent chemo-radiotherapy in limited-stage small cell lung cancer -Secondary analysis of the randomised phase 3 CONVERT trial. Lung Cancer 2021;153:165-170. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33545577.

170. Bunn PA, Jr., Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632-1641.Available at:

171. Weycker D, Li X, Tzivelekis S, et al. Burden of chemotherapy-induced febrile neutropenia hospitalizations in US clinical practice, by use and patterns of prophylaxis with colony-stimulating factor. Support Care Cancer 2016:439-447. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27734153.

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172. Lyman GH, Allcott G, Garcia J, et al. The effectiveness and safety of same-day versus next-day administration of long-acting granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced neutropenia: a systematic review. Support Care Cancer 2017;25:2619-2629. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28484882.

173. Hobbs J, Lowe J, Ferdinand A, et al. Efficacy of same-day versus next-day administration of pegfilgrastim for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients receiving dose-dense doxorubicin and cyclophosphamide: A retrospective multi-site analysis. J Oncol Pharm Pract 2023:29:1853-1861. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36579812.

174. Meropol NJ, Miller LL, Korn EL, et al. Severe myelosuppression resulting from concurrent administration of granulocyte colony-stimulating factor and cytotoxic chemotherapy. J Natl Cancer Inst 1992;84:1201-1203.Available at: http://www.ncbi.nlm.nih.gov/pubmed/1378905.

175. Rowinsky EK, Grochow LB, Sartorius SE, et al. Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor topocetan with granulocyte colony-stimulating factor in patients with solid tumors. J Clin Oncol 1996;14:1224-1235. Available at:http://www.ncbi.nlm.nih.gov/pubmed/8648378.

176. Kanbayashi Y, Ishikawa T, Kanazawa M, et al. Predictive factors in patients eligible for pegfilgrastim prophylaxis focusing on RDI using ordered logistic regression analysis. Med Oncol 2018;35:55. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29549536.

177. Lee A, Kang T, Kang SH, et al. An observational, prospective, open label, multicenter study to evaluate the safety and effectiveness of pegfilgrastim as secondary prophylaxis to decrease the incidence of febrile neutropenia in Korean female patients with breast cancer. Breast 2023;72:103585. Available at:

178. Weycker D, Bensink M, Lonshteyn A, et al. Risk of chemotherapy-induced febrile neutropenia by day of pegfilgrastim prophylaxis in US clinical practice from 2010-2015. Curr Med Res Opin 2017;33:2107-2113.Available at: https://www.ncbi.nlm.nih.gov/pubmed/28958157.

179. Kaufman PA, Paroly W, Rinaldi D. Randomized double blind phase 2 study evaluating same-day vs. next-day administration of pegfilgrastim with docetaxel, doxorubicin and cyclophosphamide(TAC) in women with early stage and advanced breast cancer. Breast Cancer Res Treat 2004;88:S59. Available at: https://insights.ovid.com/breast-cancer-research-treatment/bcart/2004/88/001/randomized-double-blind-phase-study-evaluating/167/00001803.

180. Saven A, Schwartzberg L, Kaywin P, et al. Randomized, double-blind, phase 2, study evaluating same-day vs next-day administration of pegfilgrastim with R-CHOP in non-Hodgkin's lymphoma patients. J Clin Oncol 2006;24:7570. Available at:http://ascopubs.org/doi/abs/10.1200/jco.2006.24.18 suppl.7570.

181. Eckstrom J, Bartels T, Abraham I,et al.A single-arm, retrospective analysis of the incidence of febrile neutropenia using same-day versus next-day pegfilgrastim in patients with gastrointestinal cancers treated with FOLFOX or FOLFIRI. Support Care Cancer 2019;27:873-878. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30090991.

182. Matera RM, Relias V, Saif MW. Safety and efficacy of same-day administration of pegfilgrastim in patients receiving chemotherapy for gastrointestinal malignancies. Cancer Med J 2021;4:6-11. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32656544.

183. McBride A, Alrawashdh N, Bartels T, et al. Same-day versus next-day pegfilgrastim or pegfilgrastim-cbqv in patients with lymphoma receiving CHOP-like chemotherapy. Future Oncol 2021;17:3485-3497.Available at:https://www.ncbi.nlm.nih.gov/pubmed/34241542.

184. Kitchen K, Mosier MC. Real-world comparison of febrile neutropenia rates with same-day versus next-day administration of pegfilgrastim. J Clin Oncol 2021;39:299-299. Available at:

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185. Kitchen K, Mosier MC. Real-world febrile neutropenia rates with same-day versus next-day pegfilgrastim after myelosuppressive chemotherapy. Future Oncol 2022;18:2551-2560. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35708316.

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186. Hershman DL, Bansal A, Barlow WE, et al. Intervention nonadherence in the TrACER(S1415CD) study: A pragmatic randomized trial of a standardized order entry for CSF prescribing. JCO Oncol Pract 2023;19:1160-1167. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37788414.

187. Lyman GH, Bansal A, Sullivan SD, et al. Impact of treatment experience on patient knowledge of colony-stimulating factors among patients receiving cancer chemotherapy: evidence from S1415CD-a large pragmatic trial. Support Care Cancer 2023;31:598. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37770704.

188. Scotte F, Artru P, Saghatchian M, Chouaid C. Leveraging G-CSF prescribing in the outpatient setting: considerations beyond clinical factors-a questionnaire study. Support Care Cancer 2024;32:347. Available at:https://www.ncbi.nlm.nih.gov/pubmed/38743147.

189. Yang BB, Morrow PK, Wu X, et al. Comparison of pharmacokinetics and safety of pegfilgrastim administered by two delivery methods: on-body injector and manual injection with a prefilled syringe. Cancer Chemother Pharmacol 2015;75:1199-1206. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25894719.

190. Joshi RS, Egbuna Ol, Cairns AS, et al. Performance of the pegfilgrastim on-body injector as studied with placebo buffer in healthy volunteers.Curr Med Res Opin 2017;33:379-384.Available at:https://www.ncbi.nlm.nih.gov/pubmed/27819161.

191. McBride A, Krendyukov A, Mathieson N,et al. Febrile neutropenia hospitalization due to pegfilgrastim on-body injector failure compared to single-injection pegfilgrastim and daily injections with reference and biosimilar filgrastim: US cost simulation for lung cancer and non-Hodgkin lymphoma. J Med Econ 2020;23:28-36. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31433700.

192. Mahler LJ, DiBlasi R, Perez A, et al. On-body injector: an administration device for pegfilgrastim. Clin J Oncol Nurs 2017;21:121-122. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28107322.

193. Long Z, Kurup AN, Jensen NM, et al. Initial testing of pegfilgrastim(Neulasta Onpro) on-body injector in multiple radiological imaging environments. J Appl Clin Med Phys 2021;22:343-349. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33395503.

194. Green MD, Koelbl H, Baselga J, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003;14:29-35. Available at:http://www.ncbi.nlm.nih.gov/pubmed/12488289.

195. Watanabe T, Tobinai K, Shibata T, et al. Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial. J Clin Oncol 2011;29:3990-3998. Available at: http://www.ncbi.nlm.nih.gov/pubmed/31931035.

196. Hecht JR, Pillai M, Gollard R, et al. A randomized, placebo-controlled phase II study evaluating the reduction of neutropenia and febrile neutropenia in patients with colorectal cancer receiving pegfilgrastim with every-2-week chemotherapy. Clin Colorectal Cancer 2010;9:95-101.Available at: http://www.ncbi.nlm.nih.gov/pubmed/20378503.

197. Brusamolino E, Rusconi C, Montalbetti L, et al. Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity. Haematologica 2006;91:496-502. Available at:http://www.ncbi.nlm.nih.gov/pubmed/16537117.

198. Burstein HJ, Parker LM, Keshaviah A,et al.Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol 2005;23:8340-8347. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16293865.

199. Jones RL, Walsh G, Ashley S, et al. A randomised pilot phase II study of doxorubicin and cyclophosphamide(AC) or epirubicin and cyclophosphamide(EC) given 2 weekly with pegfilgrastim(accelerated) vs 3 weekly(standard) for women with early breast cancer. Br J Cancer 2009;100:305-310. Available at:

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200. Pirker O, Lursperger E, Messner J, et al. Achieving full-dose, on-schedule administration of ACE chemotherapy every 14 days for the treatment of patients with extensive small-cell lung cancer. Lung 2006;184:279-285. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17235728.

207.Glaspy J, Daley W, Bondarenko I, et al. A phase III, randomized,multi-center, open-label, fixed dose, Neulasta active-controlled clinical trial of F-627, a novel G-CSF, in women with breast cancer receiving myelotoxic chemotherapy. Blood 2021;138:4290-4290. Available at:https://doi.org/10.1182/blood-2021-145760.

201. Minamimoto R, Baratto L, lagaru A. Association between time since administration of pegylated G-CSF(pegfilgrastim) and bone marrow uptake on FDG PET/CT: Determination of a minimum interval. AJR Am J Roentgenol 2022;218:351-358. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34467784.

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262. Resar LM, Wick EC, Almasri TN, et al. Bloodless medicine: current strategies and emerging treatment paradigms. Transfusion 2016;56:2637-2647.Available at:https://www.ncbi.nlm.nih.gov/pubmed/27473810.

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278. Weiskopf RB. Hemoglobin-based oxygen carriers: compassionate use and compassionate clinical trials. Anesth Analg 2010;110:659-662.Available at: https://www.ncbi.nlm.nih.gov/pubmed/20185643.

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304. Glaspy J, Crawford J, Vansteenkiste J, et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer 2010;102:301-315. Available at:http://www.ncbi.nlm.nih.gov/pubmed/20051958.

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National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

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306. Moebus V, Jackisch C, Lueck HJ, et al. Intense dose-dense sequential chemotherapy with epirubicin, pacitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol 2010;28:2874-2880. Available at:http://www.ncbi.nlm.nih.gov/pubmed/20458045.

307. Nitz U, Gluz O, Zuna I, et al. Final results from the prospective phase III WSG-ARA trial: impact of adjuvant darbepoetin alfa on event-free survival in early breast cancer. Ann Oncol 2014;25:75-80. Available at:http://www.ncbi.nlm.nih.gov/pubmed/24356620.

308. Moebus V, Jackisch C, Schneeweiss A, et al. Adding epoetin alfa to intense dose-dense adjuvant chemotherapy for breast cancer: randomized clinical trial. J Natl Cancer Inst 2013;105:1018-1026. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23860204.

309. Pirker R, Ramlau RA, Schuette W, et al. Safety and efficacy of darbepoetin alpha in previously untreated extensive-stage small-cell lung cancer treated with platinum et plus etoposide. J Clin Oncol 2008;26:2342-2349. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18467726.

310. Grote T, Yeilding AL, Castillo R, et al. Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2005;23:9377-9386. Available at:http://www.ncbi.nlm.nih.gov/pubmed/16361638.

311. Nagel S, Kellner O, Engel-Riedel W, et al. Addition of darbepoetin alfa to dose-dense chemotherapy: results from a randomized phase II trial in small-cell lung cancer patients receiving carboplatin plus etoposide. Clin Lung Cancer 2011;12:62-69. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21273182.

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312. Gergal Gopalkrishna Rao SR, Bugazia S, Dhandapani TPM, et al.Efficacy and cardiovascular adverse effects of erythropoiesis stimulating agents in the treatment of cancer-related anemia: a systematic review of

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313. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160:809-815. Available at:http://www.ncbi.nlm.nih.gov/pubmed/10737280.

314. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5:632-634. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17319909.

315. Levine MN, Gent M, Hirsh J, et al. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 1988;318:404-407. Available at:http://www.ncbi.nlm.nih.gov/pubmed/3340118.

316. Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 1991;9:286-294. Available at:

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317. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline; recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25:5490-5505. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17968019.

318. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-2032. Available at:

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319. Seliger SL, Zhang AD, Weir MR, et al. Erythropoiesis-stimulating agents increase the risk of acute stroke in patients with chronic kidney disease. Kidney Int 2011;80:288-294. Available at:

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National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

320. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-2098.Available at: http://www.ncbi.nlm.nih.gov/pubmed/17108343.

321. Vadhan-Raj S, Dahl NaV, Bernard K, et al. Efficacy and safety of IV ferumoxytol for iron deficiency anemia in patients with cancer. J Blood Med 2017;8:199-209. Available at:

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322. Vadhan-Raj S, Strauss W, Ford D, et al. Efficacy and safety of IV ferumoxytol for adults with iron deficiency anemia previously unresponsive to or unable to tolerate oral iron. Am J Hematol 2014;89:7-12. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23983177.

323. Imai E, Yamamoto R, Suzuki H, Watanabe T. Incidence of symptomatic stroke and cancer in chronic kidney disease patients treated with epoetins. Clin Exp Nephrol 2010;14:445-452. Available at:http://www.ncbi.nlm.nih.gov/pubmed/20589407.

324. Besarab A, Bolton WK, Browne JK,et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339:584-590.Available at: http://www.ncbi.nlm.nih.gov/pubmed/9718377.

325. Besarab A, Goodkin DA, Nissenson AR. The normal hematocrit study--follow-up. N Engl J Med 2008;358:433-434. Available at:http://www.ncbi.nlm.nih.gov/pubmed/18216370.

326. Bennett CL, Becker PS, Kraut EH, et al. Intersecting guidelines:administering erythropoiesis-stimulating agents to chronic kidney disease patients with cancer. Semin Dial 2009;22:1-4. Available at:http://www.ncbi.nlm.nih.gov/pubmed/19175532.

327. Schwartzberg LS, Yee LK, Senecal FM, et al. A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast,lung, or gynecologic cancer. Oncologist 2004;9:696-707. Available at:http://www.ncbi.nlm.nih.gov/pubmed/15561813.

328. Waltzman R, Croot C, Justice GR, et al. Randomized comparison of epoetin alfa (40,000 U weekly) and darbepoetin alfa (200 microg every 2 weeks) in anemic patients with cancer receiving chemotherapy. Oncologist 2005;10:642-650. Available at:http://www.ncbi.nlm.nih.gov/pubmed/16177289.

329. Glaspy J, Bukowski R, Steinberg D, et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 1997;15:1218-1234. Available at:http://www.ncbi.nlm.nih.gov/pubmed/9060566.

330. Gabrilove JL, Cleeland CS, Livingston RB, et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients:improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001;19:2875-2882. Available at:http://www.ncbi.nlm.nih.gov/pubmed/11387360.

331. Henry DH, Gordan LN, Charu V, et al. Randomized, open-label comparison of epoetin alfa extended dosing (80,000 U Q2W) vs weekly dosing (40,000 U QW) in patients with chemotherapy-induced anemia. Curr Med Res Opin 2006;22:1403-1413. Available at:http://www.ncbi.nlm.nih.gov/pubmed/9718377.

332. Steensma DP, Molina R, Sloan JA, et al. Phase III study of two different dosing schedules of erythropoietin in anemic patients with cancer.J Clin Oncol 2006;24:1079-1089. Available at:http://www.ncbi.nlm.nih.gov/pubmed/16505427.

333. Canon JL, Vansteenkiste J, Bodoky G,et al.Randomized, double-blind, active-controlled trial of every-3-week darbepoetin alfa for the treatment of chemotherapy-induced anemia. J Natl Cancer Inst 2006;98:273-284. Available at:http://www.ncbi.nlm.nih.gov/pubmed/16478746.

334. Boccia R, Malik IA, Raja V, et al. Darbepoetin alfa administered every three weeks is effective for the treatment of chemotherapy-induced anemia. Oncologist 2006;11:409-417. Available at:http://www.ncbi.nlm.nih.gov/pubmed/16614237.

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National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

335. Auerbach M, Silberstein RT, Webb RT, et al. Darbepoetin alfa 300 or 500 mug once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. Am J Hematol 2010;85:655-663.Available at: http://www.ncbi.nlm.nih.gov/pubmed/20661916.

336. Thames WA, Smith SL, Scheifele AC, et al. Evaluation of the US Oncology Network's recommended guidelines for therapeutic substitution with darbepoetin alfa 200 microg every 2 weeks in both naive patients and patients switched from epoetin alfa. Pharmacotherapy 2004;24:313-323.Available at: http://www.ncbi.nlm.nih.gov/pubmed/15040644.

337. Mhaskar R, Wao H, Miladinovic B, et al. The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents. Cochrane Database Syst Rev 2016;2:CD009624. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26845108.

338. Petrelli F, Borgonovo K, Cabiddu M, et al. Addition of iron to erythropoiesis-stimulating agents in cancer patients: meta-analysis of randomized trials. J Cancer Res Clin Oncol 2012;138:179-187. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21972052.

339. Aapro M, Osterborg A, Gascon P, et al. Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of i.v. iron.Ann Oncol 2012;23:1954-1962. Available at:http://www.ncbi.nlm.nih.gov/pubmed/22575608.

340. Collings R, Harvey LJ, Hooper L, et al. The absorption of iron from whole diets: a systematic review. Am J Clin Nutr 2013;98:65-81. Available at:http://www.ncbi.nlm.nih.gov/pubmed/23719560.

341. Tan J, Du S, Zang X, et al. The addition of oral iron improves chemotherapy-induced anemia in patients receiving erythropoiesis-stimulating agents. Int J Cancer 2022;151:1555-1564. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35639027.

342. Lapointe M. Iron supplementation in the intensive care unit: when,how much, and by what route? Crit Care 2004;8 Suppl 2:S37-41. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15196322.

343. Henry DH. Supplemental iron: a key to optimizing the response of cancer-related anemia to rHuEPO? Oncologist 1998;3:275-278. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10388116.

344.Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352:1011-1023. Available at:http://www.ncbi.nlm.nih.gov/pubmed/15758012.

345. Silverstein SB, Gilreath JA, Rodgers GM. Intravenous iron therapy: a summary of treatment options and review of guidelines. J Pharm Pract 2008;21:431-443. Available at:

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346. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial.J Clin Oncol 2004;22:1301-1307. Available at:http://www.ncbi.nlm.nih.gov/pubmed/15051778.

347. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter,controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol 2008;26:1611-1618.Available at:http://www.ncbi.nlm.nih.gov/pubmed/18375890.

348. Hedenus M, Bireggard G, Nasman P, et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia 2007;21:627-632. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17252006.

349.Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluonate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist 2007;12:231-242. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17296819.

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350. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related

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National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

anemia without iron deficiency treated with darbepoetin alpha. J Clin Oncol 2008;26:1619-1625. Available at:http://www.ncbi.nlm.nih.gov/pubmed/18375891.

351. Mhaskar R, Djulbegovic. B Iron supplementation for chemotherapy-induced anemia in patients receiving erythropoiesis-stimulating agents.JAMA Oncol 2016;2:1499-1500. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27387766.

352. Steensma DP, Sloan JA, Dakhil SR, et al. Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetina fera for patients with chemotherapy-associated anemia. J Clin Oncol 2011;29:97-105. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21098317.

353. Aapro M, Beguin Y, Birgegård G,et al. Too-low iron doses and too many dropouts in negative iron trial? J Clin Oncol 2011;29:e525-e526.Available at:https://www.ncbi.nlm.nih.gov/pubmed/21537041.

354. Steensma DP, Sloan JA, Loprinzi CL. Reply to M. Aapro et al. J Clin Oncol 2011;29:e527-e528. Available at:http://ascopubs.org/doi/abs/10.1200/JCO.2011.35.4597.

355. Verschraegen CF, Levy T, Kudelka AP, et al. Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol 1997;15:625-631. Available at:http://www.ncbi.nlm.nih.gov/pubmed/9053486.

356. Goldberg RM, Sargent DJ, Morton RF, et al.Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial. J Clin Oncol 2006;24:3347-3353. Available at:http://www.ncbi.nlm.nih.gov/pubmed/16849748.

357. Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol 2004;76:74-78. Available at:http://www.ncbi.nlm.nih.gov/pubmed/15114602.

358. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant 2006;21:378-382. Available at:http://www.ncbi.nlm.nih.gov/pubmed/16286429.

359. Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous iron for anaemia. Lancet 2007;369:1502-1504. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17482969.

360. Athibovonsuk P, Manchana T, Sirisabya N. Prevention of blood transfusion with intravenous iron in gynecologic cancer patients receiving platinum-based chemotherapy. Gynecol Oncol 2013;131:679-682.Available at: http://www.ncbi.nlm.nih.gov/pubmed/24099839.

361. Steinmetz T, Tschechne B, Harlin O, et al. Clinical experience with ferric carboxymaltose in the treatment of cancer- and chemotherapy-associated anaemia. Ann Oncol 2013;24:475-482. Available at:http://www.ncbi.nlm.nih.gov/pubmed/23071262.

362.Toledano A, Luporsi E, Morere JF,et al. Clinical use of ferric carboxymaltose in patients with solid tumours or haematological malignancies in France. Support Care Cancer 2016;24:67-75. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25921449.

363. Verhaeghe L, Bruyneel L, Stragier E, et al. The effectiveness of intravenous iron for iron deficiency anemia in gastrointestinal cancer patients: a retrospective study. Ann Gastroenterol 2017;30:654-663.Available at: https://www.ncbi.nlm.nih.gov/pubmed/29118560.

364. Keeler BD, Simpson JA, Ng O, et al. Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer. Br J Surg 2017;104:214-221. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28092401.

365. Keeler BD, Dickson EA, Simpson JA, et al. The impact of pre-operative intravenous iron on quality of life after colorectal cancer surgery:outcomes from the intravenous iron in colorectal cancer-associated anaemia(IVICA) trial. Anaesthesia 2019;74:714-725. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30963552.

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NCCN Guidelines Version 1.2026 Hematopoietic Growth Factors

366. Calleja JL, Delgado S, del Val A, et al. Ferric carboxymaltose reduces transfusions and hospital stay in patients with colon cancer and anemia. Int J Colorectal Dis 2016;31:543-551. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26694926.

367. Klein K, Asaad S, Econs M, Rubin JE. Severe FGF23-based hypophosphataemic oseomalacia due to ferric carboxymaltose administration. BMJ Case Rep 2018;2018. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29298794.

368. Schaefer B, Wurtinger P, Finkenstedt A, et al. Choice of high-dose intravenous iron preparation determines hypophosphatemia risk. PLoS One 2016;11:e0167146. Available at:

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369. Zoller H, Schaefer B, Glodny B. Iron-induced hypophosphatemia: an emerging complication. Curr Opin Nephrol Hypertens 2017;26:266-275.Available at:https://www.ncbi.nlm.nih.gov/pubmed/28399017.

370. Hardy S, Vandemergel X. Intravenous iron administration and hypophosphatemia in clinical practice. Int J Rheumatol 2015;2015.Available at: https://www.ncbi.nlm.nih.gov/pubmed/26000018.

371. Blazevic A, Hunze J, Boots JM. Severe hypophosphataemia after intravenous iron administration. Neth J Med 2014;72:49-53. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24457442.

372. Adkinson NF, Strauss WE, Macdougall IC, et al. Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: a randomized trial. Am J Hematol 2018;93:683-690. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29417614.

373. Hetzel D,Strauss W,Bernard K,et al.A phase III,randomized,open-label trial of ferumoxytol compared with iron sucrose for the treatment of iron deficiency anemia in patients with a history of unsatisfactory oral iron therapy. Am J Hematol 2014;89:646-650. Available at:http://www.ncbi.nlm.nih.gov/pubmed/24639149.

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表 1
EXAMPLES WITH HIGH RISK FOR FEBRILE NEUTROPENIA(>20%)
Acute Lymphoblastic Leukemia (ALL)	● Select ALL regimens as directed by treatment protocol (NCCN Guidelines for ALL)
Bladder Cancer	●DDMVAC (Dose-Dense Methotrexate/Vinblastine/Doxorubicin/Cisplatin) ${}^{1}$
Bone Cancer	●VAIA (Vincristine/Doxorubicin [alternating with Dactinomycin]/lfosfamide)2 ●VDC-IE (Vincristine/Doxorubicin [or Dactinomycin]/Cyclophosphamide-lfosfamide/Etoposide)3 ●Cisplatin/Doxorubicin4 ●VDC (Vincristine/Doxorubicin [or Dactinomycin]/Cyclophosphamide)5 ●VIDE (Vincristine/lfosfamide/Doxorubicin [or Dactinomycin]/Etoposide)6
Breast Cancer	●Dose-Dense AC (Doxorubicin/Cyclophosphamide) followed by Dose-Dense Paclitaxel7,b ●TAC (Docetaxel/Doxorubicin/Cyclophosphamide)8 ●TCa,c (Docetaxel/Cyclophosphamide)9 ●TCHa (Docetaxel/Carboplatin) + Trastuzumab10 ●Sacituzumab govetc-nziy11,12
Head and Neck Squamous Cell Carcinoma	●Cisplatin/Docetaxel/Fluorouracil13-15
Hodgkin Lymphoma	●AVD (Doxorubicin/Vinblastine/Dacarbazine) + Brentximitabine/Dacarbazine) + Brentximitabine/Dacarbazine) - Escalated BEACOPd4 (Bleomycin/Etoposide/Doxorubicin/Cyclophosphamide/Incortwine/Procarbazine/ Prednisone)17 ●BrECADD (Brentuximab vedotin/Etoposide/Cyclophosphamide/Doxorubicin/Dacarbazine) + BrECADD (Brentuximab vedotin/Etoposide/Cyclophosphamide/Doxorubicin/Dexamethasone)18
Kidney Cancer	●Doxorubicin/Gemcitabine19
Non-Hodgkin Lymphomas	●CHP (Cyclophosphamide/Doxorubicin/Prednisone) + Brentuximab vedotin Dose-Adjusted EPOCHa (Etoposide/Prednisone)/Vincristine/Cyclophosphamide/Doxorubicin)20 ●ICE (Ifosfamide/Carboplatin/Etoposide)a,21,22 ●Dose-dense CHOP-14a (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone)23,24 ●MINEa(Mesna/lfosfamide/Mitoxantrone/Etoposide)25 ●DHAPa(Dexamethasone/Cytarabine/Cisplatin)26 ●ESHAPa(Etoposide/Methylprednisolone/Cytarabine/Cisplatin)27 ●HyperCVADa(Cyclophosphamide/Vincristine/Doxorubicin/Dexamethasone)28,29 ●Pola-R-CHP (Polatuzumab vedotin-piq/Cyclophosphamide/Doxorubicin/Prednisone) + Rituximab30
Melanoma	●CVD (Cisplatin/Vinblastine/Dacarbazine)31 ●Melphalan percutaneous hepatic perfusion(PHP)32
Multiple Myeloma	●DTPACE (Dexamethasone/Thalidomide/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide)33 ± Bortezomib (VTD-PACE)34 ●DCEP (Dexamethasone/Cyclophosphamide/Etoposide/Cisplatin)35 ●High-Dose Cyclophosphamide36
Ovarian Cancer	●Topotecana,37 ● Docetaxel38 ●Carboplatin/Docetaxel39
Soft Tissue Sarcoma	●MAID (Mesna/Doxorubicin/lfosamide/Dacarbazine)40 ●Doxorubicin,a41 ●Doxorubicin/lfosamide42
Small Cell Lung Cancere	●Topotecan 43
Testicular Cancer	●VelP (Vinblastine/lfosamide/Cisplatin)44 ●VIP (Etoposide/lfosfamide/Cisplatin)44 ●TIP (Paclitaxel/	fosfamide/Cisplatin)45

表 3
EXAMPLES WITH INTERMEDIATE RISK FOR FEBRILE NEUTROPENIA (10%-20%)
Occult Primary- Adenocarcinoma	●Docetaxel/Gemcitabine46
Breast Cancer	●Docetaxel,a47,48 ●AC (Doxorubicin/Cyclophosphamide) + sequential Docetaxel(taxane portion only)a,49 ●Paclitaxel every 21 daysa,50
Cervical Cancer	●Cisplatin/Topotecan51,52 ●Cisplatin/Paclitaxela,61,51 ●Topotecan53 ●Irinotecan54
Colorectal Cancer	●FOLFIRINOX(Leucovorin/Fluorouracil/Irinotecan/Oxaliplatin)f,55-57
Esophageal and Gastric Cancers	●Cisplatin/Irinotecan,58 ●FLOT(Docetaxel/Fluorouracil/Leucovorin/Oxaliplatin)59
Non-Hodgkin Lymphomas	●GDP (Gemcitabine/Dexamethasone/Cisplatin [or Carboplatin])^a,60 ●CHOPa(Cyclophosphamide/Doxorubicin/Vincristine/Prednisone)^61,62 including regimens with pegylated liposomal Doxorubicin(CDOP)63,64 ●Bendamustinea
Non-Small Cell Lung Cancer	●Cisplatin/Pacitaxel65 ●Cisplatin/Vinorelbine66 ●Cisplatin/Docetaxel65,67 ●Cisplatin/Docetaxel65,67 ●Carboplatin/Paclitaxel^a,69 & 69 ●Docetaxel67
Pancreatic Cancer	●FOLFIRINOXh,70,71 (Leucovorin/Fluorouracil/lrinotecan/Oxaliplatin)
Prostate Cancer	●Cabazitaxel,72 ● Docetaxel,73,74
Small Cell Lung Cancere	●Carboplatin/Etoposide75
Testicular Cancer	●BEPd (Bleomycin/Etoposide/Cisplatin)76-78 ●Cisplatin/Etoposide79
Uterine Sarcoma	●Docetaxel80

表 5
	Ferric Carboxymaltose7-10,b	Ferric Derisomaltoseb	Ferric Gluconate12,b	Ferumoxyto14-17,b,c (in select cases)	Iron Sucrose21,b	Low-Molecular-Weight Iron Dextran24,b
Test dosed	Test dose not required	Test dose not required	Test dose not required	Test dose not required	Test dose not required	Test dose per institutional practices
Dosage11,e	750 mg IV for patients weighing $\>50 kg$ (110 lb) ● Repeat dose once at least 7 days later ● Total treatment course = 1500 mg or 15 mg/kg body weight IV for patients <50 kg (110 lb) ● Repeat dose once at least 7 days later ● Total treatment course not to exceed 1500 mg	1000 mg IV over 20 min for patients weighing 50 kg (110 lb) ● Repeat dose once at least 7 ● Single dose ● Total treatment course not to exceed 1000 mg	125 mg IV over 60 min for patients weighing 250 kg (110 lb) ● Total dosing given once weekly for 8 doses ● Individual doses ●125 mg kg are not recommended based on published trial results $^{13}$ ● Total treatment course = 1000 mg	510 mg IV dose over 15 min ● Repeat 510 mg dose 3-8 days later ● Total treatment course = 1020 mg	Total treatment recommended = 1000 mg ● Various dosing schedules have been tested. For additional details about dosing, see prescribing information22,23	Refer to prescribing information
Routes	IV	IV	IV	IV	IV	IV; intramuscular (IM) (not recommended)

表 6
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 7
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).

表 8
Hematocrit %	Reticulocyte maturation time (RMT) in days
40-45	1.0
35-39	1.5
25-34	2.0
15-24	2.5
<15	3.0

图示：Evaluation of risk for febrile neutropenia following chemotherapy therapy High-dose therapy Dose-dense therapy f chemical therapy in adult patients with solid tumors and non-myeloid malignancies c - Treatment intent (curative vs. palliative) Low(<10%)\rightarrow Granulocyte colony-MGF-3) / 666266cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS96cSCS9

图示：Intermediate (10%-20%) X Y Y Persistent neutropenia Bone marrow involvement by tumor Possible tests of error No risk factors $\rightarrow$ Observe Inverse Nask factors $\ge 1$ risk factor No risk factors $\rightarrow$ Observe Evaluation Prior to Second and Subsequent Chemotherapy Cycles (MG F-3) $\begin{array}{l}\text{Evaluation Prior to Second and Subsequent Chemotherapy Cycles (MG F-3) $\text{Dox}\in \mathcal{L}N\ge 1.5\pi\end{array}$ \begin{array}{l}\text{Evaluation Prior to Second and Subsequent Chemotherapy Cycles (MG F-3) $\text{Dox}\in \mathcal{L}N\ge 1.5\pi\eta\end{array}$

图示：Evaluate patient prior to second and subsequent chemotherapy cycles No febrile neutropenia or dose-limiting neutropenic event Prior use of G-CSFsh,i,j | No febrile neutropenia or dose-limiting neutropenic event | 双 subsequent cycle

图示：PRESENTATION G-CSFs USE DURING CURRENT CHEMOTHERAPY CYCLE Patients receiving daily prophylactic filgrastim or tbo-filgrastim Patients receiving or those who received prophylactic G-CSFs Present with febrile neutropenia Present with febrile neutropenia Patients patients receiving or those who received prophylactic filgrastim Patienting receiving or those who received prophylactic P-CSFs Patients who have received long-lasting prophylactic pegfilgrastim or elpegraftrim-xnst or efbemalenograst imfa-vuxw Present with febrile neutropeniae Present with febrile neutropenia Patient who did not receive prophylactic G-CSFs Present with did not receive prophylactic G-CSFs Risk factors not present for an infection-associated complication Risk factors present for an infection-associated complication Consider therapeutic MGFst,u complication\

图示：USE OF THROMBOPOIETIN RECEPTOR AGONISTS (TPO-RA) IN PATIENTS WITH CANCER MANAGEMENT ASSESSMENT PERESENTATION $LNCC SUSpected chemotherapy- induced thrombocytopenia (CIT)$\{{}^{a, 1, 2}\$ Evaluate for other potential causes of thrombocytopenia as indicated Complete blood count (CBC) with differential, including evaluation for other cytopenias Blood smear or morphology, including evaluation for platelet clumping NCCN 6954444444 NCCN 75644444 Butronic polyoPIETIN RECEPTOR AGONISTS (TPO-RA) IN PATIENTS WITH CANCER MANAGEMENT ASSESSMENT PERESENTATION L96200-2053020050302005 USE OF THROMBOPOIETIN RECEPTOR ARTificial hemogliene (PNH) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633, (TPO-RA) 66633,

图示：Risk evaluation for ICAHT prior to immune effector cell (IEC)therapies Risk factors for ICAHT include1. Bone marrow involvement by tumor >High tumor burdena > Preexisting inflammatory stateb Active infection > Prexisting inflammatory cell transplant Receipt of bridging therapy's 22-4 High of herematotoieic cell High (21 risk factors) High (21 risk factors) High (21 kri 6nN) S SFCS 2021 ▶ In factive infection Current netropenia (see below) beyond 30 days post- infusion. High (21 risk factors) High (21 risk factors) 00000-9000-9000-1-7 III(ICA) 00000-1-8 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III(ICA) 00000-1-9 III

图示：######Suspected CICAHT in patients$\underline{Re}\text{propto}\text{Hepatopio}\text{Cytosis}$\underline{ar}\text{the}\text{Hepatopoio}\text{C}(t)\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\text{c}\text{t}\te

图示：Treat as indicated No cause identified Risk Assessment and Indications for Transfusion(ANEM-2)

图示：Asymptomatic without significant comorbidities$h\longrightarrow$ Observe Periodic re-evaluation Symomatic (physiologic):● Sustained tachycardia● Tachypnea● Chest pain Inader of excitative growth for Hb with hematopoietic Growth Factors Consider red blood cell (RBC) transfusion per AABB Guidelines9 Consider red blood cell (RBC) transfusion per AABB Guidelines9 Symomatic (physiologic):● Sustained tachycardia● Tachypnea● Chest pain Inader of excitative growth for Hb with hematopoietic Growth(a) g Bacterlives Asymptomatic without significant comorbidities!● Chronic pulmonary disease Asymptomatic Asymptomatic:● Sustained tachycardia● Tachypnea● Chest pain Asymptomatic with chemical therapy H Cardiac disease ·Chronic pulmonary disease Cerebral vascular disease Symptomatic (physiologic):● Sustained tachycardia● Tachypnea● Chest pain asimptomatic:9 Symptomatic (physiologic):● Sustained tachycardia● Tachypnea● Chest pain Asymptomatic with significant good differential eigenvalue of high-quality and electrical RBC transfusion per AABB Guidelines9

图示：Cancer and chronic kidney disease(moderate to severe) Consider ESAs by FDA dosing/dosing consider based on patient preferences: ●ESAs by FDA dosing/dosing adjustmentsj,m,nor lyelos suppressive chemotherapy without other identifiable cause of anemia ● Clinical trial Consider an patient preferences: ● 283.85 of cancer and Dosing.dosing adjustmentsj,m,n Management of Cancer and Chemotherapy-Induced Anemia for ● Patients Who Refuse Blood Transfusions(ANEM-C)

图示：National Comprehensive Cancer Network®

引用 / 出处

（2026.V1）NCCN临床实践指南：造血生长因子. 2026.