Anemia NCCN 2018

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Cancer- and
Chemotherapy-
Induced Anemia
Version 2.2018 — November 21, 2017
NCCN.org
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Version 2.2018, 11/21/17 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The 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 Version 2.2018 Panel Members NCCN Guidelines Index

Table of Contents
Cancer- and Chemotherapy-Induced Anemia Discussion
* George M. Rodgers, III, MD, PhD/Chair ‡ Benjamin Djulbegovic, MD, PhD † ‡ x Rekha Parameswaran, MD ‡
Huntsman Cancer Institute Moffitt Cancer Center Memorial Sloan Kettering
at the University of Utah Cancer Center
Jennifer R. Green, MD ‡
Jeffrey A. Gilreath, PharmD/Vice Chair ∑ ‡ Vanderbilt-Ingram Cancer Center Rita Paschal, MD ‡ Þ
Huntsman Cancer Institute University of Alabama at Birmingham
at the University of Utah Stefanie L. Houseknecht, PharmD † ∑ Comprehensive Cancer Center
UC San Diego
Maureen M. Achebe, MD, MPH ‡ Moores Cancer Center Candido Rivera, MD ‡
Dana-Farber/Brigham and Mayo Clinic Cancer Center
Women's Cancer Center Eric H. Kraut, MD ‡
The Ohio State University Comprehensive Joseph Rosenthal, MD ‡ €
Laura Alwan, PharmD ∑ Cancer Center - James Cancer Hospital City of Hope Comprehensive
Fred Hutchinson Cancer Research Center/ and Solove Research Institute Cancer Center
Seattle Cancer Care Alliance
Michael Kroll, MD ‡ Satish Shanbhag, MBBS, MPH † ‡
Murat Arcasoy, MD ‡ The University of Texas The Sidney Kimmel Comprehensive
Duke Cancer Institute MD Anderson Cancer Center Cancer Center at Johns Hopkins
Seema Ali Bhat, MD † ‡ Michael M. Millenson, MD ‡ Þ † Ari VanderWalde, MD, MPH Þ †

Roswell Park Fox Chase Cancer Center St. Jude Children`s
Cancer Institute Research Hospital/
Tim Miller, PharmD ∑ The University of Tennessee
Rondeep Brar, MD † ‡ University of Wisconsin Health Science Center
Stanford Cancer Institute Carbone Cancer Center
NCCN
Erica Campagnaro, MD ‡ Anne Neff, MD ‡ Jennifer Burns
University of Michigan Case Comprehensive Cancer Center/ Lenora A. Pluchino, PhD
Comprehensive Cancer Center University Hospitals Seidman Cancer Center and
Cleveland Clinic Taussig Cancer Institute x Bone marrow transplantation
David Cella, PhD q
‡ Hematology/Hematology oncology
Robert H. Lurie Comprehensive Cancer Cindy L. O'Bryant, PharmD ∑ †
Þ Internal medicine
Center of Northwestern University University of Colorado Cancer Center † Medical oncology
# Nursing
Peter F. Coccia, MD ≠ ‡ €
≠ Pathology
Fred & Pamela Buffett Cancer Center € Pediatric oncology
Continue ∑ Pharmacology/Pharmacotherapy
q Psychiatry/Psychology
* Discussion Writing Committee Member
NCCN Guidelines Panel Disclosures
NCCN Guidelines Version 2.2018 Table of Contents NCCN Guidelines Index

Table of Contents
NCCN Cancer- and Chemotherapy-Induced Anemia Panel Members

Clinical Trials: NCCN believes that
Summary of the Guidelines Updates the best management for any cancer
patient is in a clinical trial.
Participation in clinical trials is
Evaluation of Anemia (ANEM-1) especially encouraged.
To find clinical trials online at NCCN
Risk Assessment and Indications for Initial Transfusion in Acute Setting (ANEM-2) Member Institutions, click here:
nccn.org/clinical_trials/physician.html.
Risks and Goals of ESA Use Versus Red Blood Cell Transfusion (ANEM-3)
NCCN Categories of Evidence and
Special Categories in Considering ESA Use (ANEM-4) Consensus: All recommendations
are category 2A unless otherwise
Evaluation of Iron Deficiency (ANEM-5) indicated.
See NCCN Categories of Evidence
Indications for Red Blood Cell Transfusion in Patients (ANEM-A) and Consensus.
Erythropoietic Therapy - Dosing, Titration, and Adverse Effects (ANEM-B)
Parenteral Iron Preparations (ANEM-C)
Management of Cancer- and Chemotherapy-Induced Anemia For Patients Who
Refuse Blood Transfusions (ANEM-D)
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
not be reproduced in any form without the express written permission of NCCN. ©2017.
NCCN Guidelines Version 2.2018 Updates NCCN Guidelines Index

Table of Contents
Updates in Version 2.2018 of the NCCN Guidelines for Cancer- and Chemotherapy-Induced Anemia from Version 1.2018 include:
MS-1
• The Discussion section has been updated to reflect the changes in the algorithm.
Updates in Version 1.2018 of the NCCN Guidelines for Cancer- and Chemotherapy-Induced Anemia from Version 2.2017 include:
General ANEM-A
• All details about the REMS program have been removed. Former • Last bullet and sub-bullet removed: "Anemia in setting of acute
page ANEM-C has been deleted. coronary syndromes or acute myocardial infarction: Transfusion
ANEM-1 goal is unclear and is being evaluated. Consider clinical context
• The following has been added to the list of possible causes of and published guidelines."
anemia to consider: "Hormone dysfunction (ie, hypogonadism, ANEM-B (4 of 5)
adrenal dysfunction, hyper/hypothyroidism)." • Under ESA-Neutralizing Antibodies, the last line has been
• The last line of footnote "d" has been revised: "Fasting is preferred revised: "Patients should not be immediately switched to other
when testing for serum iron and total iron-binding capacity, and ESA products as antibodies may cross-react."
serum ferritin."
ANEM-C (2 of 3)
ANEM-3 • For dosage administration of total dose infusion of low-
• Revision to line above the table: "Listed below are Discuss the molecular-weight iron dextran, added: "Calculated total iron
following risks and goals with patients when considering of each dextran dose in 500 mL of 0.9% NaCl solution administered at
anemia treatment options:" 175 mL/h." Addition was made based on the following reference:
• Bullets added below the table: Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes
Discuss the risks of ESAs with patients including the potential for the response to recombinant human erythropoietin in cancer
tumor growth, death, blood clots, and serious heart problems. patients with chemotherapy-related anemia: A multicenter,
Refer patients to the following medication guides for more open-label, randomized trial. Journal of Clinical Oncology
information on the benefits and risk of ESAs: Epoetin Alfa 2004;22:1301-1307.
Medication Guide and Darbepoetin Alfa Medication Guide
ANEM-D
ANEM-4
• Bullet revised: "Consider use of ESAs for select patients by FDA
• For patients undergoing palliative treatment, added clinical trial as
indications/dosing/dosing adjustments, under REMS guidelines,
an option for patients to consider based on preference.
• The following option has been revised where recommended for with informed consent of patient."
special categories in considering ESA use: "Consider ESAs by FDA • Bullet removed: "In addition, prior approval from third-party
indications/dosing/dosing adjustments, under REMS guidelines, payers should be sought to prevent increasing the financial
with informed consent of patient." burden of the patient."
• Footnote removed: "Health care providers prescribing ESAs need
to enroll in the ESA APPRISE Oncology Program. See REMS: Risk
Evaluation and Mitigation Strategy for Erythropoiesis-Stimulating
Agents (ESAs) (ANEM-C)."
Version 2.2018, 11/21/17 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
® ®
UPDATES
NCCN Guidelines Version 2.2018 NCCN Guidelines Index

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HEMOGLOBIN EVALUATION OF ANEMIAa,b

CONCENTRATION
TO PROMPT AN
Evaluate anemia for possible cause as
EVALUATION OF
indicatedb (see Discussion):
ANEMIA • First check
Reticulocyte countc and mean corpuscular
volume (MCV)
• Then consider Treat as indicated
Hemorrhage (stool guaiac, endoscopy)
Hemolysis (direct antiglobulin test [DAT],
Hemoglobin disseminated intravascular coagulation
• CBC with indices [DIC] panel, haptoglobin, indirect bilirubin,
(Hb) ≤11 g/dL
• Blood smear lactate dehydrogenase)
or ≥2 g/dL Nutritional (iron, total iron-binding capacity,
morphology
below baseline ferritin, B12, folate)d
Inherited (prior history, family history) See Risk Assessment
Renal dysfunction
(Glomerular filtration rate [GFR] <60 mL/ No cause identified and Indications for
min/1.73 m2) Transfusion (ANEM-2)
Radiation-induced myelosuppression
Hormone dysfunction (ie, hypogonadism,
adrenal dysfunction, hyper/hypothyroidism)
• See Evaluation of Iron Deficiency (ANEM-5)
Myelodysplastic syndromes See NCCN Guidelines for Myelodysplastic Syndromes
Myeloid malignancies or Treat underlying disease per NCCN Guideline

Acute lymphoblastic leukemia See NCCN Guidelines Table of Contents
aThe NCCN Guidelines for Cancer- and Chemotherapy-Induced Anemia were formulated in reference to adult patients.
bThis is a basic evaluation for possible causes of anemia.
cCorrect reticulocyte count for degree of anemia. See Discussion.
dThe 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. 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. Fasting is preferred when testing for serum iron and total iron-binding capacity.
Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 2.2018, 11/21/17 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ANEM-1

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RISK ASSESSMENT AND INDICATIONS FOR INITIAL TRANSFUSION IN ACUTE SETTING
Asymptomatic without significant comorbiditiese Observe Periodic re-evaluation
High risk (ie, progressive decline in Hb with

recent intensive chemotherapy or radiation)
or Consider red blood cell transfusion per guidelines
Anemia in patients
Asymptomatic with comorbiditiese: See Indications for Red Blood Cell Transfusion in
with cancer
• Cardiac disease Patients (ANEM-A)
• Chronic pulmonary disease
• Cerebral vascular disease
Symptomatic (physiologic):
• Sustained tachycardia
• Tachypnea
• Chest pain Red blood cell transfusion per guidelines
• Dyspnea on exertion See Indications for Red Blood Cell
• Lightheadedness Transfusion in Patients (ANEM-A)
• Syncope
• Severe fatiguef preventing
work and usual activity
See Comparison of Risks and Goals of ESA Use
Versus Red Blood Cell Transfusion (ANEM-3)
See Special Categories in Considering ESA Use (ANEM-4)
eDegree of severity of comorbidities in combination with the degree of severity of anemia should be taken into consideration when initiating red blood cell transfusion.
fFatigue (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.


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COMPARISON OF RISKS AND GOALS OF ESA USE VERSUS RED BLOOD CELL TRANSFUSIONg
Discuss the following risks and goals with patients when considering anemia treatment options:
ESA in the Cancer Setting Red Blood Cell Transfusion
Risks • Increased thrombotic events • Transfusion reactions (eg, hemolytic, febrile, non-
• Possible decreased survival hemolytic, lung injury)
• Time to tumor progression • Transfusion-associated circulatory overload (TACO)
shortened • Virus transmission (eg, hepatitis, HIV)
• Bacterial contamination
• Iron overload
• Increased thrombotic events
• Possible decreased survival
• Alloimmunization
• Increased risk of poor response to future platelet
transfusions due to HLA immunization
Goals • Transfusion avoidance • Rapid increase of Hb and hematocrit levels
• Gradual improvement in anemia- • Rapid improvement in anemia-related symptoms
related symptoms
See Erythropoietic Therapy - Dosing, Titration, and Adverse Effects (ANEM-B)
When considering ESAs:

• Discuss the risks of ESAs with patients including the potential for tumor growth, death, blood clots, and
serious heart problems.
• Refer patients to the following medication guides for more information on the benefits and risk of ESAs:
Epoetin Alfa Medication Guide and Darbepoetin Alfa Medication Guide
gSee Discussion for detailed information regarding the risks and benefits of ESA use and red blood cell transfusion.


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SPECIAL CATEGORIES IN CONSIDERING ESA USE
Cancer and chronic kidney disease

Consider ESAs by FDA dosing/dosing adjustmentsj,k,l
(moderate to severe)
Patient undergoing palliative treatmenth Consider based on patient preferences:

• ESAs by FDA dosing/dosing adjustmentsj,k See
or Evaluation
• Red blood cell transfusion per guidelines (See ANEM-A) of Iron
Remainder of patients with anemia on or Deficiency
myelosuppressive chemotherapy without • Clinical trial (ANEM-5)
other identifiable cause of anemiah
Select patients who refuse Consider ESAs by FDA dosing/dosing adjustmentsj,k

blood transfusions See Management of Patients Who Refuse Blood Transfusions (ANEM-D)
• Patients with cancer not receiving therapy

• Patients receiving non-myelosuppressive therapy
• Patients receiving myelosuppressive chemotherapy with curative intenti There is not enough evidence to support ESA
use in these patient populations; therefore,
(Examples of cancers for which there is therapy with curative intent: Early- ESAs are not recommended at this time
stage breast cancer, Hodgkin lymphoma, non-Hodgkin's lymphomas, testicular
cancer, early-stage non-small cell lung cancer, small cell lung cancer, etc.)
kPatients with previous risk factors for thrombosis are at higher risk for thrombosis with
hSee Comparison of Risks and Goals of ESA Use Versus Red Blood Cell the use of ESAs. If considering use of ESAs, evaluate the risk factors for thrombosis:
Transfusion (ANEM-3). history of thromboembolism, known heritable mutation, hypercoagulability, elevated
iA few studies suggest that patients with small cell lung cancer on pre-chemotherapy platelet counts, hypertension, steroids, prolonged immobilization,
myelosuppressive chemotherapy may not have an increase in mortality when recent surgery, certain therapies for multiple myeloma, hormonal agents, etc. (See
receiving ESAs. Oncologic Drugs Advisory Committee March 2008; Pirker et NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease).
al. J Clin Oncol 2008; 26:2342-3249; Grote et al. J Clin Oncol 2005;23:9377- lThe hemoglobin threshold for treatment and dosing with ESAs is different for
9386. chemotherapy-induced anemia and chronic kidney disease. For more details on the
jSee Erythropoietic Therapy - Dosing, Titration, and Adverse Effects (ANEM-B). use of ESAs in patients with cancer and chronic kidney disease, see Discussion.


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EVALUATION OF IRON STATUS MANAGEMENT

IRON DEFICIENCY
Hb increases Periodic evaluation (repeat
Absolute iron deficiencym Consider IV or oral
after 4 wk ferritin and TSAT)
(ferritin <30 ng/mL AND iron supplementation
TSAT <20%) No Hb increase See pathway below for
after 4 wk functional iron deficiency
Functional iron deficiency in
patients receiving ESAsn,o Consider IV iron supplementationq,r,s See Discussion for clinical
Iron studies: (ferritin 30–500 ng/mL AND with erythropoietic therapy examples of iron status
Iron panel (serum TSAT <50%)
iron, total iron-binding
capacity, serum ferritin)d Possible functional iron No iron supplementation needed
deficiencyn,o,p (ferritin >500– or
800 ng/mL AND TSAT <50%) Consider IV iron supplementation for select patients
No iron deficiency
(ferritin >800 ng/ IV or oral iron supplementation is not needed
mL OR TSAT ≥50%)
See Parenteral Iron Preparations (ANEM-C)
dThe ferritin value indicating iron deficiency is laboratory-specific. In general, oOnly 1 of 6 studies (Henry DH, et al. Oncologist 2007;12:231-242) of IV iron
the lower the level of ferritin, the higher the probability that the patient has true therapy in patients with cancer provided a TSAT guideline for monitoring.
pAlthough patients with ferritin levels of >500–800 ng/mL may have functional
iron deficiency anemia. However, in the cancer setting, be aware of a chronic
inflammatory state, which may falsely elevate the serum ferritin. Additionally, if iron deficiency, as evidenced by clinical trials in patients with cancer, there
serum iron studies are not performed while the patient is fasting or if the patient are insufficient data to support the routine use of IV iron in this setting.
has taken a recent oral iron tablet, serum iron levels may be falsely elevated, and Administration of IV iron to such patients should be individualized with the goal
thus also falsely elevate the percent transferrin saturation. Fasting is preferred of avoiding allogeneic transfusion.
when testing for serum iron and total iron-binding capacity. qIV iron has superior efficacy and should be considered for supplementation. Oral
mIf the ferritin and TSAT are discordant, the low ferritin value should take iron has been more commonly used but is less effective.
precedence in determining whether IV iron will be of benefit. See Parenteral Iron Preparations (ANEM-C).
nIn clinical trials using IV iron plus an ESA, a higher response rate is seen when rAlthough all combinations of serum ferritin and TSAT could be found in at least
iron is used for patients with a TSAT <20%. For patients who received IV iron one of six randomized controlled trials evaluating the use of IV iron with an ESA,
that had baseline TSATs >20%, the response rate to IV iron is both diminished eligibility criteria testing for serum ferritin and TSAT generally ranged from >10 to
and prolonged as the TSAT increased from 20% to 50%. Therefore, the decision <900 ng/mL and >15% to <60%, respectively.
sThere are insufficient data to routinely recommend IV iron as monotherapy
to offer IV iron to this subset of patients should be reserved for those in whom
benefits are likely to outweigh risks. without an ESA for the treatment of functional iron deficiency anemia.


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INDICATIONS FOR RED BLOOD CELL TRANSFUSION IN PATIENTSa,b,c
Goal: Prevent or treat deficit of oxygen-carrying capacity in blood

Asymptomatic Anemia
• Hemodynamically stable chronic anemia:
Transfusion goal to achieve Hb >7 g/dL.
Symptomatic Anemia
• Acute hemorrhage with evidence of hemodynamic instability or inadequate oxygen delivery:
Transfuse to correct hemodynamic instability and maintain adequate oxygen delivery.
• Symptomatic (including tachycardia, tachypnea, postural hypotension) anemia:

Transfusion goal to maintain Hb as needed for prevention of symptoms.
aThe AABB has also made recommendations regarding appropriate levels for red blood cell transfusion. See Discussion for details. (Carson JL, Grossman BJ,
Kleinman S, et al; for the Clinical Transfusion Medicine Committee of the AABB. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med
2012;157:49-58; Carson JL, Guyatt G, Heddle NM, et al. Clinical Practice Guidelines from the AABB: Red blood cell transfusion thresholds and storage. JAMA 2016, in
press.)
bIf there is a regimen (either research or standard protocol) for which a higher hemoglobin is required for full-dose treatment, it would be acceptable to be more
aggressive with the hemoglobin target.
cSee Management of Patients Who Refuse Blood Transfusions (ANEM-D).

Version 2.2018, 11/21/17 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ANEM-A

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ERYTHROPOIETIC THERAPY - DOSING AND TITRATION (1 of 5)1-4

INITIAL DOSING TITRATION FOR NO RESPONSE TITRATION FOR RESPONSE
PACKAGE INSERT DOSING SCHEDULE • The dose should be adjusted

for each patient to maintain the
Epoetin alfa 150 units/kg 3 times per Increase dose of epoetin alfa to 300 units/kg lowest Hb level sufficient to avoid
wk by subcutaneous injection 3 times per wk by subcutaneous injection red blood cell transfusion.
or
Epoetin alfa 40,000 units every wk Increase dose of epoetin alfa to 60,000 units • If Hb reaches a level needed to
by subcutaneous injection every wk by subcutaneous injection avoid transfusion or increases
or >1 g/dL in any 2-wk period, reduce
Darbepoetin alfa 2.25 mcg/kg every wk Increase darbepoetin alfa to up to 4.5 mcg/kg dose by 25% for epoetin alfa and
by subcutaneous injection every wk by subcutaneous injection by 40% for darbepoetin alfa.
or
Darbepoetin alfa 500 mcg* every 3 wks by subcutaneous injection
ALTERNATIVE REGIMENS
Darbepoetin alfa 100 mcg fixed dose Increase darbepoetin alfa to up to 150–200 mcg
every wk by subcutaneous injection fixed dose every wk by subcutaneous injection5
or
Darbepoetin alfa 200 mcg fixed dose Increase darbepoetin alfa to up to 300 mcg fixed
every 2 wks by subcutaneous injection7 dose every 2 wks by subcutaneous injection6
or
Darbepoetin alfa 300 mcg* fixed dose Increase darbepoetin alfa to up to 500 mcg fixed See Footnotes and References
every 3 wks by subcutaneous injection dose every 3 wks by subcutaneous injection7 (ANEM-B 2 of 5)
or
Epoetin alfa 80,000 units every 2 wks by subcutaneous injection8 See Erythropoietic Therapy -
Adverse Effects (ANEM-B 3 of 5)
or
Epoetin alfa 120,000 units every 3 wks by subcutaneous injection9
*Data indicate that darbepoetin alfa 300 mcg is equivalent in terms of efficacy to darbepoetin alfa 500 mcg for initial dosing.10

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ERYTHROPOIETIC THERAPY - DOSING AND TITRATION (2 of 5)

FOOTNOTES AND REFERENCES FOR ANEM-B (1 of 5)
Footnotes
1The head-to-head comparisons of regimens 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 G, 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.
2Less-frequent dosing regimens could be considered as an alternative to dose reduction.
3The dosages and regimens included in this table have been evaluated in patients with cancer receiving chemotherapy.
4IV 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-C).
References
5Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving
chemotherapy. J Natl Cancer Inst 2002;94:1211-1220.
6Thames 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 naïve patients and patients switched from epoetin alfa. Pharmacotherapy 2004;24:313-323.
7Canon 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.
8Henry 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.
9Steensma 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.
10Auerbach M, Silberstein PT, Webb RT, et al. Darbepoetin alfa 300 or 500 mcg once every 3 weeks with or without intravenous iron in patients with chemotherapy-
induced anemia. Am J Hematol 2010;85:655-663.
See Erythropoietic Therapy -

Dosing and Titration (ANEM-B 1 of 5)
See Erythropoietic Therapy-

Adverse Effects (ANEM-B 3 of 5)

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ERYTHROPOIETIC THERAPY - ADVERSE EFFECTS (3 of 5)

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: http://www.fda.gov/cder/drug/infopage/RHE/
default.htm. Unless new evidence demonstrates a change in benefit:risk estimates, physicians should be advised not to administer ESAs
(darbepoetin alfa, epoetin alfa) to patients outside of the treatment period of cancer-related 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,9,10-12 two meta-analyses
have indicated that ESA use did not significantly affect mortality or disease progression.13,14
• Recent pharmacovigilance trials have reported no adverse effects on survival in patients with cancer with chemotherapy-induced anemia
receiving ESAs.15-17
• 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 red blood cell transfusion.
(See Comparison of Risks and Goals of ESA Use Versus Red Blood Cell Transfusion - ANEM-3).
• Recent studies suggest that use of ESAs may be deleterious when used in patients with metastatic breast cancer. See 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).
• Erythropoietin has a thrombogenic potential independent of Hb levels.18 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.
(See 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.9,12-14,19
The absolute risk of venous thromboembolism 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.20
Erythropoietic Therapy - Adverse See References
Effects continued (ANEM-B 4 of 5) (ANEM-B 5 of 5)

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Hypertension/Seizures
• Blood pressure should be controlled in all patients prior to initiating therapy with erythropoietic drugs and must be monitored
regularly in treated patients.
• Seizures have been reported in patients with chronic renal failure receiving erythropoietic drugs.
• Hb level should be monitored to decrease the risk of hypertension and seizures. (See Titration for Response ANEM-B 1 of 5)
ESA-Neutralizing Antibodies (Pure red cell aplasia, PRCA)

• Between 1998–2004, 197 cases of PRCA were reported in patients treated with erythropoietin.21 Over 90% of these cases occurred
with Eprex, an epoetin alfa product used outside of the United States. Patients who develop a loss of response to erythropoietic
drugs should be evaluated for possible PRCA, and if present, all erythropoietic drugs should be discontinued. 22
• In 2005, the FDA's interpretation of anemia associated with neutralizing antibodies evolved to include both PRCA and severe
anemia. Since 2005, FDA safety databases have included information on 30 new cases of antibody-associated PRCA, primarily
associated with subcutaneous administration of epoetin alfa and darbepoetin alfa. 23 This interpretation resulted in a class
label change for all ESAs. The toxicity has been reported predominantly in patients with chronic renal failure receiving ESAs by
subcutaneous administration. Any patient who develops a sudden loss of response to an ESA, accompanied by a severe anemia
and low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to
erythropoietin. If anti-erythropoietin antibody-associated anemia is suspected, ESAs should be withheld and plasma should be sent
for evaluation of assays for binding and neutralizing antibodies. ESAs should be discontinued in patients with antibody-mediated
anemia. Patients should not be immediately switched to other ESA products as antibodies may cross-react.
See References (ANEM-B 5 of 5)

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ADVERSE EFFECTS REFERENCES
1Leyland-Jones B, BEST Investigators and Study Group. Breast cancer trial with 12Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms of erythropoiesis-
erythropoietin terminated unexpectedly. Lancet Oncol 2003;4:459-460. stimulating agents for anemia related to cancer: A meta-analysis. CMAJ
2Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer 2009;180(11):E62-71.
patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo- 13Glaspy J, Crawford J, Vansteenkiste J, et al. Erythropoiesis-stimulating agents in
controlled trial. Lancet 2003;362:1255-1260. oncology: A study-level meta-analysis of survival and other safety outcomes. Br J
3Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled Cancer 2010;102:301-315.
trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J 14Ludwig H, Crawford J, Osterborg A et al. Pooled analysis of individual patient-level
Clin Oncol 2007;25:1027-1032. data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa
4Hedenus M, Adriansson M, San Miguel J, et al. Efficacy and safety of darbepoetin alfa in the treatment of patients with chemotherapy-induced anemia. J Clin Oncol 2009;
in anaemic patients with lymphoproliferative malignancies: A randomized, double- 27:2838-2847.
blind, placebo-controlled study. Br J Haematol 2003;122:394-403. 15Engert A, Josting A, Haverkamp H, et al. Epoetin alfa in patients with advanced-stage
5Overgaard J, Hoff C, Sand Hansen, H, et al. Randomized study of the importance Hodgkin’s lymphoma: results of the randomized placebo-controlled GHSG HD15EPO
of novel erythropoiesis stimulating protein (Aranesp) for the effect of radiotherapy trial. J Clin Oncol 2010;28:2239-2245.
in patients with primary squamous cell carcinoma of head and neck (HNCSS): The 16Moebus V, Jackisch C, Lueck H, et al. Intense dose-dense sequential chemotherapy
Danish Head and Neck Cancer Group DAHANCA 10 rand [abstract] Eur J Cancer with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally
Suppl 2007;5:7. scheduled chemotherapy in high-risk primary breast cancer: Mature results of an AGO
6Smith R, Aapro MS, Ludwig H, et al. Darbepoetin alpha for the treatment of anemia phase III study. J Clin Oncol 2010;28:2874-2880.
in patients with active cancer not receiving chemotherapy or radiotherapy: results of 17Untch M, von Minckwitz G, Konecny GE, et al. PREPARE trial: A randomized phase
a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with
Oncol 2008;26:1040-1050. epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin– cyclophosphamide
7Thomas G, Ali S, Hoebers FJ, Darcy KM, et al. Phase III trial to evaluate the efficacy followed by paclitaxel with or without darbepoetin alfa in primary breast cancer—
of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 outcome on prognosis. Ann Oncol. Published ahead of print March 8, 2011.
g/dL without erythropoietin in anemic patients receiving concurrent radiation and 18Singh A, Szczech L, Tang K, et al. Correction of anemia with epoetin alfa in chronic
cisplatin for cervical cancer. Gynecol Oncol 2008;108:317-325. kidney disease. N Engl J Med 2006;355:2085-2098.
8Untch M, Fasching PA, Bauerfeind I, et al. PREPARE trial. A randomized phase III trial 19Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with
comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, cancer. Cochrane Database Syst Rev 2012;12:CD003407.
paclitaxel and CMF with a standard dosed epirubicin/cyclophosphamide followed by 20Pfeffer MA, Burdmann EA, Chen C, et al. Trial of darbepoetin alfa in type 2 diabetes
paclitaxel ± darbepoetin alfa in primary breast cancer: A preplanned interim analysis and chronic kidney disease. N Engl J Med 2009;361:2019-2032.
of efficacy at surgery. J Clin Oncol 26:2008 (May 20 suppl; abstr 517). 21Bennett CL, Luminari S, Nissenson, AR et al. Pure red-cell aplasia and epoetin
9Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality therapy. N Eng J Med 2004;351:1403-1408.
associated with recombinant erythropoietin and darbepoetin administration for the 22Bennett CL, Cournoyer D, Carson KR, et al. Long-term outcome of individuals
treatment of cancer-associated anemia. JAMA 2008;299:914-924. with pure red cell aplasia and aniterythropoietin antibodies in patients treated with
10Bennett CL, Henke M, Lai SY. Erythropoiesis-stimulating agents in the treatment of recombinant epoetin: A follow-up report from the Research on Adverse Drug Events
cancer-associated anemia reply. JAMA 2008;300:2855-2857. and Reports (RADAR) Project. Blood 2005;106:3343-3347.
11Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis- 23McKoy J, Stonecash R, Cournoyer D, et al. Epoetin-associated pure red cell aplasia:
stimulating agents and mortality in patients with cancer: A meta-analysis of past, present, and future considerations. Transfusion 2008;48:1754-1762.
randomised trials. The Lancet 2009;373:1532-1542.

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PARENTERAL IRON PREPARATIONS1-7 (1 of 3)
• Parenteral iron preparations studied in patients with cancer:b

Low-molecular-weight iron dextran
Ferric gluconate
Iron sucrose
Ferric carboxymaltosea
• Five2-6 of six8 studies have shown that parenteral iron products show improved Hb response rates in treating absolute or functional
iron deficiency in patients with cancer who are receiving ESAs.
None of the six studies provided instruction on how or when to redose iron after the initial cumulative dose has been given.
Generally, repeat iron studies are not recommended within 3 to 4 weeks of administration. Clinicians may consider repeating iron
studies if/when the MCV is <80 fL, or if/when evidence of hypochromic red blood cells is seen in the peripheral blood.
If treatment with iron fails after 4 to 6 weeks and after the total intended dose has been administered, repeat iron studies may be
considered. 5,8 Patients should be monitored for evidence of iron overload, including signs and symptoms of cardiomyopathy,
endocrinopathy, and hepatotoxicity. If evidence exists of iron overload, do not administer IV iron. Subsequent doses of iron should
be withheld if the serum ferritin exceeds 1000 ng/mL5,6 or TSAT exceeds 50%.2
• Test doses are required for low-molecular-weight iron dextran, but not for ferric gluconate, iron sucrose, or ferric carboxymaltose.
Test doses are strongly recommended for ferric gluconate and iron sucrose if patients have exhibited sensitivities to low-molecular-
weight iron dextran or other IV iron preparations, or if they have multiple drug allergies.
• High-molecular-weight iron dextran is not recommended.9,10
• Patients with an active infection should not receive IV iron therapy.
See Recommendations for Administering

Parenteral Iron Products (ANEM-C 2 of 3)
See References (ANEM-C 3 of 3)
aFerriccarboxymaltose has not been prospectively evaluated and therefore should only be considered when other parenteral iron preparations fail.7 Ferric
carboxymaltose is indicated for adult patients when oral iron is not tolerated or there is a limited response. It is also indicated for patients with non-dialysis–dependent
chronic kidney disease.11,12
bFerumoxytol is indicated for the treatment of iron deficiency in adult patients with chronic kidney disease. There are no data to show the efficacy of ferumoxytol in
patients with cancer. Ferumoxytol may cause interference with MRI scans causing potential false interpretation of organ iron overload.13
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PARENTERAL IRON PREPARATIONS1-6 (2 of 3)a

RECOMMENDATIONS FOR ADMINISTERING PARENTERAL IRON PRODUCTS
Low-Molecular-Weight Ferric Gluconate16,c Iron Sucrose17,c

Iron Dextran15,c
Test dose required: Test dose at MD discretion based on Test dose at MD discretion based on risk
Test dosed 25 mg slow IV push risk factors for reaction. factors for reaction.
100 mg IV over 5 min3 125 mg IV over 60 min2,4,5,8 200 mg IV over 60 min6

Dosage14,e • Repeated dosing given once weekly • Repeated dosing given once weekly • Repeated dosing given every 2–3 wks
for 10 doses to achieve total dose of for 8 doses or
1g 200 mg IV over 2–5 min
or • Individual doses above 125 mg are not • Repeated dosing given every 1–4 wks
• Total dose infusion given over several recommended based on published
trial results8 • Individual doses above
hours 18,f
300 mg are not recommended20
Calculated total iron dextran dose • Total treatment course
= 1000 mg • Total treatment course = 1000 mg
in 500 mL of 0.9% NaCl solution
administered at 175 mL/h19
IV infusion IV injection/infusion IV injection/infusion
Routes
IM (not recommended)
aFerric carboxymaltose has not been prospectively evaluated and therefore should only be considered when other parenteral iron preparations fail.7 Ferric
carboxymaltose is indicated for adult patients when oral iron is not tolerated or there is a limited response. It is also indicated for patients with non-dialysis–dependent
chronic kidney disease.11
cExamples 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.
dPremedications should be given prior to the IV iron test dose as reactions to the test dose may be severe.
eFor additional details about iron dosing, see prescribing information.
fDose (mL) = 0.0442 (Desired Hgb - Observed Hgb) x LBW + (0.26 X LBW); Dose (mg) = Dose (mL) x 50 mg/mL.
LBW = Lean Body Weight (kg); Hgb = Hemoglobin (g/dL).
See References (ANEM-C 3 of 3)
If dose exceeds 1000 mg, remaining dose may be given after 4 weeks if inadequate hemoglobin response.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. ANEM-C
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PARENTERAL IRON PREPARATIONS1-6 (3 of 3)

REFERENCES
1Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol 2004;76:74-78.
2Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients
with cancer receiving chemotherapy. Oncologist 2007;12:231-242.
3Auerbach 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.
4Pedrazzoli 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 darbepoetin alpha. J Clin Oncol 2008;26:1619-1625.
5Hedenus M, Birgegård G, Näsman 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.
6Bastit 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.
7Steinmetz 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.
8Steensma 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 darbepoetin alfa for patients with chemotherapy-associated anemia. J Clin Oncol 2011;29:97-105.
9Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant 2006;21:378-382.
10Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous iron for anaemia. Lancet 2007;369:1502-1504.
11National Institutes of Health. Ferric carboxymaltose package insert. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=517b4a19-45b3-4286-
9f6a-ced4e10447de Accessed June 23, 2017.
12Toledano 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.
13Schieda N. Parenteral ferumoxytol interaction with magnetic resonance imaging: a case report, review of the literature and advisory warning. Insights Imaging
2013;4:509-512.
14Gilreath 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.
15National Institutes of Health. Iron dextran package insert. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=abacb7fa-2fc2-471e-9200-
944eeac8ca2a Accessed June 23, 2017.
16National Institutes of Health. Ferric gluconate package insert. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1fe028ff-42ac-4329-b1a5-
a9dadfcb79f6 Accessed June 23, 2017.
17National Institutes of Health. Iron sucrose package insert. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=626dc9e5-c6b4-4f9c-9bf4-
774fd3ae619a Accessed June 23, 2017.
18Gilreath 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.
19Auerbach 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.
20Chandler G, Harchowal J, Macdougall IC. Intravenous iron sucrose: Establishing a safe dose. Am J Kidney Dis 2001;38:988-991.

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MANAGEMENT OF CANCER- AND CHEMOTHERAPY-INDUCED ANEMIA

FOR PATIENTS WHO REFUSE BLOOD TRANSFUSIONS
• 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 mm Hg, SaO2 = 1.0) has been used to increase blood oxygenation.
• To reduce blood loss, minimize phlebotomy, use pediatric tubes, 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 intravenous (IV) iron.
• Consider use of ESAs for select patients by FDA dosing/dosing adjustments.
ESAs are NOT recommended for:
◊◊Patients with cancer not receiving chemotherapy
◊◊Patients receiving non-myelosuppressive therapy
◊◊Patients receiving myelosuppressive chemotherapy with curative intent
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.

Version 2.2018, 11/21/17 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ANEM-D

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Discussion Benefits of Transfusion ............................................................ MS-7

Risks of Transfusion ................................................................ MS-7
NCCN Categories of Evidence and Consensus Transfusion Goals and Basic Principles ................................... MS-8
Category 1: Based upon high-level evidence, there is uniform Patients with Cancer Who Refuse Blood Transfusions ............. MS-9
NCCN consensus that the intervention is appropriate. Erythropoietic Therapy ............................................................. MS-9
Benefits of ESA Therapy ........................................................MS-10
Category 2A: Based upon lower-level evidence, there is uniform
NCCN consensus that the intervention is appropriate. Risks of ESA Therapy ............................................................MS-10
NCCN Recommendations.......................................................MS-12
Category 2B: Based upon lower-level evidence, there is NCCN
Dosing Schedules ..................................................................MS-14
consensus that the intervention is appropriate.
Response Assessment and Dose Titration ..............................MS-14
Category 3: Based upon any level of evidence, there is major
Iron Monitoring and Supplementation ....................................MS-15
NCCN disagreement that the intervention is appropriate.
Intravenous Iron and Oral Iron ................................................MS-15
All recommendations are category 2A unless otherwise NCCN Evaluation and Definitions of Iron Status .....................MS-18
indicated. NCCN Recommendations for the Management of Iron
Deficiency ..............................................................................MS-19
Table of Contents Clinical Examples of Iron Status .............................................MS-20
Overview .................................................................................... MS-2 Future Development ................................................................MS-21
Table 1: National Cancer Institute Anemia Scale ........................... MS-2 References ...............................................................................MS-23
Literature Search Criteria and Guidelines Update Methodology . MS-2
Etiology ...................................................................................... MS-3
Anemia Associated with Myelosuppressive Chemotherapy ....... MS-4
Screening Evaluation ................................................................ MS-4
Initial Assessment .................................................................... MS-4
Approaches to Evaluation ......................................................... MS-5
Table 2: Correction Factor for RPI Calculation ............................... MS-5
Follow-up Risk Assessment...................................................... MS-6
Red Blood Cell Transfusion ...................................................... MS-6
Version 2.2018, 11/21/17 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-1

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Overview The purpose of these NCCN Guidelines is two-fold: 1) to operationalize

the evaluation and treatment of anemia in adult patients with cancer,
Cancer- and chemotherapy-induced anemia (CIA) is prevalent,
with an emphasis on patients with anemia who are receiving
occurring in 30% to 90% of patients with cancer.1 Correction of anemia
concomitant chemotherapy; and 2) to enable the patient and clinician to
can be achieved by either treating the underlying etiology or by
assess anemia treatment options in the context of an individual patient’s
providing supportive care that may entail transfusion with packed red
condition.
blood cells (PRBCs) or administration of erythropoiesis-stimulating
agents (ESAs), with or without iron supplementation. The first ESA The NCCN Guidelines start with an evaluation of anemia to delineate
approved by the U.S. Food and Drug Administration (FDA) for the the etiology. This is followed by a risk assessment to determine the
treatment of anemia in patients receiving myelosuppressive initial intervention plan. Individual patient risk factors and comorbidities
chemotherapy was epoetin alfa, a recombinant human erythropoietin may affect the prescribed course of treatment. Further information is
(rhEpo). A second-generation rhEpo, darbepoetin alfa, has also been provided for treatment options including RBC transfusion, erythropoietic
FDA-approved for this indication. therapy, and iron monitoring and supplementation. These guidelines are
mainly focused on patients with solid tumors and lymphoid
The pathophysiologic origins of anemia can be grouped into three
malignancies. For anemia associated with myelodysplastic syndromes
categories: 1) decreased production of functional red blood cells
(MDS), myeloid malignancies, and acute lymphoblastic leukemia,
(RBCs); 2) increased destruction of RBCs; and 3) blood loss. Hence,
clinicians are referred to relevant guidelines listed in the NCCN
anemia is characterized by a decrease in hemoglobin (Hb)
Guidelines for Treatment of Cancer by Site.
concentration, RBC count, or hematocrit (Hct) to subnormal levels. The
degree of anemia can be graded according to the anemia scale Literature Search Criteria and Guidelines Update
provided by the National Cancer Institute (Table 1).
Methodology
Table 1. National Cancer Institute Anemia Scale Prior to the update of this version of the NCCN Guidelines for Cancer
Grade Scale (hemoglobin level in g/dL) and Chemotherapy-Induced Anemia, an electronic search of the
1 (mild) 10 – lower limit of normal PubMed database was performed to obtain key literature published
between 03/14/2016 and 03/10/2017, using the following search terms:
2 (moderate) 8 – <10
cancer anemia or cancer-related anemia or cancer-induced anemia or
3 (severe) 6.5 – <8 chemotherapy-induced anemia or chemotherapy anemia or
4 (life-threatening) Life-threatening chemotherapy-related anemia. The PubMed database was chosen as it
5 (death) Death remains the most widely used resource for medical literature and
indexes only peer-reviewed biomedical literature.2
Source: Adapted from the Common Terminology Criteria for Adverse
Events. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html.

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The search results were narrowed by selecting studies in humans capability. For this myriad of reasons, anemia is prevalent among
published in English. Results were confined to the following article patients with cancer at initial presentation. For example, 32% of non-
types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Hodgkin’s lymphoma patients and 49% of patients with gynecologic
Phase IV; Guideline; Meta-Analysis; Randomized Controlled Trial; cancers are anemic at diagnosis.7,8 In addition, the myelosuppressive
Systematic Reviews; and Validation Studies. effect of many chemotherapy agents is a significant contributing factor
to anemia for patients undergoing cytotoxic treatment.9,10 Radiation
The PubMed search resulted in 75 citations and their potential
therapy (RT) to the skeleton is also associated with hematologic toxicity.
relevance was examined. The data from key PubMed articles as well as
In a retrospective analysis, approximately one-third of the 210 patients
articles from additional sources deemed as relevant to these guidelines
undergoing craniospinal RT for treatment of primary tumors of the
and discussed by the panel have been included in this version of the
central nervous system developed grade 3 and 4 hematologic side
Discussion section (eg, e-publications ahead of print, meeting
effects.11
abstracts). Recommendations for which high-level evidence is lacking
are based on the panel’s review of lower-level evidence and expert Newer modalities, such as immunotherapies, may also have an
opinion. associated risk of anemia, though data are limited.12,13 A recent study
recognized hemolytic anemia as a potential complication of treatment
The complete details of the Development and Update of the NCCN
with nivolumab, an anti-PD-1 antibody.14 Although a definitive link
Guidelines are available on the NCCN webpage.
between the use of nivolumab and the development of autoimmune
Etiology hemolytic anemia has not been clearly established, several reported
cases of autoimmune hemolytic anemia after use of nivolumab have
Causes of anemia in patients with cancer are often multifactorial, adding been recently documented in the literature, including a case of fatal
to the complexity of evaluation.3 Anemia may be attributed to underlying autoimmune hemolytic anemia refractory to steroids in a patient treated
comorbidities such as bleeding, hemolysis, nutritional deficiencies, with nivolumab for metastatic lung cancer.15-17 In another case report, a
hereditary disease, renal insufficiency, hormone dysfunction, or a 52-year-old woman with malignant melanoma undergoing sequential
combination of these factors.4,5 The malignancy itself can lead to or treatment with ipilimumab (an anti-CTLA-4 antibody) and
exacerbate anemia in a number of ways.6 Cancer cells may directly pembrolizumab (another anti-PD-1 antibody) presented with acute
suppress hematopoiesis through bone marrow infiltration. They may autoimmune hemolytic anemia with pure red-cell aplasia, a potentially
also produce cytokines that lead to iron sequestration, which decreases life-threatening complication.18 Therefore, clinicians should become
RBC production and may even shorten RBC survival. Chronic blood familiar with the adverse effects of immunotherapy drugs, including
loss at tumor sites from blood vessels or organ damage can further hemolytic anemia, and be observant for other less documented clinical
exacerbate anemia in patients with cancer. Additional indirect effects conditions as these therapies become more prevalent in cancer care.
may include nutritional deficiencies caused by loss of appetite,
hemolysis by immune-mediated antibodies, or changes in coagulation

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Anemia Associated with Myelosuppressive Chemotherapy Screening Evaluation

Chemotherapeutic agents induce anemia by directly impairing Given the wide variation in Hb levels among healthy subjects, a
hematopoiesis in the bone marrow, including disruption of RBC universal “normal” value is difficult to define. According to the NCCN
precursor synthesis.6 Additionally, nephrotoxic effects of particular panel, an Hb level of 11 g/dL or less should prompt an evaluation of
cytotoxic agents (eg, platinum-containing agents) can lead to anemia anemia in a patient with cancer. For patients with a high baseline level,
through decreased production of erythropoietin by the kidneys.6 a drop of 2 g/dL or more is also cause for concern and assessment. As
Studies have identified patients with lung cancer and gynecologic discussed above, a patient with cancer may suffer from anemia as the
malignancies as having particularly high incidences of chemotherapy- result of a combination of causes, some of which may not be directly
induced anemia (CIA).8,9 Platinum-based regimens, commonly used in related to the cancer (reviewed by Gilreath et al3). The overall goals of
lung, ovarian, and head and neck cancers, are well-known to induce evaluation are to characterize the anemia and identify any potentially
anemia due to combined bone marrow and kidney toxicities.9 It is correctable underlying comorbidities prior to initiating treatment.
important to review the toxicity profile of each agent as newer regimens
Initial Assessment
may or may not cause anemia. This is evidenced by the comparison of
single-agent cabazitaxel, docetaxel, and enzalutamide, which have Initial broad characterization of anemia involves a complete blood count
been shown to cause grade 3 to 4 anemia in 11%, 9%, and 0% of (CBC) with indices to determine if other cytopenias are present. A visual
patients, respectively.19-21 review of the peripheral blood smear morphology is critical to confirm
the size, shape, and Hb content of RBCs. A detailed history and
The myelosuppressive effects of particular cytotoxic agents are likely to
physical exam must be taken. The history should include the onset and
accumulate over the course of repeated cycles of therapy, resulting in a
duration of symptoms, comorbidities, family history, and whether there
steady increase in the rate and severity of anemia with additional
has been any exposure to antineoplastic drugs or radiation. Common
chemotherapy cycles. For example, in the European Cancer Anaemia
complaints are syncope, exercise dyspnea, headache, vertigo, chest
Survey (ECAS)8, the rate of anemia (Hb level <12 g/dL) was found to
pain, fatigue that is disruptive to work and daily activities, and abnormal
increase from 19.5% in cycle 1 to 46.7% by cycle 5.8 An increase in the
menstruation in female patients. Pallor may be apparent. A key
fraction of grade 2 to 3 anemia was also associated with a greater
characteristic distinguishing fatigue related to cancer from fatigue in
number of chemotherapy cycles. Other factors to consider when
healthy individuals is that cancer-related fatigue is less likely to be
evaluating the risk for CIA include the nadir Hb level, the time to the
ameliorated by rest (see NCCN Guidelines for Cancer-Related
nadir Hb level (roughly estimated at 2 weeks, but time can vary), and
Fatigue).22 The above clinical manifestations are neither sensitive nor
whether an Hb measurement is considered to be pre- or post-nadir.6
specific to the type of anemia. Clinicians should watch out for signs of
underlying etiologies such as jaundice, splenic enlargement, neurologic

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symptoms, blood in the stool, petechiae, and heart murmur, among based on the reticulocyte count and is an indicator of the RBC
others. production capacity by the bone marrow. The normal RI ranges from 1.0
to 2.0.
Approaches to Evaluation
 RI = Reticulocyte count (%) x [(observed Hct)/(expected Hct)],
There are two common approaches to evaluating anemia: morphologic where the expected Hct is equal to 45%.
and kinetic. A complete evaluation should utilize both. The morphologic
approach is a characterization of anemia by the mean corpuscular Reticulocytes normally persist in the circulation for 24 hours before
volume (MCV), or average RBC size, reported in the initial CBC and becoming erythrocytes. However, as anemia increases, younger
classified as follows: reticulocytes are released from the marrow requiring them to remain in
circulation for 2 to 3 days before converting to erythrocytes, thereby
 Microcytic (<80 fL)—most commonly caused by iron deficiency; giving a falsely high RI value. The reticulocyte production index (RPI) is
other etiologies include thalassemia, anemia of chronic disease, an adjusted index that takes this into account and is calculated using
and sideroblastic anemia. the following formula:
 Macrocytic (>100 fL)—most commonly caused by medications23
 RPI = RI x (1/RMT), where RMT is the reticulocyte maturation
and alcoholism, both of which are forms of non-megaloblastic
time constant determined by the observed Hct (see Table 2).
anemia. MDS also causes mild macrocytosis. Macrocytosis
seen in megaloblastic anemia is most frequently caused by  Low RI/RPI ratio (<1) indicates decreased RBC production,
vitamin deficiency resulting from inadequate intake (folic acid) or suggesting iron deficiency, B12/folate deficiency, aplastic
inadequate absorption from lack of intrinsic factor. Macrocytosis anemia, or bone marrow dysfunction due to cancer or cancer-
accompanies increased reticulocyte counts following brisk related therapy (eg, radiation, myelosuppressive
hemorrhage or hemolysis. chemotherapy).
 Normocytic (80–100 fL)—may be due to hemorrhage,  High RI/RPI ratio (>1) indicates normal RBC production,
hemolysis, bone marrow failure, anemia of chronic inflammation, suggesting blood loss or hemolysis in the anemic patient.
or renal insufficiency. The key follow-up test is the reticulocyte
Table 2: Correction Factor for RPI Calculation
(immature RBC) count (see below).
Hematocrit Reticulocyte maturation time (RMT)
The kinetic approach focuses on the underlying mechanism of anemia, % in days
distinguishing among the production, destruction, and loss of RBCs. 40–45 1.0
The most basic RBC index is the reticulocyte index (RI) that corrects the 35–39 1.5
reticulocyte count against the degree of anemia as measured by Hct. 25–34 2.0
The reticulocyte count, often represented as a percentage, reflects the 15–24 2.5
number of reticulocytes per number of total RBCs. The RI is calculated <15 3.0

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A comprehensive review to the follow-up and treatment of each subtype Follow-up Risk Assessment
of anemia related to causes independent of myelosuppressive cancer
If the likely cause of anemia is cancer-related inflammation and/or
therapy is beyond the scope of this guideline. However, a summary of
myelosuppressive chemotherapy (for solid tumors or lymphoid
some additional signs and symptoms of common underlying ailments
malignancies), a risk assessment of the anemia is necessary to
and/or informative diagnostic tests are as follows:
determine the initial intervention plan. The decision regarding the best
 Nutritional deficiency—low iron and elevated total iron-binding treatment is dependent on many factors. While PRBC transfusion is the
capacity (TIBC) and/or low vitamin B12 or red cell folate levels only option if the patient requires an immediate boost in Hb levels,
(commonly tested together with iron studies). Ferritin values are consideration of ESA therapy and iron supplementation may be
also useful in evaluating iron stores. Fasting values are warranted for the long-term management of anemia as determined by
preferred for serum iron and TIBC studies. risk assessment.
 Hemorrhage—stool guaiac positive, endoscopy findings.
Red Blood Cell Transfusion
 Hemolysis—Direct antiglobulin test positive, disseminated
The decision to offer PRBC transfusion should not be made on the
intravascular coagulation panel positive, low haptoglobin levels,
basis of whether the Hb level of the patient has reached a certain
elevated indirect bilirubin, elevated lactate dehydrogenase
threshold or “trigger.” Instead, the NCCN panel outlines three general
(LDH).
categories: 1) asymptomatic without significant comorbidities, for which
 Renal dysfunction—glomerular filtration rate <60 mL/min/1.73 observation and periodic re-evaluation are appropriate; 2) high risk (ie,
m2 for three or more consecutive months. progressive decline in Hb with recent intensive chemotherapy or
radiation) or asymptomatic with comorbidities (eg, cardiac disease,
 Inherited anemia—personal and family history.
chronic pulmonary disease, cerebral vascular disease), for which
 Sideroblastic anemia—sideroblasts present in bone marrow transfusion can be considered; and 3) symptomatic, for which patients
biopsy. should receive transfusion.
Clinicians are advised to consult the Iron Monitoring and The clinical manifestations of anemia are associated with the onset,
Supplementation section for details on management of iron deficiency. severity, and duration of the anemia, as well as other factors influencing
Any other cause of anemia that may be rectified independent of cancer tissue demands for oxygen. When anemia onset is acute, symptoms
therapy should be treated as indicated. When no such etiology is are likely to be more pronounced, whereas physiologic adjustments that
identified, the effects of cancer-related inflammation and/or compensate for the lower oxygen-carrying capacity of the blood can
myelosuppressive chemotherapy (if applicable) should be considered occur with the gradual onset of anemia. These adaptive measures
the cause of anemia. include heightened cardiac output, increased coronary flow, altered
blood viscosity, and changes in oxygen consumption and extraction.

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The presence of preexisting cardiovascular, pulmonary, or cerebral Results from a number of studies evaluating the impact of transfusion
vascular disease may compromise the ability of a patient to tolerate on mortality in patients with cancer have been conflicting, with some
anemia. Hence, decisions related to whether immediate correction of studies showing a survival benefit for patients receiving transfusion. For
anemia is needed must be based on an assessment of individual example, in a study of 56 consecutive patients with unresectable
patient characteristics, severity of anemia, presence and severity of esophageal cancer receiving chemoradiation therapy, blood transfusion
comorbidities, and the clinical judgment of the physician. For example, was associated with an increase in overall survival (OS) (hazard ratio
even when an anemic patient has no physiologic symptoms or [HR], 0.26; 95% CI, 0.09–0.75, P = .01).26 A retrospective study of data
significant comorbidities, transfusion may be appropriate if there is an collected from 605 patients with carcinoma of the cervix evaluated Hb
anticipated progressive decline in Hb level following anti-cancer levels prior to therapy and through completion of therapy. Patients with
treatment. high Hb levels prior to therapy had a significant increase in disease-free
survival and OS. Patients who were transfused to increase Hb levels
PRBCs are the blood product of choice for transfusion to correct
had a survival rate that was similar to patients who had the same initial
anemia. These are concentrated from centrifuged whole blood
Hb value but did not receive transfusion. Therefore, blood transfusion
donations or collected by apheresis. They are anticoagulated and may
may reduce the negative prognostic implication of low Hb.27
contain added preservatives. Further enhancements include leuko-
reductions, γ-irradiation, freezing, and washing. Patients who are
Risks of Transfusion
immunocompromised may need PRBCs that are cytomegalovirus
negative. One unit of PRBCs (300 cc) can have an Hct ranging from Risks associated with PRBC transfusion include transfusion-related
50% to 80%, and typically contains 42.5 to 80 g of Hb (with 147–278 mg reactions, transfusion-associated circulatory overload, virus
of iron) or 128 to 240 mL of pure RBCs.24 transmission, bacterial contamination, iron overload (reviewed by
Spivak, Gascon, and Ludwig28), and alloimmunization of RBCs or
Benefits of Transfusion platelets. Since 1984, the introduction of numerous safety interventions
to screen the U.S. blood supply for infectious organisms has
The major benefit of transfusion with PRBCs, offered by no other
dramatically decreased the risk of transfusion-transmitted infections.29,30
anemia treatment, is a rapid increase in Hb and Hct levels. Hence,
Bacterial infection is the most common form, and occurred as frequently
PRBC transfusion is the only option for patients who require immediate
as 1 in 3000 random-donor samples before the mandate of bacterial
correction of anemia. Transfusion of 1 unit (300 cc) of PRBCs has been
screening in 2004.30 Since the implementation of screening, fewer than
estimated to result in an average increase in Hb level by 1 g/dL or in Hct
10 deaths from bacterial sepsis per year have been reported. Pre-
level by 3% in a normal-size adult who is not experiencing a
storage leukoreduction has been shown to decrease the incidence of
simultaneous loss of blood.24,25 It should be noted that patients receiving
febrile non-hemolytic transfusion reactions, the most common adverse
concomitant fluid resuscitation may not experience an Hb increase of 1
event.31,32
g/dL per unit of blood transfused.

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Khorana et al33 analyzed data from discharge summaries of patients liver, heart, skin, and endocrine organs. Patients experiencing iron
with cancer admitted to 60 U.S. medical centers between 1995 and overload may present with fatigue, dark skin, arthralgia, hepatomegaly,
2003 and found increased risks (P < .001) of venous thromboembolism cardiomyopathy, or endocrine disorders. Benefits of PRBC transfusion
(VTE) (overall risk [OR], 1.60; 95% CI, 1.53–1.67), arterial need to be weighed against the risks of cumulative cardiac and hepatic
thromboembolism (OR, 1.53; 95% CI, 1.46–1.61), and in-hospital toxicities.40,41
mortality (OR, 1.34; 95% CI, 1.29–1.38) associated with PRBC
Serum ferritin levels and any associated end-organ dysfunction need to
transfusions.33 However, the increased thrombotic events and
be monitored in patients requiring chronic PRBC transfusions. While a
decreased survival may reflect a bias of more severe anemia and/or
survival benefit to chelation therapy has not been shown in patients
more advanced cancer in patients who required transfusions. A cause-
requiring transfusion support for cancer-induced anemia or MDS, the
effect relationship could not be established due to the retrospective
general target value is a ferritin level of less than 800 mcg/L. Imaging
nature of the study. Therefore, greater investigation into the relationship
modalities such as FerriScan and T2 star-weighted cardiac MRI provide
between blood transfusions and the incidence of VTE and mortality is
useful organ-specific iron overload assessment.42,43
warranted.
RBC alloimmunization can be a significant complication for patients who Transfusion Goals and Basic Principles
are chronically transfused. It has been reported that 15% of transfusion- There is wide variation in reported PRBC transfusion practice,29,44 but
dependent patients with MDS or chronic myelomonocytic leukemia have institutional and clinical practice guidelines are often “restrictive”
alloimmunization.34,35 Platelet alloimmunization may also occur. regarding limiting exposure to allogeneic blood. A recent systematic
Antibodies against HLA antigens can cause platelet transfusion review comparing the efficacy and safety of restrictive versus liberal
refractoriness, which can translate into increased patient bleeding, transfusion strategies in patients with cancer found no difference in
prolonged hospitalization, and decreased survival.36,37 mortality or adverse events between the strategies.45 Furthermore,
restrictive transfusion strategies were associated with a 36% reduced
Iron Overload
risk of receiving a perioperative transfusion Therefore, restrictive
The condition of transfusion-related iron overload is observed in transfusion strategies appear to decrease blood utilization without
patients requiring frequent transfusions over several years to manage increasing morbidity or mortality in cancer patients.
their anemia (eg, patients with MDS).38 However, iron overload is
The overall goal of transfusion is to treat or prevent deficiencies in the
unlikely to occur in patients receiving transfusions that are limited to the
oxygen-carrying capacity of the blood, in order to improve oxygen
time period corresponding to chemotherapy treatment (usually <1 year).
delivery to bodily tissues. Transfusion is rarely indicated when the Hb
As previously mentioned, each transfusion of PRBCs contains 147 to
level is above 10 g/dL.46 The AABB (formerly the American Association
278 mg of unexcretable excess iron.24 When iron stores become
of Blood Banks) published guidelines based on a systematic review of
saturated, iron remains as non-transferrin–bound iron.39 Typically after
randomized trials evaluating transfusion thresholds and using GRADE
10 to 15 transfusions of PRBCs, excess iron will have deposited in the

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guidelines methodology.44 AABB recommendations include: 1) using an permit such treatment to be given without transfusion.49-51 Strategies
Hb level of 7 g/dL as a threshold for hospitalized patients who are include minimizing blood loss by restricting and/or batching routine
hemodynamically stable; 2) considering transfusions for hospitalized laboratory testing, using pediatric blood collection tubes, using anti-
patients with pre-existing cardiovascular disease who have symptoms fibrinolytic drugs for oral bleeding, aggressively treating mucositis,
and an Hb level of 8 g/dL or less; and 3) making transfusion decisions suppressing menses, and minimizing gastrointestinal bleeding by using
for all patients based on symptoms as well as Hb levels. There was a proton pump inhibitors and stool softeners. Additionally, baseline
lack of evidence to provide specific recommendations for the cancer coagulation abnormalities should be fully evaluated and corrected prior
population. NCCN panelists agree that no single target Hb level is to myelosuppressive treatment.
appropriate for all cases and that the balance between transfusion risks
Nutritional deficiencies have a low prevalence in both the general
and benefits should be evaluated on an individual basis. Clinicians are
population52,53 and in patients with cancer.3,54 However, in patients with
urged to exercise their clinical judgment based on patient symptoms,
high clinical suspicion of folate and vitamin B12 deficiency, nutritional
cancer course and treatment, comorbidities, and patient preference.
deficiency should be ruled out and iron deficiency should be corrected
Prior to transfusion, PRBCs must be crossmatched to confirm using intravenous (IV) iron. ESAs may be considered for select patients;
compatibility with ABO and other antibodies in the recipient. There is no however, patients should be made aware of the potential increased
evidence to support routine premedication with acetaminophen or an risks of thrombosis and tumor progression. ESAs are not recommended
antihistamine to prevent allergic and febrile nonhemolytic transfusion for the following: 1) patients with cancer who are not receiving
reactions.47,48 However, if repeated transfusions are required, leukocyte- chemotherapy; 2) patients receiving non-myelosuppressive therapy; or
reduced blood and the use of premedication may minimize adverse 3) patients receiving myelosuppressive chemotherapy with curative
transfusion reactions. In most instances, PRBCs should be transfused intent. Lastly, in extreme cases with severe, life-threatening anemia,
by the unit, and reassessment should be conducted after each pure oxygen (400 mm Hg, SAO2 = 1.0) has been used to increase blood
transfusion. oxygenation.50
Patients with Cancer Who Refuse Blood Transfusions Erythropoietic Therapy

Patients with cancer-induced anemia or CIA who refuse blood RBC production is normally controlled by erythropoietin, a cytokine
transfusions are occasionally seen in clinical practice. Their religious produced in the kidneys. ESAs have been shown to stimulate
beliefs or personal preferences prohibit them from using blood products erythropoiesis in patients with low RBC levels, though not all patients
in their treatment, so clinicians who agree to treat these patients must have disease that responds to ESA therapy. In a study of 2192 patients
base treatment on limited available data. However, several strategies with cancer receiving ESA therapy, an Hb increase of greater than or
may be employed to reduce anemia. For example, intensive equal to 1 g/dL was attained in 65% of patients.55 Unlike transfusion,
myelosuppressive chemotherapy would induce symptomatic anemia in which immediately boosts the Hb level, ESAs can take weeks to elicit
most patients with cancer, but investigators have outlined strategies to

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an Hb response, but they are effective at maintaining a target Hb level the need for transfusion in patients with CIA when treatment is initiated
with repeated administration. at Hb ≤10 g/dL.
Benefits of ESA Therapy Risks of ESA Therapy

Elimination of symptoms and avoidance of transfusion are the main Risk for Thromboembolism
goals of ESA therapy. Use of ESAs has been demonstrated to decrease Increased thromboembolic events, including VTE, have been
PRBC transfusion requirements in patients with cancer undergoing associated with ESA therapy in patients with cancer. The cause of VTE
chemotherapy. In a randomized, placebo-controlled study by Littlewood is complex with a heightened baseline risk related to both the
et al,56 epoetin alfa (when compared to placebo) was shown to reduce malignancy itself and to chemotherapy (see NCCN Guidelines for
transfusion requirements (24.7% vs. 39.5%, P = .0057) and increase Hb Cancer-Associated Venous Thromboembolic Disease).60-63 Other risk
levels (2.2 g/dL vs. 0.5 g/dL, P < .001) in patients with anemia receiving factors for VTE in patients with cancer include prior history of VTE,
chemotherapy.56 A double-blind, placebo-controlled, phase III study inherited or acquired mutations, hypercoagulability, elevated pre-
randomized 320 patients (Hb ≤ 11 g/dL) to receive darbepoetin alfa at chemotherapy platelet counts, recent surgery, hormonal agents,
2.25 mcg/kg/wk or placebo.57 Results showed that patients receiving immobility, steroids, and comorbidities such as hypertension.64
darbepoetin alfa required fewer transfusions (27% vs. 52%; 95% CI,
14%–36%; P < .001) than patients receiving placebo. The ability of Results from meta-analyses established a significant association
ESAs to reduce transfusions was one endpoint used in a Cochrane between ESA usage and increased risk of thrombotic events, with
review that enrolled a total of 20,102 patients undergoing treatment for statistically significant risk and odds ratios ranging from 1.48 to
cancer with concomitant ESA therapy.58 A decreased relative risk (RR) 1.69.58,65-69 A combined analysis of six trials using darbepoetin alfa by
for transfusion was observed in patients receiving ESAs (RR, 0.65; 95% Glaspy et al 68 also found an increased trend of thromboembolism for
CI, 0.62–0.68).58 Of the patients treated with ESAs, 25 out of 100 patients with Hb >12 g/dL (RR, 1.66; 95% CI, 0.9–3.04) or in patients
subsequently received a transfusion versus 39 out of 100 patients in the achieving a >1 g/dL Hb increase in 14 days (RR, 1.67; 95% CI, 0.96–
untreated group, equating to a one-unit reduction in transfusion in ESA- 2.88). An increased risk of stroke was associated with darbepoetin alfa
treated patients. in a clinical trial of patients with chronic kidney disease (CKD) (HR,
1.92; 95% CI, 1.38–2.68).70 ESA use was also associated with a
The first patient-level meta-analysis evaluating the efficacy of significantly increased risk of stroke (OR, 1.83; 95% CI, 1.26–2.65) in a
darbepoetin alfa treatment when initiated at Hb ≤10 g/dL in patients with retrospective case-controlled study of CKD patients with cancer.71
CIA found that more patients who received darbepoetin alfa than
placebo achieved an Hb increase of ≥1 g/dL (fixed-effects HR = 2.07; The increased risk for thromboembolism in patients with cancer
95% CI, 1.62–2.63) or ≥2 g/dL (HR = 2.91; 95% CI, 2.09–4.06).59 receiving ESA therapy is specified in the black-box warnings included in
Transfusions were also less common in these patients (HR = 0.58; 95% the FDA labels. The NCCN panel cautions physicians to be alert to the
CI, 0.44–0.77), confirming that darbepoetin alfa is effective at reducing

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signs and symptoms of thromboembolism in patients with cancer 1.17 (95% CI, 1.04–1.31), respectively.67 Data from the Cochrane
receiving ESAs. Database also reported increased mortality in patients with Hb >12
g/dL.58 This suggests that increased mortality could be reduced by more
Possible Increased Mortality and Tumor Progression conservative target Hb levels. In keeping with current treatment
Since 2007, the FDA has made substantial revisions to the label practice, data from a systematic review by the Agency for Healthcare
information and regulations regarding epoetin alfa and darbepoetin Research and Quality (AHRQ) determined that delaying ESA treatment
alfa,72,73 including the addition of black-box warnings. These until Hb is <10 g/dL resulted in fewer thromboembolic events and a
strengthened FDA restrictions were based mainly on the results of 8 reduced mortality. However, the optimal duration of therapy could not
randomized studies that individually showed a decrease in OS and/or be determined from the limited data set.67
locoregional disease control with ESA usage in advanced breast, The association between increased mortality and ESA therapy has
cervical, head and neck, lymphoid, and non-small cell lung cancers.74-81 been debated in other meta-analyses, including two studies reporting
Of the 8 studies, 4 studies investigated ESA effects in patients who no statistically significant effect of ESAs on mortality or disease
underwent chemotherapy, 2 studies involved patients receiving progression based on HR/odds ratios of 0.97 (95% CI, 0.85–1.1)68 and
radiotherapy alone, and 2 studies involved patients receiving neither 1.06 (95% CI, 0.97–1.15).66 Trials with off-label use of rhEpo, in both
chemotherapy nor radiotherapy. All 8 trials had an off-label target Hb the adjuvant and neoadjuvant settings, reported no decrease in survival
level over 12 g/dL. with ESA use in patients with CIA when an Hb target of 13 g/dL was
A randomized phase III noninferiority study by Leyland-Jones et al used.85-87 The PREPARE trial found no difference in 3-year OS
compared epoetin alfa versus best supportive care for the treatment of (darbepoetin alfa, 88.4% vs. no darbepoetin alfa, 91.5%; HR, 1.26; 95%
CIA in women with metastatic breast cancer (n = 2098).82 The primary CI, 0.86–1.85; P = .237), though there was a trend towards decreased
endpoint of progression-free survival (PFS) (based on investigator- disease-free survival in the darbepoetin alfa–treated group that failed to
determined disease progression) did not meet noninferiority criteria. reach statistical significance (darbepoetin alfa, 74.3% vs. no
Therefore, non-inferiority of epoetin alfa was not established and darbepoetin alfa, 80.0%; HR, 1.31; 95% CI, 0.999–1.74; P = .061).74,87
transfusions remain the preferred treatment for anemia in patients with The phase III WSG-ARA trial that included 1234 patients with early-
metastatic breast cancer. stage breast cancer receiving adjuvant ESA therapy is the first to
evaluate survival as the primary endpoint.88 In this study, no impact on
Worsened health outcomes associated with the use of ESAs have also
event-free survival (EFS) (darbepoetin alfa, 89.3% vs. no darbepoetin
been observed in 5 meta-analyses of 51 to 91 randomized controlled
alfa, 87.5%; Plog-rank = 0.55) or OS (darbepoetin alfa, 95.5% vs. no
trials when targeting Hb levels >12 g/dL.58,65,67,69,83,84 These analyses
darbepoetin alfa, 95.4%; Plog-rank = 0.77) was observed. There was an
reported increased mortality in patients receiving ESAs with statistically
increase in venous thrombosis with darbepoetin alfa (darbepoetin alfa,
significant RR/HR of 1.17 (95% CI, 1.06–1.30),83 1.15 (95% CI, 1.03–
3% vs. no darbepoetin alfa, 1%; P = .013), though no increase was
1.29),69 1.10 (95% CI, 1.01–1.20),65 1.17 (95% CI, 1.06–1.29),58 and
seen in pulmonary embolism (0.3%, both groups). The incidence of

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grade 2 anemia was higher in patients who were not treated with Risk for Hypertension/Seizures
darbepoetin alfa (darbepoetin, 10.9% vs. no darbepoetin, 23.8%; P = Seizures have been reported in patients with chronic renal failure
.025). These results suggest that the value of darbepoetin alfa may be receiving ESAs.72 While it is unclear whether patients with cancer
dependent on other risk factors, including patient comorbidities, type of receiving ESA therapy are at risk for seizures, Hb levels should be
cancer, type of cancer treatment, and treatment intent. It should be monitored before and during the use of ESAs to decrease the risk for
noted that ESAs are not recommended for patients treated with curative these adverse events. Additionally, an increased risk for hypertension
intent outside of a clinical trial. There are also data from randomized with ESA usage was reported by a Cochrane review (RR, 1.30; 95% CI,
studies that show no increase in mortality in patients receiving 1.08–1.56).58
chemotherapy for small cell lung cancer (SCLC) when ESAs are given
according to the prescribing label.89,90 Risk for Pure Red Cell Aplasia
Another meta-analysis of 3 randomized, placebo-controlled trials in Pure red cell aplasia (PRCA) is a rare syndrome of anemia
Japanese patients with CIA did not show increased mortality associated characterized by a low reticulocyte count and loss of bone marrow
with the use of ESAs.91 In this study, 511 patients with either solid erythroblasts caused by the development of neutralizing antibodies
tumors or lymphoma were treated with epoetin beta or darbepoetin alfa. against erythropoietin. A marked rise in incidence (191 cases) of PRCA
The efficacy endpoints in this study included PRBC transfusion and was observed from 1998 to 2004, though 90% of cases occurred with
transfusion trigger (ie, Hb below 8 g/dL) from week 5 until the end of an epoetin alfa product used outside of the United States.92,93 Causation
treatment. Safety endpoints were determined by OS and was attributed to formulations without human serum albumin,
thromboembolic events. The risk of transfusion was reduced by 53% subcutaneous (SC) administration, and uncoated rubber stoppers.94
with ESA treatment compared to placebo (RR, 0.47; 95% CI, 0.29– Interventions, designed accordingly, reduced the incidence of PRCA by
0.76), while OS was equivalent (HR, 1.00; 95% CI, 0.75–1.34; median, 83%. In 2005, the FDA interpretation of anemia associated with
13.3 months). The rates of thromboembolic events were 0.7% in the neutralizing antibodies evolved to include both PRCA and severe
ESA-treated patients and 1.7% in the placebo group (P = NS; no anemia, with or without other cytopenias, resulting in a class label
deaths). The study authors highlight several differences between this change for all ESAs.72,73 This toxicity has been reported predominantly
study and the Cochrane Database report. The first is the time period in in patients with chronic renal failure receiving SC ESAs.
which these trials were conducted. The recent analysis included trials
occurring between 2006 and 2009, during which there was awareness NCCN Recommendations
of the possible association between ESA use and increased mortality. In 2017, the FDA determined that the ESA Risk Evaluation and
Therefore, patients were more likely to have greater supervision as Mitigation Strategy (REMS) program is no longer necessary to ensure
indicated by the requirement of Hb monitoring at least weekly and the that the benefits of ESA therapy outweigh its risks of shortened OS
establishment of pre-determined cut-off values for the discontinuation of and/or increased risk of tumor progression or recurrence in patients with
ESAs.

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cancer.95 The FDA made this determination based on an evaluation of CKD is an independent indication for ESA therapy. Adverse events
the results of the REMS Assessments and additional FDA analyses. occurring with the use of ESAs in these patients appear to be
associated with high doses and/or high-target Hb levels. Hence, the
For patients with cancer, the black box warning on the revised FDA
FDA label mandates individualized dosing to reduce the need for RBC
label states that ESAs should only be used to treat CIA and should be
transfusions. Controlled clinical trials have associated increased risks of
discontinued once the chemotherapy course is complete.72 As
mortality and adverse cardiovascular outcomes with ESA use in CKD
discussed previously, randomized trial data suggest that ESAs may
patients when targeted to Hb levels >11 g/dL.70,71,96-99 In the study by
promote tumor growth in an off-target manner. For this reason, the FDA
Pfeffer et al70 comparing darbepoetin alfa to placebo, a significant
states that these agents should not be used when the treatment intent
increase in cancer-related death was seen in CKD patients with pre-
is curative. This includes primary and adjuvant chemotherapy for
existing cancer at baseline treated with ESA therapy (P = .002).
malignancies such as early-stage breast cancer and NSCLC,
However, another study of patients with CKD stages 4 and 5 did not find
lymphomas, and testicular cancer, among others. An exception to this
an increased incidence of cancer in patients receiving ESAs.97
may be SCLC, for which there are trials demonstrating no negative
Additionally, data from Seliger et al71 indicated that ESA treatment in
impact on survival or disease progression with ESA use (see earlier
patients with CKD was not associated with an overall increased risk for
discussion).89,90 Additionally, ESAs are not recommended for use in
stroke, except in the subpopulation diagnosed with cancer.71 Since
patients with cancer who are not receiving therapy, patients receiving
almost one-third of patients with end-stage renal disease are also
non-myelosuppressive therapy, or patients receiving myelosuppressive
afflicted with cancer, they represent a unique subgroup that requires
therapy in whom the anemia can be managed by transfusion. Patients
personalized use of ESAs based on very careful evaluation of risks and
undergoing palliative treatment may consider ESA therapy, transfusion,
benefits (reviewed by Bennett et al100). For example, CKD patients not
or participation in a clinical trial, depending on their preferences and
receiving active therapy for a malignancy should try to avoid ESAs,
personal values. The NCCN Guidelines Panel recognizes that it is not
while those receiving palliative chemotherapy may favor carefully dosed
always clear whether a chemotherapy regimen is considered curative.
ESAs over transfusion to treat severe anemia. In the scenario where the
Under these circumstances, given that no other cause of anemia has
patient with CKD has a curable solid tumor, ESAs should not be
been identified, physicians should first consider PRBC transfusion or
administered during chemotherapy. However, they may be used with
clinical trial enrollment, if available, for anemia management. When
caution after chemotherapy is complete, keeping in mind the possibility
considering anemia treatment options, physicians should discuss the
of recurring disease. Risk for thrombosis must be taken into account as
risks of ESA use with patients, including the potential for tumor growth,
part of the risk-benefit ratio.
blood clots, serious heart problems, and death. Upon the decision to
use an ESA, physicians are advised to use the lowest dose necessary Most patients receiving a hematopoietic cell transplant will require
to eliminate symptoms and avoid transfusion. transfusion support. Nonetheless, ESA therapy may be useful in some
instances.101,102 For example, ESAs may be administered post-
transplant to increase the Hct in order to allow phlebotomy to treat

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transfusional iron overload. There have also been reports of ESA dosing of 80,000 units administered SC every 2 weeks108 and a dose of
efficacy in patients who refuse blood transfusions while undergoing 120,000 units administered SC once every 3 weeks.109
autologous cell transplantation.103-105 Post-transplant use of ESAs for
Although darbepoetin alfa doses were initially administered at 2.25
patients undergoing cancer chemotherapy, patients with renal
mcg/kg SC every week,57,75,110 there has been interest in implementing
insufficiency, or patients with recurrent/secondary MDS should follow
either fixed doses or higher doses at decreased frequency. A
guidelines for chemotherapy-related anemia, CKD, or MDS,
randomized trial compared weekly dosing at 2.25 mcg/kg versus fixed
respectively.
dosing at 500 mcg every 3 weeks in 705 patients with non-myeloid
Iron studies should accompany ESA therapy to monitor the malignancies and an Hb level <11 g/dL. The percentage of patients
development of iron deficiency. These include serum iron, TIBC, and achieving the target Hb level (≥11 g/dL) was 77% in the weekly arm and
serum ferritin. The NCCN panel recommends that any patient with 84% for patients receiving darbepoetin alfa every 3 weeks.110 Both of
cancer who develops a sudden loss of response to ESAs, accompanied these schedules are listed in the package insert. Dosing once every 3
by severe anemia and a low reticulocyte count, should be evaluated for weeks was further refined in 2 studies by reducing the dose to 300 mcg.
the etiology of loss-of-effect. ESAs should be withheld while plasma is Initially, a multicenter, open-label study of 1493 patients showed that
sent to ESA-manufacturing pharmaceutical companies for evaluation by 79% of patients receiving this ESA dose achieved a target Hb level ≥11
assays that measure binding and neutralizing antibodies to g/dL.111 A head-to-head comparison with 500 mcg in a phase II,
erythropoietin. ESAs should be discontinued in patients with antibody- randomized study of patients with nonmyeloid malignancies further
mediated anemia. Patients should not be immediately switched to other confirmed the efficacy of 300 mcg. In this study, patients were given
ESA products as antibodies may cross-react. either 300 or 500 mcg of darbepoetin alfa with or without concurrent iron
therapy. No difference in the proportion of patients who achieved target
Dosing Schedules Hb levels (≥11 g/dL) was seen between those receiving 300 mcg versus
Epoetin alfa and darbepoetin alfa are considered equivalent by the 500 mcg darbepoetin alfa (75% vs. 78%, respectively).112 Other studies
NCCN panel. Recommended initial dosing schedules for patients have demonstrated the safety and efficacy of alternative dosing
receiving chemotherapy are summarized in the algorithm. The most schedules for darbepoetin alfa. These include a fixed weekly dose of
common initial dosing schedules for epoetin alfa evaluated in clinical 100 mcg57 and a fixed dose of 200 mcg every 2 weeks.113 In addition to
trials of patients with cancer are 150 units/kg 3 times weekly the dosing schedules on the package insert, the NCCN panel
administered SC56,106 and 40,000 units once weekly administered recommends these alternative regimens to support the delivery of the
SC77,80,81,107 (see Erythropoietic Therapy – Dosing and Titration in the lowest ESA dose possible while maintaining efficacy.
algorithm). Both of these initial dose schedules are listed in the package
Response Assessment and Dose Titration
insert and are recommended by NCCN. Other dosing ranges and
schedules of epoetin alfa may be considered, including an extended Response to ESA therapy is assessed to determine whether the initial
dose should be reduced, escalated, or withheld. Decisions related to

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ESA dose adjustment are based on the goal of maintaining the lowest (serum ferritin requirement ranging from >10 ng/mL to ˂900 ng/mL and
Hb level sufficient to avoid transfusion. a TSAT level requirement ranging from >15% to <60%). Only one study
provided guidelines for TSAT monitoring,118 while 2 studies provided
ESAs require at least 2 weeks of treatment before there is an increase
guidelines for ferritin monitoring.112,117
in the number of RBCs. Hb level should be measured weekly until
stabilized. Dose reduction (generally 25% for epoetin alfa and 40% for A randomized controlled trial comparing the efficacy of IV iron sucrose
darbepoetin alfa) should be implemented once Hb reaches a level versus oral ferrous fumarate in patients with gynecologic cancer (n =
sufficient to avoid transfusion or if the Hb level increases by ≥1 g/dL 64) evaluated the use of IV iron monotherapy for the “primary
during a 2-week period. prevention” of anemia (ie, patients did not present with anemia).121 In
this study, patients were given a single dose of 200 mg iron sucrose
Conversely, the ESA dose should be increased according to the
following each course of chemotherapy infusion for 6 cycles. The
algorithm (see Erythropoietic Therapy – Dosing and Titration) for
number of patients requiring blood transfusion was double in the oral
patients receiving chemotherapy who show no response (<1 g/dL Hb
iron group compared to the IV iron group (56.3% vs. 28.1%; P = .02).
increase) following 4 weeks of epoetin alfa or 6 weeks of darbepoetin
Furthermore, patients receiving IV iron required transfusion for a fewer
alfa treatment. A subsequent response at 8 or 9 weeks may necessitate
number of treatment cycles versus the oral iron group (0 vs. 0.5 cycle; P
a dose escalation to avoid transfusion. Iron supplementation can be
= .04), with fewer total units of PRBCs (0 vs. 0.5 units; P = .05). Neither
considered to improve response to ESA therapy. ESA therapy should
group experienced hypersensitivity reactions or other serious adverse
be discontinued and PRBC transfusion should be considered in patients
events. However, constipation occurred in a greater percentage of
showing no response despite iron supplementation after 8 or 9 weeks of
patients in the control group compared to the IV iron group (40.6% vs.
therapy. ESAs should be discontinued when chemotherapy is
3.1%; P < .001).121
completed or withdrawn.
A prospective, multicenter, open-label trial randomized 157 patients with
Iron Monitoring and Supplementation CIA receiving epoetin alfa to: 1) no iron; 2) oral iron; 3) iron dextran IV
Intravenous Iron and Oral Iron bolus; or 4) iron dextran total dose infusion (TDI).115 Increases in Hb
concentration were greater with IV iron (groups 3 and 4) compared to
Iron can be administered in oral form or parenteral form (low-molecular- oral supplementation or no iron (P < .02). Importantly, there was no
weight iron dextran, ferric gluconate, and iron sucrose).114 Evidence difference between the oral and no iron groups (P = .21). Additionally,
from 6 published studies utilizing iron in conjunction with an ESA there was no statistically significant difference between groups 3 and 4
suggest that IV iron is superior to oral iron.115-120 A recent study (P = .53), suggesting that lower, intermittent doses of IV iron are equally
indicated that the addition of parenteral iron to ESA therapy for the as efficacious as TDI. In a second open-label study by Henry et al,118
treatment of CIA improved hematopoietic response, reduced the need 187 anemic patients with cancer receiving chemotherapy and epoetin
for RBC transfusions, and increased Hb levels when compared to oral alfa were randomized to no iron, oral ferrous sulfate 3 times daily, or
iron supplementation.120 Eligibility criteria for these trials varied widely

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weekly IV ferric gluconate. The Hb response rate (≥2 g/dL increase) In 2011, Steensma et al122 published findings from the largest trial to
was higher in the IV arm (73%) compared to the oral (45%) or no iron date that initially challenged these positive results. Patients with CIA
(41%) arms. A third study enrolled 67 patients with lymphoproliferative (n = 502) were randomized 1:1:1 to receive IV ferric gluconate, oral
malignancies not undergoing chemotherapy.117 Patients were ferrous sulfate, or oral placebo in combination with darbepoetin alfa.
randomized to weekly epoetin beta with or without IV iron sucrose. Initial analysis of this data led the authors to conclude that IV iron
Although an oral iron arm was not included, IV iron resulted in a higher failed to confer any benefit in terms of Hb response, transfusion rate,
mean change in Hb level from baseline (2.76 g/dL vs. 1.56 g/dL, or quality of life compared to oral iron or placebo. However, problems
P = .0002) and a higher Hb level response rate (≥2 g/dL increase; 87% with the study design (including a suboptimal IV iron dosing regimen
vs. 53%, P = .0014) compared to the no iron group. and a high proportion of participant dropouts) could explain the lack of
response to IV iron observed in this study.123 Another possible reason
In a 2008 study, Bastit et al116 reported their open-label trial evaluating
for the lack of response seen initially may have been that the mean
396 CIA patients with non-myeloid malignancies undergoing
baseline TSAT level for patients in the IV iron group was 22.5%, a
chemotherapy (Hb ˂11 g/dL).116 Patients were treated with darbepoetin
value above what is considered to be associated with functional iron
alfa with or without IV iron (iron sucrose or ferric gluconate 200 mg
deficiency.122,123 Indeed, further analysis of study data indicated that
every 3 weeks for 16 weeks). Erythropoietic responses and time to
even though the change in TSAT during the study period did not differ
reach the target Hb level were better in the IV iron arm. Most
significantly between the 3 arms, the median serum ferritin rose
significantly, this was the first study to associate IV iron with fewer RBC
markedly in the IV iron group compared to the other cohorts,
transfusions in patients with cancer (9% vs. 20%, P = .005). In a study
suggesting that the total body iron balance was substantively
by Pedrazzoli et al,119 149 patients with solid tumors and CIA were
increased in the IV iron arm. 124 However, Steensma et al note that
randomly assigned to receive weekly darbepoetin alfa with or without
although this positive result suggests that IV iron offers benefits to
ferric gluconate. This was the first trial that excluded patients with
some patients, it is not yet clear which patients with CIA would benefit
absolute iron deficiency; eligibility requirements included a serum ferritin
most from IV-administered iron. Therefore, developing clearer insight
level >100 ng/mL and a TSAT level ≥20%. The ESA/IV iron group
into the parameters that make patients more or less likely to respond
showed a higher hematopoietic response rate compared to the control
to IV iron, as well as studies of alternative dose schedules of IV iron,
group (93% vs. 70%, respectively; P = .0033). Taken together, these
are warranted.124
studies demonstrated that concurrent IV iron enhanced hematologic
response to ESAs. However, there is insufficient evidence to determine A systematic review and meta-analysis evaluating the role of iron
whether iron supplementation can allow for an ESA dose decrease. supplementation included 11 randomized controlled trials analyzing IV
Long-term effects of IV iron supplementation in patients with cancer iron versus standard of care in patients with CIA.125 Nine trials
were not assessed in any of these trials. incorporated ESAs into treatment, 3 trials compared IV iron to oral iron
as the standard of care, and 6 trials compared IV iron to no iron. IV iron
supplementation versus no iron in patients treated with ESAs showed a

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significantly higher rate of hematopoietic response (n = 7 trials; RR, median Hb levels following ferric carboxymaltose alone or in
1.28; 95% CI, 1.125–1.45; I2 = 68.1%; random effects model) and combination with an ESA (1.3 g/dL vs. 1.4 g/dL, respectively) when
significantly reduced transfusion rates compared to standard of care (n measured over the 3-month observational period.137 Stable median Hb
= 7 trials; RR, 0.76; 95% CI, 0.61–0.95). Reduction in the number of levels ≥11 g/dL were reached in patients without signs of iron overload.
blood transfusions was also seen in the 2 trials without ESAs (RR, 0.52; These data suggest that ferric carboxymaltose may be an effective and
95% CI, 0.34–0.80). IV iron was superior to both no iron (n = 6 trials; well-tolerated treatment for CIA.
RR, 1.21; 95% CI, 1.12–1.31) and oral iron (n = 3 trials; RR, 1.37; 95%
There remains a paucity of both safety and efficacy data for the use of
CI, 0.92–2.05), and time to response was faster in the IV iron group
ferumoxytol in patients with cancer. Ferumoxytol is a colloidal iron oxide
(range, 36–54 days) versus the standard of care group (range, 46–94
that was FDA-approved in 2009 for the treatment of iron deficiency
days). IV iron but not oral iron was associated with improved
anemia in patients with CKD. A phase III trial (n = 812 patients)
hematopoietic response rates compared to ESAs alone. No difference
investigating the use of ferumoxytol in patients with anemia due to
in adverse events was found (n = 4 trials; RR, 0.99; 95% CI, 0.93–1.04),
various causes randomized patients to receive ferumoxytol (n = 608) or
including thromboembolic events (n = 4 trials; RR, 1.03; 95% CI, 0.59–
placebo (n = 200).138 Following treatment with ferumoxytol, 81.1% of
1.80) and cardiovascular events (n = 6 trials; RR, 1.08; 95% CI, 0.65–
patients achieved the primary endpoint (Hb increase ≥2.0 g/dL at week
1.78). There was also no difference in all-cause mortality at the end of
5) compared to only 5.5% of patients given placebo (P < .0001). After 5
follow-up (n = 7 trials, 1470 patients; RR, 1.13; 95% CI, 0.75–1.70).
weeks, Hb levels ≥12 were seen in 50.5% of patients treated with
Ferric carboxymaltose is FDA-approved for patients with CKD or an ferumoxytol versus 2.0% of patients receiving placebo (P ˂ .0001). The
intolerance or poor response to oral iron.126,127 It has also been incidence of serious adverse events was similar between the two
evaluated for the treatment of iron-deficient anemia in patients with groups (ferumoxytol, 2.6% vs. placebo, 3.0%). While this ferumoxytol
inflammatory bowel disease,128-130 chronic heart failure,131,132 and other study indicates that the drug is well tolerated and can effectively correct
conditions.118,133-135 The observational study from Steinmetz et al136 anemia, only a small percentage of patients in this study had cancer (n
evaluated its use in patients with cancer. Of the 639 adult patients from = 39); ferumoxytol was given to 29 of these patients and placebo was
68 cancer centers in Germany, safety data could be obtained for 619 given to 10 patients.138 Although a positive trend in favor of ferumoxytol
patients. With doses ranging from 600 to 1500 mg of ferric was demonstrated in the cancer subgroup compared with placebo
carboxymaltose, adverse drug reactions were seen in 14 (2.3%) (ferumoxytol, 51.7% vs. placebo, 30.0%; P < .2478), the difference was
patients and were primarily related to the gastrointestinal tract. Of the not statistically significant.138 In a randomized phase III study of patients
233 patients with follow-up Hb measurements, a median increase of 1.4 with iron deficiency anemia that had not responded to oral iron,
g/dL (range, 1.3–1.5 g/dL) was observed with an overall increase in ferumoxytol showed noninferiority to iron sucrose as measured by the
median Hb levels to >11 g/dL within 5 weeks of treatment with ferric proportion of patients who had at least a 2 g/dL increase in Hb from
carboxymaltose.136 A second observational study of 367 patients with baseline to week 5 following treatment with ferumoxytol (84%; n = 406)
solid tumors or hematologic malignancies demonstrated improved versus iron sucrose (81.4%; n = 199).139 In the cancer subgroup (n =

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31), there was a trend toward favoring ferumoxytol (54.8%) compared to Absolute Iron Deficiency
iron sucrose (38.5%). However, noninferiority was not reached, Absolute iron deficiency refers to the depletion of total body iron stores.
potentially due to the small sample size. It should be noted that It is characterized by low Hb, low iron, and high TIBC that result in a
ferumoxytol may cause interference with MRI scans causing potential TSAT level <20% and a ferritin level <30 ng/mL. If the TSAT and ferritin
false interpretation of organ iron overload.140 This is especially pertinent parameters are discordant, a low ferritin value should take precedence
for populations at risk for serious organ-threatening iron deposition and in determining whether iron supplementation will be beneficial. The
should be a consideration when selecting the agent for iron reference interval for serum ferritin depends on the specific laboratory
supplementation. used, but in general, the lower the level, the more probable that true
iron deficiency is present.
NCCN Evaluation and Definitions of Iron Status
Although IV iron is preferred, either IV or oral iron products alone
Iron deficiency is reported in 32% to 60% of patients with cancer, most
(without an ESA) are recommended for patients with cancer who
of whom are also anemic.141 Iron studies, including serum iron, TIBC,
develop absolute iron deficiency. If the patient initially receives oral iron
and serum ferritin, should be performed prior to ESA treatment in order
and the anticipated response is not seen after 4 weeks, a trial of IV iron
to rule out absolute iron deficiency, which may respond to oral or IV iron
should be considered. Periodic evaluation of ferritin and TSAT levels is
monotherapy without an ESA. Serum iron and TIBC levels may be
required as some patients, especially those with continued internal
falsely elevated by diet (reviewed in Collings et al142); therefore, fasting
bleeding, may suffer a relapse. If Hb is not improved after 4 weeks
is recommended to provide more accurate measurements. Transferrin
following IV iron supplementation, the patient should be evaluated for
saturation should be calculated from these values using the following
functional iron deficiency. Although data are conflicting in the literature,
formula:
concerns exist regarding the possibility of IV iron promoting
 TSAT = (serum iron level x 100)/TIBC inflammation and bacterial growth.143 Hence, IV iron supplementation is
Treatment for iron deficiency is guided by iron status, defined in these not recommended for patients with an active infection.
guidelines as absolute iron deficiency, functional iron deficiency, For further discussion of absolute iron deficiency, see Clinical Examples
possible functional iron deficiency, or no iron deficiency. In the absence of Iron Status, case scenarios 1 and 2.
of a universal numerical definition of iron deficiency in relevant studies,
the NCCN panel recognizes that ferritin and TSAT values defining Functional Iron Deficiency
absolute and functional iron deficiencies represent moving targets.3 Functional iron deficiency is defined in these guidelines as a ferritin
However, as general guidance, definitions and characteristics of each level between 30 ng/mL and 500 ng/mL and a TSAT level <50%.
iron status group are discussed below. Functional iron deficiency is a condition in which stored iron is sufficient
but bioavailable iron necessary for erythroblast production is deficient.
IV iron supplementation with erythropoietic therapy should be

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considered. IV iron monotherapy in patients with functional iron No Iron Deficiency

deficiency who are not receiving ESA therapy can reduce the number of Patients with ferritin values >800 ng/mL or a TSAT ≥50% are not iron
RBC transfusions. Patients who are receiving ESA therapy are also deficient. These patients do not require iron supplementation.
likely to benefit from IV iron supplementation.
While Hb and TSAT levels will be low, ferritin levels usually remain NCCN Recommendations for the Management of Iron Deficiency
within normal limits or elevated (laboratory diagnosis of this condition As previously discussed, most studies show that IV iron is superior over
was detailed by Thomas et al144). Functional iron deficiency may result oral iron and should be used in most circumstances.115-119 Low-
from cases where infection or inflammation blocks iron transport to the molecular-weight iron dextran, ferric gluconate, and iron sucrose are
bone marrow, as seen in anemia of chronic disease. Another form of recommended parental iron preparations. Ferric carboxymaltose has
functional iron deficiency often arises following continued ESA use, not been prospectively evaluated, and therefore should only be
resulting in a blunted erythropoietic response to anemia. Hence, iron considered when other parental iron preparations fail. It is indicated for
supplementation will eventually be required in most patients in order to adult patients when oral iron is not tolerated or there is a limited
maintain optimal erythropoiesis.145,146 IV iron supplementation in response. Although ferumoxytol is indicated for the treatment of iron
combination with erythropoietic therapy should be considered. deficiency in adult patients with CKD, it has not been adequately
For further discussion of functional iron deficiency, see Clinical evaluated in patients with cancer and may cause interference with MRI
Examples of Iron Status, case scenario 3. scans causing potential false interpretation of organ iron overload.140
Common adverse events following FDA-approved doses of parenteral
Possible Functional Iron Deficiency
iron include hypotension, nausea, vomiting and/or diarrhea, pain,
Possible functional iron deficiency is a condition in which stored iron is hypertension, dyspnea, pruritus, headache, and dizziness.147-149 Most
sufficient but bioavailable iron necessary for erythroblast production adverse events associated with iron dextran occurred with high-
may be deficient. These patients are defined by a TSAT level <50% and molecular-weight iron dextran.150 Therefore, the recommended iron
a ferritin level of >500 ng/mL to 800 ng/mL. Although clinical trials dextran product is low-molecular-weight iron dextran.151 Test doses are
suggest that these patients may have functional iron deficiency, there required for iron dextran, and are strongly recommended for patients
are insufficient data to support the routine use of IV iron in this setting. receiving ferric gluconate or iron sucrose who are sensitive to iron
Administration of IV iron to these patients should be individualized with dextran or have other drug allergies. As reactions to the IV iron test
the goal of avoiding allogeneic transfusion. dose may be severe, pre-medication of the patient should occur prior to
the test dose. Anaphylaxis-like reactions occur within minutes of the test
For further discussion of possible functional iron deficiency, see Clinical
dose but respond readily to IV epinephrine, diphenhydramine, and
Examples of Iron Status, case scenarios 4 and 5.
corticosteroids. It should be noted that patients may develop a reaction
to IV iron with later doses, and clinicians should be prepared to

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administer appropriate treatment. Delayed reactions to iron dextran may Patient Case
result in adverse events up to 24 to 48 hours following injection.152 FM is a 59-year-old female with no significant past medical history. In
Severe acute adverse reactions include anaphylaxis with dyspnea, addition to a 2-month history of early satiety and 9 kg weight loss, she
hypotension, chest pain, angioedema, or urticaria. Dosage details for presented to her primary care provider after acute onset of bloody
administering parenteral iron therapy are listed in the algorithm (see stools. Abdominal imaging revealed a colon mass and mesenteric
Recommendations for Administering Parenteral Iron Products). lesions. She was referred to an oncologist. Biopsy of the colon mass
Patients with a baseline TSAT level <20% had a higher response rate to demonstrated a poorly differentiated adenocarcinoma. Her oncologist
IV iron supplementation when given in addition to an ESA. As the TSAT has begun palliative treatment with FOLFOX plus bevacizumab, a
level increases from 20% to 50%, the response rate is diminished, and myelosuppressive regimen. After 2 cycles of chemotherapy, her CBC
the time to a response is prolonged. Hence, for this group, IV iron results are as follows: Hb 8.8 g/dL, Hct 26.7%, MCV 73 fL, reticulocytes
should only be offered if benefits are likely to outweigh risks. 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 and
None of the 6 studies on iron supplementation in conjunction with ESAs vitamin B12 levels are within normal limits. Indirect bilirubin and serum
provided instruction on how or when to re-dose iron after the initial LDH are within normal limits. Bleeding has ceased, but given her
cumulative dose has been given. Generally, repeat iron studies are not baseline anemia and red cell indices, iron studies have also been
recommended within 3 to 4 weeks of administration. Clinicians may ordered. Five different scenarios are provided below to illustrate the
consider repeating iron studies when the MCV declines or hypochromic potential management of this patient depending on various ferritin and
RBCs are seen on the peripheral blood smear. TSAT combinations.
For patients with anemia that fails to respond to iron supplementation 4
Scenario 1: Serum Ferritin 5 ng/mL & TSAT 4%
to 6 weeks after administration of the total intended dose, repeat iron
studies may be considered.117,122 If evidence exists of iron overload, do With a ferritin level <30 ng/mL and a TSAT level <20%, this patient has
not administer IV iron. Subsequent doses of iron should be withheld if absolute iron deficiency and would benefit from iron repletion. Reducing
the serum ferritin exceeds 800 ng/mL or if the TSAT level exceeds transfusion requirements remains the goal of therapy. With a baseline
50%.116-118 Hb of 8.8 g/dL, imminent chemotherapy initiation, and very low iron
stores, IV iron repletion is preferred. Oral iron may not supply
Individuals with a ferritin level >800 ng/mL or a TSAT level ≥50% do not
bioavailable iron rapidly enough in certain patients.115
require iron supplementation as they are not considered iron-deficient.
Clinical Examples of Iron Status
With low ferritin and normal TSAT levels, we can postulate that iron
The following clinical scenarios illustrate how iron studies may guide
stores are becoming depleted. Iron is being mobilized, but signs of iron-
iron and ESA treatment of anemia in patients with cancer.
restricted erythropoiesis are beginning to emerge. If the ferritin and

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TSAT levels are discordant, the low ferritin level should take patient may not necessarily require IV iron until the TSAT level trends
precedence to determine if IV iron therapy would be beneficial to the downward as a result of ESA use. If the anticipated response to ESA is
patient. Iron would be beneficial in this patient as these laboratory not realized by 4 to 6 weeks, consider repeating iron studies. If TSAT
values potentially reflect a transition from an iron-replete to an iron- and/or ferritin levels decrease, consider giving IV iron. If iron studies
deficient state. For the same reasons as discussed in scenario 1, IV iron remain unchanged, continue the ESA for a total of 8 weeks of therapy
is preferred. It is also possible for TIBC to be low secondary to and discontinue thereafter if lack of response persists, and consider
malnutrition, resulting in a normal TSAT level despite definitive absolute RBC transfusion.
iron deficiency. ESA use should be considered only after iron repletion.
These ferritin and TSAT parameters suggest that functional iron
With normal or elevated ferritin and low TSAT levels, we can assume deficiency is unlikely. Therefore, this patient is unlikely to benefit from
that iron is either not bioavailable or that the ferritin reflects an acute- iron therapy since he or she is iron replete. In this scenario, an ESA
phase response, potentially secondary to cancer-related inflammation may be considered. ESA use induces functional iron deficiency by
(functional iron deficiency). Functional iron deficiency may cause iron- increasing iron utilization without the compensatory ability to mobilize
restricted erythropoiesis, and there is no ferritin threshold at which we storage iron in a timely manner. Therefore, iron repletion can be
can assume iron supply is adequate for erythropoiesis if the TSAT level initiated if a response to ESA is not seen and the patient remains
is low. Thus, patients with ferritin levels in excess of 100 ng/mL could be transfusion-dependent. Of note, improved response is generally
treated with IV iron, as discussed in scenario 2. However, in this expected as the TSAT level decreases from 50% to 20%. Ultimately,
instance, an ESA should be considered first. This is because as the clinical judgment must be used to determine whether the potential
ferritin level moves across the spectrum from absolute iron deficiency to benefits of iron administration are likely to outweigh the risks.
iron overload, the response to either an ESA or iron will diminish. As a
result of limited data to currently support IV iron added to an ESA for Future Development
patients with a ferritin greater than 800 ng/mL,153 iron should be
In the face of current controversy in various aspects of anemia
withheld until hyporesponsiveness to the ESA is noted, or until other management, well-designed trials are required to answer questions
signs or symptoms of iron deficiency arise. Concomitant IV iron can be
regarding the safety of ESAs for lower-target Hb levels, the role of IV
considered as it may increase the percentage of patients who respond iron in reducing transfusion needs, the optimal dose and frequency of IV
to the ESA as well as reduce the time to response.
iron, and both short- and long-term effects of iron supplementation,
among others.
As the TSAT level increases from 20% to 50%, the percentage of Several novel IV iron agents are currently being studied as
patients with anemia that responds to iron decreases; therefore, this monotherapy (without an ESA) in patients with CIA. More information

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about these agents can be found at www.clinicaltrials.gov. Other areas

for future development include identification of iron deficiency markers.
Soluble transferrin receptor level has been suggested as a marker of
iron deficiency that can aid in differential diagnosis.154 However, studies
are still needed to evaluate the role of this marker in patients with CIA.

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Anemia NCCN 2018

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Guidelines Version 2.2018 Panel Members NCCN Guidelines Index

Seema Ali Bhat, MD † ‡ Michael M. Millenson, MD ‡ Þ † Ari VanderWalde, MD, MPH Þ †

NCCN Guidelines Version 2.2018 Table of Contents NCCN Guidelines Index

NCCN Cancer- and Chemotherapy-Induced Anemia Panel Members

NCCN Guidelines Version 2.2018 Updates NCCN Guidelines Index

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

HEMOGLOBIN EVALUATION OF ANEMIAa,b

Myelodysplastic syndromes See NCCN Guidelines for Myelodysplastic Syndromes

Myeloid malignancies or Treat underlying disease per NCCN Guideline

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

RISK ASSESSMENT AND INDICATIONS FOR INITIAL TRANSFUSION IN ACUTE SETTING

Asymptomatic without significant comorbiditiese Observe Periodic re-evaluation

High risk (ie, progressive decline in Hb with

See Special Categories in Considering ESA Use (ANEM-4)

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

ESA in the Cancer Setting Red Blood Cell Transfusion

See Erythropoietic Therapy - Dosing, Titration, and Adverse Effects (ANEM-B)

When considering ESAs:

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

SPECIAL CATEGORIES IN CONSIDERING ESA USE

Cancer and chronic kidney disease

Patient undergoing palliative treatmenth Consider based on patient preferences:

Select patients who refuse Consider ESAs by FDA dosing/dosing adjustmentsj,k

• Patients with cancer not receiving therapy

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

EVALUATION OF IRON STATUS MANAGEMENT

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

INDICATIONS FOR RED BLOOD CELL TRANSFUSION IN PATIENTSa,b,c

Goal: Prevent or treat deficit of oxygen-carrying capacity in blood

• Symptomatic (including tachycardia, tachypnea, postural hypotension) anemia:

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

ERYTHROPOIETIC THERAPY - DOSING AND TITRATION (1 of 5)1-4

PACKAGE INSERT DOSING SCHEDULE • The dose should be adjusted

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

ERYTHROPOIETIC THERAPY - DOSING AND TITRATION (2 of 5)

See Erythropoietic Therapy -

See Erythropoietic Therapy-

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

ERYTHROPOIETIC THERAPY - ADVERSE EFFECTS (3 of 5)

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

ERYTHROPOIETIC THERAPY - ADVERSE EFFECTS (4 of 5)

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

See References (ANEM-B 5 of 5)

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

ERYTHROPOIETIC THERAPY - ADVERSE EFFECTS (5 of 5)

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

NCCN Guidelines Version 2.2018 NCCN Guidelines Index

PARENTERAL IRON PREPARATIONS1-7 (1 of 3)