ASCO

Management of Cancer-Associated Anemia With

Erythropoiesis-Stimulating Agents: ASCO/ASH
special article
Clinical Practice Guideline Update
Julia Bohlius, MD, MScPH1; Kari Bohlke, ScD2; Roberto Castelli, MD, PhD3; Benjamin Djulbegovic, MD, PhD4;
Maryam B. Lustberg, MD, MPH5; Massimo Martino, MD6; Giannis Mountzios, MD, PhD7; Namrata Peswani, MD8; Laura Porter, MD9;
Tiffany N. Tanaka, MD10; Gianluca Trifirò, MD, PhD11; Hushan Yang, PhD12; and Alejandro Lazo-Langner, MD, MSc13
abstract

PURPOSE To update the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH)
recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.
METHODS PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-
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analyses of RCTs in patients with cancer published from January 31, 2010, through May 14, 2018. For
biosimilar ESAs, the literature search was expanded to include meta-analyses and RCTs in patients with cancer
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

or chronic kidney disease and cohort studies in patients with cancer due to limited RCT evidence in the cancer
setting. ASCO and ASH convened an Expert Panel to review the evidence and revise previous recommendations
as needed.
RESULTS The primary literature review included 15 meta-analyses of RCTs and two RCTs. A growing body of
evidence suggests that adding iron to treatment with an ESA may improve hematopoietic response and reduce
the likelihood of RBC transfusion. The biosimilar literature review suggested that biosimilars of epoetin alfa have
similar efficacy and safety to reference products, although evidence in cancer remains limited.
RECOMMENDATIONS ESAs (including biosimilars) may be offered to patients with chemotherapy-associated
anemia whose cancer treatment is not curative in intent and whose hemoglobin has declined to , 10 g/dL. RBC
ASSOCIATED transfusion is also an option. With the exception of selected patients with myelodysplastic syndromes, ESAs
CONTENT should not be offered to most patients with nonchemotherapy-associated anemia. During ESA treatment,
Appendix hemoglobin may be increased to the lowest concentration needed to avoid transfusions. Iron replacement may
Data Supplement be used to improve hemoglobin response and reduce RBC transfusions for patients receiving ESA with or without
Author affiliations iron deficiency. Additional information is available at www.asco.org/supportive-care-guidelines and www.
and support hematology.org/guidelines.
information (if
applicable) appear J Clin Oncol 37:1336-1351. © 2019 by American Society of Clinical Oncology
at the end of this
article. INTRODUCTION increase in appropriate prescribing practices.7 The risks
Accepted on of ESAs remain, however, highlighting the ongoing
December 12, 2018 Use of erythropoiesis-stimulating agents (ESAs) to
and published at
importance of appropriate use. ESAs are indicated in
manage anemia raises hemoglobin (HgB) levels and
jco.org on April 10, patients with cancer who are receiving myelosup-
reduces the need for RBC transfusions, but increases
2019: DOI https://doi. pressive chemotherapy with noncurative intent and
org/10.1200/JCO.18.
the risk of thromboembolic events.1,2 Studies have also
anemia that cannot be adequately managed with
02142 reported decreased survival, increased mortality dur-
transfusional support.
J.B. and A.L.L. ing active study phase, and/or an increased risk of
were Expert cancer progression or recurrence with the use of ESAs The American Society of Clinical Oncology (ASCO) and
Panel co-chairs. in patients with cancer.3-6 The risks of ESAs prompted the American Society of Hematology (ASH) first
ASCO Clinical multiple regulatory actions by the US Food and Drug published a joint evidence-based clinical practice
Practice
Guidelines
Administration (FDA) between 2004 and 2009, and in guideline for the use of ESAs in adults with cancer and
Committee 2010, the FDA approved a Risk Evaluation and Miti- anemia in 2002,8 with updates in 20079 and 2010.10
approved: gation Strategy for ESA use in patients with cancer. In Since the 2010 update, additional information has
November 28, 2018. 2017, the FDA determined that the Risk Evaluation emerged about the safety and efficacy of ESAs in
Reprint requests: and Mitigation Strategy was no longer necessary: patients with metastatic breast cancer and about the role
2318 Mill Rd, Ste
prescribers demonstrated acceptable knowledge of of iron in conjunction with ESAs. Treatment options have
800, Alexandria, VA
22314; guidelines@ the risks of ESAs and the need to counsel patients also expanded with the 2018 FDA approval of a biosimilar
asco.org. about the risks, and utilization data suggested an of epoetin alfa, warranting a guideline update.11

1336 Volume 37, Issue 15

 ASCO/ASH ESA Guideline Update

THE BOTTOM LINE

Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical
Practice Guideline Update
Guideline Question
When and how should erythropoiesis-stimulating agents (ESAs) be used to manage anemia in adults with
cancer?
Target Population
Adults with cancer and anemia.
Target Audience
Oncologists, hematologists, oncology nurses, oncology pharmacists, and other health care professionals who care
for patients with cancer, and patients with cancer.
Methods
An Expert Panel was convened to update clinical practice guideline recommendations based on a systematic review
of the medical literature.
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Recommendations
Clinical Question 1
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

To reduce the need for RBC transfusions, should ESAs be offered to patients who have chemotherapy-associated
anemia?
Recommendation 1.1. Depending on clinical circumstances, ESAs may be offered to patients with
chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin
(HgB) has declined to , 10 g/dL. RBC transfusion is also an option, depending on the severity of the anemia
or clinical circumstances (Type: evidence based; Evidence quality: high; Strength of recommendation:
strong).
Recommendation 1.2. ESAs should not be offered to patients with chemotherapy-associated anemia whose
cancer treatment is curative in intent (Type: evidence based; Evidence quality: intermediate; Strength of
recommendation: strong).

Clinical Question 2
To reduce the need for RBC transfusions, should ESAs be offered to anemic patients with cancer who are not
receiving concurrent myelosuppressive chemotherapy?
Recommendation 2.1. ESAs should not be offered to most patients with nonchemotherapy-associated
anemia (Type: informal consensus; Evidence quality: low; Strength of recommendation: strong).
Recommendation 2.2. ESAs may be offered to patients with lower risk myelodysplastic syndromes and a serum
erythropoietin level # 500 IU/L (Type: evidence based; Evidence quality: intermediate; Strength of rec-
ommendation: moderate).

Clinical Question 3
What special considerations apply to adult patients with nonmyeloid hematologic malignancies who are receiving
concurrent myelosuppressive chemotherapy?
Recommendation 3. In patients with myeloma, non-Hodgkin lymphoma, or chronic lymphocytic leukemia,
clinicians should observe the hematologic response to cancer treatment before considering an ESA.
Particular caution should be exercised in the use of ESAs concomitant with treatment strategies and diseases
where risk of thromboembolic complications is increased (see Recommendations 4 and 6). In all cases,
blood transfusion is a treatment option that should be considered (Type: informal consensus; Evidence
quality: low; Strength of recommendation: moderate).

Clinical Question 4
What examinations and diagnostic tests should be performed before making a decision about using an ESA to
identify patients who are likely to benefit from an ESA?
(continued on following page)

Journal of Clinical Oncology 1337

 Bohlius et al

THE BOTTOM LINE (CONTINUED)

Recommendation 4. Before offering an ESA, clinicians should conduct an appropriate history, physical ex-
amination, and diagnostic tests to identify alternative causes of anemia aside from chemotherapy or an
underlying hematopoietic malignancy. Such causes should be appropriately addressed before considering
the use of ESAs. Suggested baseline investigations are listed in Table 1 (Type: informal consensus; Evidence
quality: intermediate; Strength of recommendation: strong).

Clinical Question 5
Among adult patients who receive an ESA for chemotherapy-associated anemia, do darbepoetin, epoetin beta and
alfa originator, and currently available biosimilars of epoetin alfa differ with respect to safety or efficacy?
Recommendation 5. The Expert Panel considers epoetin beta and alfa, darbepoetin, and biosimilar epoetin alfa
to be equivalent with respect to effectiveness and safety (Type: informal consensus; Evidence quality:
intermediate; Strength of recommendation: moderate).

Clinical Question 6
Do ESAs increase the risk of thromboembolism?
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Recommendation 6. ESAs increase the risk of thromboembolism, and clinicians should carefully weigh the
risks of thromboembolism and use caution and clinical judgment when considering use of these agents
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

(Type: evidence based; Evidence quality: high; Strength of recommendation: strong).

Clinical Question 7
Among adult patients who will receive an ESA for chemotherapy-associated anemia, what are recommendations for
ESA dosing and dose modifications?
Recommendation 7. It is recommended that starting and modifying doses of ESAs follow FDA guidelines (see
Table 2 for specific dosing information; Type: informal consensus; Evidence quality: intermediate; Strength
of recommendation: moderate).

Clinical Question 8
Among adult patients who will receive an ESA for chemotherapy-associated anemia, what is the recommended
target HgB level?
Recommendation 8. HgB may be increased to the lowest concentration needed to avoid or reduce the need for
RBC transfusions, which may vary by patient and condition (Type: informal consensus; Evidence quality:
intermediate; Strength of recommendation: moderate).

Clinical Question 9
Among adult patients with chemotherapy-associated anemia who do not respond to ESA therapy (, 1 to 2 g/dL
increase in HgB or no decrease in transfusion requirements), does continuation of ESA therapy beyond 6 to 8 weeks
provide a benefit?
Recommendation 9. ESAs should be discontinued in patients who do not respond within 6 to 8 weeks. Patients
who do not respond to ESA treatment should be reevaluated for underlying tumor progression, iron de-
ficiency, or other etiologies for anemia (Type: informal consensus; Evidence quality: intermediate; Strength
of recommendation: strong).
Clinical Question 10
Among adult patients with chemotherapy-associated anemia, does iron supplementation concurrent with an ESA
reduce transfusion requirements?
Recommendation 10. Iron replacement may be used to improve HgB response and reduce RBC transfusions
for patients receiving ESA with or without iron deficiency. Baseline and periodic monitoring of iron, total iron-
binding capacity, transferrin saturation, or ferritin levels is recommended (Type: evidence based; Evidence
quality: intermediate; Strength of recommendation: weak).
(continued on following page)

1338 © 2019 by American Society of Clinical Oncology Volume 37, Issue 15

 ASCO/ASH ESA Guideline Update

THE BOTTOM LINE (CONTINUED)

Additional Resources
More information, including a Data Supplement with additional evidence tables, slide sets, and clinical tools and
resources, is available at www.asco.org/supportive-care-guidelines. Patient information is available at www.cancer.
net. The Methodology Manual (available at www.asco.org/guideline-methodology) provides additional information
about the methods used to develop this guideline update.

ASCO and the ASH believe that cancer clinical trials are vital to inform medical decisions and improve cancer care,
and that all patients should have the opportunity to participate.

GUIDELINE QUESTIONS The guideline recommendations were sent for an open

This clinical practice guideline addresses 10 clinical ques- comment period of 2 weeks, allowing the public to review
tions: (1) To reduce the need for RBC transfusions, should and comment on the recommendations after submitting a
confidentiality agreement. These comments were taken into
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ESAs be offered to patients who have chemotherapy-

associated anemia? (2) To reduce the need for RBC consideration while finalizing the recommendations. Mem-
transfusions, should ESAs be offered to anemic patients bers of the Expert Panel were responsible for reviewing and
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

with cancer who are not receiving concurrent myelosup- approving the penultimate version of guideline, which was
pressive chemotherapy? (3) What special considerations then circulated for external review and submitted to the
apply to adult patients with nonmyeloid hematologic ma- Journal of Clinical Oncology (JCO) for editorial review and
lignancies who are receiving concurrent myelosuppressive consideration for publication. All ASCO guidelines are ulti-
chemotherapy? (4) What examinations and diagnostic tests mately reviewed and approved by the Expert Panel and the
should be performed before making a decision about using ASCO Clinical Practice Guidelines Committee prior to pub-
an ESA to identify patients who are likely to benefit from an lication. The guideline was also reviewed and approved by
ESA? (5) Among adult patients who receive an ESA for the ASH Guideline Oversight Subcommittee, the ASH
chemotherapy-associated anemia, do darbepoetin, epoetin Committee on Quality, and ASH Officers. All funding for the
beta and alfa originator, and currently available biosimilars administration of the project was provided by ASCO.
of epoetin alfa differ with respect to safety or efficacy? (6) Do The recommendations were developed using a systematic
ESAs increase the risk of thromboembolism? (7) Among review of the literature from January 31, 2010, through May
adult patients who will receive an ESA for chemotherapy- 14, 2018, and clinical experience. For all questions except
associated anemia, what are recommendations for ESA the question on biosimilars, PubMed and the Cochrane Li-
dosing and dose modifications? (8) Among adult patients brary were searched for randomized controlled trials (RCTs)
who will receive an ESA for chemotherapy-associated ane- and meta-analyses of RCTs. Publications were included if
mia, what is the recommended target HgB level? (9) Among they assessed the efficacy and safety of ESAs in patients with
adult patients with chemotherapy-associated anemia who cancer and included at least 50 patients per arm. For the
do not respond to ESA therapy (, 1 to 2 g/dL increase in question on biosimilars, PubMed and the Cochrane Library
HgB or no decrease in transfusion requirements), does were searched for RCTs and meta-analyses of RCTs in pa-
continuation of ESA therapy beyond 6 to 8 weeks provide a tients with cancer or chronic kidney disease (CKD), or cohort
benefit? (10) Among adult patients with chemotherapy- studies in patients with cancer. For all questions, primary
associated anemia, does iron supplementation concur- outcomes of interest were mortality, frequency of RBC
rent with an ESA reduce transfusion requirements? transfusion, thromboembolic risk, and progression-free sur-
vival. In the case of biosimilars, HgB response and immu-
METHODS nogenicity were additional outcomes of interest. Secondary
outcomes included quality of life, fatigue, and overall survival.
Guideline Update Process
Search terms are provided in the Data Supplement.
This systematic review-based guideline was developed by a
Articles were excluded from the systematic review if they
multidisciplinary Expert Panel (Appendix Table A1, online
were (1) meeting abstracts not subsequently published in
only), which included a patient representative and an ASCO
peer-reviewed journals; (2) editorials, commentaries, let-
guidelines staff member with health research method-
ters, news articles, case reports, or narrative reviews; (3)
ology expertise. The Expert Panel met via webinar and
published in a non-English language; or (4) an RCT that
corresponded through e-mail. Based upon the con-
was analyzed in an included meta-analysis.
sideration of the evidence, the authors were asked to
contribute to the development of the guideline, provide The updated search was guided by the “signals”12 ap-
critical review, and finalize the guideline recommendations. proach that is designed to identify only new, potentially

Journal of Clinical Oncology 1339

 Bohlius et al

practice-changing data—signals—that might translate into Guideline and Conflicts of Interest

revised practice recommendations. The approach relies on The Expert Panel was assembled in accordance with ASCO’s
targeted routine literature searching and the expertise of Conflict of Interest Policy Implementation for Clinical Practice
Expert Panel members to help identify potential signals. Guidelines (“Policy,” found at http://www.asco.org/rwc), with
Before publication, a review of the guideline’s feasibility for additional policies mutually agreed upon with ASH. All
implementation was also conducted. Ratings for the type members of the Expert Panel completed ASCO’s disclosure
and strength of the recommendation and the quality of form, which requires disclosure of financial and other
evidence are provided with each recommendation. The interests, including relationships with commercial entities
Methodology Manual (available at www.asco.org/guideline- that are reasonably likely to experience direct regulatory or
methodology) provides additional information about the commercial impact as a result of promulgation of the
methods used to develop this guideline update. guideline. Categories for disclosure include employment;
The Expert Panel and guidelines staff will work with co-chairs leadership; stock or other ownership; honoraria, consul-
to keep abreast of the need for any substantive updates to ting or advisory role; speaker’s bureau; research funding;
the guideline. Based on formal review of the emerging lit- patents, royalties, other intellectual property; expert tes-
erature, ASCO and ASH will determine the need to update. timony; travel, accommodations, expenses; and other
This is the most recent information as of the publication date. relationships. In accordance with the Policy, the majority
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of the members of the Expert Panel did not disclose any

Guideline Disclaimer relationships constituting a conflict under the Policy.
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

The Clinical Practice Guidelines and other guidance

published herein are provided by the American Society of RESULTS
Clinical Oncology, Inc. (ASCO) and the American Society of The primary literature review included 15 meta-analyses of
Hematology (ASH) to assist providers in clinical decision RCTs1,2,13-25 and two RCTs.6,26 Three meta-analyses15,20,22
making. The information herein should not be relied upon addressed the addition of iron to an ESA. The remaining 12
as being complete or accurate, nor should it be considered meta-analyses1,2,13,14,16-19,21,23-25 addressed ESA versus
as inclusive of all proper treatments or methods of care or as control (placebo or best standard therapy). The quality of
a statement of the standard of care. With the rapid de- the meta-analyses varied based on AMSTAR2 criteria, such
velopment of scientific knowledge, new evidence may as assessment and discussion of bias and heterogeneity.
emerge between the time information is developed and The two RCTs consisted of a large phase III RCT in met-
when it is published or read. The information is not con- astatic breast cancer6 and a smaller trial in myelodysplastic
tinually updated and may not reflect the most recent evi- syndrome (MDS).26 Evidence tables and quality assess-
dence. The information addresses only the topics ments for included meta-analyses and RCTs are provided
specifically identified therein and is not applicable to other in the Data Supplement.
interventions, diseases, or stages of diseases. This in-
formation does not mandate any particular course of For biosimilars, both of the included meta-analyses27,28 and
medical care. Further, the information is not intended to one29 of the two RCTs29,30 involved patients with CKD. The
substitute for the independent professional judgment of the only RCT in patients with cancer30 had a high likelihood of
treating provider, as the information does not account for bias based on inadequate sample size, lack of an intent-to-
individual variation among patients. Recommendations treat analysis, and industry funding and authorship. The
reflect high, moderate, or low confidence that the rec- quality of the four included cohort studies of biosimilars31-34
ommendation reflects the net effect of a given course of in patients with cancer was not formally assessed.
action. The use of words like “must,” “must not,” “should,”
and “should not” indicates that a course of action is rec- RECOMMENDATIONS
ommended or not recommended for either most or many
patients, but there is latitude for the treating physician to CLINICAL QUESTION 1
select other courses of action in individual cases. In all cases, To reduce the need for RBC transfusions, should ESAs be
the selected course of action should be considered by the offered to patients who have chemotherapy-associated anemia?
treating provider in the context of treating the individual
patient. Use of the information is voluntary. ASCO and ASH Recommendation 1.1
provide this information on an “as is” basis and makes no Depending on clinical circumstances, ESAs may be offered
warranty, express or implied, regarding the information. to patients with chemotherapy-associated anemia whose
ASCO and ASH specifically disclaim any warranties of cancer treatment is not curative in intent and whose HgB
merchantability or fitness for a particular use or purpose. has declined to , 10 g/dL. RBC transfusion is also an
ASCO and ASH assume no responsibility for any injury or option, depending on the severity of the anemia or clinical
damage to persons or property arising out of or related to any circumstances (Type: evidence based; Evidence quality:
use of this information, or for any errors or omissions. high; Strength of recommendation: strong).

1340 © 2019 by American Society of Clinical Oncology Volume 37, Issue 15

 ASCO/ASH ESA Guideline Update

Recommendation 1.2 RCT.6 In the 2013 Agency for Healthcare Research and
ESAs should not be offered to patients with chemotherapy- Quality meta-analysis by Grant et al,1 patients who initiated
associated anemia whose cancer treatment is curative in ESA use at a lower HgB level (# 10 g/dL) had a greater
intent (Type: evidence based; Evidence quality: intermediate; reduction in likelihood of RBC transfusion than patients
Strength of recommendation: strong). who initiated ESA use at a higher baseline HgB level
(relative risk, 0.46; 95% CI, 0.41 to 0.49, for patients with
Literature review update and analysis. In the 2010 guide- lower HgB at ESA initiation, compared with relative risk,
line, use of ESAs in relation to intent of treatment (curative v 0.71; 95% CI, 0.65 to 0.79, for patients with higher HgB at
palliative) was addressed in a Special Note. In this update, ESA initiation; P , .01 for interaction). The effects of ESA
the Expert Panel chose to address treatment intent in a use on on-study mortality and overall survival did not differ
recommendation. significantly by baseline HgB level. In the 2012 Cochrane
The results of the updated systematic review confirmed that review by Tonia et al,2 three levels of baseline HgB were
ESAs reduce the risk for RBC transfusion1,2,6,18,19,21,24 and analyzed:# 10 g/dL, 10 to 12 g/dL, and . 12 g/dL. Patients
increase the risk of thromboembolism.1,2,6,16,19,25 ESAs with a baseline HgB level of 10 to 12 g/dL had the greatest
were associated with an increased risk of on-study mortality reduction in risk of RBC transfusion with ESA use. In the
in some1,2 but not all18,24 meta-analyses. The two meta- remaining two meta-analyses, baseline HgB did not sig-
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analyses that reported nonsignificant associations with on- nificantly modify the association between ESA use and
study mortality focused on specific subgroups of patients fatigue14 or overall survival.21 In the 2016 RCT by Leyland-
defined by cancer type24 or HgB level18 and included rela- Jones et al,6 the HRs for progression-free survival were
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

tively small sample sizes. Seven meta-analyses1,2,13,17,19,21,24 similar in patients with lower and higher baseline HgB levels
and an RCT6 reported on overall survival, with only one (HR, 1.11; 95% CI, 0.92 to 1.33, for patients with baseline
publication13 reporting a statistically significant associa- HgB , 10 g/dL; HR, 1.08; 95% CI, 0.96 to 1.21, for pa-
tion with ESA use. Aapro et al13 reported an increased risk tients with baseline HgB $ 10 g/dL); a test for interaction
of death in ESA users (odds ratio, 1.20; 95% CI, 1.03 to was not reported, but 95% CIs are widely overlapping.
1.40) based on nine RCTs in patients with breast cancer. Clinical interpretation. As of the date of this publication, the
Meta-analyses consistently reported statistically signifi- FDA-approved labels state that ESAs are indicated for the
cant reductions in fatigue with ESA use,1,2,14,23 but the treatment of anemia due to concomitant, myelosuppressive
effect sizes were small and unlikely to be clinically chemotherapy that is expected to continue for at least 2
important.35 additional months after ESA initiation. The labels state that
Little information about treatment intent is available from ESAs are not indicated for use in patients with cancer
published studies, but one RCT6 in the updated literature receiving myelosuppressive chemotherapy in whom the
review restricted to patients with metastatic breast cancer anemia can be managed by transfusion. A boxed warning
and one meta-analysis1 developed a decision model that includes several additional cautionary notes for use in
incorporated intent of treatment. The 2013 Agency for cancer, including a statement that ESAs are not indicated
Healthcare Research and Quality meta-analyses by Grant for patients receiving myelosuppressive chemotherapy
et al1 developed decision models for patients treated with when the anticipated outcome is cure.
curative or noncurative intent. The models suggest that Unfortunately, it cannot be determined from the available
ESAs increase quality-adjusted life-years but decrease life- evidence whether any particular group of potential ESA
years in both the curative and noncurative setting. The recipients has a greater or lesser risk of harm than other
2016 noninferiority trial by Leyland-Jones et al6 compared patients with chemotherapy-induced anemia. The mech-
epoetin alfa to best supportive care in 2,098 patients anisms of harm are also unclear. The FDA-approved label’s
with metastatic breast cancer. The primary outcome of distinction between patients being treated with curative
interest—progression-free survival based on investigator- versus palliative intent may assist clinicians as they com-
determined progressive disease—did not meet non- pare and discuss with patients the risk-to-benefit ratios of
inferiority criteria (hazard ratio [HR] 1.09; 95% CI, 0.99 to an ESA versus RBC transfusions. The decision to limit the
1.20; prespecified noninferiority margin was 1.15). In their indication for ESAs to patients undergoing chemotherapy
conclusion, the investigators state, “In light of these study for palliation (treatment intent) is not based on direct
results, RBC transfusion should be the preferred approach comparative analyses of data from clinical trials of ESA
for the management of anemia during first- or second-line treatment based on the intent of any particular regimen
chemotherapy for metastatic breast cancer. If EPO is to be used. Rather, it is based on the known risks, such as in-
used in the more advanced settings of metastatic breast creased risk for thromboembolic events and short-term
cancer, this should be done with caution and based on mortality and decreased overall survival. These increased
careful risk-benefit assessment.”6 (p1205) risks have been observed across different patient groups.6,36
Subgroup analyses of ESA efficacy and safety by baseline With currently available evidence, it is not possible to de-
HgB were provided by four meta-analyses1,2,14,21 and one termine a patient group that could safely use ESAs.

Journal of Clinical Oncology 1341

 Bohlius et al

Note also that determining the goal of treatment requires Two meta-analyses in the updated literature review pre-
clinical judgment. Examples of diseases for which the sented subgroup results by cancer treatment.2,14 Neither
treatment goal should generally be considered curative provided evidence that would support a change to the
include (among others) testicular cancer, first-line therapy Recommendation 2.1. In a 2014 meta-analysis of ESAs
of Hodgkin disease, and early-stage solid tumors treated and fatigue,14 a benefit of ESAs was numerically greatest
with adjuvant chemotherapy (eg, breast, colon, early lung). among patients treated with chemotherapy, although the
The Expert Panel acknowledges the FDA’s assessment that test for interaction by type of cancer treatment was not
the reported benefits of ESAs may be outweighed by risks statistically significant (P = .22). In a 2012 meta-analysis,2
considered unacceptable in patients who might otherwise type of cancer treatment did not qualify for inclusion in
expect cure or moderate to long survival from their che- multivariate models of ESA safety and efficacy.
motherapy. Clinicians are urged to exercise caution in In patients with MDS, one RCT evaluated the addition
considering ESA use in patients with malignancy being of epoetin beta to lenalidomide in 131 patients with
treated with curative intent. The Expert Panel stresses the RBC transfusion-dependent, low, or intermediate-1 risk
importance of including a detailed discussion between (according to the International Prognostic Scoring System),
health care providers and their patients about the potential ESA refractory, nondel(5q) MDS.26 The combination of
harms and benefits of ESA therapy. lenalidomide and epoetin beta increased the frequency of
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FDA-approved labeling for each ESA also states, “Initiate…in erythroid response relative to lenalidomide alone (39% v
patients on cancer chemotherapy only if the hemoglobin is 23%; P = .04), but did not significantly affect duration of
less than 10 g/dL.” The Expert Panel accepts that, although erythroid response (15 v 18 months; P = .64) or likelihood
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

evidence is lacking to establish an optimal HgB threshold of transfusion independence (24% v 14%; P = .13). In
for starting ESA therapy, it is clinically prudent to wait until subgroup analyses, patients with lower baseline serum
HgB concentration decreases to less than 10 g/dL. How- erythropoietin levels had higher rates of erythroid response.
ever, the Expert Panel acknowledges that rare clinical
Clinical interpretation. There is no evidence that the rel-
circumstances (such as severe pulmonary or cardiovas-
ative effects of ESAs to reduce the risk for RBC transfusions
cular comorbidities) may warrant careful consideration of
differ in patients with and without myelosuppressive che-
ESA use when HgB levels are $ 10 g/dL.
motherapy. However, according to current licensing, ESAs
In rare circumstances, patients with cancer and renal in- are only indicated in patients who are anemic from con-
sufficiency may have concurrent indications for the use of current myelosuppressive chemotherapy and not in pa-
ESAs. Clinicians should also consider guidelines on ESA tients with cancer who are not receiving concurrent
use for CKD-related anemia under these circumstances. myelosuppressive chemotherapy.
CLINICAL QUESTION 2 In patients with MDS, some studies suggest that patients
To reduce the need for RBC transfusions, should ESAs be with elevated baseline erythropoietin levels (. 500 IU/L)
offered to anemic patients with cancer who are not re- are unlikely to respond to ESA therapy.37 Furthermore, a
ceiving concurrent myelosuppressive chemotherapy? recent study has suggested that an even lower baseline
erythropoietin level (, 200 IU/L) is associated with a
Recommendation 2.1 better HgB response.38 ESAs should be avoided in pa-
ESAs should not be offered to most patients with tients with MDS with elevated baseline erythropoietin
nonchemotherapy-associated anemia (Type: informal con- levels (. 500 IU/L). Lower pretreatment RBC transfusion
sensus; Evidence quality: low; Strength of recommendation: dependence (, 2 units per month) has also been asso-
strong). ciated with a higher likelihood of ESA response in patients
with MDS.39 Among the potential benefits of ESA therapy
Recommendation 2.2 in patients with MDS is avoidance of secondary hemo-
ESAs may be offered to patients with lower-risk MDSs and a chromatosis, particularly for lower risk patients who may
serum erythropoietin level # 500 IU/L (Type: evidence have years of survival.
based; Evidence quality: intermediate; Strength of recom- CLINICAL QUESTION 3
mendation: moderate).
What special considerations apply to adult patients with
Literature review update and analysis. The recommenda- nonmyeloid hematologic malignancies who are receiving
tion against ESA use in patients who are not receiving concurrent myelosuppressive chemotherapy?
concomitant myelosuppressive chemotherapy (with the
exception noted in Recommendation 2.2) has been Recommendation 3
reworded, but the intent is the same as in 2010. Rec- In patients with myeloma, non-Hodgkin lymphoma, or
ommendation 2.2 has been revised to specify serum chronic lymphocytic leukemia, clinicians should ob-
erythropoietin levels at which an ESA may be appropriate serve the hematologic response to cancer treatment be-
in MDS. fore considering an ESA. Particular caution should be

1342 © 2019 by American Society of Clinical Oncology Volume 37, Issue 15

 ASCO/ASH ESA Guideline Update

exercised in the use of ESAs concomitant with treatment Recommendation 4

strategies and diseases where risk of thromboembolic Before offering an ESA, clinicians should conduct an ap-
complications is increased (see Recommendations 4 and propriate history, physical examination, and diagnostic
6). In all cases, blood transfusion is a treatment option tests to identify alternative causes of anemia aside from
that should be considered (Type: informal consensus; chemotherapy or an underlying hematopoietic malignancy.
Evidence quality: low; Strength of recommendation: Such causes should be appropriately addressed before
moderate). considering the use of ESAs. Suggested baseline in-
Literature review update and analysis. The 2012 Cochrane vestigations are listed in Table 1 (Type: informal consensus;
review by Tonia et al2 conducted subgroup analyses by Evidence quality: intermediate; Strength of recommenda-
cancer type and provided results for mortality, RBC tion: strong).
transfusion, thromboembolism, and fatigue. Interactions Literature review update and analysis. No new eligible
by cancer type were nonsignificant except for RBC publications were identified by the updated literature review.
transfusions: the reduction in risk of RBC transfusion with
ESA use was greatest among patients with solid tumors. Clinical interpretation. Given the risks associated with the
Other meta-analyses also evaluated subgroups of pa- use of ESAs, it is of the utmost importance to assess the
tients with hematologic malignancies, but only in relation need for and the risks of their use. Therefore, changes to
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to a single outcome: overall survival (nonsignificantly the previous recommendations include clarification of the
associated with ESA use based on a single study of 60 investigations suggested in the work-up of anemia prior to
patients with lymphoma),21 thromboembolism (increased considering the use of ESAs since addressing reversible
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

risk with ESA use),16 or fatigue (decreased risk with causes of anemia is the preferred initial approach. Addi-
ESA use).14 tionally, given the increased risk of thromboembolism,
evaluating thrombotic risk is very important. This is
Clinical interpretation. The FDA label now limits the in- addressed in Clinical Question 6.
dication for ESA use to patients receiving chemotherapy CLINICAL QUESTION 5
for noncurative intent. In patients with nonmyeloid he-
matologic malignancies, who are being treated with pal- Among adult patients who receive an ESA for chemotherapy-
liative intent and in whom a short survival can be associated anemia, do darbepoetin, epoetin beta and alfa
reasonably expected, use of ESAs can be considered if originator, and currently available biosimilars of epoetin
anemia does not improve with treatment of the underlying alfa differ with respect to safety or efficacy?
malignancy and cannot be supported with transfusions Recommendation 5
due to logistical or personal factors or preferences. The Expert Panel considers epoetin beta and alfa, dar-
However, given the recent advances in the treatment of bepoetin, and biosimilar epoetin alfa to be equivalent with
these diseases that have resulted in significant im- respect to effectiveness and safety (Type: informal consen-
provements in survival, very careful consideration should sus; Evidence quality: intermediate; Strength of recom-
be given to the categorization of the treatment intent. mendation: moderate).
Evaluation of individual cases must be based on the intent
of treatment and the life expectancy for each patient. Literature review update and analysis. Three meta-
Because these malignancies recur in most patients but analyses conducted subgroup analyses by type of ESA
multiple treatments are currently available for this situa- (epoetin v darbepoetin).1,2,16 The two agents showed similar
tion, determining the treatment intent and the expected safety and efficacy. One exception to this was reported in
survival requires clinical judgment of an individual pa- the 2012 Cochrane review by Tonia et al.2 Epoetin was
tient’s circumstances. Additionally, the risks of other associated with a larger improvement in fatigue than dar-
complications, in particular, thromboembolic events, bepoetin, but these results may have been confounded by
must be taken into account as many agents can increase three darbepoetin trials without anticancer treatment.
the risk of this complication (eg, immunomodulatory drugs The systematic review of biosimilar ESAs included two
in multiple myeloma). Finally, it should be noted that there meta-analyses27,28 and one RCT29 in patients with CKD,
is little to no information regarding the risks and benefits of and one RCT30 and three cohort studies31-33 in patients with
the concurrent use of ESAs and newer agents, such as cancer. In a 2017 meta-analysis of RCTs in CKD, Amato
monoclonal antibodies and targeted and cellular thera- et al27 reported that efficacy and safety outcomes did not
pies, and therefore, no recommendations can be issued in differ significantly between patients treated with epoetin
this regard. alfa originator or biosimilar but described the quality of
evidence as low to very low. A 2017 Cochrane review by Hahn
CLINICAL QUESTION 4 et al28 focused on short-acting ESAs in predialysis patients.
What examinations and diagnostic tests should be per- The review identified one trial of HX575 (a biosimilar of
formed before making a decision about using an ESA to epoetin alfa), but results were not available; the trial was
identify patients who are likely to benefit from an ESA? stopped early when two patients receiving HX575 developed

Journal of Clinical Oncology 1343

 Bohlius et al

TABLE 1. Suggested Baseline Investigations for Anemia in Patients With Cancer Receiving Chemotherapy
Suggested Investigation
Thorough drug exposure history
Review of a peripheral blood smear*
Analyses, where indicated, for iron, total iron-binding capacity, transferrin saturation, ferritin, folate, vitamin B12, or hemoglobinopathy screening
Assessment of reticulocyte count, occult blood loss, and renal Insufficiency
Baseline erythropoietin level
Testing of serum thyroid-stimulating hormone level, where indicated
Investigations may also include direct antiglobulin testing (eg, Coombs test) for patients with chronic lymphocytic leukemia, non-Hodgkin lymphoma, or a
history of autoimmune disease

NOTE. Suggestions are based on the consensus of the Expert Panel. This is not intended to be a comprehensive list of investigations.
*And in some cases, a bone marrow examination.

antibodies to epoetin and pure red cell aplasia. HX575 was were confirmed in another Italian retrospective cohort study,
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also evaluated in a 2017 RCT by Weir et al.29 The trial enrolled which did not find a difference in HgB response among new
adults with end-stage renal disease who were on dialysis and users of either biosimilars or reference product of epoetin
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

had been receiving stable doses of epoetin alfa. Patients were alfa or other ESAs in either CKD or patients with cancer
randomly assigned to continue epoetin alfa or to receive during the first 3 months of treatment.34
HX575. The two agents were similarly effective at maintaining
Clinical interpretation. Based on limited evidence, it seems
stable HgB levels. Binding anti-erythropoietin antibodies
that compared with the originator, biosimilars of epoetin alfa
developed in six patients (2.8%) in the HX575 arm and one
are safe and effective. However, the evidence is of moderate
patient (0.5%) in the epoetin alfa arm, but no patients de-
to low quality, and this is derived from studies in patients with
veloped neutralizing anti-erythropoietin antibodies.
cancer and CKD. Biosimilars have been available in Europe
The single RCT in patients with cancer was small: 60 for over 10 years, and no major concerns have arisen. In the
patients assigned to HX575 and 34 assigned to epoetin alfa United States, these agents are more recent. Users should
were included in the analysis.30 All patients had solid review pertinent approvals and indications as per their local
tumors and chemotherapy-associated anemia. HX575 regulatory authorities. Ultimately, the choice of a particular
appeared to be effective with respect to HgB response, but agent will depend on cost, availability, convenience, and
the possibility of bias in this study limits firm conclusions. A personal considerations or preference.40,41
large retrospective population-based cohort study in Italy
CLINICAL QUESTION 6
evaluated more than 13,000 new ESA users, 8161 with
CKD and 5,309 with cancer.33 A biosimilar epoetin alfa had Do ESAs increase the risk of thromboembolism?
been used by 154 (1.9%) of the patients with CKD and 453 Recommendation 6
(8.5%) of the patients with cancer. Biosimilar and originator
epoetin alfa had similar safety and efficacy in both CKD and ESAs increase the risk of thromboembolism, and clinicians
cancer with one exception: among patients with cancer, should carefully weigh the risks of thromboembolism and
biosimilar epoetin alfa was associated with lower overall use caution and clinical judgment when considering use of
mortality than the originator (HR, 0.82; 95% CI, 0.70 to these agents (Type: evidence based; Evidence quality:
0.97), but this finding is not conclusive because residual high; Strength of recommendation: strong).
confounding could not be excluded since more patients in Literature review update and analysis. The publications in
the originator group died of cancer activity. A retrospective the updated review consistently report an increased risk of
study of patients with MDS and refractory anemia evaluated thromboembolism in ESA-treated patients.1,2,6,16,19,25 This
46 patients treated with biosimilar epoetin alfa and 46 increased thromboembolic risk with ESA use was observed
patients with originator epoetin alfa. Median time to reach across categories of baseline HgB,2 type of cancer,2,16,25
an HgB level . 12 g/dL was 10.5 weeks (range, 3 to and type of ESA.1,2,16
16 weeks) among patients treated with the biosimilar and Clinical interpretation. Meta-analyses and individual
12 weeks (range, 4 to 18 weeks) among patients treated RCTs consistently report a 50%1,2 to 75%16,25 increased
with the originator product.31 Finally, a retrospective study of risk of thromboembolism and vascular arterial events
419 patients with cancer compared biosimilar epoetin alfa among patients receiving ESA therapy. The Expert Panel
with darbepoetin alfa.32 Mean HgB increase was similar in continues to urge caution in the use of ESAs for patients
the two groups. Blood transfusions were received by 8% of judged to be at increased risk for venous thromboembolism.
patients treated with biosimilar epoetin alfa and 14% of Several risk scores for predicting venous thromboembolism
patients treated with darbepoetin alfa (P = .04). These results have been developed; these are discussed in more detail in

1344 © 2019 by American Society of Clinical Oncology Volume 37, Issue 15

 ASCO/ASH ESA Guideline Update

the ASCO guideline on venous thromboembolism.42 Special Clinical interpretation. No new evidence suggests that
attention should be given to patients with multiple myeloma outcomes of ESA therapy would be improved by use of an
who are being treated with thalidomide or lenalidomide and initial dose or dose modification regimen other than those in
doxorubicin or corticosteroids since they are at particularly the FDA-approved labels. Note that some aspects of the
increased thrombotic risk.43 There are no data from RCTs labels’ dose increase recommendations have changed
investigating concomitant use of anticoagulants or aspirin to (Table 2).
lessen this risk.
CLINICAL QUESTION 8
CLINICAL QUESTION 7 Among adult patients who will receive an ESA for
Among adult patients who will receive an ESA for chemotherapy-associated anemia, what is the recom-
chemotherapy-associated anemia, what are recommen- mended target HgB level?
dations for ESA dosing and dose modifications? Recommendation 8
Recommendation 7 HgB may be increased to the lowest concentration needed
It is recommended that starting and modifying doses of to avoid or reduce the need for RBC transfusions, which
ESAs follow FDA guidelines (see Table 2 for specific may vary by patient and condition (Type: informal consensus;
Evidence quality: intermediate; Strength of recommendation:
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dosing information; Type: informal consensus; Evidence

quality: intermediate; Strength of recommendation: moderate).
moderate). Literature review update and analysis. No new eligible
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

publications were identified by the updated literature

Literature review update and analysis. This recommenda-
review.
tion remains unchanged. No publications in the updated
literature review supported nonstandard dosing. Duration Clinical interpretation. An optimal target HgB concentration
of treatment was analyzed in the 2012 Cochrane review and cannot be definitively determined from the available literature.
did not significantly modify the association between ESA Modification to reduce the ESA dose is appropriate when HgB
use and on-study mortality, overall survival, likelihood of reaches a level sufficient to avoid transfusion or the increase
RBC transfusion, risk of thromboembolism, or fatigue.2 exceeds 1 g/dL in any 2-week period to avoid excessive ESA

TABLE 2. ESA Adult Dosing

Dose and
Modifications Epoetin Alfa* Darbepoetin Alfa
Initial dose† 150 U/kg SC TIW‡ 40,000 U SC weekly§ 2.25 mg/kg SC weekly‡ 500 mg SC
Q3W§
Dose increases Increase dose to 300 U/kg SC TIW if Increase dose to 60,000 U SC weekly Increase dose to 4.5 mg/kg weekly if N/A
HgB increases by , 1 g/dL and if HgB increases by , 1 g/dL and HgB increases by , 1 g/dL and
remains below 10 g/dL after remains below 10 g/dL after remains below 10 g/dL after
4 weeks of therapy 4 weeks of therapy 6 weeks of therapy
Dose reductions Decrease dose by 25% when HgB reaches a level needed to avoid transfusion Decrease dose by 40% when HgB reaches a level
or HgB increases . 1 g/dL in 2 weeks needed to avoid transfusion or HgB increases . 1
g/dL in 2 weeks
Dose withholding If HgB exceeds a level needed to avoid transfusion, restart dose at 25% below If HgB exceeds a level needed to avoid transfusion,
previous dose when HgB approaches a level where transfusion may be restart dose at 40% below previous dose when
required HgB approaches a level where transfusion may be
required
Discontinuek Following completion of chemotherapy course or if no response after 8 weeks Following completion of chemotherapy course or if no
of therapy (measured by HgB levels or continuing need for transfusions) response after 8 weeks of therapy (measured by
HgB levels or continuing need for transfusions)

NOTE. Food and Drug Administration product labels were accessed on June 8, 2018, for epoetin (https://www.accessdata.fda.gov/drugsatfda_docs/label/
2017/103234s5363s5366lbl.pdf) and for darbepoetin (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103951s5374lbl.pdf).
Abbreviations: ESA, erythropoiesis-stimulating agent; HgB, hemoglobin; N/A, not applicable; Q3W, every 3 weeks; SC, subcutaneously; TIW, three times
per week.
*Including epoetin alfa-epbx.
†Initiate only if HgB is , 10 g/dL and there is a minimum of two additional months of planned chemotherapy. Use and dosing differ in patients with
myelodysplastic syndromes.
‡Weight-based dose.
§Fixed dose.
kPatients who do not respond to ESA treatment should be re-evaluated for underlying tumor progression, iron deficiency, or other etiologies for anemia.

Journal of Clinical Oncology 1345

 Bohlius et al

exposure, considering the risks of ESAs. Specific dose- hematopoietic response (P = .16). Findings in the two earlier
reduction recommendations are provided in Table 2. meta-analyses15,22 were generally similar.
CLINICAL QUESTION 9 Clinical interpretation. This recommendation changed
Among adult patients with chemotherapy-associated ane- from previous versions based on new information published
mia who do not respond to ESA therapy (, 1 to 2 g/dL after the last guideline. The Expert Panel believes that the
increase in HgB or no decrease in transfusion requirements), use of iron supplementation in all patients receiving ESAs
does continuation of ESA therapy beyond 6 to 8 weeks should be considered, independent of the iron status. This is
provide a benefit? based on evidence that iron supplementation reduces the
risk for RBC transfusion. Additionally, in patients with evi-
Recommendation 9 dence of iron deficiency, the cause of the deficiency should
ESAs should be discontinued in patients who do not re- be investigated and corrected.
spond within 6 to 8 weeks. Patients who do not respond to Oral and IV iron formulations are both acceptable options
ESA treatment should be reevaluated for underlying tumor for iron supplementation. Choice of agents depends on
progression, iron deficiency, or other etiologies for anemia patient and doctor preferences, formulation availability,
(Type: informal consensus; Evidence quality: intermediate; cost, and comorbidities. IV iron preparations have the
Strength of recommendation: strong).
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advantage of being able to deliver larger amounts of ele-

Literature review update and analysis. No publications in mental iron in a single application and may also be more
the updated literature review addressed ESA continuation adequate in patients with poor oral intake or absorption
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

in nonresponders. problems. They have the disadvantages of being associated

with more serious systemic reactions and higher costs.
Clinical interpretation. Given the known harms of ESAs, the There is some limited evidence that IV iron is superior to oral
exposure to ESAs should be minimized. In patients who iron based on improvement in HgB level. However, the
have received appropriate ESA dosing (see Recommen- results were not consistent across all other hematologic
dation 7) and who do not respond, ESAs should be stopped outcomes, and the quality of adverse outcomes reporting
and not continued. was poor.15,20,22 Safety has been better studied in a sys-
tematic review and meta-analysis in patients with CKD,
CLINICAL QUESTION 10
which showed no difference in mortality or serious adverse
Among adult patients with chemotherapy-associated events in patients receiving intravenous iron, although there
anemia, does iron supplementation concurrent with an were more episodes of hypotension with IV iron.44
ESA reduce transfusion requirements?
Recommendation 10
DISCUSSION
Iron replacement may be used to improve HgB response
Although the use of ESAs reduces the need for transfusions in
and reduce RBC transfusions for patients receiving ESA
anemic patients with cancer receiving chemotherapy, it is
with or without iron deficiency. Baseline and periodic
associated with increased complications, including higher
monitoring of iron, total iron-binding capacity, transferrin
mortality and increased risk of thromboembolic and cardio-
saturation, or ferritin levels is recommended (Type: evi-
vascular events. For these reasons, the use of ESAs in cancer
dence based; Evidence quality: intermediate; Strength of
is now generally limited to patients who are receiving che-
recommendation: weak).
motherapy with palliative intent and who are expected to have
Literature review update and analysis. The use of supple- short survival. The decision about using ESAs must be made
mental iron with an ESA was evaluated in three meta- in this context and with a thorough discussion regarding each
analyses.15,20,22 Compared with an ESA alone, a 2016 patient’s preferences, priorities, values, and spiritual needs.
Cochrane review by Mhaskar et al20 reported that the
combination of an ESA and iron increased the likelihood PATIENT-CLINICIAN COMMUNICATION
of hematopoietic response (RR, 1.17; 95% CI, 1.09 to
Patient counseling regarding the risks and benefits of ESA
1.26) and reduced the likelihood of RBC transfusion (RR,
therapy is essential to ensure that patients are making
0.74; 95% CI, 0.60 to 0.92) without significantly affecting
informed decisions. The Expert Panel encourages health
risk of thromboembolism (RR, 0.95; 95% CI, 0.54 to 1.65) or
care providers to have an open dialogue with their patients
quality of life (standardized mean difference, 0.01; 95%
to help them make informed decisions by considering the
CI, 20.10 to 0.12). Intravenous (IV) iron provided a greater
scientific evidence and weighing their individual risks with
benefit than oral iron with respect to mean change in HgB
potential harms and benefits of ESA therapy.
level (IV iron mean difference, 0.84; 95% CI, 0.21 to 1.46;
P = .009; oral iron mean difference, 0.07; 95% CI, 20.19 to In addition to providing a medication guide, health care
0.34; P = .59; P = .03 for interaction). Route of iron ad- providers should discuss the following with patients con-
ministration did not significantly modify the association with sidering ESA therapy:

1346 © 2019 by American Society of Clinical Oncology Volume 37, Issue 15

 ASCO/ASH ESA Guideline Update

• When used, the goal of ESA therapy for patients with As many patients for whom guideline recommendations
chemotherapy-induced anemia is to reduce RBC apply present with MCC, any treatment plan needs to
transfusion requirements. consider the complexity and uncertainty created by the
• The FDA has indicated that ESAs should not be given presence of MCC and highlights the importance of shared
to patients who are being treated for cancer when the decision making regarding guideline use and imple-
goal is to cure the patients of cancer. mentation. Therefore, in consideration of recommended
• ESAs have been found to shorten overall survival and/ care for the target index condition, clinicians should review
or speed tumor growth in some patients with cancer. all other chronic conditions present in the patient and take
• ESAs have risks of adverse events, such as throm- those conditions into account when formulating the treat-
boembolism (ie, blood clots), so individual risk factors ment and follow-up plan.
need to be considered. In light of these considerations, practice guidelines should
• ESAs are not recommended for patients with cancer provide information on how to apply the recommendations
who are not receiving chemotherapy, except in the for patients with MCC, perhaps as a qualifying statement
case of patients with lower risk MDS. for recommended care. This may mean that some or all of
For general recommendations and strategies to optimize the recommended care options are modified or not ap-
patient-clinician communication, see “Patient-Clinician plied, as determined by best practice in consideration of
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Communication: American Society of Clinical Oncology any MCC.

Consensus Guideline.”45
COST IMPLICATIONS
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

Increasingly, individuals with cancer are required to pay a

HEALTH DISPARITIES
larger proportion of their treatment costs through de-
Although ASCO and ASH clinical practice guidelines repre- ductibles and coinsurance.50,51 Higher patient out-of-
sent expert recommendations on the best practices in dis- pocket costs have been shown to be a barrier to initiating
ease management to provide the highest level of cancer care, and adhering to recommended cancer treatments.52,53
it is important to note that many patients have limited access
Discussion of cost can be an important part of shared
to medical care. Racial and ethnic disparities in health care
decision making.54 Clinicians should discuss with patients
contribute significantly to this problem in the United States.
the use of less expensive alternatives when it is practical
Patients with cancer who are members of racial/ethnic mi-
and feasible for treatment of the patient’s disease and there
norities suffer disproportionately from comorbidities, experi-
are two or more treatment options that are comparable in
ence more substantial obstacles to receiving care, are more
terms of benefits and harms.54
likely to be uninsured, and are at greater risk of receiving care
of poor quality than other Americans.46-49 Many other patients Table 3 shows estimated prices for the available treatment
lack access to care because of their geographic location and options addressed in this guideline. Of note, medication
distance from appropriate treatment facilities. Awareness of prices may vary markedly, depending on negotiated dis-
these disparities in access to care should be considered in counts and rebates.
the context of this clinical practice guideline, and health care Patient out-of-pocket costs may vary depending on in-
providers should strive to deliver the highest level of cancer surance coverage. Coverage may originate in the medical
care to these vulnerable populations. or pharmacy benefit, which may have different cost-
sharing arrangements. Patients should be aware that
MULTIPLE CHRONIC CONDITIONS different products may be preferred or covered by their
Creating evidence-based recommendations to inform particular insurance plan. Even with the same insurance
treatment of patients with additional chronic conditions, a plan, the price may vary between different pharmacies.
situation in which the patient may have two or more such When discussing financial issues and concerns, patients
conditions—referred to as multiple chronic conditions should be made aware of any financial counseling ser-
(MCC)—is challenging. Patients with MCC are a complex vices available to address this complex and heteroge-
and heterogeneous population, making it difficult to ac- neous landscape.54
count for all of the possible permutations to develop specific
recommendations for care. In addition, the best available OPEN COMMENT
evidence for treating index conditions, such as cancer, is often The draft recommendations were released to the public for
from clinical trials whose study selection criteria may exclude open comment from August 15, 2018, through August 29,
these patients to avoid potential interaction effects or con- 2018. Response categories of “Agree as written,” “Agree
founding of results associated with MCC. As a result, the with suggested modifications,” and “Disagree. See com-
reliability of outcome data from these studies may be limited, ments” were captured for every proposed recommendation
thereby creating constraints for expert groups to make recom- with two written comments received. Both respondents ei-
mendations for care in this heterogeneous patient population. ther agreed or agreed with slight modifications to the

Journal of Clinical Oncology 1347

 Bohlius et al

TABLE 3. Estimated Prices of ESAs and Supplemental Iron

HCPCS Code Medicare Payment
Agent Dosage Limit (US$) Initial Dose Regimen Price
ESAs
Darbepoetin alfa 1 mg 3.779 2.25 mg/kg SC Weekly (SC) $1,785.58 per 3-week cycle*
(non-ESRD)
500 mg SC Every 3 $1,889.50 per 3-week cycle
weeks (SC)
Epoetin alfa (non- 1,000 U 13.333 150 U/kg 3 times $1,259.97 per 3-week cycle*
ESRD) weekly
(SC)
40,000 U Weekly (SC) $1,599.96 per 3-week cycle
Iron Supplements
Iron dextran 50 mg 13.669 Variable IV $273.38 per 1,000 mg
Ferric gluconate 12.5 mg 2.179 Variable IV $174.32 per 1,000 mg
Iron sucrose 1 mg 0.234 Variable IV $234.00 per 1,000 mg
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Ferrous sulfate N/A N/A Variable Oral Available over the counter. Prices at a
sample of online retailers ranged from
$0.01-$0.11 per 325-mg tablet
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

NOTE. Drug prices were estimated from a third-party payer perspective, based on reimbursement rates from the Centers for Medicare and Medicaid
Services that are widely accepted by providers, computed at the manufacturer’s average sales price. Other treatment-related direct and indirect costs were not
considered, such as diagnostic laboratory tests. Actual treatment costs and reimbursement will vary considerably across regions, payers, institutions, and
practices, as well as over time, and readers should consult current local cost information specific to their practice setting. Costs were based on Medicare Part
B payment allowance limits effective July 1, 2018 (with no administration fees or other adjustments; Medicare Part B Drug Average Sales Price: https://www.
cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/2018ASPFiles.html).
Abbreviations: ESAs, erythropoiesis-stimulating agents; ESRD, end-stage renal disease; HCPCS, Healthcare Common Procedure Coding System; IV,
intravenously; N/A, not applicable; SC, subcutaneously.
*Based on an adult weighing 70 kg.

recommendations. Expert Panel members reviewed com- consistent evidence of harm associated with their use
ments from all sources and determined whether to maintain across a spectrum of conditions. Since in recent years the
original draft recommendations, revise with minor language number of new trials is somewhat limited yet consistent with
changes, or consider major recommendation revisions. All previous findings, we believe that rather than focusing on
changes were incorporated prior to ASCO Clinical Practice the occurrence of adverse effects, the most pressing need
Guidelines Committee review and approval. for additional research is studies that further clarify the
mechanisms of harm and, particularly, the groups of pa-
GUIDELINE IMPLEMENTATION tients or circumstances of clinical use that are least as-
ASCO and ASH guidelines are developed for implementation sociated with these risks. This information is paramount to
across health settings. Barriers to implementation include the ability of clinicians to extend the benefit of these drugs
the need to increase awareness of the guideline rec- while reducing the risks.
ommendations among front-line practitioners, survivors
of cancer, and caregivers, as well as the need to provide
adequate services in the face of limited resources. The
guideline Bottom Line Box was designed to facilitate RELATED ASCO GUIDELINES
implementation of recommendations. This guideline will
• Venous Thromboembolism Prophylaxis and
be distributed widely through the ASCO Practice
Treatment in Patients With Cancer.42 (http://
Guidelines Implementation Network. ASCO and ASH
ascopubs.org/doi/10.1200/JCO.2014.59.7351)
guidelines are posted on each organization’s Web site,
• Integration of Palliative Care Into Standard On-
and this guideline is jointly published in JCO and Blood
cology Care.55 (http://ascopubs.org/doi/10.1200/
Advances.
JCO.2016.70.1474)
• Patient-Clinician Communication.45 (http://
LIMITATION OF THE RESEARCH AND FUTURE RESEARCH
ascopubs.org/doi/10.1200/JCO.2017.75.2311)
There is clear evidence regarding the ability of ESAs to
increase HgB and avoid transfusions. There is also very

1348 © 2019 by American Society of Clinical Oncology Volume 37, Issue 15

 ASCO/ASH ESA Guideline Update

AFFILIATIONS including a Data Supplement with additional evidence tables, slide sets,
1
University of Bern, Bern, Switzerland clinical tools and resources, and links to patient information at www.
2
American Society of Clinical Oncology, Alexandria, VA cancer.net, is available at www.asco.org/supportive-care-guidelines, and
3
University of Milan, Milan, Italy as a supplement to the Blood Advances version of the article. Additional
4
City of Hope, Duarte, CA evidence-based clinical practice guidelines are also available at www.
5
Ohio State University, Columbus, OH hematology.org/guidelines.
6
Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, Italy
7
Henry Dunant Hospital Center Athens, Greece AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
8
Advocate Medical Group, Orland Park, IL AND DATA AVAILABILITY STATEMENT
9
Independent Patient Advocate, Washington, DC Disclosures provided by the authors and data availability statement (if
10
UC San Diego Moores Cancer Center, La Jolla, CA applicable) are available with this article at DOI https://doi.org/10.1200/
11
University of Messina, Messina, Italy JCO.18.02142.
12
Thomas Jefferson University, Philadelphia, PA
13
Western University, London, Ontario, Canada AUTHOR CONTRIBUTIONS
Conception and design: Julia Bohlius, Benjamin Djulbegovic, Massimo
CORRESPONDING AUTHOR Martino, Laura Porter, Gianluca Trifirò, Alejandro Lazo-Langner
American Society of Clinical Oncology, 2318 Mill Rd, Ste 800, Collection and assembly of data: Julia Bohlius, Massimo Martino, Giannis
Alexandria, VA 22314; e-mail: [email protected]. Mountzios, Namrata Peswani, Laura Porter, Tiffany N. Tanaka, Gianluca
Trifirò, Hushan Yang, Alejandro Lazo-Langner
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This guideline was developed through a collaboration between the Data analysis and interpretation: Julia Bohlius, Kari Bohlke, Roberto
American Society of Hematology and the American Society of Clinical Castelli, Benjamin Djulbegovic, Maryam B. Lustberg, Massimo Martino,
Oncology and has been published jointly by invitation and consent in both Giannis Mountzios, Laura Porter, Tiffany N. Tanaka, Gianluca Trifirò,
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

Blood Advances and Journal of Clinical Oncology. Copyright © 2019 Hushan Yang, Alejandro Lazo-Langner
American Society of Hematology and American Society of Clinical Manuscript writing: All authors
Oncology. All rights reserved. No part of this document may be Final approval of manuscript: All authors
reproduced or transmitted in any form or by any means, electronic or
Accountable for all aspects of the work: All authors
mechanical, including photocopy, recording, or any information storage
and retrieval system, without written permission by the American Society
of Hematology or the American Society of Clinical Oncology. ACKNOWLEDGMENT
The Expert Panel wishes to thank Bryan Schneider, MD, Charles Shapiro,
Editor’s note: This American Society of Clinical Oncology (ASCO) and MD, the ASCO Clinical Practice Guidelines Committee, the ASH
American Society of Hematology (ASH) Clinical Practice Guideline Guideline Oversight Subcommittee, the ASH Committee on Quality, and
provides recommendations, with comprehensive review and analyses of ASH Officers for their thoughtful reviews of this guideline.
the relevant literature for each recommendation. Additional information,

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n n n
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held
unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about
ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Benjamin Djulbegovic Gianluca Trifirò

Research Funding: GlaxoSmithKline (Inst) Consulting or Advisory Role: Bayer, Novartis, Servier, Sandoz-Novartis, Ipsen,
Sanofi, Grünenthal Group, Otsuka, Biogen
Maryam B. Lustberg
Research Funding: Amgen (Inst), Daiichi Sankyo (Inst), IBSA (Inst),
Consulting or Advisory Role: Tempus, PledPharma, Hologic/Cynosure
AstraZeneca (Inst)
Massimo Martino
Consulting or Advisory Role: Italfarmaco, Kyowa Hakko Kirin, Teva, Sandoz- Alejandro Lazo-Langner
Novartis, Amgen, Takeda Research Funding: Alexion Pharmaceuticals (Inst), Bayer (Inst), Daiichi Sankyo
Travel, Accommodations, Expenses: Takeda, Janssen-Cilag, Celgene, Sanofi (Inst), Pfizer (Inst), Bristol-Myers Squibb (Inst)
Giannis Mountzios No other potential conflicts of interest were reported.
Honoraria: Roche, Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme,
Astra Zeneca Greece
Speakers’ Bureau: AstraZeneca
Travel, Accommodations, Expenses: AstraZeneca, Ipsen
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Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

© 2019 by American Society of Clinical Oncology Volume 37, Issue 15

 ASCO/ASH ESA Guideline Update

APPENDIX

TABLE A1. Expert Panel Membership: Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: American Society of Clinical
Oncology/American Society of Hematology Clinical Practice Guideline Update
Name (and designation) Affiliation/Institution Role/Areas of Expertise
Julia Bohlius, MD, MScPH Institute of Social and Preventive Medicine, University of Systematic review and meta-analyses; evidence-based
Bern, Bern, Switzerland medicine and guideline development
Alejandro Lazo-Langner, MD, MSc Western University, London, Ontario, Canada Hematology; epidemiology
Roberto Castelli, MD, PhD Department of Biomedical and Clinical Sciences Luigi Hematology
Sacco, Luigi Sacco Hospital Milan, University of Milan,
Milan, Italy
Benjamin Djulbegovic, MD, PhD City of Hope, Departments of Supportive Medicine and Hematology, supportive care
Hematology, Duarte, CA
Maryam B. Lustberg, MD, MPH Ohio State University, Columbus, OH Medical oncology, breast cancer, treatment-related
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toxicity, survivorship
Massimo Martino, MD Azienda Ospedaliera Bianchi Melacrino Morelli, Hematology
Hematology and Stem Cell Transplant Unit, Reggio
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

Calabria, Italy
Giannis Mountzios, MD, MSc, PhD 251 General Air Force Hospital and 2nd Medical Tumor biology, genitourinary cancer, lung cancer,
Oncology Department, Henry Dunant Hospital Center, biologic therapy, clinical trials/biostatistics/
Athens, Greece epidemiology; medical oncology
Namrata Peswani, MD Advocate Medical Group, Orland Park, IL Hematology/oncology, palliative care, ASCO Practice
Guidelines Implementation Network
Laura Porter, MD Washington, DC Independent patient advocate
Tiffany N. Tanaka, MD UC San Diego Moores Cancer Center, La Jolla, CA Hematology, myelodysplastic syndrome, supportive care
Gianluca Trifirò, MD, PhD Department of Biomedical and Dental Sciences and Clinical pharmacology, pharmacovigilance, and
Morphofunctional Imaging, University of Messina, pharmacoepidemiology
Messina, Italy
Hushan Yang, PhD Division of Population Science, Department of Medical Cancer biomarkers, statistical models for cancer risk and
Oncology, Sidney Kimmel Cancer Center, Thomas prognosis assessment
Jefferson University, Philadelphia, PA
Kari Bohlke, ScD American Society of Clinical Oncology, Alexandria, VA Staff/health research methodologist

Journal of Clinical Oncology