Peter Greenberg, MD
Director, Stanford Myelodysplastic
Syndrome Center and Emeritus Professor, Stanford University School of Medicine Chairman
of the NCCN Panel on MDS
On February 16, the U.S. Food and Drug
Administration (FDA) announced that drugs categorized as
erythropoiesis-stimulating agents (ESAs) must be prescribed under a risk
management program, known as a Risk Evaluation and Mitigation Strategy (REMS),
to ensure their safe use. The FDA cited safety concerns from data in clinical
studies with ESAs in patients with solid tumors (breast, non-small-cell lung,
head and neck, lymphoid, and cervical cancers) in which shortened overall
survival and/or increased risk of tumor progression or recurrence, as well as
increased thrombotic events in those patients with renal disease, occurred (www.fda.gov/Drugs/DrugSafety/).
As part of the REMS, a Medication Guide explaining the risks and
benefits of ESAs will be provided to all patients receiving ESAs. In addition,
Amgen, the manufacturer of these products, is required to develop the ESA
Assisting Providers and Cancer Patients With Risk Information for the Safe Use of ESAs
(APPRISE) Oncology program for health-care professionals who prescribe ESAs to
patients with cancer. Only those hospitals and health-care professionals who
have enrolled and completed training in the program will be able to prescribe
and dispense ESAs to patients with cancer. The program was implemented on March
24, and doctors will have a year grace period to sign up.
Since the FDA announced the REMS
program, questions and concerns have been raised about how the program will
apply to patients with myelodysplastic syndromes (MDS). ESA use in MDS is
off-label. The FDA has indicated that patients with MDS who are prescribed ESAs
are not included in the APPRISE program, because this program does not address
off-label uses of ESAs. However, as part of the REMS program, a Medication Guide is required to be distributed to all patients whenever an ESA is
dispensed, for either an approved or an unapproved indication.
This review is written to aid the
understanding of the risks and benefits of ESAs in MDS. Numerous studies have
indicated the relative efficacy of ESAs in large numbers of adults with MDS.1,2
Of importance for enhancing the efficacy of these agents (i.e., decreasing RBC
transfusion requirements) is patient selection to include those symptomatically
anemic patients with baseline hemoglobin levels ≤10 gm/dl who have relatively
low serum erythropoietin (Epo) levels (<200 or 500 mU/ml). Improved
responses are noted in International Prognostic Scoring System (IPSS) lower
risk patients (low/intermediate-1) compared to the more advanced higher risk
(intermediate-2/high) category patients. Recommended Epo doses are 40 to 60,000
units once or twice weekly for approximately two months in order to determine
potential responsiveness. For non-responding patients, particularly those with
ring sideroblasts, the addition of lenograstim (granulocyte-colony stimulating
factor, G-CSF) is often synergistic.3
Investigations assessing the long-term
efficacy and safety of RBC transfusion support plus Epo with or without G‑CSF in an ECOG phase III study of lower-risk MDS patients
compared to either randomized controls receiving transfusion support only4 or
others using historical controls5,6 have shown effective erythroid responses to
the cytokines in approximately 40 percent of patients with no negative impact
on survival or AML evolution. In addition, Jadersten et al. reported improved
survival in lower-risk MDS patients with low transfusion who were treated with
these agents.5 A study by Park et al. indicated improved survival and decreased
AML progression of the lower-risk patients treated with Epo/G-CSF compared to the
historical control.6 In the ECOG study, no significant treatment-related
increase in incidence of either cardiovascular or thrombotic events occurred in
the ESA arm.4 Thus, published data do not show a negative impact of these drugs
for treatment of MDS.
Given these findings, the NCCN MDS
Practice Guidelines Panel endorsed its prior recommendations supporting
judicious ESA use in the management of symptomatic anemia in lower-risk MDS
patients but with a change in the target hemoglobin level to ≤12 gm/dl.7
ASH continues to seek further
clarification from the FDA about how the REMS will apply to MDS patients,
including clarification about the frequency required to provide Medication
Guides. Physicians who have questions about how the REMS will apply to your
MDS patients are encouraged to contact the ASH Government Relations &
Practice Department at email@example.com.
- Hellström-Lindberg E. Efficacy
of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205
patients from 17 studies. Br J Haematol. 1995;89:67-71.
- Gotlib J, Greenberg P, ed. “Supportive care in myelodysplastic
syndrome: hemopoietic cytokines and iron chelation therapy.” Myelodysplastic
Syndromes: Clinical and Biological Advances. Cambridge, England: Cambridge
University Press, 2006, pp 209-42.
- Hellström-Lindberg E, Negrin R, Stein R, et al. Erythroid
response to treatment with G-CSF plus erythropoietin for the anaemia of
patients with myelodysplastic syndromes: proposal for a predictive model.
Br J Haematol. 1997;99:344-51.
- Greenberg PL,
Sun Z, Miller KB, et al. Treatment
of myelodysplastic syndromes patients with erythropoietin with or without
granulocyte colony‑stimulating factor: results of a prospective randomized
phase III trial by the Eastern Cooperative Oncology Group (E1996). Blood.
- Jädersten M, Malcovati L, Dybedal I, et al. Erythropoietin
and granulocyte‑colony stimulating factor treatment associated with improved
survival in myelodysplastic syndrome. J Clin Oncol. 2008;26:3607-13.
- Park S, Grabar
S, Kelaidi C, et al. Predictive
factors of response and survival in myelodysplastic syndrome treated with
erythropoietin and G-CSF: the GFM experience. Blood 2008;111:574-82.
- Greenberg PL, Attar E, Battiwalla M, et al. NCCN Practice
Guidelines for Myelodysplastic Syndromes. National Comprehensive Cancer
Network 2008;6:902-25; Version 2: 2010.
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