Use of ESAs to Treat Patients With Myelodysplastic Syndromes

Peter Greenberg, MD

2010-04-27

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 grassroots@hematology.org.

  1. 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.
  2. 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.
  3. 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.
  4. 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. 2009;114:2393-2400.
  5. 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.
  6. 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.
  7. 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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