Editor’s Note:The Centers for Medicare and Medicaid Services (CMS) released a national coverage determination (NCD) for coverage of erythropoiesis-stimulating agents (ESAs) for non-renal uses on July 30. In response to recommendations by ASH and other organizations, the NCD does not exclude coverage of ESA therapy for patients with myelodysplasia (MDS). The new policy does not include MDS, which means that ESA treatment for Medicare beneficiaries with MDS continues to be covered without any conditions or limitations. Local Medicare carriers, however, may continue to make local coverage decisions that are not included in this NCD. As an expert in MDS and as Chair of the NCCN Panel on MDS, Dr. Peter Greenberg was asked to provide comments on the controversy surrounding the use of ESAs. This information may be useful to hematologists if local carriers require information and references in order to support the coverage of ESAs for MDS.

In March 2007, the FDA announced alerts and strengthened safety warnings for the use of erythropoiesis-stimulating agents (ESAs), predominantly recombinant human erythropoietin and darbepoietin. They noted that increased mortality, possible tumor promotion, and thromboembolic events were observed in patients receiving ESAs when dosing targeted hemoglobin levels >12 gm/dL. These studies were performed in patient groups with chronic kidney failure, head and neck cancer receiving radiation therapy, or in other patients with cancer not receiving chemotherapy, and in those patients undergoing orthopedic surgery.

As a result of these statements, the Centers for Medicare and Medicaid Services (CMS) opened a National Coverage Analysis to evaluate the use of ESAs in all non-renal disease applications. Although the prompt response of CMS to the FDA-issued warning was commendable, as it was aimed at protecting patients, the broad-based language of the FDA warning created an unfortunate dilemma.

In addition to patients with renal disease, cancer patients with symptomatic anemia resulting from chemotherapy, and patients infected with HIV taking zidovudine, there are many other patients with symptomatic anemia who clearly benefit from the use of ESAs when used in a responsible and appropriate manner. One group of patients potentially most urgently affected by the FDA alert and the possible non-coverage by CMS were patients with myelodysplastic syndromes (MDS) who receive ESAs for their refractory anemia. Patients with MDS are generally elderly and many are eligible for Medicare coverage. ESAs in these patients often have not only a positive effect on their quality of life, but data have also recently indicated beneficial effects on their survival and risk of progression to AML. As part of the process that CMS went through in the National Coverage Analysis, data were presented to CMS arguing for the efficacy of ESAs in patients with MDS.

ESAs have been used safely in large numbers of adult patients with MDS and have become important for symptomatic improvement of those affected by the anemia caused by this disease, often with a decrease in RBC transfusion requirements. Published data on the safe and effective use of ESAs in patients with MDS that span more than a decade are available. Prior National Comprehensive Cancer Network (NCCN) MDS Practice Guidelines Panel recommendations for use of ESAs in MDS have evolved from these and more recent data (NCCN MDS Practice Guidelines v.1.2007; see algorithm on MDS-6, www.nccn.org).

Regarding the potential impact of recombinant human erythropoietin (Epo) on clinical outcomes in MDS, data have been reported in several recent abstracts and in one paper that bear on this subject. Studies in MDS patients with <10 percent marrow blasts or those in the International Prognostic Scoring System (IPSS) Low/Int-1 risk categories assessing the long term use of Epo with or without granulocyte-colony stimulating factor (G-CSF, lenograstim) compared to either randomized controls1  or historical controls2,3,4  have shown no negative impact on survival or AML evolution of such treatment. In addition, reference 3 indicated improved survival in lower-risk MDS patients with low transfusion requirements treated with these agents. Reference 4 demonstrated improved survival and decreased AML progression of IPSS Low/Int-1 MDS patients treated with Epo plus G-CSF compared to historical control patients within the International MDS Risk Analysis Workshop (IMRAW) database (patients were from reference 5). Thus, these data do not indicate a negative impact of these drugs for treatment of MDS. In addition to the positive impact on survival and transformation to AML, accumulating data in MDS indicate that debilitating fatigue and transfusion dependence significantly and negatively impact patients’ quality of life6 .

A major aim in management of MDS patients having symptomatic anemia is to decrease the need for RBC transfusions. The potential negative consequences of recurrent RBC transfusions are well recognized: iron overload, viral infections, transfusion reactions, isosensitization to platelets, and negative impact on quality of life. These problems are added to the potential negative impact on national blood supply resources.

A coalescence of challenging and often interlocking co-morbid conditions occurs with aging—including the association of the refractory anemia of MDS and congestive heart failure (CHF). Both illnesses are predominantly disorders of the elderly5,7 . Extensive data in non-MDS patients have shown critical negative interactions between anemia and CHF, demonstrating an independent association between anemia in CHF and increased mortality8,9 . Effective treatment of the anemia (predominantly with Epo) in patients with CHF improved their cardiac function and quality of life8,10 . In a cohort of RBC transfused and non-transfused MDS patients, the major cause of non-leukemic death was cardiac failure (in 51 percent of patients) and it was significantly more frequent in the transfusion-dependent patients11 . The contribution to poor survival of transfusions (with associated iron overload and consequent cardiotoxicity) or from the anemia per se requires further study. Clearly, effective management of symptomatic anemia in these patients is vital.

The NCCN MDS Practice Guidelines Committee has endorsed and reiterated prior recommendations for ESA use in the management of appropriately selected symptomatic anemia in MDS patients (NCCN MDS Practice Guidelines v.1.2007), albeit with a change in the target hemoglobin—i.e., to aim for a target hemoglobin of up to 12gm/dl (v.1.2008). The NCCN guidelines recommend that MDS patients with symptomatic anemia and with serum epo levels ≤500 who are iron replete and have no other known causes for their anemia would be candidates for ESA therapy. Dosing of epo for appropriate patients with MDS is recommended as 40,000-60,000 1-3x/week subcutaneously for a period of six to eight weeks, continued so long as response occurs and possibly tapered as indicated by response. If response has not occurred by that time, the drug should be discontinued, or addition of G-CSF or use of other agents should be considered, depending on the clinical subset of MDS patient being treated (for example, addition of G-CSF is often particularly beneficial for those with the refractory anemia with ringed sideroblast subtypes).

Citing information such as that indicated above, a number of established clinical groups (including ASH, ASCO, NCCN, and the MDS foundation, along with the combined input from the Leukemia Committees of ECOG, CALGB, and SWOG) strongly advocated to CMS to continue to permit the use of ESAs for treating appropriate patients with MDS according to well-established management guidelines.

Following this input, the CMS decision memo of July 30, 2007, (CAG-00383N) has narrowed the scope of their final decision regarding use of ESAs in cancer and related neoplastic conditions to make no national coverage determination (NCD) on the use of ESAs in MDS (i.e., not restricting ESA use in MDS through the NCD). Local Medicare contractors may continue to make reasonable and necessary determinations on uses of ESAs that are not determined by the NCD. Given that controversy surrounding the use of ESAs is likely to continue, it was felt that it would be beneficial to arm clinicians with the above data about the efficacy of ESAs in MDS, such that clinicians can be well informed as they discuss this topic with their patients or other groups.

The ASH-ASCO 2007 Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin will be published soon. We will feature a story on the guideline update in the next issue of The Hematologist. There will also be a discussion of the guidelines and the latest regulatory issues surrounding ESA coverage at the Practice Forum, on Saturday, December 8, at 6:00 p.m. during the 2007 ASH Annual Meeting.

Miller KB, Kim HT, Greenberg P, et al.
Phase III prospective randomized trial of EPO with or without G-CSF versus supportive therapy alone in the treatment of myelodysplastic syndromes (MDS): Results of the ECOG- CLSG trial (E1996).
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Park S, Grabar S, Kelaidi C, et al, for the Groupe Francophone des Myélodysplasies (GFM).
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Leukemia Res.
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