April 12, Coverage of ESAs for Patients with Conditions Other than End-Stage Renal Disease

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1 [ASH Comments to the Centers for Medicare and Medicaid Services on coverage for Erythropoiesis Stimulating Agents (ESAs) filed electronically on April 12, 2007] April 12, 2007 The American Society of Hematology (ASH) represents over 11,000 hematologists in the United States who are committed to the treatment of blood and blood-related diseases. ASH members include hematologists and hematologist/oncologists who regularly render services to Medicare beneficiaries. The Society appreciates this opportunity to comment on the use of Erythropoiesis Stimulating Agents (ESAs) for conditions other than endstage renal disease as Medicare begins developing a National Coverage Determination (NCD). New research studies report an excess of serious and life-threatening events associated with the use of ESAs in non-anemic patients in various clinical settings, and the Food and Drug Administration (FDA) has recently issued new warnings regarding the use of ESAs. Thus, ASH believes it is important for Medicare to carefully review all policies related to the administration of ESAs and, in particular, the scientific evidence, to determine the appropriate use of ESAs for multiple clinical indications. Of paramount importance to ASH is to ensure the highest degree of patient safety and to protect against not only the overuse of these drugs, but their underuse and misuse as well. Consequently, ASH notes that ESAs help to reduce the need for transfusions and thereby alleviate strain on the nation s blood supply. Therefore, the impact on the blood supply should be taken into account when determining changes in the use of these products. In addition, while ASH accepts the relevance of four recently completed cancer trials that evaluated new dosing regimens and new patient populations, we recognize that additional high quality clinical trials are needed to better understand the impact of ESAs on patients with hematologic malignancies. Below are ASH s comments concerning use of ESAs for patients with conditions other than end-stage renal disease, including recommendations about treatment targets and duration. Because all ESAs have the same mechanism of action, ASH, like the FDA, believes these comments apply to all ESAs (marketed as Procrit, Epogen, and Aranesp). While some local carriers have separated policies for darbepoetin alfa (Aranesp) and epoetin alfa (Epogen and Procrit), ASH believes there should be a single national coverage policy because the products are basically interchangeable and use of one is essentially equal to the use of the other. Coverage of ESAs for Patients with Conditions Other than End-Stage Renal Disease Chemotherapy associated anemia (285.22) ESAs may be used as a treatment option for patients with chemotherapy-associated anemia. ASH notes that a patient may continue to suffer from anemia for some time following completion of chemotherapy treatment and recommends that coverage of ESAs be continued for treatment of anemia for 90 days post chemotherapy. If anemia

2 persists beyond 90 days after completion of chemotherapy, it would be reasonable to re-evaluate the anemia to determine if this continues to be a result of the chemotherapy, thereby justifying continuation of ESA treatment, or if another process is in place. ASH believes most patients should recover in this time period, but notes evidence from randomized clinical trials concerning this issue is not available and recommends prospective studies concerning this topic. Anemia of chronic disease (Anemia of chronic inflammation) (285.29) ESAs may be used as a treatment option for patients with anemia of chronic inflammation. ASH notes that the anemia of cancer is not included and is distinct from this category. Anemia of inflammation is a common consequence of chronic infections and noninfectious generalized inflammatory disorders. The diagnosis is usually exclusionary; meaning other causes of the anemia have been ruled out. Common features include: low or normal serum iron, low or normal iron-binding capacity levels, and elevated iron in reticuloendothelial cells in bone marrow; however, there may be variation. ASH recommends that Medicare cover the use of ESAs for the anemia of chronic disease when the following conditions are met: the pretreatment Hct level is 30 percent or less and/or if the patient has been transfusion dependent; the pretreatment erythropoietin level is 100MU/ml or less; and at least one of the following applies: low or normal serum iron, low or normal iron binding capacity, normal or elevated serum ferritin, iron is present in the bone marrow (requires bone marrow aspiration and/or biopsy). Patients with hematologic malignancies not on chemotherapy ESAs may be used as a treatment option for patients with hematologic malignancies but who are not on chemotherapy. There is evidence to support the use of ESAs in patients with anemia associated with low-risk myelodysplasia (less than five percent blasts). Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by dysplastic and ineffective hematopoiesis and a variable risk of transformation to acute leukemia. Low risk myelodysplasia with less than five percent blasts can include the following (World Health Organization classification) forms of myelodyplasia: Refractory anemia (RA) (238.72) Refractory anemia with ringed sideroblasts (RARS) (238.72) Refractory cytopenia with multilineage dysplasia (RCMD) (238.72) Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD- RS) (238.72) Myelodysplastic syndrome, unclassified (MDS-U) (238.75) MDS associated with isolated del(5q) (238.74) Refractory anemia can be defined as erythropoietic insufficiencies that cannot be assigned to a specific vitamin or mineral deficiency. ASH recommends that Medicare cover treatment with ESAs in patients with MDS who meet the following criteria: 1. Hemoglobin (Hgb) of 10 g/dl or Hematocrit (Hct) of 30% or less 2. Patients who have a reasonable expectancy of longer survival 3. Patients who need or are anticipated to need frequent transfusions

3 4. Treatment with ESAs will end or reduce the need for transfusions. Experts in hematology have used ESAs to treat anemic patients with multiple myeloma, non-hodgkin lymphoma and chronic lymphocytic leukemia (CLL) in the absence of chemotherapy where the ESAs have proven effective. ASH acknowledges, however, that there are no randomized clinical trials to support use of ESAs in these hematologic malignancies, and strongly recommends this to be an area for further study and evaluation. ASH notes that the large seminal studies used by FDA to support public safety warnings do not include adequate numbers of patients with hematologic malignancies not undergoing chemotherapy to allow appropriate analysis. In the absence of randomized clinical trial data, coverage for these patients should be on a case by case basis. Treatment Recommendations Starting and ending targets ASH recommends that ESAs be started in appropriate clinical settings at a hemoglobin level at or below 10 g/dl. (ASH notes that this can be considered the same as an Hct of 30%, but uses hemoglobin because it is directly measurable and used in the literature.) ASH notes, however, that there may be extenuating circumstances when treating patients with co-morbidities, such as cardiac or pulmonary disease, (which should be documented) that could justify use of ESAs before the hemoglobin has decreased to 10 g/dl. ASH believes the therapeutic goal should be a hemoglobin level of no higher than 12 g/dl and recommends that the dose of ESA be modified in accordance with the recent FDA black box warning when the hemoglobin approaches 12 g/dl. It is important to encourage doctors to be vigilant in monitoring patient blood counts when treating with ESAs, and iron levels in non-responders. Non-response ESAs should not be continued after eight weeks in the absence of response, assuming the appropriate dose increase has been attempted in low-responders. A response is a rise in hemoglobin of 1 g/dl or greater. Hematologic malignancy patients treated with chemotherapy Chemotherapy associated anemia in patients with hematologic malignancies (Myeloma and other plasma cell dyscrasias, Hodkins and non-hodgkins lymphoma, low grade myelodysplasias, and CLL) should be treated according to the parameters recommended above. Anti-tumor therapy Current data do not support the use of ESAs solely to potentiate the effectiveness of anti-tumor therapy. Again, thank you for this opportunity to share ASH s recommendations concerning use of ESAs for conditions other than ESRD. ASH is currently updating our evidence-based

4 practice guidelines concerning use of Epoetin to include other ESAs and is willing to share this information as the draft becomes available later this summer. We would welcome a meeting with Medicare medical officers and analysts to discuss our recommendations with more specificity and hope to maintain an ongoing dialog with CMS over the issue of ESA usage, particularly as additional information becomes available and ASH s ESA guidelines are finalized. In the meantime, if you need additional information or have any questions, please contact Mila Becker of the ASH staff at or mbecker@hematology.org. Sincerely, Samuel Silver, MD, PhD Chair, ASH Reimbursement Subcommittee Councilor, ASH Executive Committee References follow

5 Reference List Bohlius J, Wilson J, Seidenfeld J, et al: Recombinanat human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. 98: , 2006 Goldberg P: Study finds more deaths on Aranesp arm in cancer anemia study, no benefit seen [newsletter]. The Cancer Letter 33:1, 2007 Demetri GD, Kris M, Wade J, et al: Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: Results from a prospective community oncology study Procrit Study Group. J Clin Oncol 16: , 1998 Gabrilove JL, Gleeland CS, Livingston RB, et al: Clinical evaluation of one-weekly dosing of epoetin alfa in chemotherapy patients: Improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 19: , 2001 Littlewood TJ, Bajotla E, Nortier JW, et al: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving non-platinum chemotherapy: Results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19: , 2001 Leyland-Jones B, BEST Investigators and Study Group: Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4: , 2003 Henko M, Loszig R, Rube C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebocontrolled trial. Lancet 362: , 2003 Witzig TE, Silberstein PT, Loprinzi CL, et al: A phase III randomized double-bilnd study of epoetin alfa versus placebo in anemic patients with cancer undergoing chemotherapy. J Clin Oncol 23: , 2005 Rizzo DJ, Lichtin AE, Woolf SH, et al: Use of epoetin in patients with cancer: Evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20: , 2002 Leyland-Jones B, Semiglazov V, Pawlicki M, et al: Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol 23: , 2005