• ASH Weighs in on Review of Medicare Coverage Policy for Erythropoietin-Stimulating Agents
• "Silent" Polymorphisms: How Silent Are They?

ASH Weighs in on Review of Medicare Coverage Policy for Erythropoietin Stimulating Agents

In March, the Centers for Medicare and Medicaid Services (CMS) announced plans to review the Medicare coverage policy for darbepoetin alfa and epoetin alfa after recent studies linked the treatments with increased risk for serious side effects. CMS will review coverage of the medications for uses other than in dialysis, as well as a “monitoring policy” that requires a reduction in Medicare reimbursements for the treatments when the red blood cell counts of beneficiaries exceed a certain level. The review follows a March 9 announcement by the Food and Drug Administration (FDA) that manufacturers of the medications must include black box warnings on the labels to physicians and patients about the increased risk for serious side effects linked with the treatments. In addition, the FDA advised physicians that they should use only the lowest dose of the medications necessary to avoid the need for blood transfusions caused by anemia.

Based on the FDA safety alert, CMS issued instructions to local Medicare carriers to prohibit Medicare coverage of erythropoietin stimulating agents (ESAs) — Aranesp, Epogen, Procrit — when used for the treatment of the anemia of cancer. ESAs used for treatment of anemia due to chemotherapy would not be affected by this change in policy. Some Medicare Part B carriers immediately began to announce new local carrier decisions that require that ESAs should be used only in accordance with its approved product labeling.

ASH has been active in responding to Medicare and the FDA and encouraging coverage policies that assure patient safety. The ASH Committee on Practice’s Subcommittee on Reimbursement reviewed the latest studies concerning patient safety and worked with clinical and scientific experts to comment on the CMS policy as well as local carrier decisions. Of particular concern are potential restrictions in the use of ESAs for treatment of anemia in patients with hematologic malignancies not on chemotherapy. ASH indicated to CMS that there are data to support the use of ESAs in patients with anemia associated with low-risk myelodysplasia. ASH also recommended that use of ESAs to treat anemic patients with hematologic malignancies requires further studies, and, in the meantime, coverage for these patients should be on a case-by-case basis.

ASH also is in the process of updating its practice guideline, "Use of Epoetin in Patients with Cancer." In early May, ASH will be working with the FDA’s Oncologic Drugs Advisory Committee, which is scheduled to review additional trial data on ESAs.

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"Silent" Polymorphisms: How Silent Are They?

Xylina Gregg, MD, and Josef Prchal, MD

Drs. Gregg and Prchal indicated no relevant conflicts of interest.

Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science 2007;315:525-8.

When deciphering the human genome uncovered only ~30,000 sequences for human genes, it was difficult to reconcile this finding with the far greater number of proteins and even greater number of phenotypic variations of proteins. The discovery of mechanisms that modulate the quality and quantity of genes by alternative splicing, epigenetic regulation, and microRNA provides growing evidence that diverse phenotypes can be produced by means other than gross gene rearrangements and missense nucleotide mutations.

In this paper, Kimchi-Sarfaty and colleagues provide another mechanism contributing to phenotypic diversity. Single nucleotide substitutions that do not change the amino acid sequence are known as synonymous or "silent" polymorphisms, because it is assumed that they do not change the function of the protein. However, these "silent" polymorphisms may utilize different transfer RNAs (tRNAs) that may differ in translational efficacy. Kimchi-Sarfaty et al. show that a silent single-nucleotide polymorphism (SNP) in the Multidrug Resistance 1 (MDR1) gene alters the function of the gene product. The MDR1 gene encodes an efflux pump, P-glycoprotein (P-gp), which actively transports certain drugs out of cells and plays a major role in the multidrug resistance of cancer cells. The authors show that the presence of a synonymous SNP (C3435T) in MDR1 gene in association with another synonymous SNP (C1236T) or a non-synonymous SNP (G2677T) resulted in a reduction of inhibition of P-gp by cyclosporin A and verapamil. The non-synonymous SNP (G2677T) was excluded as the factor explaining the phenotype; rather the synonymous C3435T was responsible for different P-gp mediated efflux of paclitaxel or other drugs. The inhibition of P-gp function was more pronounced as the concentration of plasmid DNA encoding P-gp increased, suggesting that the difference between the wild-type and the polymorphism is magnified at higher rates of translation of P-gp. The authors demonstrated that there was no difference in mRNA or protein levels between the wild-type and the polymorphic MDR1, but, surprisingly, the silent polymorphism altered the conformation of the P-gp peptide. This altered conformation appears to result from the "silent" polymorphism codon’s effect on the translation rate, which in turn affects protein folding. The authors theorize that as more P-gp is produced, the role of codon usage is more critical as certain tRNA species become depleted.

Kimchi-Sarfaty et al. present a novel mechanism of altered protein function by "silent" mutations that do not affect the amino acid sequence yet alter the protein folding and function by changing the timing of cotranslational folding. This provides impetus to re-examine the effects of other silent SNPs in other genes and their possible relationship to phenotype and disease states. It remains to be seen if we will soon hear voices from the multitude of other so-called "silent" polymorphisms.

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