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CMS restricts coverage for erythropoiesis-stimulating agents
National Coverage Determination limits when treatment can start, duration of treatment and dose.
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The Centers for Medicare and Medicaid Services has restricted coverage of erythropoiesis-stimulating agents for the treatment of chemotherapy-related anemia for Medicare beneficiaries.
The final national coverage determination will permit treatment with erythropoiesis-stimulating agents for anemia related to cancer and other neoplastic conditions, but restricts initiation of therapy to patients with hemoglobin levels of less than 10 g/dL, limits the duration of treatment after chemotherapy ends and limits the starting dose and dose escalation levels.
The restrictions are in response to the FDA placing black box warning on epoetin alfa (Procrit, Johnson & Johnson; Epogen, Amgen) and darbepoetin alfa (Aranesp, Amgen). The warning was based on clinical evidence of adverse events associated with the drugs, including safety signals which were concerning for an increased risk for death due to cancer progression.
The FDA’s Oncologic Drugs Advisory Committee recently recommended additional restrictions in light of studies that indicate more risk associated with specific tumor types. The advisory panel also recommended that anemia therapy duration be restricted in patients with cancer. The panel voted against lowering the 12 g/dL ceiling hemoglobin level at which anemia should be corrected.
CMS has also placed limitations on the use of erythropoiesis-stimulating agents to treat anemia for Medicare beneficiaries with end-stage renal disease who are receiving dialysis, and the FDA will be re-examining the use of these agents in this population in mid-September.
Myelodysplastic syndromes
According to Samuel Silver, MD, PhD, director of the University of Michigan Cancer Center Network and section editor of the Health Policy, Patient and Practice Issues section for Hem/Onc Today, CMS appears to have listened to arguments made by professional societies such as ASH and dropped restrictions discussed in the proposed rule on coverage of erythropoietin agents for patients with myelodysplastic syndromes. However, coverage decisions for these patients will be left to local carriers.
CMS did not include any erythropoietin restrictions for particular types of tumors, which is a positive decision, Silver said. Another positive aspect of the coverage decision is that the trigger point to start erythropoietin treatment was raised from a hemoglobin level of 9 g/dL to 10 g/dL, a reasonable decision, according to Silver.
However, the coverage determination also mandates that if a hemoglobin level is 10 g/dL or greater after the first four weeks of therapy, then payment for erythropoietin agents will not be approved.
“What that means is that the start point is 10 g/dL and the endpoint is 10 g/dL, which makes administering this drug very difficult,” Silver said in an interview. “It is an almost impossible situation, and determining when to start and stop will theoretically require huge amounts of patient monitoring that would otherwise be unnecessary.”
According to Silver, several organizations, including ASCO, ASH and US Oncology, have asked for the national coverage determination to be reopened because of the 10 g/dL hemoglobin level maintenance requirement. Previous guidelines have recommended 10 g/dL to 12 g/dL as a reasonable maintenance level.
“Right now, this national coverage determination is the law of the land,” Silver said. “Several organizations have asked for it to be reopened, but who knows what the timeline will be?”
Other concerns include patients with special situations, including those with comorbidities, patients who live at higher altitudes that require higher hemoglobin levels, or patients who recently received blood transfusions and therefore have elevated hemoglobin levels. Physicians are to discuss these special situations on a case-by-case basis with the local carrier medical director about exceptions to the coverage determination.
“A case-by-case basis is an almost impossible way to handle exceptions, the number of which may be quite high in an oncology practice,” Silver said. “Our ability to give patients erythropoietin products is going to be curtailed because of the difficulty in giving this drug based on CMS rules.”
Possible alternatives
Researchers are working to develop alternatives to erythropoiesis-stimulating agents for the treatment of chemotherapy-related anemia.
Anthony Blau, MD, professor of medicine and codirector of the Institute for Stem Cell and Regenerative Medicine at the University of Washington in Seattle, has been working on one approach involving a drug and a gene with a modified receptor.
Erythropoiesis-stimulating agents and other hematopoietic growth factors work by binding to receptors on the surface of cells. The growth factors, however, can possibly interact with other receptors and cause off-target effects, Blau said. The toxicities associated with erythropoiesis-stimulating agents are likely caused by the off-target effects.
“The concern is that erythropoiesis-stimulating agents might be triggering tumor progression through binding to erythropoietin receptors on the tumor cells or tumor blood vessels,” Blau told Hem/Onc Today. “We can get around that because we can introduce the receptor we want into the cell we want, thus avoiding off-target effects.”
AP1903 (CellNexus) is a drug that targets modified receptors expressed by genetically modified bone marrow cells from the patient. The modified receptors are derivatives of normal receptors and are only recognized by AP1903.
The process involves genetically modifying bone marrow cells so that they express the modified receptors. The receptors are dormant unless activated by AP1903, which triggers the receptors to proliferate. According to Blau, this receptor stimulates red blood cell production effectively.
“This platform is essentially going to be an operating system for cell therapy,” Blau said. “We can target what we’re doing more specifically than we can when using cells alone or growth factors. This is a new paradigm both for growth factor development and for cell therapy.” – by Emily Shafer
Dr. Blau is a co-founder of Cell-Nexus.