• MPNRF | May 3, 2007

    By Donna Young

    Washington Editor

    Erythropoiesis-stimulating agents (ESAs), such as Aranesp, Epogen and Procrit, may increase the risk of acute leukemia in patients with a certain bone marrow disorder, researchers reported at the American Society of Hematology’s annual meeting in Atlanta.

    In a retrospective study examining 30 years of records of 311 patients with myelofibrosis, a disorder in which the body’s normal production of blood cells are disrupted, investigators at the Mayo Clinic in Rochester, Minn., identified 27 patients who had gone on to develop acute leukemia.

    The patients were followed a median of 27 months. However, noted principal investigator Ayalew Tefferi, about a quarter of the patients were followed for many years.

    Several risk factors, such as high levels of peripheral blood blast and low platelet counts, could account for the progression of myelofibrosis to leukemia, researchers said.

    However, Tefferi told BioWorld Today, an analysis of the data found that “there was a very independent and strong association between a history of treatment exposure to erythropoietin and development of acute leukemia.”

    Tefferi noted that the investigators had not set out to find a link between ESAs and leukemia. The intent of the study, he maintained, was to identify risk factors associated with leukemic transformation.

    The study’s findings linking ESAs to leukemia, said Tefferi, a professor of medicine and hematology and leader of the myeloproliferative neoplasms group at the Mayo Clinic, “was quite an unexpected finding.”

    While the study’s results are “not a definite” conclusion that exposure to ESAs causes leukemia, “there is an association, which cannot be ignored, and perhaps should be looked into in a prospective fashion if one wants to continue to use ESAs” in patients with myelofibrosis, Tefferi insisted. “I’m not saying don’t use it. But . . . look at it carefully and prospectively.”

    Amgen spokeswoman Ashleigh Koss noted that ESAs are not indicated for use in treating anemia in patients with myelofibrosis.

    Because the study was “an uncontrolled observational study spanning 30 years with several confounding factors such as patient and disease characteristics, it should be considered hypothesis generating,” she said in an email.

    While the study’s findings were “significant enough” for him to limit the use of ESAs in his patients, Tefferi said, there are other reasons physicians should consider restricting the drug.

    “First of all, it does not work very well for those patients who really need it, that is, the transfusion-dependent patients,” he said.

    The response rate of ESAs in the transfusion-dependent patients in his study was “zero percent,” Tefferi explained.

    Additionally, he said, ESAs caused an abnormal enlargement of the spleen in his patients.

    “If somebody wants to continue to use it, if they like the drug that much, then they have to worry about patient safety,” Tefferi contended. “I encourage them to prove safety in a prospective fashion. It’s not about efficacy anymore.”

    He noted that his study was not the first to find a link between ESAs and cancer progression.

    In fact, the FDA in March used studies that showed an increase in certain tumor types as part of the basis to add stronger warnings to the drugs’ labeling.

    Regulators last spring asked Thousand Oaks, Calif.-based Amgen, which markets Aranesp and Epogen, and Bridgewater, N.J.-based Ortho Biotech Products LP, which sells Procrit under an agreement with Amgen, to add a black-box warning that the agents caused tumor growth and shortened survival when patients received a dose that attempted to achieve a hemoglobin level of 12 g/dL or greater.

    Last month, the agency told Amgen and Ortho Biotech to strengthen the box with additional warnings identifying specific tumor types – advanced breast, head and neck, lymphoid and non-small-cell lung cancer – in which use of ESAs caused tumor progression. (See BioWorld Today, Nov. 9, 2007.)

    Late last month, Amgen announced interim results of a Phase III study that showed that breast cancer patients on Aranesp died earlier or their tumors progressed more compared with those not using the agent.

    Amgen last week said that it was in discussions with the FDA to again update the labeling for ESAs. The agency’s Oncologic Advisory Committee, which met in May to discuss the drugs, is set to meet again in the spring to examine new safety issues related to ESAs. (See BioWorld Today, Dec. 4, 2007.)

    Physicians and researchers, Tefferi said, should examine other databases to see if there are similar findings linking ESA use to cancer progression. Those database examinations, he added, should not only include patients with myelofibrosis, but other conditions, such as myelodysplastic syndrome, “which has a higher chance of transforming into acute leukemia.”

    “A lot of people are using this in myelodysplastic syndrome, so I would be also worried in that patient population,” Tefferi said.

    Mayo Clinic researchers also noted that use of danazol, a hormone with anemia-countering properties, was found to be linked to later development of leukemia.

    Shares of Amgen (NASDAQ:AMGN) dropped $1.21 Tuesday, or 2.48 percent, to close at $49.78.