EMBARGOED FOR RELEASE UNTIL 4 PM ET, September 23, 2002
Risks of Cardiac Problems from Mitoxantrone in Treating MS Outlined
St. Paul, Minn. – Researchers analyzing the records of 1,378 patients from three clinical trials of mitoxantrone as a treatment for multiple sclerosis (MS) reveal a small, but significant risk for developing diminished left ventricular ejection fraction (LVEF), which is a decrease in function of the left ventrical, and a lesser risk for congestive heart failure following treatment. The study is reported in the September 24 issue of Neurology, the scientific journal of the American Academy of Neurology. Mitoxantrone (MITO) is approved in the United States for the treatment of worsening relapsing-remitting, secondary-progressive, and progressive-relapsing MS. Unlike patients with leukemia and solid tumors who most often receive MITO in combination with other drugs, patients with MS are treated with MITO as a single drug to alleviate disease symptoms, said study author Donald Goodkin, MD, medical affairs director with Amgen Corp., a U.S. marketer of mitoxantrone in the United States. Cardiac toxicity, which may cause tachycardia and arrhythmia, LVEF, or congestive heart failure, has already been observed and reported in cancer patients who receive mitoxantrone as a chemotherapeutic agent. “We undertook this study because the risk of cardiac toxicity after single-agent MITO therapy for MS has not been rigorously examined,” said Goodkin. The researchers analyzed data from three separate studies. The first was a Phase 3 clinical trial of MITO in MS (the MIMS Study) where 184 patients were divided into three groups and given either a low dosage of MITO, a higher dosage of MITO, and a placebo, respectively. The second set of results was taken from an on-going French consortium of 12 centers performing an open-label trial of MITO in MS involving 802 patients. The third study was undertaken at the Clinic of Neurologic Disease of Ulm University in Germany, which involved 452 patients. In the MIMS Study, four (3.23 percent) out of 124 patients receiving MITO were reported developing LVEF of less than 50 percent. Thirteen (1.9 percent) of the 802 patients in the French study developed LVEF of less than 50 percent. In the German study, LVEF was not analyzed, but two (less than one-half percent) of 452 patients receiving MITO treatment died from congestive heart failure. In one instance, a patient had sought treatment from two different physicians and was given a cumulative dosage of 162 milligrams. In the second instance, the woman’s death occurred four years after receiving a single dose of MITO. She was immediately taken off the regimen when an echocardiogram measured LVEF less than 50 percent. Patients enrolled in these studies received a wide range of cumulative doses of MITO in monthly or 3-month treatment protocols and had follow-ups within 30 months after initiation of therapy. The average dose for patients in the three studies was 62.5 mg. Eleven percent of MITO recipients received a cumulative dose over 100 mg. Seventeen, or 2.2 percent, of 779 patients who completed baseline and follow-up testing had developed LVEF. A categorical analysis revealed a greater incidence of LVEF among those who had received a cumulative dose of more than 100 mg. Goodkin said longer follow-up will be needed to determine whether any of the other incidents of LVEF less than 50 percent develop into congestive heart failure. He said manufacturers’ warnings outline that cumulative doses should not exceed 140 mg., and that patients’ LVEF should be measured before each dose of MITO in excess of 100 mg. The researchers described some limitations to the study, adding that none of them invalidated the results. First, although the incidence proportion (2 of 1,378) of patients with congestive heart failure is accurate for all MITO recipients in the studies, follow up LVEF testing was done in only 779 (57 percent) of the 1,378 patients. Second, available data did not permit a rigorous examination of the incidence of congestive heart failure in patients who received higher cumulative doses of MITO or those with prolonged follow-up. Third, the study lacked data needed to make a meaningful comparison of the incidence of congestive heart failure for the monthly versus 3-month treatment regimens. The study was supported by a grant from Immunex Corp., now doing business as Amgen Corp., Seattle, Wash.
The American Academy of Neurology is the world's largest association of neurologists and neuroscience professionals, with 32,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer's disease, stroke, migraine, multiple sclerosis, concussion, Parkinson's disease and epilepsy.