MITOXANTRONE FOR MS IS MORE DANGEROUS THAN PREVIOUSLY REPORTED
ARTICLE IN BRIEF
MS patients taking mitoxantrone should be carefully monitored for changes in blood cell counts that predict leukemia, a new study suggests.
SEATTLE—The incidence of acute leukemia in patients with multiple sclerosis (MS) treated with mitoxantrone is higher than previously reported and implies that patients taking mitoxantrone should be carefully monitored for changes in blood cell counts that predict leukemia, according to a retrospective study on Italian patients reported here at the AAN annual meeting.
“The risk of developing acute leukemia was dose-related. Since we don't have a test to determine which MS patients are susceptible to acute leukemia, a lower dose should be considered,” said lead author Vittorio Martinelli, MD, a neurologist at the Scientific Institute H. San Raffaele in Milan, Italy.
Mitoxantrone is an immunosuppressant drug that interferes with the DNA repair mechanism. It is approved worldwide for patients with aggressive MS and is the only FDA-approved drug in the US for secondary progressive MS. It is used more commonly in Europe than in the US.
Previous studies have suggested that the incidence of acute leukemia in MS patients taking mitoxantrone ranges from 1 in 1300 (1.3/1000) to 1 in 400. Dr. Martinelli reported here that the cumulative incidence of acute leukemia in MS patients treated with mitoxantrone was 7.4 per 1000 (or 1 in 135).
The study focused on 2,854 MS patients treated at 35 Italian MS centers from 1999 to 2008. About 40 percent had relapsing-remitting MS; about 8 percent, primary progressive MS; and about 51 percent, secondary progressive MS. About two-thirds were women, and the mean age was 43.9 years. All patients were treated with at least one cycle of mitoxantrone and followed for at least one year.
At a mean follow-up of 45.6 months, 21 cases of acute leukemia were identified. Patients who had acute leukemia received a significantly greater number of cycles of mitoxantrone (8.6 cycles versus 7.2 cycles) as well as a significantly greater cumulative dose (82.4 mg/m2 versus 62.87 mg/m2) than those who did not have acute leukemia. The incidence rate ratio increased from 1.84 in patients who received a cumulative dose greater than 60 mg/m2 to 2.74 in patients who had a cumulative mitoxantrone dose greater 82.4 mg/m2. Using a cut-off point of 95 mm/m2 the incidence rate ratio was 3.2, and at a dose of 110 mg/m2, the incidence rate ratio was 3.89.
Dr. Martinelli pointed out that the risk was greatest within the first two years after the last dose of mitoxantrone, especially in patients treated with higher doses. However, acute leukemia occurred after six years in one patient.
“The risk of acute leukemia persists longer in patients with low-dose mitoxantrone administration,” he said.
These findings point to the necessity for monitoring patients on mitoxantrone carefully for signs of leukemia, especially in the first three years. Dr. Martinelli said that monitoring could be continued for as long as six years.
In addition to acute leukemia, other risks associated with mitoxantrone include cardiotoxicity and impaired fertility. “These potential risks should be considered carefully against the potential benefit for every single MS patient,” Dr. Martinelli told listeners. “A low-dose strategy should be preferred in patients with aggressive MS.”
“We need a longer study and longer follow-up to determine the duration of the period at risk,” he added.
“DEAD IN THE WATER”
“In the US, mitoxantrone is already on the bottom of most neurologists' lists of medications for MS. I think this study signals the end of using mitoxantrone,” said Lily Jung, MD, clinical associate professor of neurology at the University of Washington and medical director of neurology at the Swedish Neuroscience Institute in Seattle. She was not involved in the current study.
“Now that we know the risk of developing leukemia is 1 in 135, we realize that using mitoxantrone in a large MS practice would put greater numbers of patients at risk,” Dr. Jung pointed out.
Methylprednisolone plus interferon beta is another option for the treatment of aggressive MS, she said. This treatment has a much lower risk of any serious side effects than mitoxantrone, she said. She noted that other therapies are in the pipeline for secondary progressive MS.