SEATTLE, May 5 — Italian multiple sclerosis patients treated with mitoxantrone (Novantrone) developed leukemia at up to 10 times the rate seen in previous studies, researchers reported here.

• Explain to interested patients that the study was conducted in Italy and may not be fully generalizable to U.S. patients.
• Explain that the adverse effects described in this study occurred in a relatively small number of patients. Point out that the balance of risks and benefits is different for each patient, such that mitoxandrone may still be an appropriate choice for some patients.
• Note that the study was published as an abstract and presented orally at a conference. These data and results should be considered preliminary until published in a peer-reviewed journal.

In a retrospective study of patients treated in 35 Italian hospitals, leukemia developed in 7.4 multiple sclerosis patients per 1,000 treated, according to Vittorio Martinelli, M.D., of University Vita-Salute in Milan, Italy.

Earlier studies of the drug in multiple sclerosis patients had reported leukemia rates of 0.7 to 2.5 per 1,000 patients, Dr. Martinelli said.

But he noted that simply avoiding mitoxantrone is not necessarily a simple way to dodge leukemia risk, as the drug is frequently a last-resort treatment for MS patients.

Still, this and other side effects of mitoxantrone “should be carefully considered against the potential benefit,” he said at a press briefing to announce the results.

“On one side, we have the risk of the disease with a progressive course, which has a high risk to develop significant impairment and disability for the patient. On the other side, we have the risk related to the treatment. We all know there is no treatment without any adverse event,” Dr. Martinelli said.

Mitoxantrone is best known as an anticancer drug. It is approved for treating leukemia, as it suppresses rapidly dividing lymphocytes, B cells, and macrophages.

In 2000, it was approved by the FDA for treating multiple sclerosis, including the relapsing-remitting and primary and secondary progressive forms. However, the drug is less popular for these conditions in the U.S. than in Europe, said Dr. Martinelli.

In addition to the previously known risk for acute leukemia, the drug is also cardiotoxic and causes neutropenia with an associated risk of infection. It carries a boxed warning about these effects.

The study examined records of all patients with multiple sclerosis treated with mitoxantrone since 1999 at the participating hospitals. Inclusion criteria included a minimum of one treatment cycle and one year of follow-up.

A total of 2,854 patients were identified, of whom 21 developed acute leukemia, with eight deaths.

Dr. Martinelli said the incidence rate per month of treatment was 0.16.

He said the dose appeared related to the leukemia risk. Patients developing leukemia had received a mean of 8.6 treatment cycles and a mean total dose of 82.4 mg/m², compared with 7.2 cycles (P<0.05) and 62.9 mg/m² (P<0.009) among patients without leukemia.

However, it’s not clear whether ongoing treatment will increase or decrease the chances of developing leukemia, he said. “We do not know the duration of the period of risk,” he said.

In light of the apparent dose-relationship, he concluded, treatment with relatively low doses of mitoxantrone “could be considered.”

Lily Jung, M.D., of the Swedish Neuroscience Institute here, said the findings weren’t suprising since the drug does carry a warning about secondary leukemia. But the numbers were “frightening,” she declared.

Even so, the study probably won’t have a big effect on U.S. clinical practice because the drug is seldom used there, she added.

“The advent of Tysabri (natalizumab), even with the risk of PML (progressive multifocal leukoencephalopathy), has pushed mitoxantrone down to the very bottom of the list of drugs we would think about,” Dr. Jung said.

She said the drug is most commonly prescribed for aggressive forms of multiple sclerosis. “We were telling patients that the risk [of leukemia with mitoxantrone] was about one in 400,” she said.

The Italian study’s figure of about one in 135, she said, “is pretty dang significant. . . . It puts mitoxantrone in an even more difficult competitive position.”

External funding for the study was not reported. Dr. Martinelli reported relationships with Biogen Dompe, Merck Serono, Bayer-Schering, Teva, and sanofi-aventis. Other investigators in the trial reported relationships with Farmades and Novartis. Dr. Jung reported no potential conflicts of interest.

Primary source: American Academy of Neurology

Source reference:
Martinelli V, et al “Incidence of acute leukemia in multiple sclerosis patients treated with mitoxantrone: a multicenter retrospective study” AAN Abstract LB3.001.

Agents used to treat anaemia in cancer patients, that work by stimulating red blood cell production, also increase mortality. The increased risk of death associated with these drugs should be balanced against their benefits in cancer patients. These are the conclusions of an Article in this week’s edition of The Lancet, written by Dr Julia Bohlius, University of Bern, Switzerland, and Professor Andreas Engert, University of Cologne, Germany, and colleagues.

These drugs, called erythropoiesis-stimulating agents (or ESAs), reduce the need for red blood cell transfusions and could improve quality of life for patients with cancer. However, they have been reported to increase the risk of heart attack and stroke, and might also stimulate tumour growth. Uncertainty remains about whether and how these drugs affect survival; their safety has been discussed repeatedly at hearings of the US Food and Drug Administration and the European Medicines Agency. The authors did a meta-analysis of 53 cancer trials featuring almost 14,000 patients to establish the effect of ESAs on mortality. They assessed mortality during the active study period* and during the longest available follow-up.

The researchers found that 1530 patients died during the active study period and 4933 died overall. ESAs were associated with a relative increase in mortality during the active study period of 17%. When an analysis was done of only cancer patients receiving chemotherapy (38 trials, 10,441 patients), the relative increase in mortality attributable to ESAs was 10%. The type of anticancer treatment given did not make a difference to outcomes.

The authors say: “The findings of this individual patient data meta-analysis show that erythropoiesis-stimulating agents increase mortality in all patients with cancer, and a similar increase might exist in patients on chemotherapy… In clinical practice, the increased risks of death and thromboembolic events should be balanced against the benefits of treatment with erythropoiesis-stimulating agents, taking into account each patient’s clinical circumstances and preferences. More data are needed for the effect of these drugs on quality of life and tumour progression, and meta-analyses similar to this one will address these questions.”

Source
The Lancet

LITTLE FALLS, N.J., May 6 — The FDA gave bevacizumab (Avastin) fast-track approval for the treatment of glioblastoma patients who have been unresponsive to prior therapy, according to drugmaker Genentech.

The accelerated approval followed two pilot studies showing that it improved response rates in patients with glioblastoma.

One study, AVF3708g, included 167 patients with glioblastoma that had progressed after initial treatment with temozolomide and radiation. Patients were randomized to either bevacizumab alone or bevacizumab plus irinotecan.

Tumor responses were observed in 26% of the 85 patients treated with bevacizumab alone. Median duration of response was 4.2 months.

In a separate, single-arm study, NCI 06-C-0064E, about 20% of the 56 patients treated with bevacizumab had response rates, and median duration of response was 3.9 months.

Common adverse events included infection, fatigue, headache, high blood pressure, diarrhea, and nose bleeds.

Others included bleeding, hemorrhage, wound-healing complications, gastrointestinal perforation, and posterior leukoencephalopathy syndrome.

Gastrointestinal perforation occurred in 0.3% to 2.4% of patients. Bleeding occurred up to five times more frequently in patients taking bevacizumab, according to Genentech.

The company warned that the drug should not be initiated for at least 28 days following surgery, and until the surgical wound is fully healed.

Two deaths may have been associated with adverse events, including one retroperitoneal hemorrhage and one neutropenic infection.

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• Bevacizumab Gets FDA Panel’s Nod for Glioblastoma Multiforme