Phase II Trial of Midostaurin in Advanced SM

Transcript:Cem Akin, MD: A phase II multi-centered trial was recently published in the New England Journal of Medicine, in June 2016, with Dr. Jason Gotlib from Stanford being the first author. This was a trial involving various centers in North America and in Europe that enrolled over 100 patients; 89 of those patients were eligible for assessment of response. Most of those patients had mastocytosis with an associated hematologic disorder, but all of them had advanced varieties. Most had mastocytosis with another associated disorder, such as a myeloproliferative neoplasm. Some had aggressive systemic mastocytosis and some had mast cell leukemia.

When we looked at the overall response rate, we saw a 60% overall response rate, and the majority of those responses were major responses. The response was defined in that study as a resolution of at least 1 C-finding, which is the organ dysfunction finding, with no emergence of a new C-finding. If that particular C-finding resolved completely, it was a major response, and if it resolved between 20% to 50%, it was a minor response.

The overall response rate was 60%, and patients with aggressive systemic mastocytosis and mast cell leukemia especially had very favorable outcomes. They had to maintain their response for at least 8 weeks, so the drug was given as an oral drug: 100 mg twice daily as a continuous 30-day cycle. So, 1 cycle equals 30 days (or 1 month). They had to maintain their responses for at least 2 cycles to be qualified as a responder in that study.

The median follow-up was about 2 years, and as of the publication date of the study, the median survival time for patients with aggressive systemic mastocytosis and mast cell leukemia had not been reached, which is a very favorable outcome. If you recall, the average life expectancy for patients with mast cell leukemia is less than 6 months, and here we have a patient population that has not reached their 50% survival time in 2 years of the follow-up.

I think that was definitely an outcomes finding. The responses were generally durable. When the patients responded, they maintained that response for, again, a median of approximately 2 years. But there were no complete cures. In other words, there was still some residual mast cell disease in the marrow, although there are patients that are still on the drug and doing well. It also greatly improved the quality of life in these patients because it turns out that it not only inhibits the mast cell proliferation and survival. The drug also has an effect on mast cell activation and the release of all these mediators and chemicals the mast cells produce that cause symptoms and make life miserable for the patient.

The major toxicities of the drug were nausea and vomiting, which were seen in about 60% to 70% of the patients. Those were usually low-grade problems and usually managed by putting the patient on an antiemetic, and most patients continued to take the drug despite that side effect. Some patients did experience cytopenias, and those were the patients who had cytopenias to begin with. They either developed a new cytopenia or the existing cytopenia got worse on the drug. So, overall, about 40% to 50% required a dose adjustment, but those cytopenia effects were reversible after the dose adjustment with the drug. I think the drug was well tolerated, all things considered, especially as compared to the other treatment options. And the toxicities were also very favorable as compared to the other treatment options, such as cladribine or interferon-alpha.

Transcript Edited for Clarity