Current Treatments for Advanced SM

Transcript:Richard M. Stone, MD: Historically, patients with systemic mastocytosis have been treated to ameliorate their symptoms. Because of the release of mast cell mediators, people have high levels of histamine—antihistamines of both H1 and H2 type have been used. In other words, drugs like ranitidine and cetirizine have been used. Cromolyn sodium is another agent that can decrease mast cell degranulation and has a role in this disease.

Cem Akin, MD: The currently available treatments for advanced mastocytosis are limited. First of all, there’s no curative treatment for the disease. There are palliative options, and there are options that would increase the life expectancy, but none of those options would result in a complete remission or cure.

The most commonly used treatments at this time are interferon-alpha and cladribine. Interferon-alpha is generally used in patients with slower-progressing disease varieties. Because it has a slower onset of action, it is usually combined with prednisone. The response rates are usually around 20% to 50%, mainly in terms of symptomatic response and in patients with a lot of mast cell mediator-related symptoms. Those are good candidates for interferon-alpha. It does reduce the mast cell burden to a certain extent, although not greatly. It appears to be a good option, especially for patients who are experiencing a lot of cortical bone problems, like pathological bone fractures.

It is also associated with a lot of side effects, such as flu-like side effects or depression. So, it is not a very well-tolerated drug. The better option these days appears to be cladribine, or 2CdA. That is in a clear side analog that nonspecifically kills white cells, including mast cells. The response rates to cladribine, at least initially, appear to be around 50% to 70%. It is usually associated with a temporary response. The limiting toxicity of cladribine is bone marrow suppression and immunosuppression. The patients need to be protected against pneumocystis and opportunistic infections while on this drug. In most patients, after a few cycles, cytopenias that develop further limit the option of cladribine. In patients with very advanced disorders, like mast cell leukemias, who fail cladribine treatments, polychemotherapy options, such as those used in acute myeloid leukemia, can be used.

Finally, stem cell transplantation is an option for patients who are good candidates for that procedure and have an appropriately matched donor. It is especially useful in patients with associated hematologic disorders and mast cell leukemias. It appears that, according to a retrospective study, it was associated with improved life expectancy in those disorders.

Then, there are the tyrosine kinase inhibitors. Currently, the only FDA-approved tyrosine kinase inhibitor for treatment of advanced mastocytosis is imatinib. Imatinib does inhibit the KIT gene, and that’s why it has been tried in mastocytosis. The problem with imatinib is that it does not work against the D816V mutation that is seen in more than 90% of patients with advanced varieties. In reality, only about 10% or less of our patients are candidates for imatinib treatment.

The label reads, “Imatinib is indicated for patients with advanced mastocytosis with negative D816V mutation or undetermined D816V mutation.” In our experience, most of those patients with undetermined D816V mutation turn out to have this mutation, if techniques sensitive enough to detect that mutation have been employed. It has not been a major treatment option in our experience in the clinics.

Richard M. Stone, MD: The unmet needs are huge because people have severe symptom burdens often, and the therapies that are available—the chemotherapy, the steroids, the interferon, the cromolyns, the antihistamines—are really not disease-modifying agents. One would really like to deal with a primary pathophysiology, which is due to the activating mutation in the c-KIT enzyme, mainly D816V. Do we have drugs that inhibit this? Yes, we do, and the best example right now is midostaurin, which is a multi-targeted kinase inhibitor. It inhibits protein kinase C, which is not a tyrosine kinase; it inhibits FLT3, which is a tyrosine kinase; and it inhibits D816V KIT, which is an activated tyrosine kinase. Therefore, it has been tried, as we know successfully now, in aggressive systemic mastocytosis.

Transcript Edited for Clarity