SM refers to a group of rare diseases and affects between 20,000 and 40,000 people worldwide. The disease is characterized by the uncontrolled growth and accumulation of abnormal mast cells, a type of white blood cell, in the bone marrow, liver, spleen and other organs. This is caused in most people by a KIT gene mutation which activates the KIT enzyme, resulting in an abnormal proliferation and survival of mast cells. At this time, there are no approved treatments for a majority of patients with the disease.

 

In advanced SM, this uncontrolled growth of neoplastic mast cells leads to organ damage, low blood counts and weight loss. Patients may also suffer from debilitating systemic symptoms including pruritus (severe itching of the skin), caused by mast cells releasing inflammatory mediators such as histamine into the blood. Advanced SM comes with a poor prognosis, as survival rates vary between less than six months to 3.5 years, depending on the subtype.

 

“Patients with advanced SM are part of a very small, highly underserved community that has suffered from a lack of medical innovation for many years,” Dr. Alessandro Riva, global head of Novartis Oncology Development and Medical Affairs, commented in a press release. “Novartis is proud to have developed a treatment that shows benefit for these patients, and is now working with regulatory authorities to make midostaurin available as quickly as possible.”

 

PKC412 (midostaurin) is an investigational, oral, multitargeted kinase inhibitor that was recently granted Breakthrough Therapy Designation for adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) by the U.S. Food and Drug Administration. PKC412 additionally has orphan drug status in the European Union and United States for both AML and mastocytosis, and targets both wild-type KIT and the KIT D816V mutation, among others.

 

A recent Phase 2, single-arm, open-label study of adults, CPKC412D2201, was the largest and longest running prospective trial ever conducted on SM. It included three subtypes: aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL) and SM with an associated hematologic neoplasm. Dr. Jason Gotlib of Stanford University School of Medicine and Stanford Cancer Institute served as lead author of the study, which enrolled 116 people with advanced SM, with 89 patients found eligible for inclusion.

 

These patients were given single-agent, oral PKC412 (midostaurin) until their disease progressed or unacceptable toxicity was detected. 56 percent of the patients experienced a reduction of dosage due to toxicity. The results showed a median overall survival of 28.7 months. Additionally, 78 percent of patients showed improvements correlated to disease regression in both bone marrow mast cell burden and serum tryptase levels, a marker for mast cell burden. Quality of life was also assessed using the 12-item Short Form Health Survey, and results showed that patients experienced a 26-percent increase in mental health scores and 29-percent increase in physical heath scores.

 

The Phase 2 study results were recently reinforced in a letter published in the same issue of NEJM by the French Reference Centre of Mastocytosis (CEREMAST), which references a compassionate use program for patients with advanced SM using PKC412.

 

In both publications, most side effects that were noted were gastrointestinal, with the most frequent being nausea and vomiting. In the Phase 2 study, most of the 32 self-reported side effects significantly decreased with treatment. Patients in the CEREMAST program also reported lymphocytopenia in 61 percent without opportunistic infection and photosensitivity in 25 percent.

 

“These data show clear disease and symptom improvement with oral midostaurin treatment across a range of study participants who were reflective of the heterogeneity of this disease,” said Prof. Andreas Reiter of the Department of Hematology and Oncology in the University Hospital Mannheim of the University of Heidelberg, Germany and senior author of the study. “If approved, midostaurin will offer patients a much-needed treatment option.”

 

Since PKC412 is investigational at this time, Novartis has opened a Global Individual Patient Program, a compassionate use program to enable PKC412 access to pediatric and adult patients presenting with ASM, MCL or mast cell sarcoma. Novartis advises that physicians who would like to request PKC412 for eligible patients should contact one of the company’s medical representatives in their countries.