Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial.

Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

Pleural mesothelioma.

Pleural mesotheliomas are uncommon tumors that can be classified as localized or diffuse. Diffuse pleural mesotheliomas are invariably malignant. Although the frequency is low in the general population, it is more common in persons with a heavy occupational exposure to asbestos, and is considered as a signal tumor to asbestos exposure with medicolegal consequences. Mesothelioma incidence has been steadily rising during the past two decades, reflecting the increase in asbestos exposure during and following World War II. Clinical features include initial complaints of nonpleuritic chest pain and dyspnea. Distinguishing malignant mesothelioma from metastatic adenocarcinoma can be difficult, and can require large tissue biopsy with special stains and electron microscopy. The median survival of about 9 to 12 months confirms the poor outcome of pleural mesothelioma. The clinical deterioration is primarily attributable to locoregional spread of tumors, but metastasis is not rare. Several factors seem to have a prognostic value: performance status, stage, platelet count, age, histologic subtype, and asbestos exposure. In spite of the different therapeutic modalities such as surgery, radiotherapy, and chemotherapy used alone or in combination, the median survival is fairly different from survival among untreated patients. Because of the uncommon occurrence of this tumor and the existence of several different prognostic categories, a cooperative effort will be necessary for future therapeutic trials. If these active new therapies are identified, it would be useful to compare them to a best supportive care regimen in order to demonstrate an advantage of the treatment.