Momelotinib Long-Term Safety and Survival in Myelofibrosis: Integrated Analysis of Phase 3 Randomized-Controlled Trials.

Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis. This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, SIMPLIFY-2), representing myelofibrosis disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Patients in the control arms (danazol in MOMENTUM; ruxolitinib in SIMPLIFY-1; best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol. Across these studies, 725 patients with myelofibrosis received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27%; grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% rate of discontinuation). Incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in myelofibrosis demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity.