Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis

Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis (MF) but is associated with dose-dependent anemia and thrombocytopenia. In this open-label phase 2 study, we evaluated the efficacy and safety of 3 dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk MF and a platelet count >= 50x109/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A >= 50% reduction in total symptom score (TSS) was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, 2 patients (20%) in the 100 mg twice-daily cohort had >= 50% TSS reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts, the median spleen volume reductions at week 12 were 14.2% and 17.4%, respectively. Furthermore, 21/39 (53.8%) patients who required red blood cell (RBC) transfusions during the 12 weeks preceding treatment initiation achieved a >= 50% reduction in the number of RBC units transfused during study weeks 1-24. Only 1 patient discontinued for grade 3 thrombocytopenia. Nonhematologic adverse events were largely grade 1 or 2; the most common was fatigue. Treatment with INCB039110 resulted in clinically meaningful symptom relief, modest spleen volume reduction, and limited myelosuppression.