Abstract

Purpose Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor. Patients and Methods In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis. Results Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months. Conclusion TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.