A Phase 1-2 Trial of JAK1 and JAK2 Inhibitors in Myelofibrosis

Myelofibrosis, a Philadelphia chromosomenegative myeloproliferative neoplasm, is characterized by progressive anemia, bone marrow fibrosis and splenomegaly, and produces debilitating symptoms. About 50% of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that leads to many of the disease’s effects. There are no approved conventional drugs for myelofibrosis that provide anything more than the most palliative benefits. INCB018424, a potent, selective inhibitor of JAK1 and JAK2, has been shown to be effective in preclinical studies in models of myeloproliferative neoplasms. This investigation [N Engl J Med. 2010;363(12):1117-1127] described the clinical evaluation of this JAK1 and JAK2 inhibitor in myelofibrosis.

The investigators conducted a phase 1-2 trial of INCB018424 in patients with JAK2 V617F-positive or JAK2 V617F-negative primary myelofibrosis, postessential thrombocythemia myelofibrosis, or postpolycythemia vera myelofibrosis, all Philadelphia chromosome-negative myeloproliferative neoplasms. Patients ≥18 years of age with the above conditions were eligible for enrollment in the study if they required therapy, had had a relapse, or had severe side effects from therapy or disease refractory to previous therapy. Newly diagnosed patients were eligible if they had intermediate- or high-risk disease according to the Lille scoring system or had symptomatic palpable splenomegaly or hepatomegaly. Other eligibility criteria included an Eastern Cooperative Oncology Group performance status of ≤2. A total of 153 patients (median age, 65 years; range, 40-84 years; 63% male and 37% female) were enrolled in the study. The patients received a starting dose of 25 mg of INCB018424 twice daily, which was escalated to 50 mg twice daily; later other once-daily doses, ranging from 10 to 200 mg twice daily, were studied.

Thrombocytopenia was identified as the dose-limiting toxic effect, and 25 mg twice daily and 100 mg once daily were identified as the maximum tolerated doses. In the phase 2 part of the study, additional dosing schedules were studied to identify an effective dosing schedule that would lead to a reduced incidence of thrombocytopenia. Patients were followed for a median of 14.7 months. According to the response criteria of the International Working Group for Myelofibrosis Research and Treatment, 61 of 140 patients with an enlarged spleen at study entry (44%) had an objective response (clinical improvement), based on a reduction of ≥50% in palpable splenomegaly within the first 3 months after therapy. The response rate was highest among the 33 patients who received 15 mg and the 39 patients who received 25 mg twice daily (52% and 49%, respectively).

Among patients who had a response according to the international working group criteria, the response was maintained after 12 months of therapy in 71% of patients who received 10 mg twice daily, 73% of patients who received 15 mg twice daily, 78% of patients who received 25 mg twice daily, and 75% of patients who received 50 mg once daily. The majority of patients had a ≥25% reduction in spleen size while receiving therapy. This reduction occurred within the first 1 to 2 months of therapy and was durable beyond 1 year of therapy in all 16 patients for whom data were available at 1.5 years and all 8 patients for whom data were available at 2 years. The 15-mg twice-daily dose was associated with nonhematologic toxic adverse events in <10% of patients. The 15-mg twice-daily starting dose, with individualized dose adjustment, was found to be the most effective and safest dose of INCB018424, the investigators said. The investigational therapy was associated with rapid and sustained reduction of splenomegaly, resolution of constitutional symptoms (weight loss, fatigue, night sweats, pruritus), improvement of performance status and exercise capacity, and weight gain.