Safety and efficacy of CYT387, a JAK-1/2 inhibitor, for the treatment of myelofibrosis.

Abstract

6514 Background: CYT387 is a potent JAK-1/2 inhibitor. In an ongoing phase-1/2 multi-center study, 108 patients with myelofibrosis (MF) have so far been accrued. We present updated interim results for 60 patients who have completed a minimum of 3 cycles of treatment. Additional information for the entire study cohort will be presented at the meeting. Methods: Patients with high/intermediate-risk MF were included. CYT387 was administered orally once daily in 28-day cycles. Responses were assessed by International Working Group (IWG) criteria. Results: Dose-limiting toxicities were grade 3 hyperlipasemia and grade 3 headache. The maximum tolerated dose was 300 mg/day. The study retention rate after a median of 6.4 months was 92%. About half of the patients experienced a first-dose effect (transient lightheadedness and hypotension), which was self-limited and generally resolved within hours with rare recurrence. Grade 3/4 hematologic and non-hematologic adverse events were infrequent with the exception of thrombocytopenia, which occurred in approximately 25% of patients. Forty-two patients were evaluable for anemia response per IWG criteria (Blood 2006;108:1497) and 33 were red cell transfusion-dependent. In the latter group, anemia response required a transfusion-free period of ≥12 weeks, while on protocol drug therapy, and capped by a hemoglobin level of ≥8 g/dL. Accordingly, the overall anemia response rate was 50% and 58% in transfusion-dependent patients. The median duration of anemia response was 20 weeks (range 12-54) and only 2 (11%) of the 19 patients who achieved transfusion-independency required single episodes of PRBC transfusions. Responses in anemia were not affected by leukocyte count (p=0.39), platelet count (p=0.35), circulating blast count (p=0.35), circulating CD34 cell count (p=0.78), karyotype (p=0.67) or JAK2V617F mutational status (p=0.17). Spleen response rate by IWG criteria was approximately 45% whereas the majority of patients experienced resolution of constitutional symptoms including pruritus, night sweats and bone pain. Conclusions: CYT387 is unique among JAK inhibitors because of its ability to induce durable anemia responses in a significant number of patients with myelofibrosis.