Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis
Open Access
- 5 March 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Leukemia
- Vol. 27 (6), 1322-1327
- https://doi.org/10.1038/leu.2013.71
Abstract
JAK-STAT is a rational drug target in myelofibrosis (MF) given its association with JAK2/MPL mutations and aberrant inflammatory cytokine expression. We conducted a Phase 1/2 trial of CYT387, a potent JAK1/2 inhibitor, in patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia MF. Pre-planned safety and efficacy analysis has been completed for the initial 60 patients. In the dose-escalation phase (n=21), the maximum-tolerated dose was 300 mg/day based on reversible grade 3 headache and asymptomatic hyperlipasemia. Twenty-one and 18 additional patients were accrued at two biologically effective doses, 300 mg/day and 150 mg/day, respectively. Anemia and spleen responses, per International Working Group criteria, were 59% and 48%, respectively. Among 33 patients who were red cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7–>18.3 months). Most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasemia (5%), elevated liver transaminases (3%) and headache (3%). New-onset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). CYT387 is well tolerated and produces significant anemia, spleen and symptom responses in MF patients. Plasma cytokine and gene expression studies suggested a broad anticytokine drug effect.Keywords
This publication has 20 references indexed in Scilit:
- JAK inhibitors for myeloproliferative neoplasms: clarifying facts from mythsBlood, 2012
- A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for MyelofibrosisNew England Journal of Medicine, 2012
- JAK Inhibition with Ruxolitinib versus Best Available Therapy for MyelofibrosisNew England Journal of Medicine, 2012
- Challenges Facing JAK Inhibitor Therapy for Myeloproliferative NeoplasmsNew England Journal of Medicine, 2012
- One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic ExperienceMayo Clinic Proceedings, 2012
- Primary myelofibrosis with or without mutant MPL: comparison of survival and clinical features involving 603 patientsLeukemia, 2011
- How I treat myelofibrosisBlood, 2011
- DIPSS Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion StatusJournal of Clinical Oncology, 2011
- Physiological Jak2V617F Expression Causes a Lethal Myeloproliferative Neoplasm with Differential Effects on Hematopoietic Stem and Progenitor CellsCancer Cell, 2010
- Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1Leukemia, 2010