Preliminary safety and efficacy of navitoclax plus ruxolitinib in janus kinase inhibitor-naïve patients with myelofibrosis from the multicenter, open-label, phase 2 study (REFINE)

Myelofibrosis is characterized by perturbation of the JAK/STAT pathway and upregulation of anti-apoptotic factors leading to myeloproliferation, bone marrow fibrosis (BMF), extramedullary hematopoiesis, splenomegaly, and cytopenias. Navitoclax, a potent oral B-cell lymphoma (BCL)-X L/BCL-2 inhibitor, promotes apoptosis of malignant myelofibrosis cells. Herein, we present results of Cohort 3 of the Phase 2 REFINE study (NCT03222609), which evaluated efficacy and safety of navitoclax plus ruxolitinib in JAKi-naïve patients with myelofibrosis. JAKi-naïve patients with primary or secondary myelofibrosis (≥ 18 years with splenomegaly, DIPSS intermediate-2 and high-risk myelofibrosis, and ECOG 0-2) and platelet count > 100 × 10 9/L were enrolled and treated with navitoclax 100 mg once daily (QD) or 200 mg QD according to platelet count (≤ 150 × 10 9/L or > 150 × 10 9/L, respectively). Ruxolitinib was given twice daily (dose per label). Primary endpoint: spleen volume reduction of ≥ 35% (SVR 35) at week 24. Secondary endpoints: ≥ 50% reduction in total symptom score (TSS 50) at week 24, change in grade of BMF, anemia response, and safety. Thirty-two patients received ≥ 1 dose of navitoclax plus ruxolitinib. Median (range) duration of follow-up was 44 months (5-58). 63% (20/32) of patients achieved SVR 35 at week 24; median (range) time to first SVR 35 was 12 weeks (11─48). Of 24 evaluable patients, 21% achieved ≥ 50% reduction in driver gene variant allele frequency (VAF). Of 27 evaluable patients, 11 (41%) achieved TSS 50 at week 24; median (range) time to first TSS 50 of 3 weeks (0─16). BMF improved from baseline by ≥ 1 grade in 13/27 patients (48%) at any time on study. Anemia response rates were 38% (5/13) for transfusion-independent and 100% (2/2) for transfusion-dependent patients. No bleeding events or deaths were attributed to navitoclax. These findings suggest navitoclax plus ruxolitinib has a tolerable safety profile and provides clinically meaningful improvements for JAKi-naïve patients with myelofibrosis. TRIAL REGISTRATION: NCT03222609.