Addition of navitoclax to ruxolitinib in patients with myelofibrosis with progression or suboptimal response

• The addition of navitoclax to ongoing ruxolitinib demonstrates durable responses and evidence of potential disease modification in R/R MF

• Thrombocytopenia is the most common adverse event, and is manageable and reversible with dose reduction as necessary

Navitoclax, an oral BCL-X_L/BCL-2 inhibitor, induces apoptosis of malignant cells in myelofibrosis (MF). Here, we present results of pooled Cohort 1 of the phase II REFINE trial (NCT03222609), which evaluated navitoclax plus ruxolitinib (NAV+RUX) in patients with relapsed/refractory MF with suboptimal response to ruxolitinib (on stable dose of ≥10 mg twice daily for ≥12 weeks [Cohort 1a] or ≥24 weeks [Cohort 1b]). Patients in Cohort 1a received add-on navitoclax 50 mg/day, with escalation to ≤300 mg if platelet count was ≥75 x 10⁹/L. Patients in Cohort 1b received navitoclax 100/200 mg/day if platelet count was ≤150 or >150 x 10⁹/L, respectively. Primary endpoint was spleen volume reduction ≥35% (SVR₃₅) at Week (W) 24. Secondary endpoints included ≥50% reduction in total symptoms score (TSS₅₀) at W24, changes in bone marrow fibrosis (BMF) grade, anemia response, and safety. In total, 125 patients received ≥1 dose of NAV+RUX. With median follow-up of 21 months, SVR₃₅ rate was 23% at W24 and 39% at any time on study (median duration: 11 months). TSS₅₀ rate was 24% at W24 and 46% at any time on study. BMF improved by ≥1 grade, any time on study, in 39% of patients. Anemia responses were achieved in 23% of patients. Median overall and progression-free survival were 52.3 and 22.1 months, respectively. No new safety signals were observed. The most common adverse event was thrombocytopenia (86%) without clinically significant bleeding. NAV+RUX had tolerable safety, and resulted in early improvement in parameters of disease modification in this difficult-to-treat population.