Navitoclax (BCL-2/BCL-XL inhibitor) + ruxolitinib doubles Week-24 spleen responses in frontline myelofibrosis, with major cytopenias

Navitoclax (NAV), an oral BCL-2/BCL-XL inhibitor that can potentiate apoptosis but predictably worsens platelet counts via BCL-XL inhibition, was combined with the JAK1/2 inhibitor ruxolitinib (RUX) in the Phase 3 TRANSFORM-1 trial (NCT04472598) in JAK-inhibitor–naïve intermediate-2/high-risk myelofibrosis (n=252; NAV+RUX n=125 vs placebo+RUX n=127; median follow-up 20.3 months). SVR35 at Week 24 was 63.2% with NAV+RUX vs 31.5% with placebo+RUX (P<0.0001), and SVR35 at any time was 76.8% vs 44.1% (nominal P<0.0001)—notably higher than the ~42% SVR35-at-Week-24 benchmark historically reported for ruxolitinib monotherapy in COMFORT-I. Symptom benefit did not separate (mean TSS change at Week 24: -10.2 vs -11.6; P=0.2852), while hematologic toxicity was substantially higher with NAV+RUX (Grade 3/4 thrombocytopenia 54.0% vs 19.2%; Grade 3/4 neutropenia 40.3% vs 8.8%) plus more diarrhea (41.9% vs 16.8%), though cytopenias were reported as generally manageable/reversible with dose modifications.