The Phase 3 TRANSFORM-1 study (NCT04472598) evaluated ruxolitinib (RUX) in combination with navitoclax (NAV) or placebo (PBO) in Janus-kinase-inhibitor-naïve adults with intermediate-2 or high-risk myelofibrosis and Eastern Cooperative Oncology Group performance status ≤2. Patients were randomized 1:1 to NAV (200 mg/day starting dose or 100 mg escalated to 200 mg/day) or PBO, with RUX dosed per label. The primary endpoint was ≥35% spleen volume reduction (SVR) at Week 24 (SVR35W24). Secondary endpoints included change from baseline in Total Symptom Score (TSS) at Week 24 and SVR35 at any time. A total of 252 patients (NAV+RUX, n=125; PBO+RUX, n=127; median follow-up 20.3 months) were randomized; >80% had intermediate-2 risk and nearly 50% were high-molecular risk (HMR). SVR35W24 was achieved by 63.2% with NAV+RUX versus 31.5% with PBO+RUX (P<0.0001). Mean change in TSS at Week 24 was not significantly different between NAV+RUX and PBO+RUX (-10.2 vs -11.6; P=0.2852). SVR35 at any time was achieved in 76.8% with NAV+RUX versus 44.1% with PBO+RUX (nominal P<0.0001). A ≥20% variant allele frequency reduction (exploratory endpoint) occurred in 58.5% (95% CI: 49.0-67.5) with NAV+RUX and 45.5% (95% CI: 36.4-54.8) with PBO+RUX. NAV+RUX showed higher hematologic toxicity versus PBO+RUX (Grade 3/4 thrombocytopenia: 54.0% vs 19.2%; Grade 3/4 neutropenia: 40.3% vs 8.8%); diarrhea (any grade: 41.9% vs 16.8%) was also more common. Cytopenias were generally manageable and reversible with dose adjustments.