TRANSFORM-1 phase III study: Navitoclax + ruxolitinib in JAKi-naïve MF

Results from the randomized, double-blind, placebo-controlled, multicenter, phase III TRANSFORM-1 study (NCT04472598), evaluating navitoclax + ruxolitinib (Nav + Rux; n = 125) vs placebo + Rux (n = 127) in Janus kinase inhibitor (JAKi)-naïve adults with intermediate-2 or high-risk myelofibrosis (MF) were published in Blood by Pemmaraju et al. The primary endpoint was ≥35% spleen volume reduction (SVR) at Week 24 from baseline (SVR35W24). 

Key data: SVR35W24 was achieved by 63.2% of patients in the Nav + Rux group vs 31.5% of those in the placebo + Rux group (p < 0.0001). The mean change in Total Symptom Score (TSS) at Week 24 was −10.2 vs −11.6, respectively (p = 0.2852). Median overall survival (OS) was not estimable (NE) with Nav + Rux vs 48.5 months with placebo + Rux (hazard ratio [HR], 1.25, 95% confidence interval [CI], 0.75–2.08; nominal log-rank p = 0.3867). Grade 3/4 adverse events (AEs) were reported in 90.3% of patients in the Nav + Rux group vs 79.2% of those in placebo + Rux group. The most common Grade 3/4 AEs were thrombocytopenia (54.0% in the Nav + Rux group vs 19.2% in the placebo + Rux group), anemia (49.2% vs 44.0%), neutropenia (40.3% vs 8.8%), and diarrhea (5.7% vs 0%). Cytopenias were generally manageable and reversible with dose adjustments. 

Key learning: In JAKi-naïve adults with intermediate-2 or high-risk MF, Nav + Rux approximately doubled the SVR35W24 rate vs placebo + Rux, though no significant difference in symptom burden or OS was observed. Higher rates of hematologic AEs occurred with Nav + Rux, although these were generally manageable with dose adjustments. These findings highlight the challenge of translating deeper spleen responses into broader clinical benefit.