MANIFEST-2 long-term follow-up results: Pelabresib + ruxolitinib in JAKi-naïve patients with MF

The SoC in intermediate- and high-risk MF is JAKi monotherapy. However, some patients treated with JAKi experience suboptimal responses and TEAEs, highlighting the need for additional treatment options for this patient population. The primary analysis from the phase III MANIFEST-2 trial (NCT04603495), evaluating the efficacy and safety of the BET inhibitor pelabresib + ruxolitinib vs ruxolitinib + placebo in JAKi-naïve patients with MF, met its primary endpoint. During the European Hematology Association 2025 Congress, Alessandro Vannucchi presented the 72-week follow-up efficacy and safety results from MANIFEST-2.¹

In the MANIFEST-2 trial, eligible patients were randomized 1:1 to receive either Pela + Rux (n = 214) or Pbo + Rux (n = 216). At Week 72, 53.3% and 55.6% of patients in the Pela + Rux and Pbo + Rux groups continued to receive treatment. The primary endpoint of MANIFEST-2 was SVR35 response. Key secondary endpoints included absolute change in TSS from baseline, TSS50 response, and safety.

Key learnings

At Week 72, Pela + Rux showed sustained improvements in SVR35 response (46.3% vs 29.2%), and a higher proportion of patients maintained SVR35 responses (80% vs 73%) vs Pbo + Rux.

TSS50 response rates at Week 72 were higher with Pela + Rux vs Pbo + Rux (42.1% vs 35.2%), with an absolute change in TSS of -15.42 and -13.19, respectively.

The proportion of patients achieving both SVR35 and TSS50 responses was nearly double with Pela + Rux vs Pbo + Rux (31.3% vs 17.6%).

At 72 weeks, Hb response rates were higher (16.4% vs 9.3%) with Pela + Rux vs Pbo + Rux, with a lower proportion of patients requiring RBC transfusions during Weeks 49–72 (19.3% vs 25.3%).

Grade ≥1 BMF improvements were higher with Pela + Rux vs Pbo + Rux (51.4% vs 28.2%). Grade ≥3 anemia and thrombocytopenia were reported in 27.4% vs 40.7% and 12.7% vs 6.1% of patients with Pela + Rux vs Pbo + Rux.

Pela + Rux continues to demonstrate clinically meaningful responses vs Pbo + Rux, with correlative biomarkers such as deep and sustained spleen reduction, TSS and TSS50 improvements, and high rates of dual SRV35/TSS50 suggesting disease modification.