MANIFEST-2: Sustained benefits of pelabresib plus ruxolitinib in myelofibrosis

The combination of pelabresib and ruxolitinib displayed improvements across a variety of efficacy measures in patients with JAK inhibitor-naïve myelofibrosis. Moreover, the 72-week follow-up data of the MANIFEST-2 trial showed that the addition of pelabresib to the treatment regimen was not associated with considerable toxicity in this population.

The phase 3 MANIFEST-2 study (NCT04603495) compared the combination treatment of pelabresib plus ruxolitinib with ruxolitinib plus placebo in 430 patients with JAK inhibitor-naïve myelofibrosis [1,2]. “Ruxolitinib is a JAK inhibitor, which is the standard-of-care for intermediate- and high-risk myelofibrosis, and pelabresib inhibits BET proteins and subsequent BET-mediated expression of genes involved in myelofibrosis pathogenesis,” clarified Prof. Alessandro Vannucchi (University of Florence, Italy). The study met its primary endpoint [1]; the current analysis looked at long-term efficacy and safety [2].

At week 72, 46.3% of the participants in the pelabresib arm had a spleen volume reduction of at least 35% (SVR35), compared with 29.2% of the participants in the placebo arm, representing a significant difference of 16.7% (95% CI 7.9–25.4). Similarly, a larger proportion of participants in the pelabresib arm achieved a bone marrow fibrosis improvement of at least 1 grade (17.8% vs 9.3%). Prof. Vannucchi noted that, in participants with anaemia, 20.9% versus 16.9% had an Hb response in the pelabresib arm and placebo arm, respectively. At this time, the study arms were not significantly different for progression-free survival (PFS); however, the authors noted a trend toward improved PFS for participants on pelabresib (HR 0.87; 95% CI 0.49–1.56). Finally, grade ≥3 treatment-emergent adverse events occurred in 65.1% and 65.4% of the participants. Grade ≥3 anaemia was more common in the placebo arm (27.4% vs 40.7%), whereas grade ≥3 thrombocytopenia was more prevalent in participants on pelabresib (12.7% vs 6.1%).

“Pelabresib plus ruxolitinib demonstrated continued improvements in splenic response, symptoms, bone marrow fibrosis, and anaemia in patients with myelofibrosis,” concluded Prof. Vannucchi. “Longer term follow-up is needed to learn whether this combination therapy may outperform ruxolitinib alone in terms of PFS and overall survival.”

1. Rampal RK, et al. Nat Med. 2025;31:1531-1538.
2. Vannucchi A, et al. Pelabresib in combination with ruxolitinib for Janus kinase inhibitor-naïve patients with myelofibrosis: 72-week follow-up with long-term efficacy outcomes of the phase III MANIFEST-2 study. S223, EHA2025 Congress, 12–15 June, Milan, Italy.

Medical writing support was provided by Robert van den Heuvel.
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Posted on 16 June 20252 September 2025