A combination treatment with pelabresib plus ruxolitinib provided robust clinical benefit, resulting in a statistically significant improvement in the primary endpoint of spleen response, with trends of improvement noted across other principal hallmarks of myelofibrosis, including symptom control, proinflammatory cytokine amounts and bone marrow morphology.
Findings from the primary analysis of the randomised phase III MANIFEST-2 study provide important insights into disease biology and modification, supporting the combination of pelabresib plus ruxolitinib for JAK inhibitor-naive patients with myelofibrosis according to Dr. John Mascarenhas of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, NY, US and colleagues, who published the findings on 10 March 2025 in the Nature Medicine.
The authors wrote in the background that JAK inhibitor monotherapy is the standard-of-care for myelofibrosis in patients with splenomegaly and/or symptoms. However, JAK inhibitors do not consistently resolve pathobiological features, such as molecular markers of clonal burden and disrupted bone marrow morphology, particularly with short-term treatment. Therefore, an unmet medical need persists due to limited depth and durability of clinical response, and frequency of treatment-emergent adverse events (TEAEs) with JAK inhibitor monotherapy, the authors explained in the background.
Preclinical observations support simultaneous BET and JAK inhibition as a potent therapeutic strategy to exceed the effects of JAK inhibitor monotherapy. Pelabresib is an investigational, oral, small molecule BET inhibitor under evaluation in clinical trials for patients with myelofibrosis. Data from the phase II MANIFEST study demonstrated substantial and durable improvements in splenomegaly and symptoms with pelabresib plus ruxolitinib in JAK inhibitor-naive patients with myelofibrosis and the combination was generally well tolerated.
In MANIFEST-2, the study investigators evaluated pelabresib, a BET inhibitor plus ruxolitinib, a JAK inhibitor compared with placebo plus ruxolitinib as first-line therapy in JAK inhibitor-naive patients with myelofibrosis. Patients were randomised 1:1 to pelabresib 125 mg once daily for 14 days followed by a 7-day break, or to placebo in combination with ruxolitinib 10 or 15 mg twice daily. Primary endpoint was reduction in spleen volume of ≥ 35% from baseline at week 24. Key secondary endpoints were absolute change in total symptom score (TSS) and TSS50 response defined as ≥ 50% reduction in TSS from baseline at week 24.
The primary endpoint was met in 65.9% of 214 patients randomised to pelabresib plus ruxolitinib versus 35.2% in 216 patients randomised to placebo plus ruxolitinib (difference 30.4%; 95% confidence interval (CI) 21.6, 39.3; p < 0.001). Absolute change in TSS was −15.99 versus −14.05 (difference −1.94; 95% CI −3.92, 0.04; p = 0.0545) and TSS50 was achieved in 52.3% versus 46.3% (difference 6.0%; 95 CI −3.5, 15.5) with pelabresib plus ruxolitinib versus placebo plus ruxolitinib.
Exploratory analyses of proinflammatory cytokine amounts and bone marrow morphology showed greater improvement with the combination than with JAK inhibition alone. These include NF-κB-regulated cytokines, TNF, IL-6 and IL-8, which have a key role in myelofibrosis pathogenesis and are associated with a detrimental prognosis. Consistent with proinflammatory cytokines analysis, improvements in fibrosis and overall bone marrow morphology were also observed to a greater degree in the combination arm, collectively indicating a biological benefit of the pelabresib plus ruxolitinib combination, which supports the clinical benefits.
Thrombocytopenia and anaemia were the most common TEAEs, occurring in 52.8% (13.2% grade ≥ 3) versus 37.4% (6.1% grade ≥ 3) and 44.8% (23.1% grade ≥ 3) versus 55.1% (36.5% grade ≥ 3), respectively. The study team observed increased erythrocyte progenitor proportions in the pelabresib plus ruxolitinib arm, which may explain the amelioration of anaemia. Reduced transfusions associated with anaemia improvements are likely to have a direct benefit on the clinical and economic burden of myelofibrosis according to the authors.
The authors also commented that clinically and biologically meaningful benefits of the pelabresib and ruxolitinib combination represent valuable short-term outcomes for patients, which may translate into more profound longer-term treatment effects than ruxolitinib monotherapy. Durability of response, survival and correlation with clinical outcomes will be further evaluated with ongoing, long-term follow-up of this study.
Development of pelabresib was funded in part by the Leukemia and Lymphoma Society. The MANIFEST-2 study was supported by Constellation Pharmaceuticals, a Novartis Company.
Reference
Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial. Nature Medicine; Published online 10 March 2025. DOI: https://doi.org/10.1038/s41591-025-03572-3