A combination therapy of pelabresib and ruxolitinib has demonstrated significant clinical benefits in patients with myelofibrosis (MF) who have not previously been treated with Janus kinase inhibitors (JAKis). The Phase 3 MANIFEST-2 trial revealed that the combination significantly reduced splenomegaly and improved anemia, offering a promising new treatment approach for this patient population.
The global, randomized, double-blind MANIFEST-2 trial (NCT04603495) investigated the safety and efficacy of pelabresib in combination with ruxolitinib versus ruxolitinib with placebo. The study's primary endpoint was a ≥35% spleen volume reduction from baseline (SVR35) at week 24. Secondary endpoints included absolute change in total symptom score (TSS), ≥50% reduction in TSS from baseline (TSS50) at week 24, safety, and hemoglobin response (≥1.5 g/dL mean increase from baseline without transfusions in the prior 12 weeks).
Key Findings from MANIFEST-2
The trial randomized 430 patients to receive either pelabresib or placebo (daily for 14 consecutive days of 21) with ruxolitinib (twice daily for 21 days [1 cycle]). At 24 weeks, 65.9% of patients in the pelabresib and ruxolitinib arm achieved an SVR35 response compared with 35.2% of patients on the placebo regimen (P < .001). Patients receiving the pelabresib combination therapy demonstrated a mean absolute change in TSS of −15.99 (1.028) vs −14.05 (0.986), as well as a TSS50 response of 52.3% vs 46.3% (nominal P = .22), compared with the placebo arm. Hemoglobin response was 10.7% (23/214) vs 6.0% (13/216) of patients for pelabresib with ruxolitinib and ruxolitinib with placebo, respectively. Differences in mean hemoglobin levels were maintained at 48 weeks.
Safety Profile
Out of 426 patients evaluated for safety, anemia occurred in 43.9% treated with pelabresib and ruxolitinib compared with 54.7% in ruxolitinib and placebo. Other common adverse effects included thrombocytopenia (52.8% vs 37.4%), and diarrhea (23.1% vs 18.7%).
Implications for Myelofibrosis Treatment
These findings underscore the significant clinical benefit of combining pelabresib with ruxolitinib in treating JAKi-naïve patients with myelofibrosis, demonstrating substantial improvements in spleen volume reduction, symptom relief, and anemia management. These data provide hope for improving outcomes and marks an important step forward in the development of better therapies for MF.
Myelofibrosis is a rare, fatal myeloproliferative neoplasm characterized by the overproduction of hematopoietic stem cells leading to reduced blood cell production. Studies have shown that bromodomain and extraterminal domain (BET) and the JAK/STAT pathway are involved in the development and progression of MF. As a result, BET proteins are emerging as a potential target capable of altering the underlying causal mechanism driving MF. Pelabresib is an investigational, oral, small molecule bromodomain and extraterminal domain (BET) inhibitor intended to decrease expression of MF target genes.
