Multinational phase 3 trial of pelabresib plus ruxolitinib for JAK inhibitor-naïve myelofibrosis

Janus kinase (JAK) inhibitors, such as ruxolitinib, provide limited depth and durability of response in myelofibrosis. Pelabresib is a bromodomain and extraterminal domain (BET) inhibitor. The multinational phase 3 MANIFEST-2 trial randomized patients with previously untreated myelofibrosis 1:1 to pelabresib plus ruxolitinib (n=214) or placebo plus ruxolitinib (n=216). The primary endpoint was reduction of spleen volume of ≥ 35% from baseline at week 24. The primary endpoint was met in 65.9% of patients in the pelabresib plus ruxolitinib group versus 35.2% of patients in the placebo plus ruxolitinib group (p<0.001). Reduction of total symptom score by at least 50% was achieved in 52.3% of patients with pelabresib plus ruxolitinib versus 46.3% of patients with placebo plus ruxolitinib. Most common treatment-emergent adverse events in the combination group were thrombocytopenia (52.8%; grade ≥3 in 13.2%) and anemia (44.8.1%; grade ≥3 in 23.1%). The authors conclude that addition of pelabresib to first-line ruxolitinib for myelofibrosis was well tolerated and provided substantial clinical benefit.