Is pelabresib plus ruxolitinib the paradigm-shifting combo therapy for MF?

Treatment with pelabresib plus ruxolitinib was associated with improvements in all 4 hallmarks of myelofibrosis, the phase 3 MANIFEST-2 trial showed.

Significant spleen responses and improved anaemia

The phase 3 MANIFEST-2 study (NCT04603495) evaluated pelabresib, an investigational bromodomain and extra-terminal domain (BET) protein inhibitor, in combination with JAK inhibitor ruxolitinib for treating MF. The 430 enrolled participants with MF were randomised to pelabresib plus ruxolitinib or to ruxolitinib plus placebo. The primary endpoint was a 35% spleen volume reduction (SVR35) at week 24. Dr Raajit Rampal (Memorial Sloan Kettering Cancer Center, NY, USA) presented the latest trial results1.

At week 24, 65.9 % and 35.2 % of the participants in the pelabresib arm and placebo arm, respectively, achieved the primary endpoint (P<0.001). Dr Rampal shared that the mean absolute change in total symptom score at week 24 was -15.99 in the pelabresib and -14.05 in the placebo arm, reflecting a numerical benefit for the pelabresib arm (P=0.055). Haemoglobin responses were seen in 10.7 % and 6.0 % of the participants in the experimental and placebo arm, respectively. Furthermore, significant improvements in bone marrow fibrosis (at least 1 grade) were documented for 38.5 % on pelabresib and 24.2 % on placebo (OR 2.09; 95 % CI 1.14–3.93).

As for safety, the most common treatment-emergent adverse events in the experimental and placebo arms were anaemia (43.9 % vs 55.6 %), thrombocytopenia (32.1 % vs 23.4 %), decreased platelet count (20.8 % vs 15.9 %), and diarrhoea (23.1 % vs 18.7 %).

In conclusion, the treatment regimen of pelabresib plus ruxolitinib was associated with significant spleen responses, improved anaemia and bone marrow fibrosis, and a trend towards improved symptoms, compared to a treatment regimen of ruxolitinib and placebo in a population of patients with MF.

Medical writing support was provided by Robert van den Heuvel.

  1. Rampal RK, et al. Safety and efficacy of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-naïve patients with myelofibrosis: latest data from the phase 3 MANIFEST-2 study. Abstract #S221, EHA congress 2024, 13–16 June, Madrid, Spain.