Dr Gerds on the Clinical Implications of Pelabresib Plus Ruxolitinib in Myelofibrosis

Aaron Gerds, MD, assistant professor, medicine, Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, discusses the clinical implications of safety outcomes with of pelabresib (CPI-0610) plus ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis.

At the 2024 ASCO Annual Meeting, investigators presented updated safety and efficacy data from the phase 3 MANIFEST-2 trial (NCT04603495), which investigated pelabresib in combination with ruxolitinib in JAK inhibitor–naive patients with myelofibrosis. The study revealed significant reductions in splenomegaly with combination therapy compared with ruxolitinib alone at week 24, along with rapid, deep, and sustained spleen reduction. The combination therapy also generated a trend toward greater improvement in total symptom score and higher rates of deeper hemoglobin responses vs ruxolitinib monotherapy, with fewer patients requiring transfusions and fewer anemia-related adverse effects observed.

In this updated readout, patients receiving the combination experienced a significantly higher spleen volume response rate at week 24 compared with those receiving ruxolitinib alone. The combination therapy also resulted in more sustained spleen volume responses and greater reductions in total symptom score, although the difference in the latter did not reach statistical significance. Hemoglobin levels remained higher over time in the combination arm, and fewer patients in this arm required red blood cell transfusions. Improvements in bone marrow fibrosis and reductions in key inflammatory cytokines were also observed with the combination therapy.

Gerds reports that at week 24, the number of patients who achieved both key responses of spleen volume reduction of 35% or more (SVR35) and a 50% or greater reduction in total symptom score (TSS50) was more than doubled in those who recieved the combination therapy vs those who received ruxolitinib alone. This is significant, especially since SVR35 is associated with better survival, he notes. However, more time is needed to see whether the survival curves will separate, Gerds says.

An updated analysis will be presented later in 2024 that will provide a clearer picture of the survival outcomes in this study, he expands. This safety analysis may prove to be as important as the primary end point results observed at week 24, Gerds concludes.