Dr Rampal on Findings From the MANIFEST-2 Trial in JAK Inhibitor–Naive Myelofibrosis

Raajit K. Rampal, MD, PhD, hematologic-oncologist, director, Center for Hematologic Malignancies, director, Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center, discusses findings from the phase 3 MANIFEST-2 trial (NCT04603495) investigating pelabresib (CPI-0610) in combination with ruxolitinib (Jakafi) for JAK inhibitor–naive patients with myelofibrosis.

Investigators presented updated data from the phase 3 trial at the 2023 ASH Annual Meeting. The response rate for patients who achieved a 35% reduction in spleen volume was higher in patients treated with the combination therapy compared with ruxolitinib alone, Rampal begins. A total of 65.9% of patients achieved this response with the combination vs 35.2% with single-agent ruxolitinib, and the difference between arms was statistically significant, Rampal emphasizes. This finding corroborates numerous studies previously showing a correlation between spleen volume response and overall patient survival, and underscores the importance of reducing spleen size, he explains.

When examining key secondary end points, there was numerical superiority in the absolute reduction of total symptoms with the combination vs ruxolitinib alone, he expands. The percentage of patients achieving a 50% reduction in symptoms (TSS50), also favored the combination treatment by approximately 6%, though this was not statistically significant. Broader analysis revealed a greater reduction in bone marrow fibrosis and lower levels of inflammatory cytokines with combination treatment. The regimen’s safety profile was comparable to that of ruxolitinib alone, indicating no added toxicity with pelabresib, Rampal imparts.

Despite an upward trend in hemoglobin levels among patients receiving the combination therapy, there was an increased frequency of anemia events in those receiving single-agent ruxolitinib, he states. Collectively, these findings position the combination of ruxolitinib and pelabresib as a potentially viable upfront treatment strategy for patients with myelofibrosis. The regimen improved spleen responses, increased hemoglobin levels, and reduced inflammation and bone marrow fibrosis, which are all critical markers of disease progression, Rampal concludes.

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