Dr Kishtagari on Pelabresib Plus Ruxolitinib in JAK Inhibitor–Naive Myelofibrosis

“At week 24, there [was a] 65.9% improvement in SVR35 at week 24 in the [pelabresib plus ruxolitinib] arm vs a 35% [improvement] in the [ruxolitinib alone] arm. Clearly, the combination has shown a significant improvement in SVR35.”

Ashwin Kishtagari, MD, assistant professor, medicine, hematology oncology, Vanderbilt University Medical Center, discusses updated findings from the phase 3 MANIFEST-2 trial (NCT04603495), which evaluated the addition of pelabresib (CPI-0610) to ruxolitinib (Jakafi) in JAK inhibitor–naive patients with myelofibrosis. The study assessed improvements in spleen volume, total symptom score (TSS), anemia, and bone marrow fibrosis at 24 weeks.

The study met its primary end point, demonstrating that a significantly higher proportion of patients who received the combination regimen (n = 214) achieved a 35% or greater reduction in spleen volume (SVR35) at week 24 compared with those who received ruxolitinib alone (n = 216), at 65.9% vs 35.2%, respectively (difference, 30.4%; 95% CI, 21.6%-39.3%; P < .001). The mean percentage change in spleen volume from baseline was –50.6% (95% CI, –53.2% to –48.0%) in the combination arm vs –30.6% (95% CI, –33.7% to –27.5%) in the monotherapy arm.

Secondary end points included improvement in TSS at week 24. Patients who received pelabresib plus ruxolitinib experienced a trend toward greater reduction in symptom burden compared with those who received ruxolitinib alone. Additionally, the combination therapy was associated with improvements in anemia and bone marrow fibrosis, suggesting its potential disease-modifying effects.

Kishtagari highlights that this trial included a broad population of patients with myelofibrosis, encompassing those with primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis. Unlike other trials that only enrolled intermediate-2 and high-risk patients, MANIFEST-2 also included patients with intermediate-1 risk disease.

Given the demonstrated improvements in SVR and symptom burden, Kishtagari notes that these findings support the potential role of BET inhibition in combination with JAK inhibition as a first-line treatment approach for patients with myelofibrosis.