Pelabresib Plus Ruxolitinib Is a Promising Treatment Regimen for Myelofibrosis

The combination of pelabresib plus ruxolitinib demonstrated significant clinical activity and disease-modifying potential without treatment-limiting toxicity in patients with myelofibrosis (MF), and an ongoing phase III study is expected to provide definitive efficacy results.

Raajit K. Rampal, MD, PhD, of the Memorial Sloan-Kettering Cancer Center in New York, initiated the phase III MANIFEST-2 trial based on “compelling data” from arm III of the ongoing phase II MANIFEST study, which is currently evaluating the double therapy regimen in JAK inhibitor (JAKi) treatment-naïve patients with MF.

The double-blind, phase III study randomly stratified 431 patients by Dynamic International Prognostic Scoring System (DIPSS) risk category (Int-1 vs Int-2 vs High), platelet count (>200 × 109/L vs 100–200×109/L), and spleen volume (≥1800 cm3 vs <1800 cm3). Patients either received pelabresib at 125–175 mg or a placebo once daily for 14 days, followed by a seven-day break, plus ruxolitinib at 5-25 mg twice daily for all 21 days of the cycle.

The primary endpoint is ≥35% reduction in spleen volume from baseline (SVR35) at week 24. Secondary endpoints include ≥50% reduction in Total Symptom Score (TSS50), percentage change in TSS, safety, pharmacokinetics, changes in bone marrow fibrosis, progression-free survival, overall survival, conversion from transfusion dependence to independence, and rate of red blood cell transfusion for weeks 1-24.

In arm III of MANIFEST, 68% of 84 patients reported SVR35, and 56% reported TSS50 at 24 weeks. As for MANIFEST-2, a primary analysis after the last patient reaches the 24-week endpoint will be presented at the 65th ASH Annual Meeting and Exposition, December 9-12, 2023.

“Primary results from the pivotal phase III MANIFEST-2 trial…may have the potential to influence the MF treatment paradigm,” researchers concluded. “MANIFEST-2 will also provide important insights in assessing the benefits of starting treatment at an earlier stage of the disease.”

Reference

Rampal R, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for janus kinase inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase III study. Abstract #628. Presented at the 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, California.