The primary aim of the phase 3 MANIFEST-2 study is to evaluate the efficacy and safety of pelabresib combined with ruxolitinib in treating patients with primary myelofibrosis (MF), post-polycythemia vera MF, or post-essential thrombocythemia MF who have never been treated with a JAK inhibitor (JAKi). The study compares the effects of pelabresib + ruxolitinib against a placebo + ruxolitinib. Raajit K. Rampal, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York, NY, and colleagues presented their findings at the 2023 ASH Annual Meeting & Exposition.

For the study’s participants, Dr Rampal and colleagues took into account specific eligibility criteria, including a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1 or higher and certain medical conditions (eg, spleen volume, symptom scores, blast count, ECOG performance status). The study consisted of 431 patients from North America, Europe, Asia, and Australia. The patients were categorized into groups based on their DIPSS risk category, platelet count, and spleen volume for optimal study outcomes. These patients mainly consisted of DIPSS intermediate-1 or -2, with most having a platelet count that was above 200 × 10/L and a spleen volume that was below 1800 cm.

The patient recruitment commenced in November 2020, with the first treatment being administered on April 22, 2021. Participants received pelabresib or placebo once a day for 14 consecutive days, accompanied by a 7-day break, and ruxolitinib twice a day for all 21 days of the cycle. The researchers measured the main outcome of SVR35 response at week 24. The secondary endpoints included the percentage change in total symptom score, safety, pharmacokinetics, changes in bone marrow fibrosis, survival rates, and conversion from transfusion dependence to independence for the first 24 weeks.

The phase 3 MANIFEST-2 study was initiated based on promising findings from the ongoing phase 2 MANIFEST study, which demonstrated substantial clinical activity and disease-modifying potential in patients with MF who had not previously received JAKi but had received pelabresib + ruxolitinib combination therapy.

The phase 3 study is currently underway, with the primary results to be presented at the ASH Annual Meeting and Exposition. The researchers expect key insights from the MANIFEST-2 study, particularly for DIPSS intermediate-1 patients who were underrepresented or excluded in previous trials. The findings might provide a rationale for initiating treatment at earlier stages of the disease. In addition, the primary results from the trial may influence the MF treatment paradigm, according to the authors.

Rampal RK, 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 3 Study. Presented at: the 2023 ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, CA, and virtual; Abstract 628.