Pelabresib Plus Ruxolitinib Shows Clinical Benefit Among JAK-Naïve Patients With Myelofibrosis

Findings from the Phase 3 MANIFEST-2 Trial

Findings from the phase 3 randomized, double-blind MANIFEST-2 trial demonstrated that a combination of pelabresib and ruxolitinib yielded significant clinical activity among patients with Janus kinase inhibitor (JAK)-naïve myelofibrosis (MF), including patients with Dynamic International Prognostic Scoring System (DIPSS) intermediate-1 scores. This study was published in Blood, and findings were presented in an oral presentation at the American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.

The primary end point of phase 3 of the MANIFEST-2 trial was the SVR35 response at 24 weeks. Secondary end points included TSS50, the percentage change in TSS, safety, pharmacokinetics, differences in bone marrow fibrosis, progression-free survival (PFS), overall survival (OS), conversion from transfusion dependence to independence, and red blood cell transfusion rate for the first 24 weeks.

After initial screening, this study included 431 patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. All patients had a DIPSS score ≥ intermediate-1, platelet count ≥ 100 × 10 9/L, spleen volume ≥ 450 cm 3 by computed tomography (CT) or magnetic resonance imaging (MRI), ≥ 2 symptoms with an average score ≥ 3 or a total symptoms score of ≥10 using version 4 of the Myelofibrosis Symptom Assessment Form (MFSAF), peripheral blast count < 5% and an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Patients were randomized according to DIPSS risk category, platelet count, and spleen volume. 

Patients either received double-blind treatment of pelabresib at 125 to 175 mg, or placebo, once a day for 1 treatment cycle (14 consecutive days followed by a 1-week break). Ruxolitinib was administered at 5 to 25 mg twice daily based on platelet counts and spleen response for the full 21 days of the cycle. The study authors noted that most patients had a DIPSS score of intermediate-1 or intermediate-2, a platelet count above 200 × 10 9/L, and a spleen volume under 1800 cm3. 

According to Raajit K. Rampal, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York, New York, and coauthors, cited in a news release, “The MANIFEST-2 results demonstrated clear benefits across the four hallmarks of myelofibrosis.” He added, “The comprehensive results presented at ASH also show that the pelabresib combination improves anemia, disease-associated symptoms and bone marrow fibrosis, and that it is well-tolerated.”

“Primary results from the pivotal Phase 3 MANIFEST-2 trial of pela[bresib] and rux[olitinib] versus placebo and rux[olitinib] in JAK [inhibitor] treatment-naïve [patients] may have the potential to influence the MF treatment paradigm,” Raajit and coauthors wrote. 

Source: 

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. Blood. Published online: November 28, 2023. doi: 10.1182/blood-2023-179141

MorphoSys’ Pelabresib Improves All Four Hallmarks of Myelofibrosis in Phase 3 MANIFEST-2 Study. MorphoSys. https://www.morphosys.com/en/news/morphosys-pelabresib-improves-all-four-hallmarks-myelofibrosis-phase-3-manifest-2-study. Published online December 10, 2023.