The combination of pelabresib plus ruxolitinib significantly improved spleen volume reduction (SVR) at week 24 among patients with Janus kinase inhibitor (JAKi)-naïve primary myelofibrosis (MF), post-polycythemia vera MF, or post-essential thrombocythemia MF, according to data from the MANIFEST-2 study.
The combination of pelabresib plus ruxolitinib significantly improved spleen volume reduction (SVR) at week 24 among patients with Janus kinase inhibitor (JAKi)-naïve primary myelofibrosis (MF), post- polycythemia vera MF, or post-essential thrombocythemia MF, according to data from the MANIFEST-2 study.
“Importantly, pelabresib in combination with ruxolitinib showed reduction of pro-inflammatory cytokines and improvement in bone marrow fibrosis and anemia response. As such, these results support a potential paradigm shift in the treatment of patients with MF,” said Raajit K. Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, who presented the results of the phase III study at the 65th ASH Annual Meeting and Exposition.
MANIFEST-2 is a global study that compared pelabresib plus ruxolitinib with placebo plus ruxolitinib in 431 patients with JAKi-naïve MF. Double-blind treatment of pelabresib (125-175 mg) or placebo was administered once daily for 14 consecutive days, followed by a seven-day break, which is considered one cycle of treatment. Ruxolitinib (5-25 mg) was administered twice daily based on platelet counts and spleen response for all 21 days of the cycle. The primary endpoint of the trial was achievement of at least 35% spleen volume reduction (SVR35) at week 24.
MANIFEST-2 achieved its primary endpoint: SVR35 at week 24 was significantly greater in patients assigned to pelabresib plus ruxolitinib compared with ruxolitinib alone (66% vs. 35%; p<0.001). This was true across all predefined subgroups, which included DIPSS risk category (Intermediate-1 vs. Intermediate-2 vs. High), platelet count (>200 × 109/L vs. 100-200 × 109/L) and spleen volume (≥1800 cm3 vs. <1800 cm3).
Total Symptom Score (TSS), a key secondary endpoint, was reduced by almost 16 points at week 24 with pelabresib plus ruxolitinib compared with 14.05 points at week 24 for placebo plus ruxolitinib, a numerical reduction in favor of the combination that had borderline statistical significance (p=0.0545), Dr. Rampal noted. There was also numerical improvement in the proportion of patients achieving a 50% or greater reduction in TSS (TSS50) at week 24 for patients assigned to pelabresib plus ruxolitinib compared with ruxolitinib (52.3% vs. 46.3%, respectively).
There was a two-fold increase in the percentage of patients who achieved both SVR35 and TSS50 assigned to the combination compared with ruxolitinib plus placebo (40.2% vs. 18.5%, respectively).
Looking at hemoglobin response — defined as at least a 1.5 g/dL increase — there was a numerically greater proportion of patients who achieved response with pelabresib plus ruxolitinib compared with placebo plus ruxolitinib (9.3% vs. 5.6%, respectively).
At week 24, bone marrow fibrosis had worsened by at least one grade in 16% of patients assigned to combination compared with 28% of those assigned to ruxolitinib alone (odds ratio [OR] = 0.47; 95% CI 0.23-0.92) and had improved by at least one grade in 38.5% of patients assigned to the combination compared with 24.2% of those assigned to ruxolitinib alone (OR=2.09; 95% CI 1.14-3.93).
The rate of treatment-emergent adverse events (TEAEs) was similar in both arms, and, overall, there were no new TEAEs seen in the combination arm.
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Rampal RK, Grosicki S, Chraniuk S, 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. Abstract 628. Presented at the 65th American Society of Hematology Annual Meeting and Exposition; December 10, 2023; San Diego, California.