Pelabresib/Ruxolitinib Improves Spleen Responses in JAK Inhibitor–Naive Myelofibrosis

Pelabresib/Ruxolitinib in JAK Inhibitor–Naive

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Pelabresib (CPI-0610) combined with ruxolitinib (Jakafi) yielded a statistically significant improvement in spleen response vs placebo plus ruxolitinib in patients with myelofibrosis who were naive to JAK inhibitors, meeting the primary end point of the phase 3 MANIFEST-2 trial (NCT04603495).

Findings from the study, published in Nature Medicine, revealed that spleen volume reduction of 35% or greater (SVR35) at 24 weeks was observed 65.9% of patients treated with pelabresib plus ruxolitinib (n = 214) compared with 35.2% of those treated with placebo plus ruxolitinib (n = 216; Cochran-Mantel-Haenszel difference, 30.4%; 95% CI, 21.6%-39.3%; P < .001). Of note, the mean percentage changes in spleen volume at 24 weeks were –50.6% (95% CI, –53.2% to –48.0%) vs –30.6% (95% CI, –33.7% to –27.5%) in the pelabresib and placebo arms, respectively. SVR35 at any time was observed in 80% of patients (n = 172/214) treated with pelabresib plus ruxolitinib and in 50% (n = 108/216) of patients treated with placebo plus ruxolitinib.

“Pelabresib plus ruxolitinib provided robust clinical benefit…with trends of improvement noted across other principal hallmarks of myelofibrosis, including symptom control, proinflammatory cytokine amounts, and bone marrow morphology,” lead study author Raajit K. Rampal, MD, PhD, and coauthors wrote in the publication. “The phase 3 MANIFEST-2 study provides important insights into disease biology and modification, supporting the combination of pelabresib plus ruxolitinib for JAK inhibitor-naive patients with myelofibrosis.”

Rampal is the director of the Center for Hematologic Malignancies and the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center in New York, New York.

MANIFEST-2 Trial Design and Baseline Patient Characteristics

The global, randomized, double-blind study evaluated pelabresib plus ruxolitinib vs placebo plus ruxolitinib in patients with myelofibrosis who were naive to JAK inhibitors. Specifically, patients had confirmed diagnoses of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. Those on the study were also required to have a dynamic international prognostic scoring system (DIPSS) score of intermediate-1 or higher, a platelet count of 100 x 1091–1 or greater without growth factors or transfusions in the prior 4 weeks, a spleen volume of 450 cm3 or greater by MRI or CT, at least 2 symptoms measurable with a score of 3 or higher or an average total symptom score (TSS) of 10 or higher, a peripheral blast count of less than 5%, and an ECOG performance status of 0 to 2.

In the pelabresib arm, patients were treated with pelabresib plus ruxolitinib daily for 14 consecutive days followed by a 7-day break, in 21-day cycles.2 Those in the placebo/ruxolitinib arm were treated with ruxolitinib plus placebo tablets visibly identical to pelabresib.

The primary end point was splenic response at 24 weeks; secondary end points included absolute change in TSS at 24 weeks vs baseline and a TSS decrease of 50% or greater from baseline at 24 weeks.1

In the study, the median ages were 66 years (range, 19-84) and 66 years (range, 26-88) in the pelabresib and placebo arms, respectively. In both arms, most patients were male (pelabresib, 60.3%; placebo, 56.5%) and White (74.8%; 75.5%). Additionally, myelofibrosis subtypes included primary myelofibrosis (50.0%; 50.9%), post-polycythemia vera myelofibrosis (21.0%; 24.5%), and post-essential thrombocythemia myelofibrosis (29.0%; 24.5%). Furthermore, DIPSS scores included intermediate-1 (59.8%; 58.8%), intermediate-2 (35.0%; 34.3%), and high-risk (5.1%; 6.9%). The most common mutation was JAK2 V617F (58.4%; 56.5%).

The median hemoglobin levels were 10.9 g/dL–1 (range, 5.8-18.0) vs 11.0 g/dL–1 (range, 6.7-17.9) in the pelabresib and placebo arms, respectively. The median levels of platelet counts were 285 x 1091–1 (range, 99-1303) vs 287 1091–1 (range, 66-1084), respectively. In both arms, approximately half of the patients had an ECOG performance status of 0 (pelabresib, 50.0%; placebo, 50.5%). Notably, the median spleen volume was 1308.89 cm3 (range, 200.24-7117.03) vs 1382.97 cm3 (range, 277.87-5540.45) in the respective arms; the median TSS was 26.6 (range, 7.3-66.4) vs 24.7 (range, 9.0-68.4). Moreover, the most common bone marrow fibrosis grade was grade 3 (27.1; 31.0), although data were missing in the highest proportions of patients in each arm (32.2; 31.0).

Additional Efficacy and Safety Data

The absolute change in TSS at week 24 reflected significant improvements with treatment in both treatment arms. However, there was a trend toward greater benefit in patients treated with pelabresib plus ruxolitinib vs placebo plus ruxolitinib. Of note, the least squares mean change from baseline at week 24 was –15.99 compared with –14.05 in the respective arms (difference, –1.94; 95% CI, –3.92 to 0.04; P = .0545). A greater proportion of patients in the pelabresib/ruxolitinib arm (52.3%) also had a 50% or greater reduction in TSS at week 24 vs those in the placebo/ruxolitinib arm (46.3%; Cochran-Mantel-Haenszel difference, 6.0%; 95% CI, –3.5 to 15.5). Furthermore, from baseline at week 24, the mean percentage change in TSS was –50.3% (95% CI, –56.6% to –44.0%) vs –45.9% (95% CI, –51.8% to –40.0%) in the respective arms.

The safety analysis included 212 and 214 patients from the pelabresib/ruxolitinib and placebo/ruxolitinib arms, respectively. In both arms, 96.7% of patients experienced at least 1 treatment-emergent adverse effect (TEAE). The overall incidence of grade 3 or greater TEAEs was less prevalent in the pelabresib arm (49.1%) compared with the placebo arm (57.0%). Additionally, the mean time to onset for any-grade TEAEs was 23 days vs 27 days in the respective arms.

The most frequent hematological TEAEs that were observed in at least 10% of patients from the pelabresib arm included thrombocytopenia (any grade, 52.8%; grade ≥ 3, 13.2%) and anemia (44.8%; 23.1%). In the placebo arm, the most frequent hematological TEAEs that were reported in at least 10% of patients included anemia (composite term, 55.1%; grade ≥ 3, 36.5%) and thrombocytopenia (37.4%; 6.1%).

Dose reductions of pelabresib, ruxolitinib, and placebo due to TEAEs were observed in 51.9% and 44.9% of patients in the respective arms. Notably, the most frequent TEAEs that led to dose reduction included thrombocytopenia (pelabresib, 23.1%; placebo, 15.0%), decreased platelet counts (17.0%; 13.1%), and anemia (10.4%; 16.4%). Dose interruptions occurred in 32.5% vs 24.8% of patients in these respective arms, with the most frequent reasons for interruptions including thrombocytopenia (6.6%; 4.7%), COVID-19 (0.9%; 4.2%), decreased platelet counts (3.3%; 1.4%), and anemia (2.4%; 2.3%). Moreover, TEAEs leading to withdrawal of pelabresib or placebo occurred in 12.3% and 7.5% of patients, respectively, and serious TEAEs were reported in 29.7% vs 29.4% of patients, respectively.

“Reduced transfusions associated with anemia improvements are likely to have a direct benefit on the clinical and economic burden of myelofibrosis,” the study authors concluded. “The clinically and biologically meaningful benefits of the pelabresib/ruxolitinib combination represent valuable short-term outcomes for patients, which may translate into more profound, longer-term treatment effects than ruxolitinib monotherapy.”

References

1. Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial. Nat Med. 2025;31(5):1531-1538. doi:10.1038/s41591-025-03572-3
2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2). ClinicalTrials.gov. Updated October 28, 2024. Accessed May 28, 2025. https://clinicaltrials.gov/study/NCT04603495