Pelabresib Plus Ruxolitinib Improves Spleen Responses in Myelofibrosis

The combination regimen was well tolerated in JAK inhibitor-naïve myelofibrosis, with instances of thrombocytopenia managed with dose modifications.

Pelabresib (CPI 0610) in combination with ruxolitinib (Jakafi) significantly improved spleen responses and elicited robust clinical activity compared with placebo/ruxolitinib in patients with JAK inhibitor-naïve myelofibrosis, according to results from the phase 3 MANIFEST-2 trial (NCT04603495) published in Nature Medicine.¹

Efficacy data from the trial revealed that the primary end point of spleen volume reduction of at least 35% at week 24 favored the investigational combination vs the placebo arm: 65.9% vs 35.2%, respectively (difference, 30.4%; 95% CI, 21.6%-39.3%; P <.001). Additionally, the mean percent change at week 24 in the respective arms was –50.6% (95% CI, –53.2% to –48.0%) vs –30.6% (95% CI, –33.7% to –27.5%). Spleen volume response was consistently higher with pelabresib vs placebo across predefined subgroups.

Furthermore, the hemoglobin response rate, defined as a 1.5 g/dl or greater mean increase, occurred in in 10.7% of the pelabresib arm (95% CI, 6.60%-14.90%) vs 6.0% of the placebo arm (95% CI, 2.85%-9.19%). Transfusions were received in the first 24 weeks of treatment in 27.6% and 37.5% of respective arms.

Greater reductions in NF-κB-regulated cytokines (–32.1% [95% CI, –34.9% to –29.2%] vs –19.4% [95% CI, –22.5% to –16.2%]), tumor necrosis factor (TNF; –43.5% [95% CI, –47.0% to –39.8%] vs –26.4% [95% CI, –30.5% to –22.1%]), and interleukin-6 (IL-6; –35.4% [95% CI, –44.2% to –25.2%] vs –14.5% [95% CI, –25.2% to –2.3%]) were seen in the investigational arm vs the placebo arm. Of note, a reduction in IL-8 levels was observed with pelabresib (–14.3% [95% CI, –22.3% to –5.5%]), but an increase was observed in the placebo arm (31.2% [95% CI, 17.5%-46.5%).

“[P]elabresib plus ruxolitinib provided robust clinical benefit, resulting in a statistically significant improvement in the primary endpoint of spleen response, with trends of improvement noted across other principal hallmarks of myelofibrosis, including symptom control, proinflammatory cytokine amounts and bone marrow morphology,” Raajit K. Rampal, MD, PhD, director of the Center for Hematologic Malignancies and Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, wrote in the publication with study coinvestigators.¹ “The phase 3 MANIFEST-2 study provides important insights into disease biology and modification, supporting the combination of pelabresib plus ruxolitinib for [patients who are] JAK inhibitor-naive with myelofibrosis.”

Patients enrolled on the double-blind, active control phase 3 MANIFEST-2 trial were randomly assigned 1:1 to receive either pelabresib/ruxolitinib (n = 214) or placebo/ruxolitinib (n = 216). Patients received 125 mg of oral pelabresib or matching placebo once daily for 14 days, followed by 7 days without, encompassing a 21-day cycle. Pelabresib or placebo dose could be increased by 25 mg increments up to 175 mg in the event of no spleen response after 4 cycles.

Ruxolitinib was given at an initial dose of 10 mg or 15 mg orally twice daily dependent on baseline platelet counts. Additionally, a mandatory 5 mg per dose increase was given after 1 cycle if prespecified criteria were met. Furthermore, with adequate blood counts, doses could be increased in the event of no spleen response by 5 mg increments up to 25 mg twice daily. Treatment reductions of 50 mg once daily for pelabresib or placebo, as well as 5 mg for ruxolitinib, were permitted for the management of adverse effects (AEs).

Patients in the combination and placebo arms, respectively, had a median age of 66 years (range, 19-84) and 66 years (range, 26-88), respectively. Additionally, 60.3% and 56.5% of the respective arms were male; 74.8% and 75.5% were White; and 50.0% and 50.9% had primary myelofibrosis. In each arm, 59.8% and 58.8% had a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1; 58.4% and 56.5% had JAK2 V617F mutations; and 32.7% and 35.2% had hemoglobin levels of 10 g/dl or lower.

Additionally, in the respective arms, the median platelet counts were 285 x 10⁹ I^-1 (range, 99-1303) vs 287 x 10⁹ I^-1 (range, 66-1084), with 72.0% and 72.7% of each arm having more than 200 x 10⁹ I^-1 platelets. A total of 10.3% and 9.7% of the respective arms needed red blood cell transfusion at baseline; 26.2% vs 23.6% had grade 2 bone marrow fibrosis; and 27.1% vs 31.0% had grade 3 bone marrow fibrosis. Furthermore, 50.0% and 50.5% of each respective arm had an ECOG performance status score of 0; the median spleen volume was 1308.89 cc (range, 200.24-7117.03) vs 1382.97 (range, 277.87-5540.45); and the median total symptom score was 26.6 (range, 7.3-66.4) vs 24.7 (range, 9.0-68.4).

The primary end point of the trial was splenic response rate at 24 weeks. Secondary end points included total symptom score change from week 24 and total symptom score response rate at week 24.²

Any-grade treatment-emergent AEs (TEAEs) were observed in 96.7% of the investigational arm and 96.7% of the placebo arm. Additionally, 77.4% and 74.8% were related to pelabresib and placebo, respectively. Grade 3 or higher TEAEs occurred in 49.1% and 57.0% of the respective arms.

The most common hematological TEAEs in the pelabresib arm included thrombocytopenia (any-grade, 52.8%; grade 3 or higher, 13.2%) and anemia (44.8%, 23.1%). In the placebo arm, they were anemia (55.1%, 36.5%) and thrombocytopenia (37.4%, 6.1%). TEAEs leading to dose reduction occurred in 51.9% of the investigational arm and 44.9% of the placebo arm; the most common TEAEs resulting in dose reduction included thrombocytopenia (23.1% vs 15.0%), platelet count decreases (17.0% vs 13.1%), and anemia (10.4% vs 16.4%).

A total of 11 deaths occurred during treatment. All deaths were assessed as unrelated to study treatment, as 1 patient died of a road traffic accident and all other patients had medical history considered a contributory factor to death or concurrent disease.

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. Published online March 10, 2025. doi:10.1038/s41591-025-03572-3
2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated October 28, 2024. Accessed March 13, 2025. https://tinyurl.com/4ckadc2z