Pelabresib Combo Improves Efficacy Vs Ruxolitinib Alone in Myelofibrosis

Spleen reduction and symptoms were meaningfully improved with pelabresib plus ruxolitinib (Jakafi) vs ruxolitinib alone among patients who received no prior JAK inhibitiors for myelofibrosis in the phase 3 MANIFEST-2 trial (NCT04603495), according to a presentation at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.

The 96-week results were presented by Raajit Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center.

The pelabresib plus ruxolitinib combination demonstrated deep and durable improvements across primary and secondary efficacy end points compared to ruxolitinib monotherapy.

In patients who were evaluable at week 96, combination therapy was associated with least a 35% reduction in spleen volume (SVR35) in 91.5% of patients (97/106) vs 57.5% (65/113) with ruxolitinib plus placebo, indicating a sustained benefit from previous evaluation at week 24. At week 24, the SVR35 was 82.9% (141/170) with the combination vs 41.8% (76/182) with placebo plus ruxolitinib. The median duration of spleen response was not reached in the combination arm vs 138.3 weeks in the placebo arm (HR, 0.692; 95% CI, 0.454-1.056).

In the intent-to-treat population, SVR35 was maintained at week 96 by 45.3% (n = 97/214) in the pelabresib plus ruxolitinib arm vs 30.1% (65/216) in the placebo plus ruxolitinib arm. At week 24, the SVR35 for the respective arms were 65.9% (141/214) and 35.2% (76/216).

Patients in the intent-to-treat population receiving pelabresib plus ruxolitinib experienced a greater and more durable improvement in their total symptom score (TSS). The absolute change from baseline in TSS was -15.07 in the pelabresib plus ruxolitinib arm vs -12.48 in the placebo plus ruxolitinib arm (95% CI, -5.23 to 0.05). The difference in the arms was -2.59, which was greater than the -1.96 difference at week 24. A reduction in TSS from baseline of at least 50% (TSS50) was achieved by 36.9% (79/214) of patients in the pelabresib plus ruxolitinib arm vs 28.2% (61/216) in the placebo plus ruxolitinib arm.

The rate of achieving both a significant SVR and a significant symptom improvement was more than double in the combination therapy arm: 31.8% (68/214) of patients in the pelabresib plus ruxolitinib arm vs 15.7% (34/216) in the placebo plus ruxolitinib arm. This maintained the dual response benefit of 40.2% vs 18.5%, respectively, seen at week 24.

The pelabresib plus ruxolitinib combination demonstrated favorable effects on anemia, a common and challenging complication of myelofibrosis. In the pelabresib plus ruxolitinib arm, the hemoglobin response was 17.8% vs 11.6% in the placebo plus ruxolitinib arm. Red blood cell transfusions were required up to week 96 in 33.1% of patients in the pelabresib plus ruxolitinib arm vs 39.9% in the placebo plus ruxolitinib arm.

While the study was not statistically powered for survival end points, the longer-term follow-up showed numerically fewer deaths and progression-free survival (PFS) events in the pelabresib plus ruxolitinib arm.

In the pelabresib plus ruxolitinib arm, there were 28 deaths vs 32 in the placebo plus ruxolitinib arm (HR, 0.986; 95% CI, 0.590–1.647). In the pelabresib plus ruxolitinib arm the number of PFS events was 22 vs 34 in the placebo plus ruxolitinib arm (HR, 0.746; 95% CI, 0.432–1.291).

Bone marrow fibrosis was improved in 52.5% of evaluable patients with pelabresib plus ruxolitinib vs 27.5% with placebo plus ruxolitinib, and there were also greater reductions in bone marrow morphology seen with the combination. Similar reductions in variable allele frequency of JAK2 V617F, CALR, and MPL were seen in both arms.

Safety Profile

The long-term safety profile of pelabresib plus ruxolitinib was comparable to that of placebo plus ruxolitinib. Treatment-emergent adverse events (TEAEs) were mainly low-grade and remained similar between the arms over the follow-up period.

Any-grade TEAEs occurred in 99.5% of patients in the pelabresib plus ruxolitinib arm vs 98.1% in the placebo plus ruxolitinib arm. Grade 3 or higher TEAEs occurred in 67.5% of patients in the pelabresib plus ruxolitinib arm vs 70.1% in the placebo plus ruxolitinib arm.

Externally and independently adjudicated cases of leukemic transformation were reported in both arms. The frequency was noted to be in line with what is historically seen in myelofibrosis, and an early imbalance between the arms decreased over time (5.1% vs 3.7%).

Study Design of the MANIFEST-2 Trial

The MANIFEST-2 study is a double-blind, randomized, phase 3 trial designed to assess the efficacy and safety of combining pelabresib with ruxolitinib in patients with myelofibrosis who have not previously been treated with a JAK inhibitor.

Standard-of-care treatment with JAK inhibitor monotherapy improves splenomegaly and symptom burden but provides responses of limited depth and durability. There is a significant need for new combination strategies that can address the underlying biology of the disease and improve long-term clinical outcomes.

Patients were randomized on a 1:1 basis to receive either pelabresib or placebo once daily in combination with ruxolitinib administered twice daily.

The data cut off for this analysis was March 2, 2025, with a median follow-up period of 115.9 weeks.

At the cut off, approximately half of the patients in both arms remained on their assigned treatment (48.6% in the pelabresib plus ruxolitinib arm vs 48.1% in the placebo plus ruxolitinib arm). A total of 56.5% of patients in the pelabresib plus ruxolitinib arm and 59.3% in the placebo plus ruxolitinib arm completed 96 weeks of the assigned treatment.

The most common reasons for treatment discontinuation included AEs (21.0% vs 13.4%), physician decision (7.5% vs 14.8%), withdrawal of consent (10.3% vs 6.0%), and protocol-defined disease progression (5.1% vs 6.9%).

The findings strongly suggest that the pelabresib plus ruxolitinib combination provides clinically meaningful benefits over the standard of care for JAK inhibitor–naive patients with myelofibrosis.

“The week 96 results from the phase 3 MANIFEST-2 trial of pelabresib and ruxolitinib vs placebo and ruxolitinib constitute the longest follow-up to date of a randomized combination trial in JAK inhibitor-naive patients with [MF],” concluded Rampal during the presentation.

Reference

Rampal R, Mascarenhas J, Grosicki S, et al. Durable efficacy and long-term safety with pelabresib plus ruxolitinib in JAK inhibitor-naive myelofibrosis: 96-week results from the phase III MANIFEST-2 study. Blood. 2025;146(suppl 1):910. doi:10.1182/blood-2025-910