Background
Phase 3 double-blind, placebo-controlled RCT (MANIFEST-2). 430 JAK inhibitor-naïve patients with primary or post-ET/PV myelofibrosis (DIPSS intermediate-1 or higher), spleen volume ≥450 cm³, platelets ≥100×10⁹/L, and TSS ≥10, randomized 1:1. Pelabresib is a selective oral BET (bromodomain and extraterminal domain) inhibitor; ruxolitinib remained the backbone JAK inhibitor.
Interventions and follow up
Arm A: Pelabresib 125 mg QD (days 1–14 of 21-day cycle; range 50–175 mg) + ruxolitinib 10 or 15 mg BID
Arm B: Placebo (days 1–14) + ruxolitinib 10 or 15 mg BID
Primary endpoint: SVR35 (spleen volume reduction ≥35%) at week 24
Median follow up: 115.9 weeks
Arm B: Placebo (days 1–14) + ruxolitinib 10 or 15 mg BID
Primary endpoint: SVR35 (spleen volume reduction ≥35%) at week 24
Median follow up: 115.9 weeks
Results
SVR35 at week 24: 65.9% vs 35.2%, difference 30.4% (95% CI 21.6–39.3), P<.001
Absolute TSS change at week 24: −15.99 vs −14.05, difference −1.94 (95% CI −3.92 to 0.04), P=.0545 — not significant
TSS50 at week 24: 52.3% vs 46.3%, difference 6.0% — not significant
Bone marrow fibrosis improvement ≥1 grade: 18.8% vs 11.2% (exploratory)
Absolute TSS change at week 24: −15.99 vs −14.05, difference −1.94 (95% CI −3.92 to 0.04), P=.0545 — not significant
TSS50 at week 24: 52.3% vs 46.3%, difference 6.0% — not significant
Bone marrow fibrosis improvement ≥1 grade: 18.8% vs 11.2% (exploratory)
Adverse events
Thrombocytopenia (any grade): 52.8% vs 37.4% (grade ≥3: 13.2% vs 6.1%)
Anemia (any grade): 44.8% vs 55.1% (grade ≥3: 23.1% vs 36.5%)
Other: no additive hepatotoxicity; discontinuation-related TEAEs comparable; no treatment-related deaths
Anemia (any grade): 44.8% vs 55.1% (grade ≥3: 23.1% vs 36.5%)
Other: no additive hepatotoxicity; discontinuation-related TEAEs comparable; no treatment-related deaths
Conclusions
Adding pelabresib (a BET inhibitor) to ruxolitinib significantly improved spleen volume reduction (SVR35 65.9% vs 35.2%) in first-line myelofibrosis — roughly doubling the spleen response vs ruxolitinib alone. The primary endpoint was met; however, the TSS50 secondary endpoint was not statistically significant, creating debate over the clinical meaningfulness of symptom benefit.
Key Limitations
Endpoints: co-secondary TSS endpoint not significant (P=.0545), questioning symptom benefit; SVR35 is a surrogate — no OS benefit demonstrated
Safety: substantially more thrombocytopenia with the combination, potentially limiting use in thrombocytopenic patients
Other: 21-day on/off schedule adds complexity; predominantly Western population; pelabresib not yet FDA approved as of early 2025
Safety: substantially more thrombocytopenia with the combination, potentially limiting use in thrombocytopenic patients
Other: 21-day on/off schedule adds complexity; predominantly Western population; pelabresib not yet FDA approved as of early 2025
Clinical Context
MANIFEST-2 is the first positive phase 3 BET + JAK inhibitor combination trial in MF and may change first-line paradigms pending FDA approval; the phase 2 MANIFEST cohort (Mascarenhas, JCO 2023) showed 68% SVR35, establishing proof of concept. Fedratinib (JAKARTA), pacritinib (PERSIST-2), and momelotinib (MOMENTUM) remain options for specific subgroups; this combination targets dual JAK/BET blockade for patients with adequate baseline platelets. ESMO MPN guidance continues to position ruxolitinib as standard JAK-inhibitor backbone.