MANIFEST-2
Trial question
What is the role of pelabresib, a BET inhibitor, in combination with ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis?
Study design
Multi-center
Double blinded
RCT
Population
Characteristics of study participants
42.0% female
58.0% male
N = 430
430 patients (179 female, 251 male).
Inclusion criteria: JAK inhibitor-naïve patients with myelofibrosis (primary, post-polycythemia vera, or post-essential thrombocythemia).
Key exclusion criteria: splenectomy or splenic irradiation in the past 6 months; chronic or active conditions and/or concomitant medication use that would prohibit treatment; prior treatment with any JAK inhibitor or BET inhibitor for myeloproliferative neoplasm.
Interventions
N=214 pelabresib plus ruxolitinib (pelabresib 125 mg/day for 14 days followed by a 7-day break plus ruxolitinib 10 or 15 mg BID).
N=216 placebo plus ruxolitinib (matching placebo per day for 14 days followed by a 7-day break plus ruxolitinib 10 or 15 mg BID).
Primary outcome
Reduction in spleen volume of ≥ 35% at week 24
65.9%
35.2%
65.9 %
49.4 %
33.0 %
16.5 %
0.0 %
Pelabresib plus
ruxolitinib
Placebo plus
ruxolitinib
Significant
increase ▲
NNT = 3
Significantly greater reduction in spleen volume of ≥ 35% at week 24 (65.9% vs. 35.2%; AD 30.4%, 95% CI 21.6 to 39.3).
Secondary outcomes
No significant difference in reduction in total symptom score at week 24 (15.99 points vs. 14.05 points; AD 1.94 points, 95% CI -0.04 to 3.92).
No significant difference in ≥ 50% reduction in total symptom score at week 24 (52.3% vs. 46.3%; AD 6%, 95% CI -3.5 to 15.5).
Safety outcomes
No significant difference in treatment-emergent adverse events.
Conclusion
In JAK inhibitor-naïve patients with myelofibrosis (primary, post-polycythemia vera, or post-essential thrombocythemia), pelabresib plus ruxolitinib was superior to placebo plus ruxolitinib with respect to reduction in spleen volume of ≥ 35% at week 24.
Reference
Raajit K Rampal, Sebastian Grosicki, Dominik Chraniuk et al. Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial. Nat Med. 2025 Mar 10. Online ahead of print.
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