For patients with myelofibrosis naïve to Janus kinase inhibitor (JAKi) therapy, treatment with pelabresib plus ruxolitinib was associated with durable improvements in spleen volume reduction (SVR), and other findings, in a recent phase 2 study. Study results were reported in the Journal of Clinical Oncology.

Pelabresib (CPI-0610) is an agent being investigated as an inhibitor of bromodomain and extraterminal domain (BET) proteins. Ruxolitinib is a JAKi used as a standard therapy for myelofibrosis.

A cohort of the open-label, global, phase 2 MANIFEST study ( Identifier: NCT02158858) included patients with myelofibrosis naïve to JAKi therapy. Patients in this cohort (Arm 3) received treatment with pelabresib and ruxolitinib, with pelabresib given orally at a starting dose of 125 mg per day. The primary endpoint of the study was an SVR by 35% or more (SVR35), measured at 24 weeks. A secondary endpoint was the reduction by 50% or more in the total symptom score (TSS50) from baseline to 24 weeks.

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The analysis at week 24 included 84 patients, with a median age of 68 years (range, 37-85), and approximately two-thirds (66%) having a baseline hemoglobin level of below 10 g/dL. Based on Dynamic International Prognostic Scoring System (DIPSS) scores, the risk status was intermediate-1 in 24% of patients, intermediate-2 in 61%, and high in 16%.

In the primary endpoint analysis, 68% of patients (95% CI, 57-78) showed SVR35 at 24 weeks. The best SVR35 response at any time was 80%. Additionally, TSS50 was reached in 56% of patients (95% CI, 45-67) at week 24.

By risk status, at week 24, SVR35 was reached in 70% of patients with DIPSS intermediate-1 risk and in 67% of those with intermediate-2 or high risk. When patients were evaluated according to risk based on International Prognostic Scoring System criteria, SVR35 was seen in 82% who had intermediate-1 status and in 66% of those with intermediate-2 or high risk.

At week 24, there also was an improvement in reticulin fibrosis by ≥1 grade in 28% of evaluable patients and a reduction in the JAK2V617F allele fraction of >25.0% in 29.5% of evaluable patients. At week 24, 55% of patients showed stabilization or improvement in hemoglobin levels, reflecting an absolute change of -1 to ≥1.5 g/dL in comparison with baseline. Overall, the SVR35 response rate was 59.5% when measured at 48 weeks.

Treatment-emergent adverse events of grade 3 or higher were reported in 63% of patients, with anemia and thrombocytopenia being the most common. Grade 3 cytopenias reportedly led to discontinuation in 3 patients.

There were 5 deaths reported during treatment or within 30 days of the last pelabresib dose; 4 were considered unrelated to pelabresib, with 1 considered related to pelabresib involving sepsis secondary to pneumonia.

“In MANIFEST Arm 3, pelabresib combined with ruxolitinib was well tolerated and showed durable spleen and symptom responses, with potential disease-modifying activity as indicated by biomarker findings, in JAKi treatment-naïve patients with myelofibrosis,” the study investigators wrote in their report.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Mascarenhas J, Kremyanskaya M, Patriarca A, et al. MANIFEST: pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve myelofibrosis. J Clin Oncol. Published online March 7, 2023. doi:10.1200/JCO.22.01972