Combination Therapy Demonstrates ‘Potential Disease-Modifying Activity’ in Myelofibrosis

When combined with ruxolitinib, pelabresib was well tolerated and improved spleen and symptom burden in Janus kinase inhibitor (JAKi)-naïve patients with myelofibrosis (MF), according to results from the phase II MANIFEST trial.

The global, open-label, multicohort study was led by John Mascarenhas, MD, of the Icahn School of Medicine at Mount Sinai and published in the Journal of Clinical Oncology.

The study’s primary endpoint was a ≥35% spleen volume reduction (SVR35) from baseline to 24 weeks, and the secondary endpoint was a ≥50% total symptom score reduction (TSS50) from baseline to 24 weeks.

Of 84 patients included in the study, 24% were intermediate-1 risk, 61% were intermediate-2 risk, and 16% were high risk. Meanwhile, 66% of patients had a hemoglobin level of <10 g/dL at baseline.

Patients received pelabresib in 21-day cycles at an initial dose of 125 mg once daily for 14 days, followed by a seven-day break, and continuous ruxolitinib (median dose, 10 mg) twice dialy. The ruxolitinib dose was increased to 15 or 20 mg twice daily for four patients who did not achieve an SVR35 at week 12.

At 24 weeks, 68% of patients achieved SVR35, and 56% achieved TSS50. Hemoglobin levels improved in 36% of patients, with an average count of 1.3 g/dL and a median count of 0.8 g/dL. Additionally, 28% experienced ≥1 grade improvement in fibrosis and 29.5% experienced >25% reduction in JAK2V617F-mutant allele fraction, which was associated with SVR35 response (P = 0.018).

At 48 weeks, 60% of patients had SVR35 response, and 43% had a TSS50 response.

Grade 3 or 4 adverse events, including thrombocytopenia (12%) and anemia (35%), were observed in ≥10% of patients and lead to treatment discontinuation in three patients. Almost all patients (95%) continued pelabresib plus ruxolitinib therapy after 24 weeks.

Reference

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