In the phase II MANIFEST trial, reported in the Journal of Clinical Oncology, John Mascarenhas, MD, and colleagues found that the combination of the bromodomain and extraterminal domain inhibitor pelabresib and ruxolitinib was active in patients with myelofibrosis who had received no prior Janus kinase (JAK) inhibitor treatment.
Study Details
In the international multicohort study, as of September 2021, 84 patients had received oral pelabresib in 21-day cycles at an initial dose of 125 mg once daily for 14 days followed by a 7-day break, combined with continuous twice-daily ruxolitinib. Hemoglobin level < 10 g/dL was present in 55 patients (66%) at baseline. The primary endpoint was spleen volume reduction of ≥ 35% (SVR35) at 24 weeks.
John Mascarenhas, MD
Key Findings
At 24 weeks, SVR35 response was achieved in 57 (68%, 95% confidence interval [CI] = 57%–78%) of 84 patients. Median SVR was –50% (range = –84% to 28%). At 48 weeks, SVR35 response was observed in 47 (60%) of 79 evaluable patients. Among 67 patients (80%) with SVR35 at any timepoint, 93.5% had sustained response at 36 weeks after response onset.
At 24 weeks, 46 (56%, 95% CI = 45%–67%) of 82 evaluable patients had a total symptom score reduction of ≥ 50% on the Myelofibrosis Symptom Assessment Form v4.0. At week 48, 34 (43%) of 79 evaluable patients had a score reduction of ≥ 50%.
Other benefits observed at week 24 included improved hemoglobin levels in 29 (36%) of 84 patients (mean increase = 1.3 g/dL, median increase = 0.8 g/dL); and ≥ 1 grade improvement in fibrosis in 16 (28%) of 57 evaluable patients. In addition, 13 (30%) of 44 evaluable patients had a > 25% reduction in JAK2 V617F-mutant allele fraction, with this reduction being significantly associated with likelihood of SVR35 response (P = .018).
Grade ≥ 3 adverse events occurred in 63% of patients, most commonly anemia (35%) and thrombocytopenia (12%). The most common grade ≥ 3 nonhematologic adverse events were respiratory tract infection (8%) and dyspnea (5%). One death considered related to pelabresib was observed, due to multiorgan failure from sepsis secondary to pneumonia. Transformation to acute myeloid leukemia was observed in two patients (2%).
The investigators concluded, “The rational combination of… pelabresib and ruxolitinib in JAK inhibitor–naive patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity.”
Dr. Mascarenhas, of Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Constellation Pharmaceuticals Inc, a MorphoSys Company. For full disclosures of the study authors, visit ascopubs.org.
