December 11, 2023
By Catlin Nalley
During the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 9-12 in San Diego, findings from the pivotal, Phase III MANIFEST-2 trial of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAK inhibitor treatment-naïve patients with myelofibrosis were presented (Abstract 628).
“Myelofibrosis is a clonal stem cell malignancy that is associated with, among other things, bone marrow fibrosis, cytopenias, namely anemia and thrombocytopenia, symptoms, and splenomegaly,” noted study author Raajit K. Rampal, MD, PhD, a leukemia specialist at Memorial Sloan Kettering Cancer Center. “The disease arises from dysregulation of the JAK/STAT pathway and further downstream BET-associated proteins.
“JAK inhibitors have been the mainstay of therapy, but as we're all aware, there are significant limitations in terms of their efficacy,” he continued. “Pelabresib is an investigational, oral, small molecule drug designed to inhibit BET proteins and decrease BET-mediated gene expression involved in myelofibrosis pathogenesis.”
Background & Methods
Rampal and colleagues conducted the MANIFEST-2 study to assess the efficacy and safety of the combination of pelabresib plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. This global, Phase III, randomized, double-blind, active-control study (NCT04603495) included patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis.
Key eligibility criteria included the following: DIPSS score of intermediate-1 (Int-1) or higher, platelet count ≥100 × 109/L, spleen volume ≥450 cm3 by CT or MRI, ≥2 symptoms with an average score ≥3 or a TSS of ≥10 using the MFSAF v4.0, peripheral blast count <5 percent, and an ECOG performance status ≤2.
Patients were randomized 1:1 to receive pelabresib plus ruxolitinib or placebo plus ruxolitinib. The study authors stratified randomization by DIPSS risk category (Int-1 vs. Int-2 vs. High), platelet count (>200 × 109/L vs. 100-200 × 109/L), and spleen volume (≥1,800 cm3 vs. <1,800 cm3). The primary endpoint of this analysis is SVR35 response at Week 24. Key secondary endpoints include TSS absolute change from baseline at Week 24, TSS50 at Week 24, and safety.
Key Takeaways
A total of 430 patients were randomized, with 214 and 216 in the pelabresib plus ruxolitinib and placebo plus ruxolitinib arms, respectively. Among these patients, 99.1 percent went on to treatment, and patient discontinuation occurred in 27.1 percent of patients on combination versus 25 percent of patients treated with ruxolitinib alone.
In terms of ongoing treatment, Rampal reported that 72 percent of patients in the pelabresib plus ruxolitinib cohort and 74.1 percent of those in the ruxolitinib group continue on therapy. MANIFEST-2 achieved its primary endpoint of SVR35 response at Week 24. The researchers observed significantly greater response in patients treated with pelabresib plus ruxolitinib when compared with those who received placebo plus ruxolitinib (65.9% vs. 35.2%).
“In regard to absolute change in the TSS at Week 24, there was a greater reduction numerically in the absolute TSS of 1.94 favoring the combination arm over ruxolitinib, and this borders on statistical significance,” Rampal said during his presentation, while also reporting there was a numerical improvement in the proportion of patients achieving TSS50—52.3 percent with the combination versus 46.3 percent with ruxolitinib alone. However, this did not meet statistical significance.
When discussing safety, Rampal noted that the safety profile of pelabresib plus ruxolitinib was consistent with prior trials. “There were fewer anemia adverse events, a higher rate of hemoglobin response, and fewer patients with transfusion requirements on combination therapy,” he said. “Importantly, the safety profile appeared generally comparable to that which was observed with ruxolitinib as a single agent and, in fact, there were fewer Grade 3 events in combination therapy versus ruxolitinib.”
Concluding his presentation, Rampal said, “Pelabresib in combination with ruxolitinib compared with placebo in combination with ruxolitinib in JAK inhibitor treatment-naïve patients at Week 24 significantly reduced splenomegaly, demonstrated a strong trend towards reducing the mean absolute TSS and improving the TSS50, and doubled the percentage of patients who had both SVR35/TSS50 response.
“Pelabresib in combination with ruxolitinib showed a reduction of proinflammatory cytokines, improvement in bone marrow fibrosis, and anemia response,” he emphasized. As such, we believe these results support a potential paradigm shift in the treatment of patients with myelofibrosis.”
Catlin Nalley is a contributing writer.