Pelabresib (CPI-0610) plus Jakafi (ruxolitinib) continued to reduce splenomegaly, anemia, symptoms and bone marrow fibrosis in patients with JAK inhibitor-naive myelofibrosis, recent study findings demonstrated.
Results from the phase 3 MANIFEST-2 study were presented in a poster during the 2024 ASH Annual Meeting.
At a median follow-up of 72 weeks, the primary end point of spleen volume reduction of 35% (SVR35) was maintained, with a 48-week response rate of 57% with pelabresib and Jakafi versus 37.5% with Jakafi plus placebo. Total symptom score (TSS) improvement of at least 50% at week 48 was 45.3% versus 39.4%, respectively. Fewer patients required red blood cell transfusions, and bone marrow fibrosis improvement of at least one grade was reported in 41% versus 15%, respectively.
“Results at 48 weeks showed deep and sustained SVR35 response with biomarker evidence suggesting additional benefit of the combination of pelabresib plus [Jakafi] versus [Jakafi] alone,” said Dr. John O. Mascarenhas, director of the Center of Excellence for Blood Cancers and Myeloid Disorders at Mount Sinai, in his poster presentation.
Pelabresib is an investigational small molecule BET inhibitor that can decrease the BET-mediated gene expression associated with MF.
The MANIFEST-2 trial is a study that assigned 430 patients to receive Jakafi twice daily plus pelabresib or placebo once daily for 14 consecutive days of 21-day cycles. At the 2023 ASH Meeting, the MANIFEST-2 trial investigators reported that it had met its primary end point of 24-week SVR. Key secondary end points were absolute change in TSS and 50% or greater reduction in TSS from baseline (TSS50) at week 24, with other end points including SVR35 at week 48, hemoglobin response, bone marrow fibrosis and safety.
Patients had to have intermediate-1 or higher risk myelofibrosis, platelet count of at least 100,000/μL, spleen volume of at least 450 cm3, TSS of 10 or greater (≥3 for two symptoms), and ECOG performance status of 2 or lower.
At the data cutoff of March 29, 2024, 126 of 214 patients (58.9%) receiving the combination and 134 of 216 patients (62%) receiving Jakafi plus placebo were still being treated.
In addition to a higher number of patients showing SVR35 response at week 48, 13.1% of patients had a loss of SVR35 response and an increase of 25% from nadir with pelabresib versus 20% with placebo, or 21% versus 36.8%, respectively by alternate definition of loss of SVR35 response. The mean change was -54.5% with the combination versus -33.5% with Jakafi plus placebo, and 82.2% had a response at any time with the combination versus 57.9% with Jakafi plus placebo.
The absolute change from baseline TSS was -15.99 for pelabresib plus Jakafi versus -14.05 for Jakafi plus placebo at week 24, and -16.24 versus -14.11, respectively at week 48. TSS individual domain scores were similar between the two groups and similar to national norms for people without MF, according to the investigators. An analysis of the Myelofibrosis Symptom Assessment Form excluding fatigue showed a least square mean change from baseline of -16.19 with pelabresib plus Jakafi versus -13.86 with placebo plus Jakafi. Mascarenhas said that “additional symptom benefit of pelabresib could be difficult to detect due to a ceiling effect in TSS, especially in the fatigue domain.”
When looking at patients who had both SVR35 and TSS improvement of 50%, there were 77 (36%) who received the combination versus only 41 (19%) in the placebo group.
A hemoglobin response as defined as a 1.5 g/dL or greater mean increase from baseline in the absence of transfusions in the past 12 weeks was observed in a numerically greater proportion of patients who received pelabresib (13.1% versus 7.9%), and hemoglobin levels rose and approached baseline in patients with anemia. In the combination group, 27.6% required transfusion in the first 24 weeks and 21.8% required it in the next 24 weeks, compared with 38.6% and 33.2%, respectively, in the placebo plus Jakafi group.
At week 48, bone marrow fibrosis had improved in 41%, remained unchanged in 45%, and worsened in 14% of those receiving pelabresib versus improving in 15%, remaining unchanged in 54.2%, and worsening in 30.8% of those receiving placebo. The improvement of bone marrow fibrosis of at least one grade at week 24 was 38.3% versus 25.3% in the respective groups, showing that the difference widened at week 48.
Disease-relevant proinflammatory cytokines showed a numerically greater reduction at week 48 in the pelabresib plus Jakafi group. The level of proinflammatory cytokines was lower in those who had an SVR35 response, regardless of which treatment they received.
Another exploratory end point was the change in mutant clone burden in peripheral blood samples by next-generation sequencing. At week 48, there was greater reduction in the pelabresib plus Jakafi group, with a variant allele frequency reduction of 50% in 15% versus 9% of those receiving placebo plus Jakafi. The mean change from baseline was -24.1% versus -16.3% in the respective groups, and a correlation was found between SVR35 response and reduced mutation clone burden.
In terms of safety, grade 3 (severe) or higher treatment-emergent side effects were reported in 57.1% of the pelabresib plus Jakafi group versus 62.1% of the placebo plus Jakafi group. Grade 3 or higher anemia was reported in 25.9% and 38.3%, respectively, and grade 3 or higher thrombocytopenia was reported in 15.1 and 6.1%, respectively. The most common nonhematologic treatment-emergent side effects include diarrhea, constipation, dysgeusia, cough and nausea. Death occurred in 20 of 214 patients (9.3%) in the pelabresib plus Jakafi group and 18 of 216 (8.3%) in the placebo plus Jakafi group.
Accelerated and blast-phase progression to leukemia transformation was reported in 6.1% of the pelabresib plus Jakafi group and 4.2% of the placebo plus Jakafi group at a data cutoff of August 30, 2024. Newly acquired mutations were detected in 26% and 22%, respectively, and high molecular risk mutations were seen in 4% and 2%, respectively. Mutations were no longer detectable in 11% and 12%, and high molecular risk mutations were no longer detectable in 3% and 1%, respectively. Investigators proposed that a similar number of patients indicated that pelabresib does not have an additional mutagenic effect when combined with Jakafi.
The investigators intend to present longer follow-up data from MANIFEST-2 at future medical congresses. “Rates of grade 3 or greater [treatment-emergent side effects] were similar in both groups and leukemia transformation continues to be followed up closely,” said Mascarenhas.
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