Claire Harrison, MD, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom, discusses results from the phase 3 MANIFEST-2 study which assessed pelabresib in combination with ruxolitinib among patients with myelofibrosis without prior Janus kinase (JAK) inhibitor therapy. Study results demonstrated that the combination of pelabresib and ruxolitinib, compared with ruxolitinib alone, demonstrated promising clinical efficacy and reduced symptom burden. 

These data were presented at the European Hematology Association (EHA) 2025 Congress in Milan, Italy. 

Key Clinical Takeaways:

• Population/baseline: Adults with intermediate-1 or higher risk myelofibrosis were enrolled; 58% were DIPSS intermediate-1, most had JAK2 mutation, ~40% had high molecular risk mutations, and ~10% required transfusions at baseline.
• Design: Phase 3, double-blind, 1-to-1 randomized trial comparing ruxolitinib plus pelabresib vs ruxolitinib plus placebo in JAK inhibitor–naive patients.
• Primary endpoint: The trial met its primary endpoint with a statistically significant improvement in spleen volume reduction (SVR) favoring pelabresib plus ruxolitinib.
• SVR35 at week 72: SVR35 was achieved by 46% with pelabresib combination vs 29% with ruxolitinib alone, with median spleen volume change −57% vs −34.9%, respectively.
• Durability of spleen response: Loss of SVR occurred in ~22–25% of patients in both arms, indicating durability for most responders.
• Symptom improvement: Total symptom score improvements consistently favored pelabresib but were not statistically significant, and benefits were sustained over time.
• Composite clinical benefit: Concurrent spleen and symptom responses occurred in 31.3% with pelabresib combination vs 17.6% with ruxolitinib alone.
• Hemoglobin/anemia: Hemoglobin levels were significantly higher at all time points with pelabresib combination, with fewer transfusions required.
• Bone marrow fibrosis: Improvement in marrow fibrosis was observed in 51% with pelabresib combination vs 28% with ruxolitinib alone.
• Safety profile: Treatment-emergent adverse events were mostly low grade and balanced; thrombocytopenia was slightly higher with pelabresib, while grade ≥3 anemia was approximately doubled with ruxolitinib alone.
• Notable adverse event: Dysgeusia occurred in 19% with pelabresib vs 3% with ruxolitinib alone, consistent with known effects of pelabresib.
• Leukemic/accelerated phase transformation: Early imbalance prompting enhanced monitoring lessened over time; by week 72, accelerated/blast phase events were 13/214 in the pelabresib arm vs 9 in the placebo arm.
• Time-to-event outcomes: Progression-free survival, leukemia-free survival, and overall survival were equivalent between arms at 72 weeks, acknowledging the study was not powered for survival endpoints.
• Treatment exposure: Approximately 45% of patients in both arms had discontinued by this analysis, with reasons balanced between arms.
• Clinical takeaway: The pelabresib plus ruxolitinib combination delivered deep and sustained spleen reductions, higher likelihood of dual spleen-and-symptom benefit, improved hemoglobin with reduced transfusion needs, and higher rates of marrow fibrosis improvement, without new safety signals and with the early transformation signal attenuating over time.

Transcript:

Hello, my name is Claire Harrison. I'm a hematologist working in London in the UK. I want to tell you about a study that was presented by myself and colleagues at the recent EHA meeting. This is an updated 72-week follow-up from the phase 3 MANIFEST-2 study investigating pelabresib in combination with ruxolitinib for JAK inhibitor-naive patients with myelofibrosis.

Now, this study was a double-blind, 1-to-1 randomization comparing ruxolitinib for both arms with either pelabresib or placebo in patients who had intermediate risk 1 or higher myelofibrosis. The study met its primary end point showing a statistically significant improvement in spleen volume, 35% reduction, and what we presented at EHA was a 72-week update from the study, longer term analysis for progression, overall, and leukemia-free survival although the study wasn't powered for survival outcomes. In total, 430 patients were treated in the study and at this point, around 45% of patients in both arms of the study have discontinued treatment with balanced reasons across both study arms.

The baseline features of these patients have been presented before, but in brief, there were about 58% of patients who were intermediate 1 risk by the dips scoring system, and most patients had a JAK2 mutation. Considering high molecular risk mutations, around 40% of patients had these and 10% of patients were requiring transfusions at baseline. At any time in the study, there was a significantly increased number of patients achieving 35% reduction in spleen volume, and by week 72, this was 46% of pelabresib-treated patients versus 29% of placebo-treated patients, with a median change in spleen volume of 57% for the pelabresib arm and 34.9% for the placebo arm. Spleen volume reductions were durable, 22 and 25% of patients had lost spleen volume response and were 25% above in both arms.

Concerning symptom improvements, these were still consistently in favor of pelabresib, although the difference was not statistically significant and symptom improvements were sustained. If you consider patients who have both spleen and symptom response, that was 31.3% of the pelabresib combination versus 17.6% of the placebo plus ruxolitinib combination. I particularly like this analysis because it talks about patients benefiting in both aspects.

Concerning hemoglobin and anemia, which is a significant problem for patients with myelofibrosis, patients treated with the pelabresib combination had significantly higher hemoglobin at all time points in the study and required fewer fusions. There were also 51% of patients treated with pelabresib who had improvement in their bone marrow fibrosis compared to only 28% of patients receiving ruxolitinib alone.

Treatment-emergent adverse events were mostly low-grade and were balanced between the 2 arms with a slight increase in thrombocytopenia for the pelabresib arm, but double the number of patients receiving ruxolitinib alone, having grade 3 or above anemia. Dysgeusia is a known side effect of pelabresib, and this was seen in 19% of patients treated with this agent versus 3% of the patients treated with ruxolitinib alone.

Now, this study has been on enhanced monitoring because of increased rates of leukemic and accelerated phase transition in the pelabresib, and as at 72 weeks follow up, this imbalance has reduced somewhat. Overall, in the pelabresib arm by 72 weeks, there were 13 of 214 patients who had either accelerated or blastic phase and 9 in the placebo arm. This early imbalance appears to have sort of normalized over time. Progression-free, leukemia-free, and overall survival were equivalent between the 2 arms.

In conclusion, with the ongoing results of this study, and we're expecting to see week 96 soon, we've seen deep and sustained spleen reduction, improvements in symptom score, with nearly double the percentage of patients having both of these responses, higher rates of hemoglobin responses, continued improvement in marrow fibrosis, and no new treatment-emergent adverse events. Plus, the important message about the early imbalance in cases of leukemic transformation appearing to come more in line with what would be typically seen in myelofibrosis. 

This is an important study. We continue to gather evidence, and we are very grateful to the patients, their families, investigators, and staff at participating study sites.

Source:

Vannucchi A, Rampal R, Harrison C, et al. Pelabresib in combination with ruxolitinib for Janus kinase inhibitor-naïve patients with myelofibrosis: 72-week follow-up with long-term efficacy outcomes of the phase III MANIFEST-2 study. Presented at EHA 2025 Congress. June 12-June 15, 2025; Milan, Italy. Abstract 4159300