Behind MANIFEST-2: Pelabresib Plus Ruxolitinib in Myelofibrosis


Raajit K. Rampal, MD, PhD, discusses the MANIFEST-2 trial, a phase 3 study comparing ruxolitinib vs pelabresib and ruxolitinib combined with placebo for the treatment of myelofibrosis.

Raajit K. Rampal, MD, PhD, hematologic oncologist at Memorial Sloan Kettering Cancer Center, discusses the MANIFEST-2 trial, a phase 3 study comparing ruxolitinib (Jakafi) to pelabresib (CPI-0610) and ruxolitinib combined with placebo.

The trial enrolled untreated patients with symptomatic and enlarged spleens due to myelofibrosis.


0:09 | I presented the phase 3 data for the MANIFEST-2 trial, which was a phase 3 trial that was comparing ruxolitinib and pelabresib, which is a BET inhibitor, vs ruxolitinib and placebo. This was a trial of untreated patients with myelofibrosis who had symptoms and an enlarged spleen. It was a double-blind, placebo-controlled trial, the primary end point being the spleen volume reduction by 35%, as well as the key secondary end points of total symptom score reduction and the proportion of patients who achieved a 50% reduction in their total symptom score.

0:49 | The top-line data from this study demonstrated that as compared with ruxolitinib monotherapy, there was a clear superiority of the combination therapy in terms of reducing the spleen size, which was almost a 2-fold magnitude increase in the proportion of patients whose spleen was reduced in size. I think the significance of that is that, at least historically, it has shown that there is a survival benefit that correlates with spleen volume reduction. That was not what was directly assessed with this trial, but I think that is part of what makes it important.

1:25 | With regards to symptom reduction, there was a numerical benefit in terms of the combination vs single-agent ruxolitinib, although it did not quite reach statistical significance. I think beyond those end points were some other compelling and important data, including reductions in inflammatory cytokines that we are seeing with a combination [that are] not seen quite so much with ruxolitinib alone, better hemoglobin parameters for the combination, more patients had anemia with ruxolitinib alone and better preservation with the combination therapies. [For] bone marrow fibrosis, a greater proportion of patients appeared to have an improvement in their bone marrow fibrosis with combination than what we have seen with ruxolitinib alone. I think those are kind of the key positive takeaways.

2:20 | Importantly, there were not any new adverse event signals from the combination therapy. The 1 thing that if we think about hematologic and non-hematologic toxicity, there was a little bit more thrombocytopenia seen with combination therapy, and in nonhematologic toxicities, that was observed with combination therapy than with ruxolitinib. But again, largely there [were] no new safety signals from the combination therapy over what we have seen with ruxolitinib.

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