SOHO 2025 | Combination therapy in MPNs: current perspectives & ongoing studies

This is an exciting era that we’re in right now because for the longest time it really was monotherapy JAK inhibitor treatment trials and approaches and discussions and now we’ve really full-force moved into combination therapy. What we don’t know is if combination therapy is truly better than JAK inhibitor monotherapy but that’s what we’re trying to prove that there is substantive benefit to adding a rational therapy to an existing JAK inhibitor to get deeper spleen responses, symptom responses, improvements in cytopenias, and then what we’re all looking at very keenly, which has not been proven, that biomarkers of disease modification, whether it’s reduction in bone marrow fibrosis, driver mutation, VAF, circulating CD34 cells, cytokine levels, whether these are good predictors or surrogates for progression-free survival, overall survival. So all of these things have to be proven, but there are many exciting combination therapy approaches that have been presented and are still in clinical development. So for example, I think the one that has gotten the most attention right now that continues to be developed is pelabresib, the oral pan-BET inhibitor in the MANIFEST-2 study. We’re going to be presenting 96-week data at ASH. So really following these patients out longer to see if there is a difference in longer-term outcomes. We see a very significant reduction in spleen and a nominal improvement in symptoms and improvement in anemia and disease modification biomarkers. But is the ultimate outcome of survival, is that different? That takes time. So we’re continuing to follow that study out. There are some studies that haven’t read out yet that I think are highly anticipated, like the SENTRY study, which is selinexor, the XPO1 inhibitor, again, up front with RUX. These are JAK inhibitor naive patients we’re talking about. And that study just finished accrual this week. So we’re anticipating seeing some data from 24 week readout, hopefully by Q1 of next year. So I think that’s highly anticipated as well as navtemadlin, the MDM2 inhibitor, which we’ve shown with the BOREAS study, clinical activity, both in spleen and symptom with a single agent navtemadlin after JAK inhibitor failure compared to best available therapy. But the direction of that study, of that drug, has really gone into a different study called the POEISIS study, which is actively accruing right now, which is really an important innovative study design, taking JAK inhibitor-naive patients, giving them ruxolitinib, and then assessing response about 18 weeks later. Those that have a suboptimal response are randomized to navtemadlin versus placebo as an add-on strategy. But those who have a great response, who have really good spleen and symptom, they stay on their JAK inhibitor. So it’s really asking the question, who needs a JAK inhibitor and when, a non-JAK inhibitor combination and when to add it. So I think these are really important studies. The study that I’m also highly excited to see finally read out is the ImpactMF study. That’s the phase three study of the imetelstat, the telomerase inhibitor, as a single agent in the JAK inhibitor relapsed refractory MF population versus BAT, excluding a JAK inhibitor. So the question there is overall survival is unique in the field. Can we improve survival in these patients who don’t do well after JAK inhibitor failure? And I think all of these trials, even when they’re negative, like navitoclax, was considered a negative trial, but it was a rational drug that had activity. It helps us understand as a field how to better design, develop the next therapies that are going to be used. A great example is luspatercept, the activin ligand trap that’s approved for lower risk transfusion dependent anemia in MDS. The top line data from the INDEPENDENCE study, the randomized phase three study of adding Luspatercept every three weeks as a sub-Q injection to a steady dose of RUX to alleviate transfusion independence just was released a week or two ago. And at first glance, it would seem to be negative. But I think the devil’s in the details. That’s a very active drug that has substantial improvements in other aspects of anemia. And I think seeing that data is going to be very important as a field. So I think that there is still a lot to be done, whether it’s addressing anemia. There’s drugs like elritercept that are also TGF beta superfamily traps. And many other drugs, actually, in clinical development, like Sumitomo’s PIM1 kinase inhibitor, I think is an important drug as well that has shown very nice single agent activity and now is in being evaluated in combination with ruxolitinib and momelotinib. That drug is nuvisertib. So understanding the biology or better understanding the biology has forced us to look at non-JAK inhibitor therapies both as monotherapy, but I think more interestingly and probably more relevant to the treatment as combination therapies.

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