ESH CML/MPN 2025 | The potential for disease modification with combination therapy in myelofibrosis

So it was an exciting meeting with a large focus on myelofibrosis and newer therapies that are available. And for me, what’s particularly exciting is moving forward towards some combination therapy, so combining JAK inhibitors as a backbone with molecules that target novel pathways. So, particularly two large Phase III trials that are currently open and enrolling internationally to discuss. 

One is using an agent that targets Exportin, so an XPO1 inhibitor, selinexor, and this is combined with ruxolitinib in a Phase III trial comparing the combination to ruxolitinib or placebo. The Phase I data is very encouraging, suggesting a reduction in spleen size and potentially actually a reduction in the mutant allele burden, which hints potentially towards disease modification. 

There’s also, in parallel, another trial, the POIESIS study, comparing another agent, navtemadlin. This is an MDM2 inhibitor, and this targets the MDM2 pathway, which is shown to be abnormal in patients with myelofibrosis, with a slightly different but quite elegant, interesting trial design where patients are randomized to receive ruxolitinib. These are patients who are JAK inhibitor naive in both studies, but in this study, they’re randomized to ruxolitinib alone, and depending on the response, so if it’s an optimal response, they will continue ruxolitinib or if it’s suboptimal response, after a period of time, they will be randomized to either placebo in addition or navtemadlin in addition. So quite a new trial design, which is exciting. 

And again, in the post-ruxolitinib setting, there’s been quite exciting data and promising data with navtemadlin. And so, you know, it’s starting to look at, can we start modifying the disease and potentially treat patients earlier to halt the progression of the disease, which is really the big sort of exciting question with this. And there are signals that there may be reductions with both agents in combination, reducing the mutant allele burden. But I guess, you know, watch this space with these Phase III trials. Will that actually, you know, bear out? 

And I suppose finally to mention in this, so these are studies that are recruiting and we don’t yet have data for them, but there was data presented on another novel target, PIM1 kinase inhibitor. So this is an oral medication and again being tested in combination, but also as a monotherapy. So there’s a Phase I trial enrolling and quite nicely allowing patients to either have exposure to ruxolitinib or momelotinib. And I think it’s one of the only trials that patients were exposed to the sort of more recent generation JAK inhibitor momelotinib onto a trial. And again, the data that was presented showed quite encouraging results with improvements in symptoms, spleen size, and also improvements in abnormal cytokine profiles, which again is quite exciting to see that there’s a number of different targets, targeting novel pathways available and under investigation.

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