SOHO 2026 | TRANSFORM-1 and navitoclax in myelofibrosis: is it time to reconsider trial endpoints?

Well, the field of MPNs is in a new golden era of drug development. What’s happening now is we’re trying to move beyond JAK inhibitor monotherapy, which largely is not curative by itself for the majority of our patients. It needs to be paired with something else, whether that’s allogeneic stem cell transplant or other modalities, we hypothesize to increase disease modification. One approach that we’ve been trying over the last decade plus is combination therapy. The first approaches were combining interferons and hypomethylating agents such as azacitidine and decitabine. Those results are published and ongoing. But then in the novel targeted therapy era, we’ve tried various approaches. Pelabresib, which is a BET bromodomain inhibitor, navitoclax, BCLXL, selinexor, XP01, MDM2 inhibitor with navtemadlin, et cetera. All these are ongoing or completed Phase I through III trials. I was honored, really delighted that I was able to lead from start to finish, from Phase I to Phase III, the BCL-XL approach with navitoclax. So briefly, the TRANSFORM-1 was a large international global Phase III randomized ruxolitinib and navitoclax, so JAK inhibitor plus BCL-XL inhibitor, versus ruxolitinib and placebo. So a true double-blind placebo-controlled study. And in brief, in this randomized Phase III, it was clearly a positive study for the primary endpoint, which was SVR 35, spleen volume reduction 35% by imaging, which really essentially showed double, 60-plus percent in the rux-navitoclax arm versus only 30-plus percent in the placebo-controlled arm. However, the symptom burden benefit was not found to be statistically significant. And that’s been the case with each of the presented publicly available data on the prior other combinations with the BET inhibitor and XPO1. So it brings up three questions to feel. Number one, what is the benefit of a symptom burden benefit in a combination therapy? In other words, if we’re doubling the spleen but not getting statistical significance, is that a reason to not approve these drugs? So do we need to reconsider that? Number two, when you’re going beyond JAK inhibitor, shall we now consider different endpoints beyond spleen and symptoms? And I can put some forward just for discussion, perhaps including but not limited to PFS, EFS, OS, some sort of an MRD marker, biochemical modification, et cetera, et cetera. And then finally, the third aspect is what is disease modification? As we have the entrance of more and more molecular targeted therapies, CALR, JAK2, approaches and targets beyond these standard targets, I wonder if it’s now time as a field to start rethinking in this new golden era of drug development, new endpoints based on exciting molecular breakthroughs, potential identification, new biomarkers, and respecting and understanding the novel mechanisms beyond the standard of care.

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