MPN Workshop of the Carolinas 2025 | The current and emerging therapies for systemic mastocytosis

Systemic mastocytosis has come a long way for a rare neoplasm. You know, it’s a rare myeloid neoplasm. It’s similar to MPNs, but actually not classified within MPNs. It’s actually separate. But again, the main point here, and there’s a lot to say on it, obviously, but the main point is that it’s a KIT mutation-driven disease. So up to 95% of patients have an activating mutation in KIT, and it is usually D816V. So the era we are in now, I’d say the last, you know, in the last four or five years is the era of very potent and selective inhibitors of mutant KIT. So in the past, we had midostaurin, for example, and that was approved in 2017. But that is a drug that has multiple targets. It’s a multi-kinase inhibitor. But with avapritinib in 2021, that was when it was approved for advanced SM, and 2023 when it was approved for indolent SM, we’re now in this new era of selective potent inhibition of the mutated KIT, right? 

So that is already established, already on the market. It’s been pretty much a game changer for patients, particularly with advanced disease. You’re seeing CRs where we didn’t see that before. You’re seeing the disease literally going away in terms of disease burden markers, like, you know, like the KIT variant frequency, the tryptase, the bone marrow mast cells really going down, you know, very profoundly. And that is a whole new era in the field. In indolent disease too, which is much more common, you know, frequency-wise, way more common to see an indolent SM than an advanced. And there too, avapritinib approved now for two plus years with a nice tolerability profile, amazing tolerability profile, in the indolent population where the dose is lower and excellent efficacy with the symptoms with patients as they stay on it, feeling better and better and able to discontinue some of their best supportive care medications. So all that is great. Just quickly, important to point out that advanced SM the dosing of avapritinib is very different and its tolerability profile is also very different. 

Having said that, bezuclastinib is really the biggest news right now. This year, 2025, we had top-line results from the SUMMIT trial, the Phase III SUMMIT trial in indolent and smoldering SM met all its endpoints. We are waiting for these to be presented at a conference for more detail. We just have a press release. But this is also, you know, similar to avapritinib, it’s also a highly potent, highly selective inhibitor of the mutant KIT. It does have some inhibition of the wild-type KIT as well. But this is certainly a drug that is differentiated in the sense that it does not penetrate the blood-brain barrier. So no issues with, you know, brain bleeds and cognitive impairment, which we saw at high doses of avapritinib. So that is going to be nice, you know, so far really not seen in the trials, those types of side effects. And also very, very selective and avoiding other, you know, off-target kinases. So that I would say is primarily what’s going on. There are other drugs like elenestinib, also from Blueprint, the makers of avapritinib, which is also similar to bezuclastinib in the sense that it doesn’t get into the brain and it’s, you know, it’s more selective for the D816V. But we don’t have a lot of results on that. We just have like the Part I results in indolent disease, and we’ll see what the ongoing HARBOR trial brings on that.

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