iwAL 2026 | Differentiation syndrome in menin-inhibitor-treated patients: recognition, management & next steps

Eytan Stein:

Hi there, I’m Eytan Stein. I’m the Chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center in New York City. We just had a wonderful workshop on the biology, diagnosis, and management of differentiation syndrome. And I’m joined here by my colleagues, Dr Wang from Roswell Park, Dr Zeidner from University of North Carolina Chapel Hill, and Dr Issa from the MD Anderson Cancer Center. And we’re going to hear a little bit about what they talked about in sort of summing up their thoughts of this wonderful session. I’m going to start with you, Dr Wang. Give us just a brief overview of what you talked about and what you took away from the session.

Eunice Wang:

Sure. So my talk was really an example of initial recognition of differentiation syndrome with the drug ziftomenib, which is currently approved for relapsed refractory NPM1 mutant disease. And so I really just talked as a case example about lessons learned from our early Phase I experience. Ziftomenib is a unique menin inhibitor with a prolonged half-life and significant tissue penetration and accumulation. And what we saw in the Phase I trial when we put relapsed and refractory, particularly KMT2A patients on, is that the agent caused profound differentiation, particularly in the KMT2A patients where up to a 40% incidence of differentiation was seen, including grade four and even grade five events, in part because of the potent menin inhibition mechanism. And I discussed a little bit about the partial clinical hold that was placed on that early study because of a grade five event and how we’ve actually moved past that now with initiation of both prophylactic and treatment algorithms for differentiation, early incorporation of hydroxyurea, cytoreduction, steroids, and most importantly, how we’ve been able to attenuate the risk of differentiation syndrome in KMT2A and in NPM1 patients with combination therapy, particularly cytarabine, daunorubicin approaches intensive chemo. So that was meant to illustrate how far we’ve kind of come from our initial recognition of that, the rapidity in which it developed, and how we’ve been able to move past that with our strategies and therapies and, importantly, combinatorial approaches.

Eytan Stein:

Great. Thank you so much. Dr. Issa, what about you?

Ghayas Issa:

I talked about the particular manifestations of DS with menin inhibitors. I initially talked about the presentation of DS with acute promyelocytic leukemia, and everyone is mostly familiar with that, the manifestations of dyspnea, chest infiltrates, lung edema, etc. Whereas with menin inhibitors, they share a lot of these manifestations, but there could be some unique manifestations. It could be related to how acute myeloid leukemia presents with monocytic infiltrates of various organs and those differentiating cells in each of these organs causing almost like a mass effect or even local cytokine secretion that presents these symptoms. So specifically joint aches or swelling of a neck mass or a leukemia cutis that expands or even as severe as an ileus caused by leukemia infiltrating the intestines. And for now, our best management is to have early recognition of differentiation syndrome. So have a high index of suspicion when someone has leukemia and they’re started on an effective agent, such as menin inhibitors, and start steroids as soon as possible. Otherwise, the discussion was a little bit about combination with menin inhibitors, and we’re seeing far less rate of differentiation syndrome with menin inhibitor combination, but it’s still important to recognize. So I wouldn’t be completely relaxed about someone who’s on combination, especially with aza and ven, where it still could happen.

Eytan Stein:

Okay, that’s really helpful. And Dr. Zeidner, you ended out the session with a call to arms. What did you talk about, and what do you think we need to do going forward to make things better?

Joshua Zeidner:

Yeah, I think I tried to put everything in perspective we heard about throughout the session the pathophysiology of differentiation syndrome how to diagnose it and how to manage it with all the different menin inhibitors and other new therapies that we have but we have to all acknowledge that all of our criteria really came from acute promyelocytic leukemia as Dr Issa just alluded to, and that was outlined this morning. And we really don’t know how all those criteria and signs and symptoms apply to patients with menin inhibitors. So my call to arms and action really was to really try to get a pooled data set of all patients who have been identified as having differentiation syndrome by investigators on all the available menin inhibitors, especially the approved therapies with ziftomenib and revumenib. And I think we need to come up with our own classification system and criteria specifically for menin inhibitor-related differentiation syndrome because I think they may be nuanced and unique compared with APL and even what we’ve seen with IDH inhibitors. And I think this will help us evaluate these patients in the clinic, especially as patients are being treated with these agents in a more widespread community fashion. And I think more importantly, within that sort of criteria and new classification system, identifying the highest risk patients who may develop this syndrome to potentially prevent the onset of differentiation syndrome and ultimately improve outcomes. We talked a little bit about prospectively assessing, you know, serial lab markers and inflammatory markers to be able to better identify who these patients are who are developing severe menin inhibitor-related syndrome. So I’m excited about the enthusiasm, and hopefully there’ll be more to come with a more unified, standardized criteria for menin inhibitor-related differentiation syndrome.

Eytan Stein:

Okay, thank you so much to all of our panelists and for everyone who joined in the workshop. We have a lot of work to do, but we think we’re going to get there over the course of the next few months to a year. Thank you so much.

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