ISAL 2025 | Venetoclax resistance in AML

Daniel Pollyea

Hi everyone, we’re here at the ISAL Munich 2025 meeting and speaking on behalf of VJHemOnc. I’m Dan Pollyea from the University of Colorado.

Curtis Lachowiez

And I’m Curtis Lachowiez from the Oregon Health and Science University at Portland, Oregon.

Daniel Pollyea

And we’re going to talk a little bit today about mechanisms of resistance to venetoclax-based regimens and different ways to maybe overcome this. So, Curtis, you gave a really great talk earlier today on this topic. What’s your kind of assessment of where the field is at?

Curtis Lachowiez

Yeah, I think this is a hot topic in the field, and we’re going to see lots of talks on it at this meeting as well as others, as HMA-VEN-based therapies have really become the predominant treatment for older, unfit patients, meaning that unfit patients that are unable to receive intensive chemotherapy with AML. And now we’re actually seeing studies, some of them led by you yourself, Dan, of HMA-VEN combinations showing high efficacy in younger patients with AML too. And so setting that groundwork to understand the resistance mechanisms for these treatments is really imperative. I think when I begin to think about resistance mechanisms to HMA-VEN-based therapy, I think on both molecular-based resistance mechanisms as well as cellular-based or phenotypic-based resistance mechanisms. Some of the most prevailing ones that we’ve observed through across multiple studies are certain genetic mutations, I should say, such as mutations in NRAS, KRAS, PTPN11, FLT3-ITD, and then, of course, TP53, I think being the most prevailing mutation that really confers venetoclax resistance and lack of response, or I should say lack of durable responses, right? We know about approximately 55% of patients in the initial VIALE-A study with TP53 mutated AML had some sense of, some form of a CR or CRi, though they tend to be fleeting and not durable. And then moving away from the molecular-based mechanisms of resistance, we think about cellular-based mechanisms or resistance, whether that be metabolic resistance mechanisms, which I think you’re probably more inclined to speak towards, or cell state resistance mechanisms where we actually identify different cellular processes and transcriptional programs within cells with monocytic differentiation versus more primitive AML cell types. And within that, we see different BCL2 family protein expression with BCL2 expression. BCL2 being the target of venetoclax, higher in more primitive AML subtypes, and lower in more monocytic or mature AML subtypes. And so I think those are the two prevailing models right now. And of course, you and I know that those do not occur in isolation and there’s actually a lot of interrelationships between both genetics and cell differentiation state. I mean, what’s your take on it? What do you think?

Daniel Pollyea

Yeah, no, I think it seems like maybe we’re at a point where a lot of the rules of the road have been established. We know, like you said, categorically, what a lot of these different groups are and what they bring to the table in terms of resistance. And now maybe the next step is to kind of start to do what you’ve begun doing is put them together and see how they interact and in which cases one factor is important and another maybe is less important. And so, you know, it seems like that’s kind of where we’ve arrived at in terms of knowing the language and just trying to figure out how it all fits together now. But, you know, I think you and others in the field have done a really good job in just getting us to this point. I think, you know, another thing when we talk about overcoming resistance, it’s just sort of recognizing who is going to be resistant and making those predictions. And so I know a lot of work has already begun in doing those models. And what’s your take on kind of what do we need to do next to model this out and to really get the right prognostic rules for patients likely to respond?

Curtis Lachowiez

Yeah, I think that’s a really good and important question, really. You know, we need to be able to identify the patients who, in my view, I look at it in the opposite lens, identifying those patients that are poor responders aside from the TP53 mutated population, because that’s, if we had to identify a population with a great unmet need, that is it. Though I would say that our drug development to date has not been particularly fortuitous in that department or in that molecular subgroup of patients, unfortunately. But I think that’s important too, because that can also tell us, you know, help us identify patients that maybe we minimize therapy for the time being until we have more effective therapies. So that way we’re minimize off-target toxicities. But I think really where there’s a lot of room for improvement is in these patients that fall into these intermediate risk categories. These are patients with these active signaling mutations, or really, based on an analysis that you and I performed together, Dan, patients that do not have these more VEN-sensitive mutations, so mutations in NPM1, IDH1, IDH2, DDX41 that really confer venetoclax sensitivity. You know, there’s a large swath of patients with heterogeneous cytogenetic and molecular changes that really may benefit from an augmented therapy approach. And when we think about risk stratification right now, you being the senior author on the four gene molecular risk signature score, I think that’s a really great foundation. and really it lays out the three levels of those patients that are considered in the higher benefit group that are wild type for signaling mutations, TP53, patients in the intermediate benefit group that have one of these active signaling mutations, and then the lower benefit group that we’ve already alluded to today, but the TP53 mutated AML. And this helps stratify patients, but as you mentioned before also, I think there’s more nuance there. And this can be improved upon by incorporation of AML differentiation states, specifically monocytic AML, where we have an analysis that is currently working its way through the publication cycle or process, where it appears that patients that are NPM1 wild type but with monocytic differentiation have inferior survival, more similar to RAS-mutated or TP53-mutated AML. And so to get back to your initial question, how do we further refine prognostication for these patients that are receiving venetoclax-based therapy, I really think it’s going to be an incorporation of genetics as well as potentially cell differentiation state, where we even saw some data today where you can incorporate the anti-apoptotic protein family ratios or expression of BCL2 to other anti-apoptotic protein family members and further stratify within these genetic subgroups. I think I was going to ask you, Dan, you know, something that’s really, I’m really keen to hear from you is, you know, being someone who was a part of the initial Phase Ib/Phase II studies of HMA-VEN combinations, you really have been on the forefront of drug development. And so what do you see as the next, you know, real big changes coming to the field within this VEN-resistant population?

Daniel Pollyea

Yeah, that’s a great question. I think, you know, identifying VEN resistance is step one and then overcoming it strategically, therapeutically is going to be step two. And, you know, I think it’s going to come down to, you know, novel therapies that might help overcome resistance to venetoclax. But then also, I think hopefully we’re going to find some therapies that, you know, don’t really need venetoclax. You know, in other words, sort of replace venetoclax in patients that are least likely to respond to it. And so, you know, I think that’s going to be the challenge for the field for those high risk patients that are less likely to respond or have a good outcome. And then on the opposite end of the spectrum, you know, I think we are not doing a great job even for the patients that we call favorable risk. And so certainly there are some favorable risk patients that are going to have long-term remission durations and being able to identify who those patients are and maybe backing off therapy for them is a goal I think we should have. And then those patients that are favorable risk in terms of being able to achieve a remission but then relapse, I think identifying who they are and intervening to prevent that from happening is going to be something we should be working on. So I think that’s sort of the sum total of, you know, the different clinical trial strategies we should have for each of these groups. And I think it really strongly suggests the reason why it’s so important to clearly identify who these good, intermediate, and poor risk groups are, because I think it will inform the clinical trial design of these studies going forward.

Curtis Lachowiez

Yeah, I agree. And I think there’s so much complexity layered in when you think about what mutations or predictive biomarkers, if you will, are predictive to therapy, which ones are prognostic, and then as we really have this boom in the development of molecularly targeted therapies, IDH1, IDH2 inhibitors, FLT3 inhibitors, the menin inhibitors for NPM1 mutated and KMT2A rearranged AML, I think what would be really interesting, as you just mentioned, is within some of these more VEN-sensitive subgroups, IDH1, IDH2, NPM1 mutated AML. Can you obtain a response but then mitigate myelosuppression and untoward toxicity by using a molecularly targeted maintenance approach? You know, those studies are ones that I would like to see performed in the field.

Daniel Pollyea

Definitely. Well, I think this is a really great conversation and I really enjoyed it. So thanks so much, Curtis.

Curtis Lachowiez

Yeah, thank you for your time too.