ISAL 2025 | A new method to predict venetoclax response in AML and identifying subsets of patients who respond

Here at the conference I talked about two different topics. First of all I discussed MAC scoring. MAC scoring is a new method to predict response to venetoclax in patients with AML. The way we do that is we isolate leukemic stem cells and then we measure BCL2, that’s the target of venetoclax, as well as two other proteins, BCLXL as well as MCL1, which are antagonizing the effect of BCL2. And so by measuring in leukemic stem cells BCL2, BCLXL and MCL1, we generate a MAC score. And we can show that if the MAC score is above 0.4, that patients, almost all patients, do respond to venetoclax. And vice versa, if they have a lower score than 0.4, then actually they are almost certainly not responding to venetoclax treatment. So this turns into very different overall survival data with patients who have higher than 0.4 have a reasonably good survival versus the ones which have a lower than 0.4 have actually a rather poor response as well as poor survival. So this method is cheap because it’s flow cytometry. It’s very fast. It takes only about four hours from when the patient enters the clinic until we do have the result. And it’s relatively easy to implement. It’s also personalized. So for each patient we know relatively quickly whether they will or will not respond to venetoclax azacitidine treatment. And those patients would then actually be favorably treated with classical combination chemotherapy, 7 plus 3 or others. So we have now established MAC scoring in the routine clinical flow laboratory of the University of Heidelberg in the department of Carsten Müller-Tidow. We will establish it in several different NCT sites in Germany, as well as in the US and also in Mexico. So why? And that is coming to part two. Who determines whether actually you have a high or low MAC score? And for that, we isolated leukemic stem cells using GPR56 as a cell surface marker. And then we generated deep transcriptomic data and put them on a single cell differentiation map of normal hematopoiesis. And what we find, we find basically four subsets of leukemic stem cells. First, the hematopoietic stem cell-like, the most primitive one. Then the LMPP-like, that’s the majority with over 50%, as well as the megakaryocyte erythroid progenitor-like, MEP-like. They all show very different response to venetoclax azacitidine. The LMPP ones, they actually respond rather well, while the HSC and the MEP ones, they are rather poor responders. We also identified a fourth category of stem cells, which are not classic. They don’t generate a hierarchy and they are basically much more differentiated cells however have very high self-renewal capacity. We call them MODIS for monocytic dendritic cells. It’s almost like a new disease. They generate very aggressive disease. They are pan-resistant to chemotherapy as well as to venetoclax azacitidine. And we have now identified a marker for that, a specific cell surface marker, where we also, by flow cytometry, very quickly can identify those patients which need very special care because they are often dying very early during disease progression, and are pan-resistant, and we are currently trying to figure out what’s so special about these patients.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.