EHA 2023 | Outcomes of patients with monocytic AML treated with venetoclax & azacitidine
Marina Konopleva, MD, PhD, Albert Einstein College of Medicine, New York City, NY, provides an update on a study evaluating venetoclax plus azacitidine treatment in patients with monocytic acute myeloid leukemia (mAML). The analysis, based on the Phase Ib M14-358 (NCT02203773) and Phase III VIALE-A (NCT02993523) studies, categorized patients using French-American British (FAB) subtyping (M4, M5) and gene expression profiling (GEP). The study findings reveal comparable response rates and survival across all FAB-defined patient groups, while patients with a KRAS mutation and mAML show lower response rates and overall survival (OS). This suggests that FAB subtyping does not determine the response to venetoclax and azacitidine, but rather the presence or absence of mutations like N/KRAS are more closely associated with the treatment outcome. This interview took place at the 28th Congress of the European Hematology Association (EHA) 2023 in Frankfurt, Germany.
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Transcript (edited for clarity)
So we’re presenting the poster tomorrow which represents the results of the VIALE-A and also Phase Ib study of HMA-venetoclax looking specifically at the monocytic AML, because there has been a lot of confusion whether these people respond better, worse or generally worse than the non-monocytic AML. And the thinking is that monocytic leukemias have high levels of MCL1 and low levels of BLC2 and therefore they do not respond as well...
So we’re presenting the poster tomorrow which represents the results of the VIALE-A and also Phase Ib study of HMA-venetoclax looking specifically at the monocytic AML, because there has been a lot of confusion whether these people respond better, worse or generally worse than the non-monocytic AML. And the thinking is that monocytic leukemias have high levels of MCL1 and low levels of BLC2 and therefore they do not respond as well.
So the actual data from this trial suggests that using either FAB classification or gene expression profiling, separating monocytic from non-monocytic leukemias, that the response rate and survival are similar. So, there’s really no disadvantage of using HMA venetoclax for monocytic leukemias. But what we found is that the genetics of this leukemia really what makes a difference, because monocytic leukemias could be NPM1, FLT3 mutated, IDH1/2 mutated, or RAS mutated. So the data seem to suggest, again it’s a small data set, that patients who have Ras mutations and monocytic leukemias, their response rates are lower only about 33% CR/CRi rates and also overall survival tends to be lower.
And looking at gene expression, we found that, in general, Monocytic leukemias have lower BCL2 as has been reported before, higher MCL1 and higher BCL2A1. So these are all factors that’s supposed to make them less sensitive to venetoclax. However, the RAS-mutated leukemias also had higher levels of Bcl-xL – whether that’s the reason that they’re not doing well or maybe there’s something else that we haven’t looked at, we’re not quite sure. But the conclusion from the studies are that just looking at the FAB monocytic versus non-monocytic is probably not going to determine how people will respond to HMA venetoclax and you should not shy from this therapy if you just have FAB defined m4-m5. But really looking at genetics, it’s what probably drives the outcomes. In particular, I think RAS-mutated monocytic leukemias, they don’t do as well.
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