ASH 2025 | Impact of ASXL1 mutations in favorable risk AML treated with ven-containing low-intensity therapy

So ASXL1 is one of the most frequently mutated genes in newly diagnosed AML. And classically, it’s been considered a kind of poor prognostic marker, particularly with intensive regimens. So both the ELN 2017 and the ELN 2022 classify a single ASXL1 mutation as poor risk. When we look at the kind of newer, lower intensity regimens, it’s kind of become a little bit more complex with the new molecularly targeted therapeutics, including venetoclax. So the new ELN 2024 risk stratification, it currently groups basically all mutations outside of TP53, FLT3-ITD, and the RAS mutations as kind of favorable risks, just because we don’t have as much data in that space. And so what we really wanted to do was look at the impact of ASXL1 mutations in patients treated with kind of our contemporary lower intensity therapy plus venetoclax regimens. 

So we retrospectively looked at a pool of 500 patients, and about 13% of those patients had ASXL1 mutations. And when we looked at them treated with lower intensity therapy plus venetoclax, we found that the response rates were lower in patients with ASXL1 mutations. We also found that the relapse-free survival and overall survival was worse in those groups of patients and actually kind of resembled those with more intermediate-risk disease, so those with FLT3-ITD mutations or RAS mutations. We then wanted to kind of break down the different backbones that these patients received, as some of our patients received kind of HMA-venetoclax backbones, and some of them received cladribine, low-dose Ara-C, and venetoclax. And we found that the effect of the ASXL1 mutations was actually more prominent in the patients that received the cladribine and low-dose Ara-C backbones. There was still a trend towards worse outcomes in those with HMA and venetoclax, though it didn’t reach statistical significance on its own. 

Then when we looked at multivariable analyses combining kind of other clinical factors and the treatment backbones, overall ASXL1 mutation still had a kind of worse prognosis. And so our main conclusion was this, is kind of with the modern-day lower-intensity venetoclax-based therapies, ASXL1 mutations still seem to be an independent prognostic factor that indicates kind of poor response to therapy and worse overall outcomes.

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