ASH 2025 | Outcomes with low-intensity venetoclax in NPM1-mutated AML depend on co-mutational profile

This abstract was another international collaboration. This one was really led by Curtis Lokenitz from OHSU. And we put this cohort together because we felt that the current prognostic systems for patients treated with venetoclax-based lower intensity therapy were really not optimal yet. And while the new ELN classification is specifically designed for these patients, it doesn’t particularly stratify patients well. So the overall goal of the project was to design a prognostic group, but we were also interested in looking at the NPM1 subgroup, of which there are about 300 patients out of them, more than 2,000 in the cohort. The first important finding in the NPM1 patients treated with venetoclax and hypermethylating agents or venetoclax and low-dose cytarabine was that the survival was quite good in these patients with a median overall survival of 22 months. We know from other studies that NPM1 is sensitive to venetoclax. And interestingly, the survival in these real-world treated patients is actually longer than the median survival of NPM1 patients in the trials. What we next found was drilling down further into these patients was that the co-mutations that occurred alongside NPM1 determined the outcomes. We saw that patients with IDH1 or 2 mutations had better outcomes. Patients with FLT3ITD mutations had worse outcomes. And interestingly, something that hasn’t been shown before, which is the patients with TET2 mutations also had worse outcomes. This is an interesting finding. It may be because TET2 is essentially mutually exclusive with IDH1 and 2. It may be that TET2 identifies more monocytic disease. We’re still trying to figure that out, but it was quite a robust finding that both FLT3ITD and TET2 were associated with poor outcomes. We specifically looked at what we call the triple mutant group of NPM1, FLT3ITD and DNMT3A because that’s a group that’s been shown to have poor outcomes with intensive therapy and we again showed that these patients had poor outcomes with venetoclax-based therapy with a median survival of 10 months in that triple mutant group. And finally, an important finding which has been suggested by other data sets, which is that the survival in these patients is actually identical, regardless of whether you give them venetoclax with azacitidine or venetoclax with low-dose cytarabine. And I think that’s a finding that’s unique to the NPM1s. I don’t think it applies across other AML subsets, but we showed this in a larger cohort of NPM1 mutant patients.
This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.