ASH 2024 | Influence of AML differentiation state on outcomes of patients treated with frontline HMA + ven

Certainly, yeah. So this was an exciting collaboration between several different centers in the United States as well as 12 institutions across France where we were able to combine a cohort of patients of 450 patients to really understand what the influence of monocytic differentiation is in AML in addition to underlying genetics which are known to be, you know, very well known to be prognostic at the time of diagnosis following HMA-Ven therapy. And what we discovered is that patients with monocytic AML are enriched for common mutations in signaling pathways, so NRAS mutations, KRAS mutations, but also mutations in NPM1, which confer increased resistance to venetoclax-based therapy and a favorable prognosis, as well as KMT2A rearrangements. 

When we evaluated responses, we saw that responses were lower in patients with monocytic AML at 59% versus about 70 to 71% in those that were considered non-monocytic. Patients with monocytic AML also had increased rates of 30-day mortality at 11% versus 6% in the non-monocytic subgroup. And this translated to a significant survival difference. 

I think what was important though is, we went on and performed a multivariate analysis that adjusted for common mutations found in monocytic and non-monocytic AML, as well as mutations that have been shown to be prognostic in the context of HMA-Ven therapies, mutations such as IDH1, IDH2, TP53, NPM1, NRAS, KRAS, FLT3 ITD, for instance. And we included transplant in the analysis as well, as that’s a treatment modality that really affects long-term survival. What we found was that within this context, if patients were NPM1 wild type and had monocytic AML, they were more likely to have inferior overall survival. 

And so I think from this analysis, what this shows us is that there’s still room for improvement in understanding who the patients are that will or won’t respond well to HMA-Ven therapy in the frontline setting. And it appears that monocytic AML, irrespective of some of these mutations, may be one of those subgroups. 

Now, the one caveat there is that patients that were NPM1-mutated and had monocytic differentiation actually fared quite well. And so this being a very Ven-sensitive mutation may be a genetic subgroup where AML differentiation state is less impactful in the setting of prognostication.

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