ASH 2024 | A subgroup analysis of the FUSION trial: azacitidine plus durvalumab in SF-mutated AML or MDS

The background for this project was the randomized FUSION trial, which was presented a couple of years ago by Amer Zeidan. And that was a randomized Phase II trial where patients ineligible for intensive chemotherapy who had newly diagnosed AML or high-grade MDS were treated with either azacitidine plus durvalumab, which is an anti-PD-1 antibody that’s approved for various solid malignancies, or azacitidine alone. And while the addition of the durvalumab did not improve the response rate or overall survival outcomes in those patients, there’s some preclinical data that shows that splicing mutations might confer an increased sensitivity to checkpoint inhibition. And the background for this is that the splicing mutations can lead to the generation of new antigens on tumor cells, and that can then provide an additional target for immune therapies, including checkpoint inhibitors. So we performed a post hoc analysis of patients who were enrolled in this trial and had a splicing factor mutation, and compared then those patients to patients who didn’t have a splicing factor mutation. And what we could show is that the presence of a splicing factor mutation did not improve either the response rate or the overall survival. And there were also, we then looked at various measurements of the immune landscape, including flow cytometry, gene expression profile, and there were also no significant differences between the splicing factor mutant patients and patients with wild type splicing factor genes. So maybe that is probably the biologic basis for why we did not see a better outcome in patients with splicing mutations that were treated with checkpoint inhibitors. It’s a little bit unsatisfying to just say like, well, in preclinical data it looks amazing and impressive, but unfortunately that did not translate to what we saw in our clinical trial. But I think splicing factor mutations are such an important target that hopefully there’s more effective therapies in development that ultimately will improve outcomes for patients.

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