Molecular taxonomy of MDS/CMML patients influences responses to hypomethylating agents and clinical outcomes.

We analyzed 268 patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) to determine the impact of their molecular taxonomic features on patient's clinical outcomes and responsiveness to therapy with hypomethylating agents (HMA). They were hierarchically classified via next-generation sequencing into molecular taxonomic groups based on previously described hierarchical mutational clusters (Bernard E et al, Blood 2024). The groups varied in size, molecular complexity and patient outcomes. With a median of 4 cycles of HMA-based regimens, 54 % patients were treated, with an overall response rate (ORR) of 35 % (IWG 2023 criteria). Focused evaluation of specific taxonomic subgroups demonstrated ORR in U2AF1 50 %, bi-TET2 44 %, SF3B1 40 %, TP53-multihit or CK 39 %, IDH-STAG2 36 %, SETBP1/-7 33 %, No molecular event 33 %, mNOS 28 %, CCUS-like 7 %. Notably, HMA response was not associated with International Prognostic Scoring System (IPSS-M) risk categories. The median follow-up time for the entire cohort was 4 years, with overall survival of 66 % and leukemia-free survival of 81 % at 3 years following initial diagnosis. Within the specific taxa these prognostic risk features were relatively higher for several taxonomic subgroups which were related to the patient's IPSS-M categorization. In contrast, our data demonstrated distinct differences of HMA responses within taxonomic subgroups, but without significant association between patients' HMA responses and their IPSS-M categorization. These findings indicate that molecular taxonomic classification could help refine therapeutic strategies for MDS and CMML, particularly in identifying subgroups more likely to benefit from HMA therapy.