Optimizing treatment selection and timing of allogeneic haematopoietic stem cell transplantation in acute myeloid leukaemia with concurrent feline McDonough sarcoma (FMS)‐like tyrosine kinase 3 internal tandem duplication, nucleophosmin 1 and deoxyribonucleic acid (DNA) methyltransferase 3 alpha mutations

Summary Acute myeloid leukaemia (AML) patients with concurrent FMS‐like tyrosine kinase 3 internal tandem duplication ( FLT3‐ ITD ), nucleophosmin 1 ( NPM1 ) and DNA methyltransferase 3 alpha ( DNMT3A ) mutations exhibit heterogeneous treatment outcomes. To identify optimal strategies for this subset, we retrospectively analysed 2541 AML patients with next‐generation sequencing from 2016 to 2023. Among them, 113 harboured triple mutations and had treatment outcomes: 79 received allogeneic haematopoietic stem cell transplantation (allo‐HSCT), and 34 underwent continuous chemotherapy (CMT). Compared with CMT, allo‐HSCT was associated with superior 2‐year overall survival (OS) (62.2% vs. 17.8%, p < 0.001). However, no clear additional benefit from allo‐HSCT was observed in patients who achieved composite complete remission (CRc) with DNMT3A measurable residual disease (MRD) negativity or complete remission with negative multiparameter flow cytometry MRD after the first cycle of CMT (CMT 1st ). Among patients who underwent allo‐HSCT, those in CRc after CMT 1st had significantly improved post‐transplant 2‐year OS (71.9% vs. 44.1%, p = 0.028), leukaemia‐free survival (65.4% vs. 40.2%, p = 0.029) and non‐relapse mortality (17.4% vs. 40.4%, p = 0.037). CRc rates were higher with venetoclax‐based intensive (88.2%) or non‐intensive (63.6%) CMT than with CMT alone ( p = 0.001). In conclusion, this study offers a potential treatment paradigm for AML patients with co‐occurring FLT3‐ ITD, NPM1 and DNMT3A mutations.