AML with myelodysplasia-related gene mutations (AML-MR)
Eight genes (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2) are almost never mutated in leukaemia that arises out of nowhere but are typical of leukaemia that grew out of a smouldering marrow disorder; finding one on the diagnostic gene panel labels the AML as myelodysplasia-related, puts it in the adverse-risk group and changes the chemotherapy chosen.
Overview
What is measured: mutations that mark an acute myeloid leukaemia as having evolved from myelodysplasia or clonal haematopoiesis. How: a myeloid next-generation sequencing panel at diagnosis; WHO 2022 defines AML, myelodysplasia-related by a mutation in any of the eight genes (the ICC adds EZH2 and a list of cytogenetic abnormalities such as complex karyotype, del(5q), monosomy 7 or del(7q) and del(17p)) in the absence of a defining fusion or an NPM1 mutation, with a history of prior MDS or CMML (secondary AML) or of chemotherapy and radiotherapy (AML post-cytotoxic therapy) recorded alongside; multi-hit TP53 now forms its own entity. What a result changes: the European LeukemiaNet 2022 classification places these mutations in the adverse-risk group unless a favourable marker coexists; fit patients aged 60 to 75 with secondary or therapy-related AML or myelodysplasia-related cytogenetics are treated with CPX-351 (liposomal daunorubicin and cytarabine, which lengthened survival from 5.9 to 9.6 months against standard induction) and taken to allogeneic transplant in first remission; unfit patients receive azacitidine with venetoclax, which works less well against these mutations and poorly against TP53; residual-disease monitoring by sequencing is unreliable because ASXL1, DNMT3A and TET2 clones persist in remission. Where it matters: AML, secondary AML, and older or unfit AML.
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