Validation of ICC hierarchical classification in secondary AML

Secondary acute myeloid leukemia (AML) comprises heterogeneous entities, unified by poor prognosis, defined by patients' previous history. We evaluated the associations of genetic profiles with blast counts and patients' history in a cohort of 924 patients with MDS/AML or AML, classified according to the International Consensus Classification (ICC). The cohort included 109 cases with "mutated TP53", 497 with "myelodysplasia-related (MDR) gene mutation" and 93 with "MDR-cytogenetic abnormality", 77 therapy-related and 136 "not otherwise specified" (NOS) AML as controls. Exploring the ICC hierarchy, "mutated TP53" and "MDR-cytogenetic abnormality" AML and MDS/AML categories presented similar biology and prognosis, irrespective of blast counts. Conversely, in MDS/AML with "MDR gene mutation" and NOS, profiles significantly differed from AML and characterized by a higher number of mutations in STAG2, SRSF2, ASXL1 and TET2. This corresponded to improved survival in MDS/AML vs AML (MDR-gene mutation: median OS 24.8 vs. 13.6 months, p<0.0001, and NOS: 49.9 vs. 19.2 months, p=0.028). Within each ICC-defined AML category, a prior MDS history versus de novo onset did not impact on patients' prognosis. We then analyzed secondary AML, defined by "prior MDS or MDS/MPN" or "therapy-related" (t-AML), as diagnostic qualifiers. According to ELN 2022, AML post-MDS mostly clustered in the adverse-risk group (84.1%), while t-AML showed more heterogeneous ELN profiles (12.9% favorable, 33.8% intermediate, and 53.3% adverse risk) reflecting diverse overall survival. Our findings underscore that genetic features and the ICC classification reliably capture disease biology, refine risk stratification, and ultimately guide treatment decisions in most secondary AML and MDS/AML.