Validation of ICC hierarchical classification in secondary AML

Secondary acute myeloid leukemia (AML) comprises heterogeneous entities, unified by poor prognosis. We evaluated the associations of genetic profiles with blast counts and patients' history in a cohort of 924 patients with myelodysplastic syndrome (MDS)/AML or AML, classified according to the International Consensus Classification (ICC). The cohort included 109 patients with "mutated TP53," 497 with "myelodysplasia-related (MDR) gene mutation," 93 with "MDR-cytogenetic abnormality," 77 were therapy-related, and 136 controls, categorized as "not otherwise specified" (NOS) AML. Exploring the ICC hierarchy, AML and MDS/AML categories with "mutated TP53" and "MDR-cytogenetic abnormality" 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 were 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 overall survival 24.8 vs 13.6 months, P< .0001; and NOS: 49.9 vs 19.2 months, P = .028). Within each ICC-defined AML category, a prior MDS history vs 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 European LeukemiaNet (ELN) 2022, AML progressing from MDS or MDS/myeloproliferative neoplasm (MPN) (AML post-MDS) mostly clustered in the adverse-risk group (84.1%), whereas 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.