Abstract
The combination of azacitidine and venetoclax (Aza/Ven) is an effective treatment for acute myeloid leukemia (AML); however, biological factors underlying heterogeneous treatment responses across diverse genetic backgrounds remain incompletely defined. We analyzed 97 AML patients treated with Aza/Ven in the prospective HM-SCREEN-Japan 02 study using targeted next-generation sequencing (NGS) of 53 genes, cytogenetic analyses, and clinical variables. Somatic mutations were categorized into type 1 (
FLT3, PTPN11, WT1, IDH1/2, NPM1, NRAS
) and type 2 (
GATA2, KRAS, TP53, RUNX1, STAG2, ASXL1, ZRSR2, TET2
) groups based on a previously proposed framework describing clonal characteristics. Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 53.8%, 52.1%, and 50.0% of patients treated in the first-, second-, and ≥third-line settings, respectively. Among 53 first-line patients with pre-treatment NGS data, type 1–only mutations were more frequently observed in responders (CR/CRi 72%), whereas type 2–only mutations were enriched in non-responders (CR/CRi 33%). In the first-line setting, achievement of CR/CRi following Aza/Ven was associated with improved overall survival. In addition, an exploratory mathematical model integrating baseline clinical variables demonstrated strong discriminatory performance for treatment response, including in cases without established prognostic mutations. In conclusion, Aza/Ven demonstrated consistent clinical activity across treatment lines in this real-world cohort. Mutational patterns classified by a type 1/type 2 framework were associated with differential response patterns in the first-line setting. Integrative modeling approaches may support the interpretation of response heterogeneity, particularly in genetically uninformative AML.