Risk stratification of low-dose cytarabine and venetoclax in patients with AML ineligible for intensive chemotherapy Open Access

• Molecular sub-classification is relevant for defining treatment outcomes after venetoclax-based therapies

• Complex karyotype and TP53 mutation confer adverse prognosis in patients treated with LDAC plus venetoclax

Prognostic risk categorization aids treatment selection for patients with acute myeloid leukemia (AML). Although the European LeukemiaNet (ELN) classifications (2017, 2022) for AML have been used to stratify outcomes for patients receiving intensive chemotherapy, application to patients receiving less intensive therapy, like azacitidine plus venetoclax, has been less satisfactory. In response, a 4-gene classifier that stratifies older patients with AML unfit for intensive chemotherapy into those with higher benefit (wild type), intermediate benefit (FLT3-internal tandem duplication [ITD] or NRAS/KRAS mutation) or lower benefit (TP53 mutation) after azacitidine plus venetoclax treatment was developed. We hypothesized that this 4-gene classifier may also have prognostic utility in patients receiving low-dose cytarabine (LDAC) plus venetoclax. Surprisingly, neither the ELN 2022 criteria nor the 4-gene azacitidine-venetoclax classifier model adequately stratified prognosis in a cohort of 139 patients receiving LDAC plus venetoclax. Patients with concurrent NPM1 and FLT3-ITD/RAS variants performed surprisingly well with LDAC plus venetoclax (92% complete remission [CR]/CR with incomplete blood count recovery [CRi] rate and 29.67 months median overall survival [OS]). Data driven (sequential bootstrapping and tree based) and empirical analyses identified complex karyotype and/or presence of TP53 mutation as prognostically relevant molecular/cytogenetic risk markers. Patients with complex karyotype and/or TP53 mutation displayed poor clinical outcomes (25% CR/CRi and 3.48 months median OS). Notably, 74% of the study population lacked these poor prognostic markers and had 67% CR/CRi with 14.92 months median OS. Overall, these data support the importance of molecular sub-classification in defining treatment outcomes to venetoclax-based therapies. NCT02287233; NCT03069352