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

Wei, AH; Enjeti, A; Panayiotidis, P; Mendes, W; Montesinos, P; Laribi, K; Ivanov, V; Kim, I; Novak, J; Champion, R; Fiedler, W; Pagoni, M; Bergeron, J; Ting, SB; Hou, JZ; Yamauchi, T; Wang, J; Strickland, SA; Savona, MR; Lin, TL; Tiong, IS; Lee, S; Roboz, GJ; Popovic, R; Jiang, Q; Liu, Z; Sun, Y; Chyla, B; DiNardo, CD

Author(s): Wei, AH; Enjeti, A; Panayiotidis, P; Mendes, W; Montesinos, P; Laribi, K; Ivanov, V; Kim, I; Novak, J; Champion, R; Fiedler, W; Pagoni, M; Bergeron, J; Ting, SB; Hou, JZ; Yamauchi, T; Wang, J; Strickland, SA; Savona, MR; Lin, TL; Tiong, IS; Lee, S; Roboz, GJ; Popovic, R; Jiang, Q; Liu, Z; Sun, Y; Chyla, B; DiNardo, CD;
Details: Publication Year 2026-02-24,Volume 10,Issue #4,Page 987-998
Journal Title: Blood Advances
Publication Type: Research article
Abstract: Prognostic risk categorization aids treatment selection for patients with acute myeloid leukemia (AML). Although the European LeukemiaNet (ELN) classifications (2017 and 2022) for AML have been used to stratify outcomes for patients receiving intensive chemotherapy, their application to patients receiving less intensive therapy, such as 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 (complete remission [CR]/CR with incomplete blood count recovery [CRi] rate, 92%; median overall survival [OS], 29.67 months). 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 (CR/CRi, 25%; median OS, 3.48 months). Notably, 74% of the study population lacked these poor prognostic markers and had a 67% CR/CRi rate with a median OS of 14.92 months. Overall, these data support the importance of molecular subclassification in defining treatment outcomes to venetoclax-based therapies. These trials were registered at www.clinicaltrials.gov as #NCT02287233 and #NCT03069352.
Publisher: Elsevier
Keywords: Humans; *Leukemia, Myeloid, Acute/drug therapy/genetics/mortality/diagnosis; *Sulfonamides/administration & dosage/therapeutic use; *Bridged Bicyclo Compounds, Heterocyclic/administration & dosage/therapeutic use; Male; Female; Aged; *Cytarabine/administration & dosage/therapeutic use; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use; Middle Aged; Prognosis; Risk Assessment; Nucleophosmin; Aged, 80 and over; Mutation; Adult
Department(s): Haematology; Pathology
Publisher's Version: https://doi.org/10.1182/bloodadvances.2025017083
Open Access at Publisher's Site: https://doi.org/10.1182/bloodadvances.2025017083
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-09 02:59:45

Last Modified: 2026-03-02 05:02:26