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

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.

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Journal
Blood Advances
Published
2025-11-21
DOI
https://doi.org/10.1182/bloodadvances.2025017083
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
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article

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

Rebecca Champion, Jing‐Zhou Hou, Pau Montesinos, Andrew H. Wei et al.
Blood Advances
Acute Myeloid Leukemia Research
article

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

Rebecca Champion, Jing‐Zhou Hou, Pau Montesinos, Andrew H. Wei, Courtney Denton Dinardo, Gail J. Roboz, Kamel Laribi, Anoop Kumar Enjeti, Julie Bergeron, Yan Sun, Wellington Mendes, Ing Soo Tiong, Stephen A. Strickland, Panayiotis Panayiotidis, Tara L. Lin, Takahiro Yamauchi, Maria Pagoni, Qi Jiang, Michael Robert Savona, Stephen B. Ting, Relja Popovic, Brenda Chyla, Jan Novák, Vladimir Ivanov, Walter Fiedler, Jianxiang Wang, Sang‐Min Lee, Inho Kim, Zihuan Liu
article en

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.

Blood AdvancesVol. 10(4)
University of Fukui (JP), The Royal Melbourne Hospital (AU), The University of Texas MD Anderson Cancer Center (US), Universität Hamburg (DE), Walter and Eliza Hall Institute of Medical Research (AU), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), National and Kapodistrian University of Athens (GR), Cornell University (US), Charles University (CZ), Peter MacCallum Cancer Centre (AU), The Alfred Hospital (AU), Seoul National University Hospital (KR), Hôpital Maisonneuve-Rosemont (CA), AbbVie (United States) (US), Federal Almazov North-West Medical Research Centre (RU), Hospital Universitari i Politècnic La Fe (ES), Centennial Medical Center (US), Monash Alfred Psychiatry Research centre (AU), Eastern Health (AU), University of Fukui Hospital (JP), University Medical Center Hamburg-Eppendorf (DE), Laiko General Hospital of Athens (GR), University Cancer Center Hamburg (DE), Centre Hospitalier du Mans (FR), UPMC Hillman Cancer Center (US), University of Kansas Medical Center (US), University of Pittsburgh Medical Center (US), Calvary Mater Newcastle Hospital (AU), Institute of Hematology & Blood Diseases Hospital (CN), Centre Intégré Universitaire de Santé et de Services Sociaux du Centre-Sud-de-l'Île-de-Montréal (CA), University Hospital Kralovske Vinohrady (CZ), Instituto de Investigación Sanitaria La Fe (ES), Evangelismos Hospital (GR), Weill Cornell Medicine (US), Monash University (AU), University of Newcastle Australia (AU), Vanderbilt University Medical Center (US)
Amgen, Bristol-Myers Squibb, Pfizer, Sanofi, Gilead Sciences, Teva Pharmaceutical Industries, Ariad Pharmaceuticals, Celgene, Karyopharm Therapeutics, Jazz Pharmaceuticals, Astex Pharmaceuticals, BeiGene, Incyte, Nippon Shinyaku, Ascentage Pharma, Astellas Pharma, Servier, Genentech, Daiichi Sankyo Europe
Openalex Percentile: Top 53%
Acute Myeloid Leukemia Research
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