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

Autores de IIS La Fe

• Pau Montesinos Fernández

  Autor

Participantes ajenos a IIS La Fe

• Wei, Andrew H
• Panayiotidis, Panayiotis
• Laribi, Kamel
• Ivanov, Vladimir
• Kim, Inho
• Novak, Jan
• Champion, Rebecca
• Fiedler, Walter
• Pagoni, Maria
• Bergeron, Julie
• Ting, Stephen B
• Hou, Jing-Zhou
• Yamauchi, Takahiro
• Wang, Jianxiang
• Strickland, Stephen A
• Savona, Michael R
• Lin, Tara L
• Enjeti, Anoop K
• Tiong, Ing Soo
• Lee, Sangmin
• Roboz, Gail J
• Popovic, Relja
• Jiang, Qi
• Liu, Zihuan
• Sun, Yan
• Mendes, Wellington L
• Chyla, Brenda
• DiNardo, Courtney D

Grupos

• Hematología y Hemoterapia

Abstract

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.

Copyright © 2025 American Society of Hematology.

Keywords

• azacitidine; cytarabine; venetoclax; acute myeloid leukemia; aged; Article; ASXL1 gene; BCOR gene; cancer chemotherapy; CEBPA gene; clinical outcome; clinical trial (topic); cohort analysis; controlled study; disease exacerbation; DNA extraction; ECOG Performance Status; EZH2 gene; female; FLT3 gene; gene; gene mutation; high throughput sequencing; human; intensive chemotherapy; KRAS gene; low drug dose; major clinical study; male; myelodysplastic syndrome; NPM1 gene; NRAS gene; overall survival; progression free survival; risk assessment; RUNX1 gene; SF3B1 gene; SRSF2 gene; STAG2 gene; TP53 gene; treatment outcome; U2AF1 gene; ZRSR2 gene