Prognostic impact of ASXL1 mutations in acute myeloid leukemia treated with lower intensity therapy

ASXL1 mutations (ASXL1^MUT) are common in acute myeloid leukemia (AML) and have historically conferred an adverse prognosis with intensive chemotherapy. Given the increasing use of venetoclax (VEN)-based lower intensity therapy (LIT), the European LeukemiaNet introduced a four-gene genetic risk classifier in 2024 that categorizes ASXL1 ^MUT as favorable risk in the absence of FLT3-ITD, RAS, and TP53 mutations. However, the prognostic significance of ASXL1^MUT across different contemporary LIT+VEN backbones remains controversial.

A retrospective analysis in 554 adults with newly diagnosed AML treated with LIT was conducted, stratified by ASXL1 mutation status and treatment backbone.

Within the European LeukemiaNet 2024 favorable-risk strata, ASXL1^MUT were associated with lower response rates and inferior overall survival, with outcomes more closely resembling those of intermediate-risk disease. Survival differences were most pronounced in patients treated with cladribine plus low-dose cytarabine and VEN, but inferior outcomes were also observed with hypomethylating agent + VEN-based regimens. On multivariable analyses accounting for age, cytogenetics, co-mutations, treatment backbone, and stem cell transplantation, ASXL1^MUT remained independently associated with inferior overall survival.

Collectively, these findings suggest that ASXL1^MUT AML may be more appropriately classified as intermediate risk in the context of LIT+VEN-based therapy, with the depth of impact influenced by the specific LIT backbone.