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

BACKGROUND

ASXL1 mutations (ASXL1MUT) 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 ASXL1MUT across different contemporary LIT+VEN backbones remains controversial.

METHODS

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

RESULTS

Within the European LeukemiaNet 2024 favorable-risk strata, ASXL1MUT 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, ASXL1MUT remained independently associated with inferior overall survival.

CONCLUSIONS

Collectively, these findings suggest that ASXL1MUT 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.