Cladribine and low-dose cytarabine as first salvage after hypomethylating agent and venetoclax in acute myeloid leukemia.

The combination of a hypomethylating agent (HMA) and venetoclax (Ven) is the standard frontline therapy for older adults with acute myeloid leukemia (AML) ineligible for intensive chemotherapy and is increasingly used in broader patient populations. However, the optimal approach for patients following progression on HMA/Ven remains undefined. Here, we retrospectively analyze 28 patients with AML who received cladribine plus low-dose cytarabine (Clad/LDAC)-based therapy as second-line treatment after frontline HMA/Ven failure. In this real-world cohort of older patients enriched for secondary AML features, Clad/LDAC-based therapy achieved an overall response rate (ORR) of 41% and composite complete remission (CR/CRi) rate of 33%. Median PFS (mPFS) in responders was 90 days compared to 30 days in non-responders (log-rank p < 0.001), and median OS (mOS) was 185 days versus 66 days (log-rank p = 0.056); for the overall cohort, mPFS was 45 days and mOS was 105 days. Prior HMA/Ven response did not predict Clad/LDAC outcomes, supporting this approach even in patients with primary refractory disease. Genetic risk stratification by ELN 2024 less-intensive-therapy classification was prognostic for both PFS (p = 0.028) and OS (p = 0.012), whereas ELN 2022 was not prognostic. TP53-mutated AML was uniformly refractory to both HMA/Ven and Clad/LDAC, with rapid disease progression and high early mortality following Clad/LDAC treatment. Serial molecular profiling identified heterogeneous patterns of clonal evolution across the treatment trajectory, including exploratory observations of high Clad/LDAC ORR in patients with emergent RAS-pathway clones at HMA/Ven failure. These findings highlight Clad/LDAC-based therapy as a salvage option with modest clinical activity following HMA/Ven.