Cladribine and Low-Dose Cytarabine-Based Salvage Therapy for Relapsed/Refractory AML in a Predominantly Venetoclax-Exposed Cohort

Introduction: Relapsed/refractory acute myeloid leukemia (R/R AML) remains challenging to treat. Unfit patients receive either targeted therapy for actionable mutations or low-intensity chemotherapy, often a hypomethylating agent with venetoclax (HMA/ven). Aggressive regimens, such as a purine analog with high-dose cytarabine, are reserved for fit patients. A regimen using similar drug classes, comprised of cladribine (clad), low-dose cytarabine (LDAC), and venetoclax (clad/LDAC/ven), has demonstrated favorable efficacy and safety for frontline AML treatment in older patients, according to recent phase 2 studies [Kadia 2018 Lancet Hematology; Kadia 2022 Journal of Clinical Oncology]. Interestingly, monocytic differentiation is a proposed mechanism of venetoclax resistance, and monocytic leukemic stem cells rely on purine metabolism, thus suggesting unique cladribine sensitivity [Pei 2023 Cancer Discovery]. The utility of clad/LDAC with or without venetoclax in R/R AML is not well characterized, especially in today's evolving treatment landscape.