Irina Amitai, Maya Zlotnik, Ron Ram, Odelia Amit, Adi Sherban, Ofir Wolach, Adi Shacham-Abulafia, Itay Silbershatz, Boaz Nachmias, Chezi Ganzel, Yoav Amitai, Drorit Merkel, Meirav Kedmi, Dahlia Greidinger, Avichai Shimoni, Abraham Avigdor, Liat Shargian, Israeli Acute Leukemia Group (IALG)
Treatment options after venetoclax-hypomethylating agent (Ven-HMA) failure in acute myeloid leukemia (AML) remain limited, with a median overall survival of 2-3 months. Cladribine targets biologically distinct leukemia stem cells, including monocytic populations implicated in venetoclax resistance. We conducted a multicenter retrospective study across six Israeli academic centers to evaluate cladribine-based salvage therapy, predominantly cladribine, low-dose cytarabine, and venetoclax (CAV), in 31 patients with relapsed/refractory AML. Median age was 70 years (range 21-81); 87% had prior venetoclax exposure, 61% had undergone prior allogeneic transplantation, and 55% were classified as ELN-2022 adverse risk. After a single treatment course, the composite complete remission rate (CRc) was 45% and the overall response rate was 52%. Median overall survival was 5 months, with a 1-year survival of 30%. Patients achieving CRc had significantly longer survival (16.2 vs. 2.9 months; p < 0.0001). Twelve patients (39%) were bridged to cellular therapy, with a median survival of 12.6 months. Toxicity was predominantly hematological; invasive fungal infection occurred in 23% and was associated with fluconazole rather than mold active prophylaxis. The 30-day mortality was 19%. Cladribine-based salvage demonstrates clinically meaningful activity after Ven-HMA failure and can bridge patients to cellular therapy.