Cladribine (CLAD) + low-dose AraC (LDAC) + venetoclax (VEN) in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome: Real-world analysis from a large community-based oncology practice.

6542 Background: A lower intensity combination cladribine (CLAD), low dose cytarabine (LDAC), and venetoclax (VEN), alternating with hypomethylating agents (HMA) + VEN has been shown to be highly effective in the treatment of older and/or unfit patients with newly diagnosed AML, producing high rates of MRD negative complete remission (CR), low early mortality, and successful transition to allogeneic stem cell transplant. While this was conducted in a large academic center in a prospective phase II study, we aimed to assess the efficacy and safety of this approach in a community practice setting, with important implications of broader applicability. Methods: This is a single-center retrospective study evaluating the efficacy and safety of using the CLAD/LDAC/VEN alternating with HMA/VEN regimen in a large oncology practice in the community setting. Dosing of CLAD/LDAC/VEN was according to published experience (Kadia, et al. JCO 2022). Patients with high risk MDS or AML treated in our institution from January 13, 2023-November 18, 2025 were included. Pts with prior treatment, including HMA for prior MDS transforming to AML (treated secondary AML, ts-AML) were also included. Results: A total of 72 patients received at least 1 cycle of CLAD/LDAC/VEN. The median age was 74 yrs (range: 43-90). Median PS was 1 (0-2), including 21 (29%) pts with ECOG PS of 2 (29%). 58 pts had AML, including 44 (78%) with untreated AML, 10 (18%) with ts-AML, and 12 (22%) with relapsed AML; 14 pts had high risk MDS, of which 5 (36%) had failed prior HMA . 37 pts (51%) had adverse risk karyotype by ELN 2022 , 16 (22%) had TP53 mutation and 29 29 (40%) had secondary AML. Twenty-nine (40%) pts had received prior therapy, including 13 pts (18%) with prior HMA. The median number of cycles received was 2 (range 1-14). Among untreated AML and MDS, the composite CR (CRc) rates were 63% and 58%, respectively. Six out of 16 pts with p53 (38%) achieved CRc and of 16 pts with prior HMA 6 (38%) achieved CRc. The median survival (OS) was 8 months (range 0.16-33m). Eleven pts (15%) went on to have allo-SCT. Five pts (7%) died within 28 days of first treatment. Three of these died of infectious complications, 1 died of an acute coronary event and 1 patient decided to go on comfort care mid-way through treatment. Conclusions: CLAD/LDAC/VEN was feasible and effective in a high-risk, older patient population including pts with prior treatment who were able to achieve meaningful disease control and used as a bridge to transplant. The regimen translated well to a community setting, with relatively low 28-day mortality and good tolerability.