Phase II study of cladribine, low-dose cytarabine, and venetoclax, alternating with azacitidine and venetoclax, in higher-risk chronic myelomonocytic leukemia and myelodysplastic syndromes.

6503 Background: Responses to hypomethylating agents (HMAs) in patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML) are short-lived, with a high risk of transformation to acute myeloid leukemia (AML). Cladribine (CDA) induces monocyte apoptosis and is active in AML when combined with low dose cytarabine (LDAC) and venetoclax (VEN). We aimed to evaluate the safety and activity of CDA, LDAC and VEN in HR-MDS and CMML. Methods: We designed a phase II clinical trial (NCT05365035) for pts with newly diagnosed (ND) or relapsed/refractory (R/R) HR-MDS or CMML. Induction consisted of CDA 5 mg/m 2 daily IV on days 1-3, LDAC 20 mg s.c bid days 1-5 and VEN 400 mg daily days 1-5 followed by azacitidine 75 mg/m 2 daily days 1-7 with VEN 400 mg daily days 1-7 or CDA 5 mg/m 2 days 1-3, LDAC 20 mg s.c bid days 1-5 and VEN 400 mg days 1-5 alternating every 2 cycles. The primary end point was to evaluate safety and efficacy of the combination. Results: Between 10/2022 and 01/2025, 50 pts have been treated (19 [38%] ND and 31 [62%] R/R). Thirty pts (60%) had MDS, and 20 (40%) had CMML. Thirty-seven (74%) pts had high/very high IPSS-Molecular risk and 5 (10%, 4 R/R, 1 ND) pts had biallelic TP53 ( biTP53 ) loss. The median age was 75 years (range 52-83). Among R/R pts, the median number of prior therapies was 1 (range 1-4) with 6 (19%) having received prior VEN treatment and 2 (4%) having undergone allogeneic stem cell transplant (SCT). The median number of cycles received was 2 (range 1-15). The 4- and 8-week mortality was 2% and 4%, respectively. Overall, the combination was well tolerated with thrombocytopenia (n=17, 35%), febrile neutropenia (n=6, 13%) and neutropenia (n=5, 10%) being the most common grade ≥3 adverse events. Among the 48 pts with evaluable responses, the overall response rate (ORR) based on the IWG 2006 response criteria was 43% (complete response [CR] rate of 13% [n=4]) in R/R pts and 72% (CR rate of 39% [n=7]) in ND pts. Based on the IWG 2023 response criteria, the ORR was 40% (n=12, CR: 5 [17%]) and 72% (n=13, CR: 10 [56%]) in R/R and ND pts, respectively. Median number of cycles to best response was 1 (range 1-5). Among responders, 85% and 73% of pts demonstrated neutrophil (>1x10 9 /L) and platelet (>100x10 9 /L) recovery after cycle 1 after a median of 27 and 21 days, respectively. Eight (16%) pts required dose reductions due to cytopenias. Fifteen (30%) pts underwent subsequent SCT. After a median follow up of 15.1 months, the median overall survival (OS) was 5.8 months and not reached in R/R and ND pts, respectively. The median leukemia-free survival was 4.1 months and not reached in R/R and ND pts, respectively. Among R/R pts, biTP53 was associated with shorter OS (3.1 vs 12.3 months, p=0.0344). Conclusions: CDA, LDAC and VEN is safe in pts with HR-MDS and CMML, demonstrating promising results in ND pts. Clinical trial information: NCT05365035 .