Results of a Phase II Study of Cladribine, Low Dose Cytarabine and Venetoclax, Alternating with Azacitidine and Venetoclax in Patients with Higher Risk Chronic Myelomonocytic Leukemia or Myelodysplastic Syndromes

INTRODUCTION: Clinical responses to hypomethylating agents (HMAs) in patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) and myeloproliferative chronic myelomonocytic leukemia (CMML) remain short-lived, with high risk of transformation to acute myeloid leukemia (AML). Prior data suggests use of the purine analogue cladribine can induce monocyte apoptosis and is active in AML, particularly in combination with low dose cytarabine (LDAC) and venetoclax. We aimed to evaluate the safety and activity of cladribine, LDAC and venetoclax in HR-MDS and CMML.

METHODS: We designed a phase II basket clinical trial of cladribine combined with LDAC and venetoclax alternating with azacitidine and venetoclax for pts with HR-MDS or CMML. Pts were divided into 4 cohorts: cohort A: MDS with int-1 to high risk by IPSS and >5% blasts with prior HMA-failure (HMA-F); cohort B: CMML-1/CMML-2 with prior HMA-F; cohort C: previously untreated MDS with Int-2 or High risk by IPSS and >10% bone marrow (BM) blasts; cohort D: previously untreated CMML-2 or CMML-1 with at least one high-risk feature (extramedullary disease, splenomegaly of >5cm below costal margin, platelets <100x10⁹/L, Hgb level <10g/dL, WBC >13x10⁹/L, clonal cytogenetic abnormality [other than monosomy Y]). HMA-F was defined as no response after 6 cycles of therapy with HMA or relapse/progression after any number of cycles. Induction consisted of cladribine 5mg/m² daily IV on days 1-3, cytarabine 20mg s.c bid days 1-5 and venetoclax 400mg daily days 1-5. Re-induction was allowed in pts not achieving response after induction. Consolidations consisted of azacitidine 75mg/m² daily days 1-7 with venetoclax 400mg daily days 1-7 alternating with cladribine 5mg/m² days 1-3, cytarabine 20mg s.c bid days 1-5 and venetoclax 400mg days 1-5 every two 28-day cycles. The primary end point was to evaluate safety, efficacy, and tolerability of the combination. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meir product-limit method was used to estimate median survival.

RESULTS: Between October 2022 and June 2023, 20 pts have been treated: 10, 5, 3 and 2 in cohorts A, B, C and D, respectively. Thirteen pts had MDS, and 7 had CMML. Median age was 74 years (range 52-83). Among MDS pts, 8 (62%) had int-2 and 5 (38%) had high risk by IPSS. By the Molecular IPSS, 10 (79%) had very high, 1 (8%) had high, 1 (8%) had moderate high and 1 (8%) had low risk. Among CMML pts, 4 (57%) had high, 2 (29%) had intermediate-2 and 1 (14%) had intermediate-1 risk by the CPSS Molecular score. Among HMA-F cohorts, median number of prior therapies was 1 (range 1-4), median cycles of prior HMA was 6 (range 2-63) and 4 (27%) pts had failure to prior venetoclax therapy.

Most common adverse events (AEs) were hypoalbuminemia (40%), nausea (40%), sinus bradycardia (40%), alanine aminotransferase increase (35%), constipation (35%), lower extremity edema (35%), fatigue (35%) and hypocalcemia (35%) Most common grade 3-4 AEs were leukopenia (20%) and febrile neutropenia (15%). The 4-week and 8-week cumulative incidences of mortality were 0%. Median number of cycles was 2 (range 1-6). Median cycles to best response was 1 (range 1-3). Among HMA naïve pts (cohorts C and D), the ORR was 80% (n=4): CR in 2 (40%), mCR in 2 (40%). Based on 2023 IWG response criteria, responses in cohort C (n=3) included: CR in 2 (67%) and CR bilineage (CRbi) in 1 (33%). Based on 2015 IWG MDS/MPN criteria, responses in cohort D (n=2) included optimal marrow response and clinical benefit in 1 (50%) and 1 (50%) pts, respectively. Among HMA-F pts (cohorts A and B) the ORR was 20%: 1 CR (10%) and 1 (10%) mCR with HI. Median follow up is 5.3 months (95% CI 2.4-81). Median EFS is 2.1 months in cohorts A and B and not reached in C and D (Fig 1A). Median OS has not been reached for all cohorts (Fig 1B). At the time of data cut-off, all pts in cohorts C and D discontinued study to proceed with hematopoietic stem-cell transplantation (HSCT). Among cohorts A and B, 2 pts (13%) discontinued study to proceed with HSCT, 5 (33%) due to transformation to AML, 2 (13%) due to no response, 2 (13%) due to physician choice, 1 (7%) due to patient choice and 2 (13%) pts remain on study.

CONCLUSIONS: Preliminary data suggests the use of cladribine, LDAC and venetoclax can be safely administered in pts with very high risk MDS and CMML with early promising results in pts with de novo disease.