Safety Data for Triplet Combination in High Risk MDS, CMML

Cladribine in combination with low dose cytarabine (LDAC) and venetoclax is safe to treat patients with high-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), according to a phase II clinical trial.

The study, conducted by investigators from the University of Texas MD Anderson Cancer Center, in Houston, Texas, included 20 patients (13 with MDS, 7 with CMML) who were treated between October 2022 and June 2023 and were a median age of 74 years. All patients had at least one prior therapy. Safety, efficacy, and tolerability of the combination were the primary endpoints.

Patients were divided into four cohorts: cohort A (n=10) included patients with MDS with intermediate 1 to high risk by IPSS and >5% blasts with prior hypomethylating agent-failure (HMA-F); cohort B (n=5) was patients with CMML-1/CMML-2 with prior HMA-F; cohort C (n=3) was patients with previously untreated MDS with intermediate 2 or high risk by IPSS and >10% bone marrow blasts; and cohort D (n=2) was patients with previously untreated CMML-2 or CMML-1 with at least one high-risk feature, such as extramedullary disease.

The investigators treatment regimen combined cladribine with LDAC and venetoclax alternating with azacitidine and venetoclax. The median number of cycles was two and median cycles to best response was one.

Although median overall survival has not been reached in any of the cohorts, the overall response rate (ORR) in cohorts C and D—patients who were HMA-naïve—was 80%.

In cohorts A and B, patients who experienced HMA-F, the ORR was 20%.

Hypoalbuminemia (40%), nausea (40%), sinus bradycardia (40%), alanine aminotransferase increase (35%), constipation (35%), lower extremity edema (35%), fatigue (35%), and hypocalcemia (35%) were the most frequently seen adverse events (AEs). Leukopenia (20%) and febrile neutropenia (15%) were the most common grade 3 and 4 AEs.

Only two patients remain enrolled in the study. All the patients in cohorts C and D discontinued the study to move onto hematopoietic stem cell transplantation (HSCT). Two patients from cohorts A and B proceeded with HSCT after discontinuing treatment. Others discontinued because they had no response (n=2), due to physician choice (n=2), or due to patient choice (n=1). Five patients had disease that transformed into acute myeloid leukemia.

Reference

Montalban-Bravo G, Short NJ, Chien KS, et al. 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. Abstract #1876. Presented at 65th American Society of Hematology Annual Meeting & Exposition; December 9-12; San Diego, California.