Venetoclax/Cladribine Improves Response Rates in AML/MDS Cohorts

“Cladribine plus venetoclax is a highly effective curative regimen, producing deep and durable remissions in newly diagnosed MDS and AML,” according to study author Tapan M. Kadia, MD.

Cladribine (Mavenclad) plus venetoclax (Venclexta) improved complete response (CR)/CR with incomplete count recovery (CRi) rates for patients who were minimal residual disease (MRD)-negative with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), according to findings from a phase 2 trial (NCT02115295) presented at the 2024 American Society of Hematology Annual Meeting and Exposition (ASH).

In the overall population, the overall response rate (ORR) was 96%, including 95% for those with AML and 100% for those with MDS. For those with AML, the CR rate was 82%, and the CRi rate was 12%. Of note, 89% of patients were MRD-negative. For patients with MDS, the CR rate was 29%.

“Cladribine plus venetoclax is a highly effective curative regimen, producing deep and durable remissions in newly diagnosed MDS and AML,” Tapan M. Kadia, MD, professor in the Department of Leukemia, Division of Cancer Medicine at MD Anderson Cancer Center, said during the presentation.

The trial assessed venetoclax plus cladribine, idarubicin, and cytarabine. The primary end point was the CR rate for the aforementioned patient population. The secondary end points included ORR, overall survival (OS), event-free survival (EFS), response duration, and safety.

Patients were included in the study if they had newly diagnosed, treatment-naïve AML or high-risk MDS with 10% or more blasts or International Prognostic Scoring System (IPSS) risk score of 2 or more; were 65 years old or younger; had an ECOG performance status of 2 or less; and had adequate organ function.

During induction, patients were given cladribine at 5 mg/m²on days 1 to 5, idarubicin at 8 to 10 mg/m² on days 1 to 3, cytarabine at 1 to 1.5 mg/m²on days 1 to 5, and venetoclax at 400 mg on days 2 to 8. During maintenance, patients were given cladribine at 5 mg/m²on days 1 to 3, idarubicin at 8 mg/m² on days 1 and 2, cytarabine at 0.75 to 1.5 mg/m² on days 1 to 3, and venetoclax at 400 mg on days 2 to 8.

The median patient age was 49 years old, 40% of patients in the AML group had adverse European Leukemia Network (ELN) 2022 risk, and 13% had AML with myelodysplasia-related changes. In the MDS group, the median number of marrow blasts was 11, and the median IPSS-revised score was 6.5.

Molecular characteristics in the AML group included NPM1 (34%), DNMT3A (32%), TET2 (21%), NRAS (19%), and IDH2 mutations (12%).

Of note, in the AML subgroup, the ORR defined by the ELN 2022 was 100% for those with favorable-risk , 96% for intermediate-risk, and 92% for adverse-risk disease. Based on molecular diagnostics, the ORR was 100% for patients with NPM1 mutations, 100% for KMT2A rearrangements, 33% for TP53-mutated disease, and 50% for complex karyotype.

At a median follow-up of 2.9 years, the probability of relapse-free survival in 83 patients with AML was 76% at 2 years and 74% at 5 years. The 2-year EFS rate for patients with AML was 72% and 68% for 5 years. For the 7 patients with MDS, the 2-year OS rate was 100%, and the 5-year OS rate was 100%.

A total of 61 patients received a stem-cell transplant, and the 2-year OS rate for this group was 84%, and the 5-year OS rate was 82%. In the 15 patients who did not receive a transplant, the 1-year OS rate was 63%, and the 5-year OS rate was 63% (P = .141). Regarding the ELN 2022 scores, 2-year OS rates were 90% for patients with favorable risk, 74% for intermediate risk, and 67% for adverse risk (P = .144).

For patients who had KMT2A-rearranged AML, the 2-year OS rate was 73%, and the 5-year OS rate was 73%. Those with NPM1 mutations had a 2-year OS rate of 78% and a 5-year OS rate of 78%. Those with TP53 mutations or complex cytogenetics had a 2-year OS rate of 43% and a 5-year OS rate of 43%.

The most common hematologic adverse effects (AEs) were anemia (100%), neutropenia (100%), and thrombocytopenia (100%). Non-hematologic AEs included neutropenic fever (84%), infection (60%), bacteremia (36%), pneumonia (21%), colitis (13%), and skin or soft tissue infection (10%).

Within 30 days of treatment, 1 patient died, and within 60, 2 patients had died. The disease status at death included MRD-negative response (52%), MRD-positive response (10%), residual AML (33%), and unknown (5%).

Reference

Bouligny IM, Kantarjian HM, Yilmaz M, et al. A phase II trial of venetoclax in combination with cladribine, idarubicin, and cytarabine in newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2024;144(suppl 1):734. doi.10.1182/blood-2024-203459