A phase 2 trial presented at the 2024 ASH Annual Meeting demonstrated that the combination of cladribine (Mavenclad) and venetoclax (Venclexta), along with idarubicin and cytarabine, significantly improved complete response (CR) and CR with incomplete count recovery (CRi) rates in patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) who were minimal residual disease (MRD)-negative.
The study's findings indicate a high overall response rate (ORR) of 96% across the entire cohort, with 95% for AML patients and 100% for MDS patients. Specifically, in AML patients, the CR rate was 82%, and the CRi rate was 12%. Notably, 89% of these patients achieved MRD-negativity. For MDS patients, the CR rate was 29%.
Efficacy and Outcomes
According to Tapan M. Kadia, MD, professor at MD Anderson Cancer Center, this regimen of cladribine plus venetoclax represents "a highly effective curative regimen, producing deep and durable remissions in newly diagnosed MDS and AML."
The trial evaluated venetoclax in combination with cladribine, idarubicin, and cytarabine. The primary endpoint was the CR rate. Secondary endpoints included ORR, overall survival (OS), event-free survival (EFS), response duration, and safety.
Patient Population and Treatment Protocol
The study included patients aged 65 years or younger with newly diagnosed, treatment-naïve AML or high-risk MDS (defined as 10% or more blasts or an International Prognostic Scoring System [IPSS] risk score of 2 or more), an ECOG performance status of 2 or less, and adequate organ function.
During induction, patients received cladribine at 5 mg/m2 on days 1-5, idarubicin at 8-10 mg/m2 on days 1-3, cytarabine at 1-1.5 mg/m2 on days 1-5, and venetoclax at 400 mg on days 2-8. Maintenance therapy consisted of cladribine at 5 mg/m2 on days 1-3, idarubicin at 8 mg/m2 on days 1 and 2, cytarabine at 0.75-1.5 mg/m2 on days 1-3, and venetoclax at 400 mg on days 2-8.
Patient Characteristics
The median patient age was 49 years. In the AML group, 40% had adverse European Leukemia Network (ELN) 2022 risk, and 13% had AML with myelodysplasia-related changes. The MDS group had a median of 11 marrow blasts, and the median IPSS-revised score was 6.5. Common molecular characteristics in the AML group included NPM1 (34%), DNMT3A (32%), TET2 (21%), NRAS (19%), and IDH2 mutations (12%).
Subgroup Analysis
In the AML subgroup, the ORR by ELN 2022 criteria was 100% for 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 and KMT2A rearrangements, 33% for TP53-mutated disease, and 50% for complex karyotype.
Survival Outcomes
With a median follow-up of 2.9 years, the probability of relapse-free survival in 83 AML patients was 76% at 2 years and 74% at 5 years. The 2-year EFS rate for AML patients was 72%, and the 5-year rate was 68%. For the 7 MDS patients, both the 2-year and 5-year OS rates were 100%.
Among patients who underwent stem-cell transplant (n=61), the 2-year OS rate was 84%, and the 5-year OS rate was 82%. For 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). Based on ELN 2022 scores, 2-year OS rates were 90% for favorable risk, 74% for intermediate risk, and 67% for adverse risk (P = .144).
For patients with KMT2A-rearranged AML, the 2-year and 5-year OS rates were 73%. Those with NPM1 mutations had 2-year and 5-year OS rates of 78%. Patients with TP53 mutations or complex cytogenetics had 2-year and 5-year OS rates of 43%.
Adverse Events
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 days, 2 patients died. Disease status at death included MRD-negative response (52%), MRD-positive response (10%), residual AML (33%), and unknown (5%).
