A Phase II Trial of Venetoclax in Combination with Cladribine, Idarubicin, and Cytarabine in Newly Diagnosed Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome
Authors: Bouligny Ian M. , Kantarjian Hagop M. , Yilmaz Musa , Daver Naval , Borthakur Gautam , DiNardo Courtney D. , Montalban-Bravo Guillermo , Short Nicholas J. , Alvarado Valero Yesid , Jabbour Elias , Jain Nitin , Pemmaraju Naveen , Hammond Danielle , Chien Kelly S. , Takahashi Koichi , Issa Ghayas C. , Abbas Hussein A. , Garcia-Manero Guillermo , Ravandi Farhad , Kadia Tapan M. 
Published: December 2024

Introduction
The combination of the BCL2 inhibitor venetoclax with intensive chemotherapy with cladribine, idarubicin, and cytarabine (CLIA) has been shown to be safe and effective in younger, fit patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Here, we report on an expanded cohort with mature longer-term follow-up and subgroup analyses of the phase II study of venetoclax combined with CLIA as first-line induction therapy.
Methods
This phase II trial (NCT02115295) enrolled patients aged ≤65 years with newly diagnosed AML, mixed phenotype acute leukemia (MPAL), high-risk MDS (defined as ≥10% blasts or IPSS risk ≥2), or myeloid blast phase CML (BP-CML). Patients received cladribine 5 mg/m2 D1-5, cytarabine 1-1.5 mg/m2 D1-5, idarubicin 8-10 mg/m2 D1-3, and venetoclax 400 mg on days 2-8, with dose adjustments for CYP3A inhibitors. Patients in remission underwent up to 5 additional cycles of dose-attenuated consolidation. Antimicrobial prophylaxis and, after an amendment, G-CSF support were administered to all patients. Eligible patients proceeded to allogeneic stem cell transplant (SCT).
Results
Ninety-five patients have been treated, including 85 (90%) with AML, 3 (3%) with MPAL, and 7 (7%) with MDS. Over one-third of patients were from racial and ethnic minority groups (15% Hispanic, 14% Black, 6% of Middle-Eastern descent, and 2% Asian). The median age at diagnosis was 49 (range, 18-64) years among patients with AML and 46 (36-58) years among those with MDS. Among patients with AML, the ELN 2022 risk was 25% favorable, 34% intermediate, and 41% adverse. AML was classified as therapy-related in 8% and secondary in 4%; 14% had AML-MRC. NPM1 was the most common mutation in the overall cohort at 31%; additional mutations included: 18% FLT3-ITD, 16% NRAS, 13% IDH2, 9% IDH1, 9% KRAS, 8% FLT3-TKD, and 4% TP53.
Patients were given a median of 2 (1-6) cycles of therapy, with a median of 1 (1-4) cycles to remission. The composite complete response (CRc) rate was 93%, including 84% CR and 8% CRi. One (1%) patient with MDS achieved HI and one (1%) with AML achieved PR; the overall response rate was 95% (ORR: CR + CRi + HI + PR). Among AML patients achieving CRc, 82% achieved MRD-negative CR measured by multiparameter flow cytometry. The ORR was 100%, 97%, and 89% for AML patients classified as favorable, intermediate, and adverse risk by ELN 2022, respectively.
With a median follow-up time of 2.5 years, the median overall survival was not reached. In patients with AML, the probability of OS was 85% at 1 year, 73% at 2 years, and 71% at 4 years. The relapse-free survival (RFS) was 78% at 1 year and 75% at 2 years. In patients with MDS, the 1- and 2-year probability of OS was 100%. The RFS for patients with MDS was 86% at 1 year and 86% at 2 years. Sixty-five patients (74%) with AML underwent allogeneic SCT in the first remission. In a landmark analysis, the 1- and 2-year OS was 88% and 82% for those receiving SCT after CLIA-venetoclax vs. 82% and 59% for those who did not (log-rank for overall survival, p = 0.229).
The most common grade ≥3 toxicities in patients with AML were hematologic: all patients had grade ≥3 anemia, leukopenia, neutropenia, and thrombocytopenia. Sixty-five (74%) patients had neutropenic fever in the first cycle, and 72 (82%) had neutropenic fever in any cycle. Additional grade ≥3 toxicities included: 28% bacteremia, 22% pneumonia, 19% ALT elevation, 14% colitis, 7% AST elevation, and 7% bilirubin elevation. The median time to count recovery during induction was 27 (18-52) days. In the overall cohort, the 30- and 60-day mortality was 1% and 2%, respectively.
Conclusion
CLIA-venetoclax is associated with a CRc exceeding 90%, with most patients achieving an MRD-negative response. High complete response rates and low early mortality rates facilitate the majority of patients to allogeneic SCT. Low relapse rates following SCT translate to an estimated overall survival of 71% at 4 years in patients with newly diagnosed AML. CLIA-venetoclax is a highly effective regimen, producing deep and durable remissions in patients with newly diagnosed AML.