Venetoclax Combined with Cladribine, Idarubicin, Cytarabine (CLIA) Results in Higher Remission Rates over Conventional 7+3 Chemotherapy without Increased Toxicity in Newly Diagnosed Acute Myeloid Leukemia
Authors: Lee Benjamin J. , Griffin Shawn P. , Doh Jean , Ciurea Stefan O. , Kongtim Piyanuch , Jeyakumar Deepa , Naqvi Kiran 
Published: December 2024

Background: Induction chemotherapy in acute myeloid leukemia (AML) has historically combined an anthracycline with standard-dose cytarabine (“7+3”) in fit patients and is considered the standard of care despite complete remission (CR) rates of 50-70%. Recently, the addition of venetoclax (V) to the chemotherapy combination of cladribine, cytarabine, and idarubicin (“CLIA”) demonstrated an impressive 94% composite CR (CCR) rate with 82% undetectable measurable-residual disease (MRD) among de novo AML patients. Based on these findings, we adopted the utilization of CLIA+V for intensive induction therapy since May 2023 at our institution.

Methods: We retrospectively reviewed all newly diagnosed AML patients who received intensive upfront chemotherapy between 2017 and 2024. Patients diagnosed with acute promyelocytic leukemia, core-binding factor AML, and CML myeloid blast phase were excluded from this review as well as patients with FLT3(+), Ph(+), and IDH1/2 (+) mutations who received oral targeted therapies. Outcomes of interest included CCR defined as CR or CR with incomplete count recovery (CRi) after chemotherapy induction, event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS). Time-to-event endpoints were summarized via the Kaplan-Meier method, and treatment groups were compared using a 2-sided log-rank test. Adverse events (ADEs) in alignment with National Cancer Institute Common Terminology Criteria for Adverse Events V5.0 were also evaluated to compare the tolerability and safety of each respective regimen.

Results: A total of 50 patients were included in this analysis, 14 in the CLIA+V arm and 36 in the 7+3 arm. The median [IQR] age was 54 [42-63] years and 54% were male. More than half of the study population had European LeukemiaNet (ELN) 2022 adverse-risk AML (58%), and was significantly higher among CLIA+V treated patients (92.9% vs 44.4%; P=0.003). All other baseline characteristics were similar between the two cohorts. Median follow-up time for survivors was 7.6 months for CLIA+V and 54 months for 7+3 treated patients. Two patients in the 7+3 cohort expired prior to bone marrow assessment and were excluded from the response evaluation. CCR was significantly higher among patients who received CLIA+V compared to 7+3 (100% vs 50%; P=0.001). MRD testing by multicolor-flow cytometry post-induction therapy was performed in 85.7% (n=12/14) of CLIA+V and 76.5% (n=13/17) of 7+3 patients, respectively, who achieved CCR; MRD-negative CCR was significantly higher in the former (91.7% [n=11/12] vs 46.2% [n=6/13]; P=0.03). Median number of cycles required to achieve CR1 was 1 (range, 1-1) for CLIA+V and 2 (range, 1-4) for 7+3 treated patients (P=0.001). A greater percentage of patients who received CLIA+V induction therapy proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT) (78.6% vs 31.6%; P=0.004). Patients who received CLIA+V had higher EFS (92.3% vs 31.6% at 6-months; P&lt;0.001), RFS (92% vs 21.1% at 6-months; P=0.023), and OS (92.3% vs 68.4% at 6-months; P=0.05) compared to those who received 7+3 induction chemotherapy. Patients who received CLIA+V had similar rates of grade ≥2 febrile neutropenia (78.6% vs 61.1%; P=0.33) and infection (21.4% vs 25%; P&gt;0.99), as well as cardiovascular- (14.3% vs 13.9%; P&gt;0.99), gastrointestinal- (35.7% vs 22.2%; P=0.33), and nephrotoxicity (0% vs 11.1%; P=0.57), compared to those who received 7+3, while a lower rate of grade ≥2 hepatotoxicity (0% vs 41.7%; P=0.004) was seen in the former. Early mortality (within 30-days of chemotherapy initiation) was not increased in patients receiving CLIA+V (0% vs 13.2%; P=0.31).

Conclusion: This single center analysis shows that induction therapy using CLIA+V resulted in significantly higher CCR, MRD-negativity, and proportion of patients proceeding to alloHSCT compared to 7+3 among newly diagnosed AML patients without increased toxicity. Survival outcomes were also improved among CLIA+V treated patients however, longer follow-up time is needed.