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Adding venetoclax to cladribine, high-dose cytarabine, and idarubicin appears to yield high rates of minimal residual disease negativity and promising survival in patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome.
The addition of venetoclax (Venclexta) to cladribine (Mavenclad), high-dose cytarabine (Cytosar-U), and idarubicin (CLIA;Idamycin) may result in increased minimal residual disease (MRD) negativity and promising event-free survival (EFS) and overall survival (OS) for patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), according to data from the phase 2 CLIA trial (NCT02115295).
A total of 82% (n = 37) of patients had undetectable measurable residual disease (95% CI, 68-92) following treatment with venetoclax and CLIA. After a median follow-up of 13.5 months, the median duration of response, EFS, and OS were not reached. The estimated duration of response at 12 months was 74% (95% CI, 60% -92%), as well as 68% for EFS (95% CI, 54%-85%), and 85% for OS (95% CI, 75%-97%).
The study enrolled 50 patients, 90% (n = 45) of whom had AML, 8% (n = 4) had MDS, and 2% (n = 1) had mixed phenotype acute leukemia. One patient had initial marrow that was insufficient for cytogenetics, but had peripheral blood fluorescence in-situ hybridization that showed RUNX1-RUNXT1 t(8;21) (q22;q22) after the patient had started treatment on protocol. Additionally, 50% (n = 25) of patients had diploid karyotype present and 16% (n = 8) had other intermediate risk karyotype present. Moreover, 20% (n = 10) of patients had adverse-risk or complex cytogenetics present.
During treatment, no patients with MDS required cytoreduction, although 58% (n = 29) of patients required emergent cytoreduction. A total of 54% (n = 27) of patients received hydroxyurea at a median cumulative dose of 10 g, and 24% (n = 12) of patients received cytarabine at a median cumulative dose of 2 g. Additionally, 6% (n = 3) of patients were treated with an all-trans retinoic acid at a median dose of 60 mg.
The median time to count recovery in responding patients was 27 days. Notably, 1 patient died during induction. The median time to recovery of neutrophil count of 1000 cells or more per μL was 29 days, the recovery of platelet count of 50,000 or more platelets per μL was 24 days, and 100,000 platelets per μL was 27 days after induction.
At data cutoff, 62% (n = 29/47) of patients went on to receive allogeneic hematopoietic stem-cell transplantation (HSCT) in remission following a median of 2 courses, with 1 non-responding patient receiving allogeneic HSCT after responding to salvage therapy in the second complete response. Additionally, 36% (n = 18) of responding patients who did not undergo treatment with allogeneic HSCT were given a median of 2.5 courses of therapy.
A composite complete response rate (CR) of 94% (n = 47; 95% CI, 83%-98%) was reported by investigators. Moreover, 84% (n = 42) of patients had a CR (95% CI, 79%-92%), and 10% (n = 5) had a CR with incomplete blood count recovery (95% CI, 4%-21%). The Bayesian posterior estimated probability of CR was 0.92 (95% CI, 0.83-0.98). Additionally, the median number of courses given to response was 1.
Additional findings from the study indicated that the estimated 12-month survival rate among the favorable European Leukemia Network (ELN) risk group was 78% (95% CI, 59%-100%), the intermediate ELN risk group was 93% (95% CI, 80%-100%), and the adverse ELN risk group was 81% (95% CI, 60%-100%).
Patients who received a concomitant FLT3 inhibitor experienced a similar OS (HR, 1.88; 95% CI, 0.46-7.70; P = .38), and EFS (HR, 2.20; 95% CI, 0.66-7.33; P =.20), compared with those receiving venetoclax plus CLIA alone.
The 12-month OS rate for those being treated with a concomitant FLT3 inhibitor was 64% (95% CI, 38%-100%) and the 12-month EFS rate was 51% (95% CI, 26%-100%), compared with 90% (95% CI, 80%-100%) and 73% (95% CI, 58%-92%), respectively, in the venetoclax and CLIA cohort. Among responders, neither OS (HR, 1.19; 95% CI, 0.14-10.27; P = .88) and EFS (HR, 1.59; 95% CI, 0.19-13.00; P = .67) were not affected by the presence of MRD-negative state.
The most common grade 3 or 4 adverse effects (AEs) during the first course of treatment were febrile neutropenia (78%), alanine aminotransferase elevations (10%), and aspartate aminotransferase elevations (4%). Overall, during any treatment, the most common AEs of grade 3 or higher were febrile neutropenia (84%), infection (12%), and alanine aminotransferase elevations (12%).
From the start of induction, there was only 1 death at 4 weeks. Additionally, 2 patients who had a complete response died. No deaths are believed to be treatment related.
Kadia TM, Reville PK, Borthakur G, et al. Venetoclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a cohort from a single-centre, single-arm, phase 2 trial. Lancet Haematol. 2021;8(8):e552-e561. doi:10