Sixty percent of newly diagnosed patients with acute myeloid leukaemia (ND-AML) receiving frontline therapy attain a complete response, yet 30-40% of patients relapse. Recent study results demonstrated that FLAG-IDA plus venetoclax represents an effective intensive induction regimen for ND-AML and relapsed/refractory AML (R/R-AML), with particular utility as a bridge to allogeneic stem cell transplantation in the R/R-AML population.
“Courtney DiNardo is the queen of venetoclax studies in myeloid diseases. In this publication, she shows that adding venetoclax to FLAG-IDA is a safe regimen, associated with deep remissions and successive transplantation. This brings new hope for patients in need of a FLAG-IDA regimen that is often underperforming.“
Induction chemotherapy in acute myeloid leukaemia (AML) typically results in complete remission (CR) rates of approximately 60%. However, 30-40% of patients ultimately relapses and treatment regimens capable of producing long-term remissions are needed. Therefore, this trial evaluates the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin, combined with the B-cell lymphoma-2 inhibitor venetoclax in newly diagnosed AML (ND-AML) and relapsed/refractory AML (R/R-AML).
Adult patients with ND-AML, high-risk myelodysplastic syndrome or R/R-AML were eligible. Only R/R-AML patients were eligible for the phase IB (dose escalation) portion of the trial. The phase IB portion applied a 3 + 3 dose escalation and de-escalation algorithm to determine the maximal tolerated dose (MTD). The phase II (dose-expansion) portion enrolled separate cohorts of ND-AML (phase IIA) and R/R-AML (phase IIB) patients at the recommended phase II dose. FLAG-IDA induction consisted of 28-day cycles of intravenous fludarabine (30 mg/m2) and cytarabine (1.5-2 g/m2 IV) on days 2-6, idarubicin (IV, ND-AML, 8 mg/m2 on days 4-6; R/R-AML, 6 mg/m2 on days 4-5), and filgrastim (5 mcg/kg on days 1-7). Consolidation used reduced durations of fludarabine and cytarabine (days 2-4) and filgrastim (days 1-5); idarubicin was permitted (days 3-4) in up to two consolidation cycles at the discretion of the treating physician. At the recommended phase II dosing, venetoclax was administered on days 1-14 during induction and days 1-7 in consolidation. PEGylated filgrastim was permitted after day 5 (induction) or day 3 (consolidation) to replace remaining G-CSF doses.
To date, 68 patients have enrolled; 16 in phase IB, 29 in phase IIA and 23 in phase IIB. Median age of study participants was 46 years. Diploid or other intermediate-risk cytogenetics were frequent in ND-AML (76%), whereas adverse –risk or complex cytogenetics were common in R/R-AML (41%). Patients received a median of two treatment cycles. Grade 3-4 adverse events occurring in at least 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for phase IB, IIA and IIB was 75%, 97% and 70%, respectively, with 75%, 90% and 61% achieving a composite complete response. No significant response difference was observed between patients with refractory versus relapsed AML (56% vs. 70%, p= 0.53). Median time to best response was 30 days, with ongoing responses in 70% of patients. In total, 83% of patients in composite complete response attained MRD negativity, including 96% and 69% of patients with ND-AML and R/R-AML, respectively. After a median follow-up of 12 months, median overall survival (OS) for both phase II cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic haematopoietic stem-cell transplantation (HSCT) resulted in a significant improvement in OS (median OS not reached and 12-month OS rate of 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML. Thirty and 60-day post-HSCT mortality was 3%.
Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin plus venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.
DiNardo C, Lachowiez CA, Takahaski K, et al. Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed and relapsed or refractory acute myeloid leukemia. J Clin Oncol. 2021;39(25):2768-78.