Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed and relapsed/refractory AML

September 2021 Clinical practice Jolien Blokken

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.

Expert opinion of dr. Bert Heyrman, Haematologist, ZNA

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).

Study design

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.

Study results

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.