FLAG-IDA as frontline induction improves outcomes in pediatric patients with core-binding factor or KMT2A-rearranged acute myeloid leukemia: A multicenter cohort study in southern China

Abstract Background: The FLAG-IDA (fludarabine, high-dose cytarabine, granulocyte colony-stimulating factor, and idarubicin) regimen is rarely used as frontline induction therapy for pediatric patients with de novo acute myeloid leukemia (AML). Therefore, this study aimed to assess the efficacy and safety of FLAG-IDA for frontline induction in pediatric patients with de novo AML and to analyze the treatment responses across various molecular subgroups. Methods: In this multicenter retrospective study, we evaluated the efficacy of FLAG-IDA (n=681; Group A) versus DAE (daunorubicin, Ara-C, and etoposide; n=194; Group B) induction as induction therapy, followed by two courses of consolidation therapy in 875 pediatric patients with de novo AML (2015–2023) in southern China. High-risk patients were advised to undergo hematopoietic stem cell transplantation (HSCT). Outcomes assessed included complete remission (CR), overall survival (OS), event-free survival, and treatment-related mortality. Results: In total, 875 patients were included in this study [median age at diagnosis: 6.4 years (range, 0.5–14.0 years)]. Although cumulative CR and treatment-related mortality rates after two induction cycles did not differ significantly between Group A and Group B (CR rate: 92.4%vs. 88.9%, p=0.134; treatment-related mortality rate: 4.3% vs. 6.0%, p=0.324); Group A demonstrated a better 5-year OS (79.6% vs. 69.3%, p=0.006). Among patients with core-binding factor AML (CBF-AML), FLAG-IDA induction significantly improved OS compared with DAE (5-year OS: 90.4% vs. 78.4%; p=0.031). Similarly, superior outcomes were observed in KMT2A-rearranged AML (80.8% vs. 61.3%; p=0.044). FLT3-ITD patients derived significant benefit from HSCT in first CR. However, non-MLLT3 KMT2A-rearranged patients who achieved first CR demonstrated comparable outcomes whether consolidated with chemotherapy alone or HSCT. Conclusions: These findings indicate that frontline induction with FLAG-IDA, followed by two courses of consolidation, shortens chemotherapy duration, confers a significant survival advantage in pediatric CBF-AML, and achieves long-term outcomes, comparable with those achieved with HSCT in non-MLLT3 KMT2A-rearranged AML.