FLAG IDA Venetoclax in Newly Diagnosed Pediatric and AYA Patients with AML
Authors: Raj Reeja , Catueno Samanta , Gibson Amber , McCall David , Garcia Miriam B. , Nunez Cesar , Roth Michael E. , Sasaki Koji , Tewari Priti , Cuglievan Branko , DiNardo Courtney D. 
Published: December 2024

Background: Despite advancements, 5-year event-free survival (EFS) rates for pediatric AML remain 49% to 68%. Standard frontline therapy, mainly cytarabine and anthracycline, has seen little progress over the past 25 years. In contrast, adult AML regimens like FLAG-IDA venetoclax have shown superior outcomes and extended follow-up, particularly in high-risk groups. However, data on the efficacy and safety of frontline venetoclax-based regimens in pediatric and adolescent/young adult (AYA) populations remains limited. To address this, we conducted a retrospective study on the use of this combination in high-risk pediatric and AYA patients. This analysis could lay the groundwork for future cooperative group studies.

Methods: A retrospective review was conducted at The University of Texas MD Anderson Cancer Center to evaluate the efficacy, adverse events (AEs), and toxicities of the FLAG-IDA venetoclax regimen in pediatric and AYA patients. Treatment included Fludarabine (30 mg/m²/day on days 2-6), Cytarabine (1.5 g/m²/day on days 2-6), Idarubicin (8 mg/m²/day on days 4-6), and Venetoclax (400 mg adult equivalent dose on days 1-7). Doses were adjusted based on body surface area (BSA), CYP3A4 inhibitors, and myelosuppression, with all patients following a three-day ramp-up regimen. Response was assessed using the revised International Working Group Response Criteria for AML, and minimal residual disease (MRD) was measured by multiparameter flow cytometry (sensitivity: 0.01%). Toxicities were graded according to the Common Terminology Criteria for Adverse Events (version 5.0), using clinical records. Diagnoses were made following the World Health Organization classification for myeloid neoplasms and acute leukemias, and data collected included cytogenetic and molecular mutations, venetoclax dosage, regimen, and cycle count.

Results: Twelve patients were included, six males and six females, with a median age of 20 years (range: 2 to 25) who had adverse risk AML per ELN criteria. Patients received a median of 2 treatment cycles (range: 1-7). Treatment was generally well-tolerated, with no discontinuations due to toxicity and no 60-day mortality. All patients experienced grade 3 or 4 thrombocytopenia, anemia, and neutropenia. The median time for platelet (&gt; 50,000/ml ) and absolute neutrophil (&gt;500/ml) recovery was 18 and 19 days, respectively. 7 patients had febrile neutropenia; confirmed infections included Influenza B and streptococcus viridans and staph aureus bacteremia. One patient had a candida abscess. Electrolyte and metabolic imbalances included grade 2 reversible hypomagnesemia, hypokalemia, and hyperbilirubinemia.

With a median follow-up of 10 months (range: 1-44 months), ten out of twelve patients achieved complete remission (CR), one is pending, and one patient with Der (1:7) cytogenetics had no response. Of the ten patients in CR, eight were minimal residual disease (MRD) negative after the first cycle, while two were MRD positive. Among those in CR, four underwent stem cell transplantation (SCT) and remain in remission. At the time of submission, three patients were proceeding to transplantation. Currently, nine patients are alive and in remission; one patient is pending response and the non responder is deceased.

Conclusion: Flag IDA Venetoclax showed favorable safety and efficacy in children with newly diagnosed AML, with a toxicity profile comparable to other induction regimens. Further research is needed to confirm these findings and assess the long-term benefits of early venetoclax use in high-risk AML patients.