Efficacy and safety of FLAG‐IDA as front‐line therapy in de novo paediatric acute myeloid leukaemia population

Abstract

Acute myeloid leukaemia (AML) requires intensive chemotherapy for cure. Regimens from the Children's Oncology Group (COG) represent the most common treatment approach to paediatric AML in North America. These regimens utilize up to five cycles of intensive chemotherapy, with a high anthracycline burden (~492-684 mg/m 2 doxorubicin equivalents), 1 contributing to acute morbidity and long-term cardiotoxicity. 2 The United Kingdom Medical Research Council (MRC) AML 15 randomized trial tested a new double induction regimen of fludarabine, high-dose cytarabine (HDAc), G-colony stimulating factor (GCSF) and idarubicin (FLAG-IDA) in adults and a small subset of paediatric patients. 3 MRC 15 included four cycles of chemotherapy with lower intensity and less anthracycline exposure (cumulatively, ~240 mg/m 2 doxorubicin equivalents), and demonstrated excellent survival. 3 As a result, we adopted MRC-15-based therapy as routine care. Between 2014 and 2021, we treated 30 patients with de novo AML (Table 1) and describe here disease response, morbidity and survival. Each case was characterized by cytogenetics, chromosomal microarray and a proprietary molecular testing panel (OncoKids®). 4 Treatment was delivered per MRC 15, 5 adapted to reflect institutional standard of care. Briefly, patients received double induction chemotherapy (fludarabine 30 mg/m 2 and cytarabine 2 g/m 2 IV days 2-6, idarubicin 8 mg/m 2 IV days 4-6, GCSF 5 mcg/kg days 1-7 [optionally omitted for patients with leukocytosis]) followed by double consolidation (cytarabine 3 g/m 2 q12 hours days 1,3,5). Following regulatory approval in 2017, patients with CD33+ received gemtuzumab ozogamicin (GO, 3 mg/m 2 IV day 7, maximum dose 4.5 mg) as per treating physician discretion. Tyrosine kinase inhibitors (TKI) were optionally included for patients with FLT3 mutations. Disease response was assessed by flow-cytometric minimal residual disease (MRD) following Induction I (and II, if positive) using a 'difference from normal' approach. 6 MRD+ was defined using COG threshold at the time of treatment (≥0.1%). 7 Final risk category was assigned from presenting molecular analyses and post-Induction I MRD using COG classification at the time of diagnosis (per AAML1031 or AAML1831) (Table S1).