Gilteritinib and chemotherapy in children with relapsed/refractory FLT3-ITD AML: results from the phase 1/2 SKIPPER trial.
In phase 1 of the multinational SKIPPER trial, gilteritinib plus FLAG chemotherapy produced a 66.7% composite complete remission rate in nine children with relapsed/refractory FLT3-ITD AML, with sustained FLT3 inhibition, adult-comparable pharmacokinetics, no dose-limiting toxicities, and establishment of a pediatric phase 2 dose.
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In phase 1 of the multinational SKIPPER trial, gilteritinib plus FLAG chemotherapy produced a 66.7% composite complete remission rate in nine children with relapsed/refractory FLT3-ITD AML, with sustained FLT3 inhibition, adult-comparable pharmacokinetics, no dose-limiting toxicities, and establishment of a pediatric phase 2 dose.
Research significance
The reported clinical, pharmacokinetic, and pharmacodynamic findings support the hypothesis that adding gilteritinib to chemotherapy can inhibit FLT3 and induce remissions that may facilitate transplantation in pediatric FLT3-ITD AML; however, comparative efficacy, survival benefit, and applicability in frontline treatment remain unproven in this small, noncomparative phase 1 cohort.
Source abstract
Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) occurs in ∼15% of pediatric patients with acute myeloid leukemia (AML) and is associated with a high relapse risk with conventional chemotherapy. Gilteritinib is a selective, next-generation FLT3 inhibitor (FLT3i) approved for adults with relapsed/refractory FLT3-mutated AML, but pediatric-specific data remain limited. The multinational phase 1/2 SKIPPER study evaluated gilteritinib combined with fludarabine and cytarabine chemotherapy and granulocyte colony-stimulating factor (FLAG) in children and adolescents/young adults with relapsed/refractory FLT3-ITD AML. Nine patients, aged 8 to 15 years, were enrolled in phase 1 of the study between 2020 and 2023. Recruitment challenges, including disease rarity, off-label FLT3i availability, and competing trials, led to study termination after phase 1. The composite complete remission rate in the study population was 66.7% (95% confidence interval, 29.9-92.5). The 2-year event-free and overall survival probabilities were 41.7% and 55.6%, respectively. Treatment-emergent adverse events, most commonly reversible hepatic enzyme elevations and cytopenias, were consistent with known toxicity profiles of gilteritinib and FLAG. Pharmacokinetic parameters were comparable to those of adults, and pharmacodynamic plasma inhibitory activity assays confirmed sustained FLT3 inhibition. No dose-limiting toxicities were observed, and the recommended phase 2 dose of gilteritinib was established at 2 mg/kg per day for patients aged ≥2 years. The gilteritinib and FLAG regimen had manageable safety, induced high remission rates, and enabled allogeneic hematopoietic stem cell transplant for several patients. Although limited by a small sample size, these findings support further evaluation of gilteritinib in pediatric patients with FLT3-mutated AML, particularly in frontline settings. This trial was registered at www.ClinicalTrials.gov as NCT04240002.