Outcomes of Children and Adolescents with Acute Myeloid Leukemia and FLT3-ITD Treated with Low- or Standard-Dose Chemotherapy Plus Sorafenib on the Cals III-AML18 Trial (ChiCTR1800015883)

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Background: FLT3 -ITD mutations are linked to a poor prognosis in pediatric acute myeloid leukemia (AML). Combining targeted therapies, such as sorafenib, with chemotherapy may enhance outcomes for these patients. Low-dose chemotherapy (LDC) has demonstrated safety and effectiveness in some cases. We aimed to investigate whether combining LDC or standard-dose chemotherapy (SDC) with sorafenib can improve the prognosis of patients with FLT3-ITD-positive AML. Methods: From June 2018 to June 2022, this multicenter clinical trial enrolled 497 children with newly diagnosed acute myeloid leukemia (AML), who were randomly assigned to receive either low-dose chemotherapy (LDC) or standard-dose chemotherapy (SDC). Among these, 60 patients were positive for FLT3-ITD mutations. Sorafenib was administered based on recommendations of physicians at a dosage of 200 mg/m²/day. We compared clinical characteristics and outcomes between patients receiving sorafenib (n=40) and those not receiving sorafenib (n=20), focusing on rates of complete morphologic remission with or without platelet recovery (CR/CRi), overall survival (OS), and event-free survival (EFS). Results: There were no significant differences in clinical and biological characteristics between the sorafenib and non-sorafenib groups. Of the 60 patients with AML harboring FLT3-ITD mutations, 33 received sorafenib starting from Induction I. After Induction I, complete morphologic remission with or without platelet recovery (CR/CRi) was achieved in 48.5% of patients in the sorafenib group and 59.3% in the non-sorafenib group (P = .405). However, the CR rate was significantly higher in the for the patients in the LDC group compared to the ones treated with SDC (73.3% vs. 33.3%, P = .002), regardless of sorafenib administration. The median time to neutrophil count recovery was 24 days for patients receiving sorafenib compared to 19.5 days for those not receiving sorafenib after Induction I (P = .0482). The median time to platelet count recovery was 16 days for the sorafenib group and 17.5 days for the non-sorafenib group (P = .0938). Sorafenib did not improve OS or EFS). Patients in the sorafenib group had a 3-year OS of 84.5% ± 5.8% compared to 69.9% ± 11.6% in the non-sorafenib group (P = .336) and a 3-year EFS of 53.1% ± 8.2% versus 54.0% ± 11.4% (P = .862). Eighty-five percent of patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) during their first complete remission (CR1), which significantly improved OS and EFS in patients with FLT3-ITD AML (P = .000). The combination of sorafenib with LDC significantly improved 3-year EFS compared to SDC (66.9% vs. 40.0%, P = .030). In multivariate analysis, sorafenib was not associated with improved outcomes in FLT3-ITD-positive pediatric AML. Conclusion: Patients with FLT3-ITD-positive AML treated with LDC with and without sorafenib achieved favorable remission. Allogeneic hematopoietic stem cell transplantation (HSCT) during first complete remission (CR1) significantly improved overall survival (OS) and event-free survival (EFS). However, sorafenib did not show a significant improvement in prognosis for pediatric patients with FLT3-ITD positive AML in this study, indicating that further randomized controlled trials may be needed to confirm its efficacy.