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.
No relevant conflicts of interest to declare.
Sorafenib was administered based on recommendations of physicians at a dosage of 200 mg/m²/day for chemotherapy.
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