Sorafenib in Combination With Standard Chemotherapy for Children With High Allelic Ratio FLT3/ITD+ Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML1031

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DOI: 10.1200/JCO.21.01612; PMCID: PMC9197362


Purpose: High allelic ratio (HAR) FLT3/ITD (AR > 0.4) mutations confer poor prognosis in pediatric acute myeloid leukemia (AML). COG AAML1031 studied the feasibility and efficacy of adding sorafenib, a multikinase tyrosine kinase inhibitor to standard chemotherapy and as single-agent maintenance therapy in this population.

Materials and methods: Patients were treated in three cohorts. The initial safety phase defined the maximum tolerated dose of sorafenib starting in induction 2. Cohorts 2 and 3 added sorafenib in induction and as single-agent maintenance. Clinical outcome analysis was limited to n = 72 patients in cohorts 2/3 and compared with n = 76 HAR FLT3/ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients.

Results: The maximum tolerated dose of sorafenib was 200 mg/m2 once daily; dose-limiting toxicities included rash (n = 2; 1 grade 3 and 1 grade 2), grade 2 hand-foot syndrome, and grade 3 fever. Pharmacokinetics/plasma inhibitory activity data demonstrated that measured plasma concentrations were sufficient to inhibit phosphorylated FLT3. Although outcomes were superior with sorafenib in cohorts 2 and 3, patients treated with sorafenib also underwent hematopoietic stem-cell transplant more frequently than the comparator population. Multivariable analysis that accounted for both hematopoietic stem-cell transplant and favorable co-occurring mutations confirmed sorafenib's benefit. Specifically, risk of an event was approximately two-fold higher in HAR FLT3/ITD+ patients who did not receive sorafenib (event-free survival from study entry: hazard ratio [HR] 2.37, 95% CI, 1.45 to 3.88, P < .001, disease-free survival from complete remission: HR 2.28, 95% CI, 1.08 to 4.82, P = .032, relapse risk from complete remission: HR 3.03, 95% CI 1.31 to 7.04, P = .010).

Conclusion: Sorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR FLT3/ITD+ AML.

Journal Title

Journal of clinical oncology : official journal of the American Society of Clinical Oncology





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MeSH Keywords

Child; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Mutation; Phenylurea Compounds; Protein Kinase Inhibitors; Remission Induction; Sorafenib; fms-Like Tyrosine Kinase 3


Hematopoietic Stem Cell Transplantation; Acute Myeloid Leukemia; Mutation; Phenylurea Compounds; Protein Kinase Inhibitors; Remission Induction; Sorafenib; fms-Like Tyrosine Kinase 3

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