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

Abstract

High allelic ratio (HAR) <i>FLT3</i>/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. 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 <i>FLT3</i>/ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients. 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 <i>FLT3</i>/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, <i>P</i> < .001, disease-free survival from complete remission: HR 2.28, 95% CI, 1.08 to 4.82, <i>P</i> = .032, relapse risk from complete remission: HR 3.03, 95% CI 1.31 to 7.04, <i>P</i> = .010). Sorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR <i>FLT3</i>/ITD+ AML.