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

Academic Article

Abstract

  • PURPOSEHigh 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 METHODSPatients 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.RESULTSThe maximum tolerated dose of sorafenib was 200 mg/monce 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).CONCLUSIONSorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR FLT3/ITD+ AML.
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    Author List

  • Pollard JA; Alonzo TA; Gerbing R; Brown P; Fox E; Choi J; Fisher B; Hirsch B; Kahwash S; Getz K
  • Start Page

  • 2023
  • End Page

  • 2035
  • Volume

  • 40
  • Issue

  • 18