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

Jessica A. Pollard, Todd A. Alonzo, Robert Gerbing, Patrick Brown, Elizabeth Fox, John Choi, Brian Fisher, Betsy Hirsch, Samir Kahwash, Kelly Getz, John Levine, Lisa Eidenschink Brodersen, Michael R. Loken, Susana Raimondi, Katherine Tarlock, Andrew Wood, Lillian Sung, E. Anders Kolb, Alan Gamis, Soheil MeshinchiRichard Aplenc

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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/m 2 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.

Original languageEnglish (US)
Pages (from-to)2023-2035
Number of pages13
JournalJournal of Clinical Oncology
Issue number18
StatePublished - Jun 20 2022

Bibliographical note

Publisher Copyright:
© American Society of Clinical Oncology.


  • Child
  • Hematopoietic Stem Cell Transplantation/adverse effects
  • Humans
  • Leukemia, Myeloid, Acute/drug therapy
  • Mutation
  • Phenylurea Compounds/adverse effects
  • Protein Kinase Inhibitors/adverse effects
  • Remission Induction
  • Sorafenib/therapeutic use
  • fms-Like Tyrosine Kinase 3/genetics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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