Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations

Yesid Alvarado, Hagop M. Kantarjian, Rajyalakshmi Luthra, Farhad Ravandi, Gautam Borthakur, Guillermo Garcia-Manero, Marina Konopleva, Zeev Estrov, Michael Andreeff, Jorge E. Cortes

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67 Scopus citations

Abstract

BACKGROUND FLT3-internal tandem duplication (ITD) mutations are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 inhibitors have shown clinical activity in AML with FLT3-ITD, but responses are usually short-lived. METHODS This study examined 69 FLT3-mutated patients with AML, who were treated with different FLT3 inhibitors to analyze emergence of new mutations. RESULTS At baseline, 87% of patients had an ITD mutation, 7% had a D835/I836 mutation, and 6% had combined ITD and D835/I836 mutations. Responses occurred in 32% of patients, all with FLT3-ITD; none of the patients with D835/I836 or ITD+D835/I836 responded. Mutational assessment at the time of FLT3 inhibitor discontinuation showed that 68% of patients were unchanged, 10% had become undetectable, and 22% of patients progressed from a single ITD to have combined ITD+D835/I836 mutations. In those patients with unchanged FLT3 mutation at progression, the median survival was 5 months, whereas in those with undetectable and with combined ITD+D835/I836 mutations, the median survival was 7 months, respectively. CONCLUSIONS These data confirm in vitro observations that a secondary tyrosine kinase domain mutation may arise after the use of FLT3 inhibitors in patients with single FLT3-ITD mutated AML, a phenomenon that is associated with resistance and a poor prognosis.

Original languageEnglish (US)
Pages (from-to)2142-2149
Number of pages8
JournalCancer
Volume120
Issue number14
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Keywords

  • acute myeloid leukemia
  • FLT3 inhibitors
  • FLT3-ITD
  • FLT3-TKD
  • secondary FLT3 mutations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Alvarado, Y., Kantarjian, H. M., Luthra, R., Ravandi, F., Borthakur, G., Garcia-Manero, G., Konopleva, M., Estrov, Z., Andreeff, M., & Cortes, J. E. (2014). Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations. Cancer, 120(14), 2142-2149. https://doi.org/10.1002/cncr.28705