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

Research output: Contribution to journalArticle

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

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations. / Alvarado, Yesid; Kantarjian, Hagop M.; Luthra, Rajyalakshmi; Ravandi, Farhad; Borthakur, Gautam; Garcia-Manero, Guillermo; Konopleva, Marina; Estrov, Zeev; Andreeff, Michael; Cortes, Jorge E.

In: Cancer, Vol. 120, No. 14, 01.01.2014, p. 2142-2149.

Research output: Contribution to journalArticle

Alvarado, Y, Kantarjian, HM, Luthra, R, Ravandi, F, Borthakur, G, Garcia-Manero, G, Konopleva, M, Estrov, Z, Andreeff, M & Cortes, JE 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, vol. 120, no. 14, pp. 2142-2149. https://doi.org/10.1002/cncr.28705
Alvarado, Yesid ; Kantarjian, Hagop M. ; Luthra, Rajyalakshmi ; Ravandi, Farhad ; Borthakur, Gautam ; Garcia-Manero, Guillermo ; Konopleva, Marina ; Estrov, Zeev ; Andreeff, Michael ; Cortes, Jorge E. / Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations. In: Cancer. 2014 ; Vol. 120, No. 14. pp. 2142-2149.
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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.",
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T1 - Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations

AU - Alvarado, Yesid

AU - Kantarjian, Hagop M.

AU - Luthra, Rajyalakshmi

AU - Ravandi, Farhad

AU - Borthakur, Gautam

AU - Garcia-Manero, Guillermo

AU - Konopleva, Marina

AU - Estrov, Zeev

AU - Andreeff, Michael

AU - Cortes, Jorge E.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - acute myeloid leukemia

KW - FLT3 inhibitors

KW - FLT3-ITD

KW - FLT3-TKD

KW - secondary FLT3 mutations

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DO - 10.1002/cncr.28705

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