title: Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations.
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.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yesid
authors.initials: Y
authors.lastname: Alvarado
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052160:Benzothiazoles / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D005260:Female; D005663:Furans; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D000077157:Sorafenib; D016019:Survival Analysis; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D002227:Carbazoles; D005663:Furans; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; C544967:quizartinib; D000077157:Sorafenib; C119379:lestaurtinib; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3
keywords: FLT3 inhibitors; FLT3-ITD; FLT3-TKD; acute myeloid leukemia; secondary FLT3 mutations
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