title: Acute myeloid leukaemia blast cells with a tyrosine kinase domain mutation of FLT3 are less sensitive to lestaurtinib than those with a FLT3 internal tandem duplication.
abstract: FLT3 tyrosine kinase domain mutations (FLT3/TKDs) are associated with a favourable prognosis in acute myeloid leukaemia (AML), unlike FLT3 internal tandem duplications (FLT3/ITDs) that have a poor prognosis. Whilst FLT3/ITD+ cells are more susceptible to the cytotoxic effects of FLT3 inhibitors than wild type (WT) cells, the sensitivity of FLT3/TKD+ cells to therapeutic agents is unclear, as is the importance of the mutant level. We therefore studied the effect of cytarabine and the FLT3 inhibitor lestaurtinib, either alone or in combination, on in vitro survival of blast cells from 36 cases of AML (14 FLT3/WT, 11 FLT3/ITD+ and 11 FLT3/TKD+). All three groups showed similar sensitivity to the cytotoxic effects of cytarabine but FLT3/ITD mutant level was inversely correlated with cytarabine cytotoxicity (P = 0.04) whereas FLT3/TKD mutant level had no impact. FLT3/TKD+ cells showed a similar response to lestaurtinib as FLT3/WT cells, whereas FLT3/ITD+ cells were more sensitive (P = 0.004). There was no correlation between mutant level and lestaurtinib sensitivity for either FLT3/ITD+ or FLT3/TKD+ cells. Synergistic cytotoxicity of lestaurtinib plus cytarabine was demonstrated in all three groups. These results suggest that FLT3/TKD+ and FLT3/WT cases should not be differentiated when considering patients for treatment with FLT3 inhibitors.
authors.affiliation: Department of Haematology, Royal Free and University College Medical School, London, UK. adam.mead@ucl.ac.uk
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Mead
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.forename: Panagiotis D
authors.initials: PD
authors.lastname: Kottaridis
authors.forename: Satomi
authors.initials: S
authors.lastname: Matsuda
authors.forename: Asim
authors.initials: A
authors.lastname: Khwaja
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005663:Furans; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D047428:Protein Kinase Inhibitors; D003561:Cytarabine; C119379:lestaurtinib; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3