FLT3 Inhibitors in Acute Myeloid Leukemia

Khaled el-Shami; Richard M. Stone; B. Douglas Smith


Expert Rev Hematol. 2008;1(2):153-160. 

In This Article

FLT3 Receptor in AML: Molecular Genetics and Clinical Aspects

FLT3 is one of the most commonly mutated genes in AML.[9] In the process of analyzing FLT3 expression levels in AML specimens, Kiyoi et al. made the seminal observation that there was an additional PCR product that was longer than the germline species. This moiety was due to an addition in the juxtamembrane domain through the first TKD. Further analysis demonstrated that the aberrant transcripts represented internal tandem duplication (ITD) mutations of FLT3 (FLT3/ITD mutations) in which a presumed DNA replication error results in varied length (but usually between nine and over 100 DNA base pairs), head-to-tail duplications in the juxtamembrane portion of the molecule. These in-frame insertions in the juxtamembrane domain destabilize its negative regulatory function and produce mutant proteins, which are constitutively activated via autodimerization, leading to constitutive phosphorylation. In addition, three different point mutations at aspartate 835 (D835) within the activation loop of the TKD were described in patients with AML, most notably aspartate to tyrosine missense mutations.[29,30] More recently, Bacher et al. identified eight additional mutations in the TKD in over 3,000 patients with AML.[31] While some of these mutations correlated with certain morphologic and cytogenetic features of AML, the clinical significance of such mutations is yet to be fully determined. Both ITD and TKD mutated sequences, however, transform the myeloid progenitor cell line 32D, suggesting that FLT3 mutations confer ligand-independent proproliferation signaling.[29,32,33] The mutation-driven signaling was not simply quantitative through constitutive activation, but also qualitative as FLT-ITD signaling primarily activated the STAT5 and FOXO transcription factors, whereas ligand-activated wild-type FLT3 signals work through upregulation of the Ras/Raf/MAP kinase pathways.[34,35,36,37]

The frequency of FLT3-ITD is 24% in adult AML, 10% in pediatric AML[9] and in nearly a third of cases of acute promyelocytic leukemia (APL).[38] Perhaps because of the availability of highly effective therapy, a FLT3-ITD does not carry an adverse prognosis in APL, although such patients are more likely to present with the microgranular variant associated with an elevated white blood cell count.[39,40,41,42,43] TKD FLT3 mutations are found in only 7% of AML, 3% of myelodysplastic syndrome (MDS) and 3% of acute lymphoblastic leukemia.[44] FLT3-ITD is readily detected by PCR amplification of genomic DNA using primers that span the internal tandem repeat region.[45] Confirming the presence of FLT3 mutation in AML is now an integral part of the prognostic evaluation of newly diagnosed disease, particularly in the presence of normal cytogenetics. In addition to the poor outcome, a FLT3-ITD is associated with clinical features including hyperleukocytosis, rapid proliferation rate and hypercellular bone marrow packed with blasts. While the rate of achieving a complete remission does not seem to be altered by a FLT3-ITD, its presence impacts many relevant end points, including the length of remission, event-free survival and overall survival.[46,47] Additionally, the prognostically adverse phenotype imparted by FLT3-ITD negates the good prognostic value of a concurrent nucleophosmin mutation in AML with normal karyotype.[48] Moreover, in a recent analysis of the impact of mutant level, size and number on clinical outcome in a large cohort of 354 young adult FLT3/ITD+ patients, the relative level of FLT3/ITD(s) as a proportion of total FLT3 alleles was a strong predictor of relapse risk and overall survival. However, no significant correlation between FLT3/ITD mutant number or size with clinical outcome was found.[49] Finally, in a large study by the German-Austrian AML group that evaluated the association of different mutations with treatment outcomes and their role in guiding postremission therapy in patients with AML, the Flt3-ITD-positive leukemias were identified as the subtype that had a clear benefit of a consolidative transplant, indicating the importance of this genotype as a prognostic and predictive marker. Together, this ever-increasing body of data regarding the incidence, biology and prognostic impact of FLT3 mutations has supported its value as a therapeutic target and resulted in tremendous interest in the development of targeted FLT3 inhibitors for therapeutic use in AML.


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