The mutation load is usually expressed as FLT3 allelic ratio (FLT3-mutations/wild-type ratio). With a few exceptions, 18 most studies have shown that AML patients with a high FLT3 mutant-to-wild-type ratio have a less favourable outcome that those with lower ratios. [17] and [19] Loss of the FLT3wt allele in FLT3-ITD mutated cases usually occurs through mitotic recombination that leads to partial uniparental disomy of chromosome 13q and it is associated with a particularly poor outcome. 20 This negative prognostic effect is likely due to the fact that the wild-type FLT3 interferes with and blocks

the aberrant signalling of the ITD-mutant receptor allele. 21 It is unclear whether the site and

length of find more FLT3-ITD mutation is prognostically relevant. In fact, patients carrying ITD mutations that extend to I-BET-762 supplier the TK1 region showed a particularly poor outcome in one study 22but not in another. 16 The prognostic relevance of the FLT3-TKD mutations also remains controversial. In fact, they have been associated with no, negative or positive impact on prognosis. 23 Treatment of AML patients harbouring FLT3-ITD mutations is problematic since they usually respond poorly to standard chemotherapy regimens. 6 Allogeneic HSCT may be of benefit and this procedure is recommended for this subset of patients. [24], [25], [26] and [27] However, FLT3-ITD positivity remains a poor prognostic factor even after allogeneic HSCT since patients are at high risk of early relapse, 28 with a 100-day cumulative risk of 45% (95% CI, 33–57). 28 Molecular targeted therapy directed to the genetic lesion is under investigation. Several FLT3 inhibitors have been developed, including first generation (midostaurin, lestaurtinib, sunitinib, sorafenib)

and second generation (quizartinib) compounds.29 Unfortunately, results with early FLT3 inhibitors used as single agents have been disappointing since they showed only a limited clinical activity, mainly manifesting Astemizole as transient reduction in the count of circulating blasts. The major limitation to the use of these compounds for the treatment of AML has been their relative lack of selectivity or potency against FLT3 and suboptimal pharmacokinetics. More encouraging results have been reported with the second generation, more selective and potent anti-FLT3 agent AC220 (quizartinib).30 This small molecule exhibits excellent pharmacokinetics properties and has shown significant activity in a phase 1 study.29 Other expected obstacles to the development of an effective therapy with FLT3 inhibitors include the levels of FLT3 ligand31 and the emergence of FLT3 kinase domain mutants resistant to FLT3 inhibitors.32 Moreover, some FLT3-ITD AML may not be addicted to FLT3 signaling and response of AML to FLT3 inhibitors may be conditioned by the FLT3-mutant allelic burden.