These include the brokers semaxinib [80], sunitinib [81, 82], tandutinib [83] and KW-2449 [84]. chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these brokers Most of these compounds are structural mimics of the purine component of ATP, and occupy the ATP-binding pocket of the tyrosine kinase [46, 47]. Studies have suggested that specific FLT3 inhibitors induce preferential cytotoxicity in FLT3-mutant AML cells, and that sustained and potent FLT3 inhibition appear essential in bringing about cytotoxicity against myeloblasts [4, 48]. In recent years, multiple inhibitors of FLT3, some more potent and specific than others, have been transitioned from your laboratory and analyzed in clinical trials. Those which are most advanced in clinical trials are summarized in Table 1, and layed out in detail below. Table 1 A summary of the advanced phase trials of FLT3 inhibitors in AML studies of lestaurtinib combined with Ethylparaben traditional cytotoxic chemotherapy found synergistic cytotoxicity when it was used concurrently or subsequent to chemotherapy. In contrast, when leukemia cells were exposed to lestaurtinib followed by exposure to chemotherapy, antagonism was noted. The biological basis for this observation was postulated Ethylparaben to be G1 cell cycle arrest in leukemic cells exposed to lestaurtinib, leading to a decreased efficacy of chemotherapeutic brokers [66]. A phase I/II trial of lestaurtinib in FLT3-mutant AML patients exhibited that lestaurtinib was well-tolerated and that it produced clinical responses, although mostly just reductions in the peripheral blast count. Additionally, a sustained and effective suppression of FLT3 phosphorylation, as measured with an ex lover assay, correlated strongly with these clinical responses [48, 67]. In a phase II trial of newly diagnosed elderly patients, three of five patients with FLT3 mutations experienced transient hematologic responses. Interestingly, a number of patients with wildtype FLT3 experienced decreases in bone marrow blasts as well, which was attributed to possible over-expression of FLT3 in these patients [68]. A phase II trial of relapsed FLT3-mutant AML Ethylparaben randomized patients to re-induction chemotherapy alone or re-induction followed by lestaurtinib. The study was subsequently expanded to a phase III trial, the results of which were recently reported by Levis et al. Rabbit Polyclonal to CNTN2 In contrast to the sequence used in the combination sorafenib studies, lestaurtinib, at a dose of 80mg twice daily, was initiated two days after conclusion of induction chemotherapy and continued until day 112. Regrettably, the investigators reported no benefit in any survival parameters or response rate with the addition of lestaurtinib to induction chemotherapy. However, effective and sustained inhibition of FLT3 was achieved in only 58% of patients by day 15 of treatment, and therefore definitive conclusions regarding the efficacy of FLT3 inhibition in combination with chemotherapy could not be made and argued for any different dosing routine of lestaurtinib [69]. Lestaurtinib has also been incorporated into induction and consolidation chemotherapy regimens for FLT3-mutated patients in the British MRC AML17 trial. Similar to the above study, lestaurtinib in this trial was not administered concurrently with chemotherapy, but rather initiated two days after conclusion of and discontinued two days prior to initiation of consecutive cycles of cytotoxic chemotherapy. Preliminary reports have suggested effective inhibition of FLT3 activity in the large majority of evaluated patients. Additionally, to date, more than 90% of the evaluated patients have achieved a CR, which is usually higher than historical response rates and final results are eagerly anticipated [70]. Midostaurin Midostaurin, a staurosporine derivative, was initially described as an inhibitor of protein kinase C. However, like other comparable agents, it was subsequently found to suppress the tyrosine kinases VEGFR, PDGFR, c-KIT, as well as FLT3 with significant cytotoxicity in FLT3-ITD cell lines [71, 72]. A phase I trial of midostaurin in patients with relapsed/refractory AML showed that seven of twenty patients experienced transient decreases Ethylparaben in peripheral blasts and five showed reductions in bone marrow blasts as well [8]. A phase I trial of midostaurin with induction chemotherapy was also conducted, with preliminary data exposing that FLT3-mutant patients had similar rates of overall survival at 2 years when compared to those with FLT3-wildtype AML. In this study, midostaurin was administered both concomitantly (days 1-7) and sequentially (days 8-21) with chemotherapy, and both regimens were shown to be well-tolerated [73]. A phase IIb trial of single-agent midostaurin, at two different dosages (50mg or 100mg twice daily), in patients.