• Azacytidine and sorafenib are effective in patients with relapsed and refractory FLT3-mutated AML.Patients received 5-azacytidine (AZA) 75 mg/m 2 intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ∼1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890. (Blood. 2013;121(23): 4655-4662)

• Crenolanib displays activity against several of the important kinase domain mutations (at position D835) found in FLT3.• Patients receiving crenolanib achieve FLT3-inhibitory plasma levels.Mutations of the type III receptor tyrosine kinase FLT3 occur in approximately 30% of acute myeloid leukemia patients and lead to constitutive activation. This has made FLT3-activating mutations an attractive drug target because they are probable driver mutations of this disease. As more potent FLT3 inhibitors are developed, a predictable development of resistance-conferring point mutations, commonly at residue D835, has been observed. Crenolanib is a highly selective and potent FLT3 tyrosine kinase inhibitor (TKI) with activity against the internal tandem duplication (FLT3/ITD) mutants and the FLT3/D835 point mutants. We tested crenolanib against a panel of D835 mutant cell lines and primary patient blasts and observed superior cytotoxic effects when compared with other available FLT3 TKIs such as quizartinib and sorafenib. Another potential advantage of crenolanib is its reduced inhibition of c-Kit compared with quizartinib. In progenitor cell assays, crenolanib was less disruptive of erythroid colony growth, which may result in relatively less myelosuppression than quizartinib. Finally, correlative data from an ongoing clinical trial demonstrate that acute myeloid leukemia patients can achieve sufficient levels of crenolanib to inhibit both FLT3/ITD and resistance-conferring FLT3/D835 mutants in vivo. Crenolanib is thus an important next-generation FLT3 TKI. This study is registered at clinicaltrials.gov (ID: NCT01657682). (Blood. 2014;123(1):94-100)

We examined 6 different FMS-like tyrosine kinase-3 (FLT3) inhibitors (lestaurtinib, midostaurin, AC220, KW-2449, sorafenib, and sunitinib) for potency against mutant and wild-type FLT3, as well as for cytotoxic effect against a series of primary blast samples obtained from patients with acute myeloid leukemia (AML) harboring internal tandem duplication (FLT3/ITD) mutations. We found that inhibition of FLT3 autophosphorylation in a FLT3/ITD specimen does not always induce cell death, suggesting that some FLT3/ITD AML may not be addicted to FLT3 signaling. Relapsed samples and samples with a high mutant allelic burden were more likely to be responsive to cytotoxicity from FLT3 inhibition compared with the samples obtained at diagnosis or those with a low mutant allelic burden. These FLT3 inhibitors varied to a considerable degree in their selectivity for FLT3, and this selectivity influenced the cytotoxic effect. These results have important implications for the potential therapeutic use of FLT3 inhibitors in that patients with newly diagnosed FLT3-mutant AML might be less likely to respond clinically to highly selective FLT3 inhibition. (Blood.