kw-2449 and midostaurin

Topics: Acute Disease; Clinical Trials as Topic; Drug Design; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Humans; Indazoles; Leukemia; Mutation; Piperazines; Quinazolines; Signal Transduction; Staurosporine

We examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated FLT3 inhibition and cytotoxicity for each of 5 different FLT3 inhibitors (lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220). The dramatic increase in FL level after chemotherapy represents a possible obstacle to inhibiting FLT3 in this clinical setting. These findings could have important implications regarding the design and outcome of trials of FLT3 inhibitors and furthermore suggest a rationale for targeting FL as a therapeutic strategy.

Topics: Antineoplastic Agents; Benzenesulfonates; Carbazoles; Cells, Cultured; Drug Antagonism; fms-Like Tyrosine Kinase 3; Furans; Humans; Indazoles; Inhibitory Concentration 50; Leukemia, Myeloid, Acute; Membrane Proteins; Multicenter Studies as Topic; Niacinamide; Phenylurea Compounds; Piperazines; Protein Kinase Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Sorafenib; Staurosporine; Treatment Outcome

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.

Topics: Alleles; Antineoplastic Agents; Benzenesulfonates; Benzothiazoles; Carbazoles; Cell Death; Cell Line, Tumor; Drug Resistance, Neoplasm; fms-Like Tyrosine Kinase 3; Furans; Humans; Indazoles; Indoles; Leukemia, Myeloid, Acute; Mutation; Niacinamide; Phenylurea Compounds; Phosphorylation; Piperazines; Pyridines; Pyrroles; Sorafenib; Staurosporine; Sunitinib