gilteritinib and quizartinib

FLT3 inhibitors are important drugs in the therapy of FLT3 positive acute myeloid leukemia (AML). Midostaurin was registered in combination with chemotherapy to treat newly diagnosed AML. Gilteritinib and quizartinib demonstrate effectiveness in a randomized trial in relapsed/refractory AML. Several promising FLT3 inhibitors are being evaluated in clinical research.. This review will report the safety of FLT3 inhibitors that are registered for acute myeloid leukemia induction and rescue therapy.. In the near future, it is possible that all the FLT3 positive non M3-AML patients will receive a FLT3 inhibitor. Therapy adherence and strategies to mitigate adverse events must be pursued. The treatment with FLT3 inhibitors may be optimized in terms of toxicities with a rational evaluation of antifungal prophylaxis and concomitant therapy, cardiology monitoring, and keeping in mind rare adverse events. Future studies on unfit patients, special populations, and maintenance settings are warranted, together with post-market studies and real-life experiences. Whenever new FLT3 inhibitors will come to the clinic, we could face a scenario in which profound knowledge of effectiveness, toxicities, and off-target effects will be relevant to choose the best drug for each patient.

Topics: Aniline Compounds; Antineoplastic Agents; Benzothiazoles; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrazines; Randomized Controlled Trials as Topic; Staurosporine

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in approximately one third of patients with acute myeloid leukemia (AML), either by internal tandem duplications (FLT3-ITD), or by a point mutation mainly involving the tyrosine kinase domain (FLT3-TKD). Patients with FLT3-ITD have a high risk of relapse and low cure rates. Several FLT3 tyrosine kinase inhibitors have been developed in the last few years with variable kinase inhibitory properties, pharmacokinetics, and toxicity profiles. FLT3 inhibitors are divided into first generation multi-kinase inhibitors (such as sorafenib, lestaurtinib, midostaurin) and next generation inhibitors (such as quizartinib, crenolanib, gilteritinib) based on their potency and specificity of FLT3 inhibition. These diverse FLT3 inhibitors have been evaluated in myriad clinical trials as monotherapy or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front-line, relapsed or refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. In this practical question-and-answer-based review, the main issues faced by the leukemia specialists on the use of FLT3 inhibitors in AML are addressed.

Topics: Aniline Compounds; Antineoplastic Agents; Benzimidazoles; Benzothiazoles; Carbazoles; DNA Methylation; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Furans; Humans; Leukemia, Myeloid, Acute; Mutation; Neoplasm Recurrence, Local; Phenylurea Compounds; Piperidines; Prognosis; Pyrazines; Randomized Controlled Trials as Topic; Sorafenib; Staurosporine; Treatment Outcome

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene arise in 25-30% of all acute myeloid leukemia (AML) patients. These mutations lead to constitutive activation of the protein product and are divided in two broad types: internal tandem duplication (ITD) of the juxtamembrane domain (25% of cases) and point mutations in the tyrosine kinase domain (TKD). Patients with FLT3 ITD mutations have a high relapse risk and inferior cure rates, whereas the role of FLT3 TKD mutations still remains to be clarified. Additionally, growing research indicates that FLT3 status evolves through a disease continuum (clonal evolution), where AML cases can acquire FLT3 mutations at relapse - not present in the moment of diagnosis. Several FLT3 inhibitors have been tested in patients with FLT3-mutated AML. These drugs exhibit different kinase inhibitory profiles, pharmacokinetics and adverse events. First-generation multi-kinase inhibitors (sorafenib, midostaurin, lestaurtinib) are characterized by a broad-spectrum of drug targets, whereas second-generation inhibitors (quizartinib, crenolanib, gilteritinib) show more potent and specific FLT3 inhibition, and are thereby accompanied by less toxic effects. Notwithstanding, all FLT3 inhibitors face primary and acquired mechanisms of resistance, and therefore the combinations with other drugs (standard chemotherapy, hypomethylating agents, checkpoint inhibitors) and its application in different clinical settings (upfront therapy, maintenance, relapsed or refractory disease) are under study in a myriad of clinical trials. This review focuses on the role of FLT3 mutations in AML, pharmacological features of FLT3 inhibitors, known mechanisms of drug resistance and accumulated evidence for the use of FLT3 inhibitors in different clinical settings.

Topics: Aniline Compounds; Antineoplastic Agents; Benzimidazoles; Benzothiazoles; Carbazoles; Drug Resistance, Multiple; Drug Resistance, Neoplasm; fms-Like Tyrosine Kinase 3; Forecasting; Furans; Hematopoietic Stem Cell Transplantation; Humans; Imidazoles; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Mutation; Phenylurea Compounds; Piperidines; Point Mutation; Protein Kinase Inhibitors; Pyrazines; Pyridazines; Recurrence; Sorafenib; Staurosporine

The natural history of FLT3-mutated AML is changing after the approval of midostaurin for frontline therapy and gilteritinib for relapsed or refractory patients. Recently reported, positive randomized trials of the drugs gilteritinib, quizartinib, and sorafenib predict even wider use of FLT3 inhibitors going forward. FLT3 inhibitors now emerge as an important, if not indispensable, part of therapy for a large subset of high-risk patients.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Benzothiazoles; Clinical Trials as Topic; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrazines; Sorafenib; Staurosporine

The past 15 years have seen major leaps in our understanding of the molecular genetic mutations that act as drivers of acute myeloid leukemia (AML). Clinical trials of agents against specific mutant proteins, such as FLT3-internal tandem duplications (ITDs) and isocitrate dehydrogenase mutations (IDHs) are ongoing. This review discusses agents in clinical trials that target specific gene mutations and/or epigenetic targets.

Topics: Aniline Compounds; Antineoplastic Agents; Benzimidazoles; Benzothiazoles; Clinical Trials as Topic; Epigenesis, Genetic; fms-Like Tyrosine Kinase 3; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Mutation; Phenylurea Compounds; Piperidines; Proto-Oncogene Proteins c-bcl-2; Pyrazines

Topics: Aniline Compounds; Antineoplastic Agents; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Mutation; Protein Kinase Inhibitors

AXL has been shown to play a pivotal role in the selective response of. Herein, we compared the effect of dual FLT3/AXL-TKI gilteritinib with quizartinib through. We observed that gilteritinib maintained a stronger proapoptotic effect in hypoxia and coculture with bone marrow stromal cells compared with quizartinib, linked to a dose-dependent inhibition of AXL phosphorylation.. Overall, these findings suggest that gilteritinib as a single agent, compared with quizartinib, is more likely to reach leukemic cells in their protective microenvironment, particularly AML clones highly dependent on

Topics: Aniline Compounds; Axl Receptor Tyrosine Kinase; Benzothiazoles; Cell Line, Tumor; Drug Resistance, Neoplasm; fms-Like Tyrosine Kinase 3; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Proto-Oncogene Proteins; Pyrazines; Receptor Protein-Tyrosine Kinases

Recently, several targeted agents have been developed for specific subsets of patients with acute myeloid leukaemia (AML), including midostaurin, the first FDA-approved FLT3 inhibitor for newly diagnosed patients with FLT3 mutations. However, in the initial Phase I/II clinical trials, some patients without FLT3 mutations had transient responses to midostaurin, suggesting that this multi-targeted kinase inhibitor might benefit AML patients more broadly. Here, we demonstrate submicromolar efficacy of midostaurin in vitro and efficacy in vivo against wild-type (wt) FLT3-expressing AML cell lines and primary cells, and we compare its effectiveness with that of other FLT3 inhibitors currently in clinical trials. Midostaurin was found to synergize with standard chemotherapeutic drugs and some targeted agents against AML cells without mutations in FLT3. The mechanism may involve, in part, the unique kinase profile of midostaurin that includes proteins implicated in AML transformation, such as SYK or KIT, or inhibition of ERK pathway or proviability signalling. Our findings support further investigation of midostaurin as a chemosensitizing agent in AML patients without FLT3 mutations.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Benzimidazoles; Benzothiazoles; Cell Line, Tumor; Cell Proliferation; Drug Synergism; fms-Like Tyrosine Kinase 3; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Mice; Mutation; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazines; Sorafenib; Staurosporine; Syk Kinase

Mutations in two type-3 receptor tyrosine kinases (RTKs), KIT and FLT3, are common in both acute myeloid leukaemia (AML) and systemic mastocytosis (SM) and lead to hyperactivation of key signalling pathways. A large number of tyrosine kinase inhibitors (TKIs) have been developed that target either FLT3 or KIT and significant clinical benefit has been demonstrated in multiple clinical trials. Given the structural similarity of FLT3 and KIT, it is not surprising that some of these TKIs inhibit both of these receptors. This is typified by midostaurin, which has been approved by the US Food and Drug Administration for mutant FLT3-positive AML and for KIT D816V-positive SM. Here, we compare the in vitro activities of the clinically available FLT3 and KIT inhibitors with those of midostaurin against a panel of cells expressing a variety of oncogenic FLT3 or KIT receptors, including wild-type (wt) FLT3, FLT3-internal tandem duplication (ITD), FLT3 D835Y, the resistance mutant FLT3-ITD+ F691L, KIT D816V, and KIT N822K. We also examined the effects of these inhibitors in vitro and in vivo on cells expressing mutations in c-CBL found in AML that result in hypersensitization of RTKs, such as FLT3 and KIT. The results show a wide spectrum of activity of these various mutations to these clinically available TKIs.

Topics: Aniline Compounds; Antineoplastic Agents; Benzimidazoles; Benzothiazoles; Cell Line, Tumor; Drug Screening Assays, Antitumor; fms-Like Tyrosine Kinase 3; Hematologic Neoplasms; Humans; Mutant Proteins; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-cbl; Proto-Oncogene Proteins c-kit; Pyrazines; Pyrazoles; Pyrroles; Sorafenib; Staurosporine; Triazines