RESUMEN
BACKGROUND: Tyrosine kinase inhibitors (TKIs) targeting fms-like tyrosine kinase 3 (Flt3) such as quizartinib were specifically designed for acute myeloid leukemia treatment, but also multi-targeting TKIs applied to solid tumor patients inhibit Flt3. Flt3 is expressed in the heart and its activation is cytoprotective in myocardial infarction (MI) in mice. OBJECTIVES: We sought to test whether Flt3-targeting TKI treatment aggravates cardiac injury after MI. METHODS AND RESULTS: Compared to vehicle, quizartinib (10 mg/kg/day, gavage) did not alter cardiac dimensions or function in healthy mice after four weeks of therapy. Pretreated mice were randomly assigned to MI or sham surgery while receiving quizartinib or vehicle for one more week. Quizartinib did not aggravate the decline in ejection fraction, but significantly enhanced ventricular dilatation one week after infarction. In addition, apoptotic cell death was significantly increased in the myocardium of quizartinib-treated compared to vehicle-treated mice. In vitro, quizartinib dose-dependently decreased cell viability in neonatal rat ventricular myocytes and in H9c2 cells, and increased apoptosis as assessed in the latter. Together with H2O2, quizartinib potentiated the phosphorylation of the pro-apoptotic mitogen activated protein kinase p38 and augmented H2O2-induced cell death and apoptosis beyond additive degree. Pretreatment with a p38 inhibitor abolished apoptosis under quizartinib and H2O2. CONCLUSION: Quizartinib potentiates apoptosis and promotes maladaptive remodeling after MI in mice at least in part via a p38-dependent mechanism. These findings are consistent with the multi-hit hypothesis of cardiotoxicity and make cardiac monitoring in patients with ischemic heart disease under Flt3- or multi-targeting TKIs advisable.
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Leucemia Mieloide Aguda , Infarto del Miocardio , Humanos , Ratones , Ratas , Animales , Tirosina Quinasa 3 Similar a fms/genética , Peróxido de Hidrógeno , Apoptosis , Leucemia Mieloide Aguda/metabolismo , Benzotiazoles/farmacología , Compuestos de Fenilurea/farmacología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/genética , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Systemic inflammatory response syndrome (SIRS), at least in part driven by necroptosis, is characterized by life-threatening multiple organ failure. Blocking the progression of SIRS and consequent multiple organ dysfunction is challenging. Receptor-interacting serine/threonine protein kinase 1 (RIPK1) is an important cell death and inflammatory mediator, making it a potential treatment target in several diseases. Here, using a drug repurposing approach, we show that inhibiting RIPK1 is also an effective treatment for SIRS. We performed cell-based high-throughput drug screening of an US Food and Drug Administration (FDA)-approved drug library that contains 1953 drugs to identify effective inhibitors of necroptotic cell death by SYTOX green staining. Dose-response validation of the top candidate, quizartinib, was conducted in two cell lines of HT-22 and MEFs. The effect of quizartinib on necroptosis-related proteins was evaluated using western blotting, immunoprecipitation, and an in vitro RIPK1 kinase assay. The in vivo effects of quizartinib were assessed in a murine tumor necrosis factor α (TNFα)-induced SIRS model. High-throughput screening identified quizartinib as the top "hit" in the compound library that rescued cells from necroptosis in vitro. Quizartinib inhibited necroptosis by directly inhibiting RIPK1 kinase activity and blocking downstream complex IIb formation. Furthermore, quizartinib protected mice against TNFα-induced SIRS. Quizartinib, as an FDA-approved drug with proven safety and efficacy, was repurposed for targeted inhibition of RIPK1. This work provides essential preclinical data for transferring quizartinib to the treatment of RIPK1-dependent necroptosis-induced inflammatory diseases, including SIRS.
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Necroptosis , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Factor de Necrosis Tumoral alfa , Animales , Ratones , Serina , TreoninaRESUMEN
BACKGROUND: FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is a common mutation type in acute myeloid leukemia (AML) and is usually associated with poor patient prognosis. With advancements in molecular diagnostics and the development of tyrosine kinase inhibitors (TKI), the overall survival (OS) of AML patients with FLT3-ITD mutations has been prolonged to some extent, but relapse and drug resistance are still substantial challenges. Ningetinib is a novel TKI against various kinases in relation to tumour pathogenesis and is undergoing clinical trials of lung cancer. In this study, we explored the antitumor activity of ningetinib against AML with FLT3 mutations both in vivo and in vitro. METHODS: Cell proliferation assays were performed in AML cell lines and Ba/F3 cells expressing various FLT3 mutations to validate the antileukemic activity of ningetinib in vitro. Immunoblot assays were used to verify the effect of ningetinib on the FLT3 protein and downstream pathways. Molecular docking and CETSA were used to validate the interaction of ningetinib with target proteins. The survival benefit of ningetinib in vivo was assessed in Ba/F3-FLT3-ITD-, MOLM13, Ba/F3-FLT3-ITD-F691L-, MOLM13-FLT3-ITD-F691L-induced leukemia mouse models. We also used patient-derived primary cells to determine the efficacy of ningetinib. RESULTS: Ningetinib inhibited cell proliferation, blocked the cell cycle, induced apoptosis and bound FLT3 to inhibit its downstream signaling pathways, including the STAT5, AKT and ERK pathways, in FLT3-ITD AML cell lines. In the mouse models with FLT3-ITD and FLT3-ITD-F691L mutation, ningetinib showed superior anti-leukemia activity to existing clinical drugs gilteritinib and quizartinib, significantly prolongating the survival of mice. In addition, ningetinib exhibited activity against patient-derived primary cells harboring FLT3-ITD mutations. CONCLUSION: Overall, our study confirmed the therapeutic role of ningetinib in AML with FLT3-ITD mutations, providing a potential new option for clinically resistant patients.
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Proliferación Celular , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda , Inhibidores de Proteínas Quinasas , Tirosina Quinasa 3 Similar a fms , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Humanos , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Proliferación Celular/efectos de los fármacos , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Apoptosis/efectos de los fármacos , Mutación , Transducción de Señal/efectos de los fármacosRESUMEN
Acute myeloid leukemia (AML) is a heterogeneous clonal disease characterized overall by an aggressive clinical course. The underlying genetic abnormalities present in leukemic cells contribute significantly to the AML phenotype. Mutations in FMS-like tyrosine kinase 3 (FLT3) are one of the most common genetic abnormalities identified in AML, and the presence of these mutations strongly influences disease presentation and negatively impacts prognosis. Since mutations in FLT3 were identified in AML, they have been recognized as a valid therapeutic target resulting in decades of research to develop effective small molecule inhibitor treatment that could improve outcome for these patients. Despite the approval of several FLT3 inhibitors over the last couple of years, the treatment of patients with FLT3-mutated AML remains challenging and many questions still need to be addressed. This review will provide an up-to-date overview of our current understanding of FLT3-mutated AML and discuss what the current status is of the available FLT3 inhibitors for the day-to-day management of this aggressive disease.
RESUMEN
FMS-like tyrosine kinase 3 (FLT3) mutation is present in 25% of acute myeloid leukemia (AML) cases. It is associated with poor prognosis due to a high relapse rate and short remission duration. Consequently, various FLT3 inhibitors were developed. Two second-generation FLT3 inhibitors, including gilteritinib and quizartinib, are used for treating relapsed/refractory FLT3-mutated AML. Additionally, in May 2023, quizartinib was approved for newly-diagnosed FLT3-mutated AML, in combination with standard remission induction, consolidation, and maintenance therapies based on a phase 3 trial. Furthermore, high relapse rates were observed even in patients who underwent allogeneic hematopoietic cell transplantation while in their first complete remission, and post-transplant maintenance therapy using oral FLT3 inhibitors has been tried. This review summarizes breakthroughs in treatments of FLT3-mutated AML aiming for a better prognosis.
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Leucemia Mieloide Aguda , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Compuestos de Fenilurea , Mutación , Recurrencia , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
INTRODUCTION: The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with Acute Myeloid Leukemia (AML). Midostaurin, quizartinib, and gilteritinib have been approved in the last years for the treatment of AML, and more Tyrosine Kinase Inhibitors (TKIs) targeting FLT3 are being developed such as crenolanib. AREAS COVERED: In this systematic review, we will analyze the available clinical data on FLT3 inhibitors in development and describe the potential role that these FLT3-TKIs may play in the future management of FLT3-mutated (FLT3mut) AML. EXPERT OPINION: Although several aspects may challenge the use of FLT3 inhibitors in AML (resistance mechanisms, on- and off-target toxicities or drug-drug interactions), these drugs are generally well tolerated, particularly if we compare their safety profile with classical chemotherapy agents or even with newer immunotherapies, thus enabling their use in fit and unfit AML patients, alone or combined. As AML is a polyclonal disease and FLT3 mutations are a late leukemogenic event, combinations of these FLT3 inhibitors with other antileukemic agents (like venetoclax or hypomethylating agents) seem a necessary research pathway.
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Antineoplásicos , Leucemia Mieloide Aguda , Antineoplásicos/efectos adversos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/uso terapéuticoRESUMEN
OPINION STATEMENT: Treatment options in acute myeloid leukemia (AML) have improved significantly over the last decade with better understanding of disease biology and availability of a multitude of targeted therapies. The use of FLT3 inhibitors (FLT3i) in FLT3-mutated (FLT3mut) AML is one such development; however, the clinical decisions that govern their use and dictate the choice of the FLT3i are evolving. Midostaurin and gilteritinib are FDA-approved in specific situations; however, available data from clinical trials also shed light on the utility of sorafenib maintenance post-allogeneic stem cell transplantation (allo-SCT) and quizartinib as part of combination therapy in FLT3mut AML. The knowledge of the patient's concurrent myeloid mutations, type of FLT3 mutation, prior FLT3i use, and eligibility for allo-SCT helps to refine the choice of FLT3i. Data from ongoing studies will further precisely define their use and help in making more informed choices. Despite improvements in FLT3i therapy, the definitive aim is to enable the eligible patient with FLT3mut AML (esp. ITD) to proceed to allo-SCT with regimens containing FLT3i incorporated prior to SCT and as maintenance after SCT.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Trasplante Homólogo , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/uso terapéuticoRESUMEN
In the last two decades, simultaneous global development of novel drugs become more common by conducting multiregional clinical trials. However, regulatory authorities of different regions often make different decisions on the approvals of the same new drugs. We would like to discuss the appropriateness of Japanese regulatory approach through a case study of quizartinib, a novel anti-leukemia drug developed in Japan. The pivotal clinical trial "QuANTUM-R" conducted in 19 countries showed a modest increase in median overall survival with quizartinib than the conventional chemotherapy. However, because several critical defects in this trial were pointed out by the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA), quizartinib has not been approved in the US and Europe to date. On the contrary, the regulatory authority of Japan gave a notice of approval to quizartinib as a "standard of care", and the country becomes the sole country that granted market authorization. In our paper, we provide more detailed discussion about the methodology for scientific evaluation of the new drug.
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Benzotiazoles/uso terapéutico , Ensayos Clínicos como Asunto/organización & administración , Aprobación de Drogas/organización & administración , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , United States Food and Drug Administration/normas , Benzotiazoles/administración & dosificación , Benzotiazoles/efectos adversos , Ensayos Clínicos como Asunto/normas , Humanos , Japón , Estudios Multicéntricos como Asunto , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Estados Unidos , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidoresRESUMEN
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.
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Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Estaurosporina/análogos & derivados , Tirosina Quinasa 3 Similar a fms/genética , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bencimidazoles/farmacología , Benzotiazoles/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Mutación/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Piperidinas/farmacología , Pirazinas/farmacología , Sorafenib/farmacología , Estaurosporina/farmacología , Quinasa Syk/genética , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidoresRESUMEN
Treatment of pediatric acute leukemia might involve combined therapies targeting the FMS-like tyrosine kinase 3 (FLT3) receptor (i.e. quizartinib - AC220) and nucleotide metabolism (cytarabine - AraC). This study addressed the possibility of FLT3 modulating nucleoside salvage processes and, eventually, cytarabine action. Bone marrow samples from 108 pediatric leukemia patients (B-cell precursor acute lymphoblastic leukemia, BCP-ALL: 83; T-ALL: 9; acute myeloid leukemia, AML: 16) were used to determine the mRNA expression levels of FLT3, the cytarabine activating kinase dCK, and the nucleotidases cN-II and SAMHD1. FLT3 mRNA levels positively correlated with dCK, cN-II and SAMHD1 in the studied cohort. FLT3 inhibition using AC220 promoted the expression of cN-II in MV4-11 cells. Indeed, inhibition of cN-II with anthraquinone-2,6-disulfonic acid (AdiS) further potentiated the synergistic action of AC220 and cytarabine, at low concentrations of this nucleoside analog. FLT3 inhibition also down-regulated phosphorylated forms of SAMHD1 in MV4-11 and SEM cells. Thus, inhibition of FLT3 may also target the biochemical machinery associated with nucleoside salvage, which may modulate the ability of nucleoside-derived drugs. In summary, this contribution highlights the need to expand current knowledge on the mechanistic events linking tyrosine-kinase receptors, likely to be druggable in cancer treatment, and nucleotide metabolism, particularly considering tumor cells undergo profound metabolic reprogramming.
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Antimetabolitos Antineoplásicos/uso terapéutico , Citarabina/uso terapéutico , Nucleótidos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Tirosina Quinasa 3 Similar a fms/metabolismo , Adolescente , Línea Celular Tumoral , Niño , Preescolar , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Flt3 is expressed by early myeloid and lymphoid progenitor cells and it regulates the proliferation and differentiation of hematopoietic cells. Flt3 is activated by the Flt3 ligand, the monomeric form of which is a polypeptide of about 200 amino acid residues. Both membrane-associated and soluble Flt3 ligands, which are a product of the same gene, function as noncovalent dimers. FLT3 mutations occur in about one-third of newly diagnosed acute myelogenous leukemia (AML) patients. This disease is a malignancy of hematopoietic progenitor cells with a variable clinical course; the incidence of this disorder is more than twice that of patients with chronic myelogenous leukemias (20,000 vs. 8500 new patients per year, respectively, in the United States). FLT3 internal tandem duplication (ITD) results from the head-to-tail duplication of from one to more than 100 amino acids within the juxtamembrane domain and such duplication occurs in about 20-25 % of patients with acute myelogenous leukemias. FLT3 tyrosine kinase (FLT3 TK) mutations, usually within the activation segment, occur in 5-10 % of these patients. The mainstay for the care of acute myelogenous leukemias include daunorubicin or idarubicin and cytarabine. Older patients who are not candidates for such traditional therapy are usually given 5-azacitidine, decitabine, or clofarabine. The addition of orally effective small molecule Flt3 inhibitors to these therapies may prolong event-free and overall survival, a subject of ongoing clinical studies. Midostaurin is US FDA-approved in combination with standard cytarabine and daunorubicin for first-line induction chemotherapy and in combination with cytarabine for second-line consolidation chemotherapy in the treatment of acute myelogenous leukemias with FLT3-postive mutations. Moreover, gilteritinib is a Flt3 multikinase inhibitor that is also FDA approved for the care of adult patients with relapsed or refractory acute myelogenous leukemias with FLT3 mutations. Quizartinib is a Flt3 multikinase inhibitor that was approved by the Ministry of Health, Labor and Welfare (MHLW) of Japan for the treatment of adult patients with relapsed/refractory Flt3-positive acute myelogenous leukemias. Gilteritinib and quizartinib bind to Flt3 with the inactive DFG-Dout structure and are classified as type II inhibitors. Furthermore, ponatinib is a multikinase inhibitor that is approved as therapy for Philadelphia chromosome-positive acute lymphoblastic and chronic myelogenous leukemias; it is used off label for the treatment of patients with acute myelogenous leukemias. Moreover, sorafenib is FDA-approved for the treatment of hepatocellular, renal cell, and differentiated thyroid cancers and it is used off label as maintenance therapy following allogeneic hematopoietic stem cell transplantation in the treatment of acute myelogenous leukemias. Other drugs that are in clinical trials for the treatment of this disorder include sunitinib, crenolanib, FF10101, and lestaurtinib. Unlike chronic myelogenous leukemias, which result solely from the formation of the BCR-Abl chimeric protein kinase, acute myelogenous leukemias result from multi-factorial causes and are prone to be resistant to both cytotoxic and targeted therapies. Consequently, there is a pressing need for better understanding the etiologies of acute myelogenous leukemias and for the development of more effective therapies.
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Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Administración Oral , Animales , Humanos , Leucemia Mieloide Aguda/metabolismo , Proteínas de la Membrana/metabolismo , Dominios Proteicos , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the monoclonal proliferation of immature progenitors. It is the most common acute leukemia in adults and its incidence increases with age. The standard traditional treatment in fit patients was the '3 + 7' regimen and cytarabine consolidation followed or not with allogeneic stem cell transplantation. Recently, several targeted therapies such as gemtuzumab ozogamicin targeting the CD33+ AML, midostaurin, gilteritinib and crenolanib inhibiting FLT3-positive AML and ivosidenib and enasidenib blocking IDH-mutated AML have been approved. These new drugs led to the change of the landscape of the treatment of AML and transforming this disease to a targetable one. We aimed in this paper to review the implications of each new target, the mechanisms of action of these new drugs and we discuss all the studies leading to the approval of these new drugs in their indications according to each target.
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Leucemia Mieloide Aguda/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/etiología , Resultado del TratamientoRESUMEN
AIMS: Quizartinib is an oral, highly potent and selective next-generation FMS-like tyrosine kinase 3 (FLT3) inhibitor under investigation in patients with FLT3-internal tandem duplication-mutated acute myeloid leukaemia. This drug-drug interaction study assessed the pharmacokinetics (PK) of quizartinib when coadministered with strong or moderate cytochrome P450 3A (CYP3A) inhibitors. METHODS: In this parallel-group study, subjects were randomised to receive: (i) quizartinib + ketoconazole; (ii) quizartinib + fluconazole; or (iii) quizartinib alone. On Days 1-28, subjects received ketoconazole 200 mg or fluconazole 200 mg twice daily, and on Day 8, all subjects received a single 30-mg quizartinib dose. Blood samples were collected for PK analyses, steady-state PK parameters were simulated by superpositioning, and safety was assessed. RESULTS: Ninety-three healthy subjects were randomised; 86 completed the study. When administered with ketoconazole, geometric mean ratios (90% confidence interval) for quizartinib maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity were 117% (105%, 130%) and 194% (169%, 223%), respectively, vs quizartinib alone. Steady-state PK simulation demonstrated ~2-fold increase of both steady-state Cmax and AUC from time 0 to the end of the dosing interval when quizartinib was administered with ketoconazole due to accumulation of quizartinib at steady state. When administered with fluconazole, geometric mean ratios (90% confidence interval) for quizartinib Cmax and AUC from time 0 extrapolated to infinity were 111% (100%, 124%) and 120% (104%, 138%), respectively, vs quizartinib alone. Overall, 5.4% of subjects experienced quizartinib-related adverse events; no serious adverse events or deaths occurred. CONCLUSIONS: These results suggest reducing the dose of quizartinib when coadministered with a strong CYP3A inhibitor, but not with a moderate or weak CYP3A inhibitor. This dose reduction was implemented in phase 3 evaluation of quizartinib.
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Antifúngicos/farmacocinética , Benzotiazoles/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Compuestos de Fenilurea/farmacocinética , Administración Oral , Adolescente , Adulto , Antifúngicos/administración & dosificación , Área Bajo la Curva , Benzotiazoles/administración & dosificación , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Fluconazol/administración & dosificación , Fluconazol/farmacocinética , Voluntarios Sanos , Humanos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/inmunología , Cetoconazol/administración & dosificación , Cetoconazol/farmacocinética , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/administración & dosificación , Adulto Joven , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
FLT3 mutations, characterized by an internal-tandem duplication or missense mutations in the tyrosine kinase domain, are observed in a third of patients with newly diagnosed acute myeloid leukemia. FLT3-ITD mutations are associated with high relapse rates and short overall survival with conventional chemotherapy. Several tyrosine kinase inhibitors targeting FLT3 have been developed in an effort to improve survival and therapeutic options. This review focuses on quizartinib, a second-generation FLT3 inhibitor that has demonstrated efficacy and safety as a single agent and in combination with chemotherapy. We discuss its clinical development as well as its place in the treatment of FLT3-mutated acute myeloid leukemia among the other FLT3 inhibtors currently available and its mechanisms of resistance.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzotiazoles/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa 3 Similar a fms/genética , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzotiazoles/uso terapéutico , Modelos Animales de Enfermedad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos/genética , Duplicación de Gen , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/genética , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Quizartinib, an inhibitor of class III receptor tyrosine kinases (RTKs), is currently in phase 3 development for the treatment of acute myeloid leukemia (AML) bearing internal tandem duplications in the FLT3 gene. Aberrant RTK signaling is implicated in the pathogenesis of a variety of solid tumors, suggesting that inhibiting quizartinib-sensitive RTKs may be beneficial in precision cancer therapy. METHODS: This was a phase 1, open-label, modified Fibonacci dose-escalation study of orally administered quizartinib in patients with advanced solid tumors whose disease progressed despite standard therapy or for which there was no available standard treatment. Patients received quizartinib dihydrochloride (henceforth referred to as quizartinib) once daily throughout a 28-day treatment cycle. The primary endpoint was evaluation of the maximum tolerated dose (MTD) of quizartinib. Secondary endpoints included preliminary evidence of antitumor activity and determination of the pharmacokinetic and pharmacodynamic parameters of quizartinib. RESULTS: Thirteen patients were enrolled. Five patients received a starting dose of quizartinib 135 mg/day; dose-limiting toxicities (DLTs) of grade 3 pancytopenia, asymptomatic grade 3 QTc prolongation, and febrile neutropenia were observed in 1 patient each at this dose. A lower dose of quizartinib (90 mg/day [n = 8]) was administered without DLTs. The most common treatment-related treatment-emergent adverse events (AEs) were fatigue (n = 7, 54%), dysgeusia (n = 5, 38%), neutropenia (n = 3, 23%), and QTc prolongation (n = 3, 23%). Overall, all patients experienced at least 1 AE, and 4 experienced serious AEs (2 patients each in the 135-mg and 90-mg dose groups) including hematologic AEs, infections, and gastrointestinal disorders. Six patients (including 3 patients with gastrointestinal stromal tumors [GIST]) had a best response of stable disease. CONCLUSION: The MTD of quizartinib in patients with advanced solid tumors was 90 mg/day. Overall, the safety and tolerability of quizartinib were manageable, with no unexpected AEs. Quizartinib monotherapy had limited evidence of activity in this small group of patients with advanced solid tumors. TRIAL REGISTRATION: Clinical Trials Registration Number: NCT01049893 ; First Posted: January 15, 2010.
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Antineoplásicos/administración & dosificación , Benzotiazoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Administración Oral , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzotiazoles/efectos adversos , Benzotiazoles/farmacocinética , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Neoplasias/enzimología , Neoplasias/patología , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Transducción de Señal/efectos de los fármacos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Estados Unidos , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Quizartinib is a highly potent inhibitor of the fms-like tyrosine kinase receptor, which is one of the most commonly mutated genes in acute myeloid leukemia. Quizartinib has shown a significant antileukemic clinical influence among relapsed/refractory acute myeloid leukemia patients. This study aimed at developing and validating an analytical method for the measurement of quizartinib in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was validated according to US Food and Drug Administration guidelines, and the results obtained in this work met the set criteria. Liquid-liquid extraction was used and chromatographic separation was achieved on a BEHTM C18 column. Detection of quizartinib was achieved in multiple reaction monitoring mode using positive-ion mode electrospray ionization. The MS/MS ion transitions at mass-to-charge ratios (m/z) of 561.129/114.09 and 441.16/84.03 were monitored for quizartinib and ibrutinib, respectively. The linear detection range was 2-1000 ng/mL (r > 0.998), with intra- and inter-day assay precisions ≤13.07 and 13.17%, respectively. This rapid, simple and sensitive method was validated and successfully applied to the pharmacokinetic study of quizartinib in rat samples.
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Benzotiazoles/sangre , Benzotiazoles/farmacocinética , Cromatografía Liquida/métodos , Compuestos de Fenilurea/sangre , Compuestos de Fenilurea/farmacocinética , Espectrometría de Masas en Tándem/métodos , Animales , Benzotiazoles/química , Modelos Lineales , Masculino , Compuestos de Fenilurea/química , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
1. Quizartinib absorption, metabolism and excretion were characterized in six healthy men receiving a single oral dose of 60 mg (≈100 µCi) of [14C]-quizartinib. Blood, plasma, urine and faeces were collected ≤336 h postdose. 2. Four hours postdose, maximum mean ± SD blood radioactivity concentrations were 296 ± 67.4 ng equivalents/g. A mean ± SD of 1.64 ± 0.482% and 76.3 ± 6.23% of the dose was recovered in urine and faeces, respectively, within 336 h postdose. 3. Radio-detector high-performance liquid chromatography (radio-HPLC) and liquid chromatography-mass spectrometry (LC-MS) showed two main radioactive peaks in plasma, unchanged quizartinib and mono-oxidative metabolite, AC886. Five additional metabolites in plasma were identified by LC-MS, but low levels prevented radio-HPLC detection. Although unchanged quizartinib was the main radioactive component in faeces (mean, 4.0% of administered dose), 15 metabolites representing a mean of 1.0-3.5% of administered dose were found. Quizartinib was predominantly metabolized by phase I biotransformations (oxidation, reduction, dealkylation, deamination, hydrolysis and combinations thereof). 4. This study indicated that quizartinib was rapidly and orally bioavailable, extensively metabolized, with AC886 as the major circulating metabolite, and predominantly eliminated in faeces. Quizartinib was well tolerated in the subjects.
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Benzotiazoles/metabolismo , Inhibidores Enzimáticos/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos de Fenilurea/metabolismo , Benzotiazoles/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Humanos , Masculino , Compuestos de Fenilurea/uso terapéuticoRESUMEN
OPINION STATEMENT: Granulocytic sarcoma (GS) is a rare manifestation of myeloid proliferation, characterized by formation of a mass comprised of immature cells of myeloid origin. Orbital granulocytic sarcoma is rarer still, with only a small fraction of GS patients having orbital involvement. Given the rarity of orbital GS, no unified therapy plan has been identified, as large prospective trials are not feasible, but it is widely accepted that patients with GS ought to be treated with systemic intensive chemotherapy consistent with standard of care regimens for acute myelogenous leukemia (AML) or chronic myelogenous leukemia (CML). Development of a treatment plan for GS in poor responders involves a systemic leukemia plan as novel therapeutics have not been investigated for treatment GS per se, but used more widely for AML. GS is most commonly associated with AML and thus will be addressed in that context in this review. Patients with GS associated with CML should receive CML-specific therapy. When conventional and traditional cytotoxic GS/AML chemotherapy regimens are insufficient, patients often require a combination of novel therapeutics, stem cell transplantation (SCT), and radiation. Much of the recent advancement in AML therapy, as well as in AML translational research, has been in targeting molecular facets of the disease and enabling more specificity with treatment. The aim of treating patients for whom conventional treatment was unsuccessful with personalized therapy has not yet been realized, but many of the novel therapeutics reviewed below have demonstrated promise and are cause for optimism. In our center, when a GS/AML patient is refractory to frontline therapy, we rely on novel chemotherapy therapeutic options as outlined below.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Orbitales/tratamiento farmacológico , Sarcoma Mieloide/tratamiento farmacológico , Biomarcadores de Tumor , Terapia Combinada , Resistencia a Antineoplásicos , Humanos , Terapia Molecular Dirigida , Terapia Neoadyuvante , Neoplasias Orbitales/metabolismo , Neoplasias Orbitales/patología , Recurrencia , Retratamiento , Sarcoma Mieloide/metabolismo , Sarcoma Mieloide/patología , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
A consistent pattern of response has been observed when FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have been used as monotherapy to treat patients with relapsed or refractory FLT3- internal tandem duplication (ITD) acute myeloid leukaemia (AML). Circulating blasts are cleared from the peripheral blood, while bone marrow blasts are either unaffected or are cleared from the marrow at a much slower rate. We used an in vitro model of FLT3-ITD AML blasts co-cultured with normal human bone marrow stromal cells to investigate the basis for this dichotomous response pattern to FLT3 inhibitors. We have found that in blasts on stroma, potent FLT3 inhibition predominantly results in cell cycle arrest rather than apoptosis. The anti-apoptotic effect is mediated through a combination of direct cell-cell contact and soluble factors. The addition of exogenous FLT3 ligand (FL) augments the protection, primarily by shifting the 50% inhibitory concentration for FLT3 inhibition upwards. Cytokine-activated extracellular regulated kinase (ERK), rather than STAT5, appears to be the most important downstream signalling protein mediating the protective effect, and inhibition of MEK significantly abrogates stromal-mediated resistance. These findings explain the phenomenon of peripheral blood versus bone marrow blast responses and suggest that the combination of potent FLT3 inhibition and MEK inhibition is a promising strategy for the treatment of FLT3-ITD AML.
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Células de la Médula Ósea/citología , Comunicación Celular/fisiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Células de la Médula Ósea/enzimología , Técnicas de Cocultivo , Resistencia a Antineoplásicos , Activación Enzimática , Duplicación de Gen , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas de la Membrana/farmacología , Mutación , Fosforilación , Células del Estroma/citología , Células Tumorales Cultivadas , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
FLT3/ITD acute myeloid leukemia is a poor prognosis disease driven by a constitutively activated receptor tyrosine kinase, making it an obvious target for drug development. The development of clinically effective FLT3 inhibitors has been slow, in part because many are multi-targeted inhibitors that are not selective or specific for FLT3. Quizartinib is the first small molecule FLT3 tyrosine kinase inhibitor expressly developed as a FLT3 inhibitor. It is potent, selective and has ideal pharmacokinetics in comparison to other compounds previously tested. This article summarizes its advantages and limitations, and details the insights into the biology of the disease that have been uncovered through the laboratory and clinical use of quizartinib.