RESUMO
Despite the better understanding of the molecular mechanisms contributing to the pathogenesis of acute myeloid leukemia (AML) and improved patient survival in recent years, AML therapy still remains a clinical challenge. For this reason, it is important to search for new therapies that will enable the achievement of remission. Recently, the Food and Drug Administration approved three mutant IDH (mIDH) inhibitors for the treatment of AML. However, the use of mIDH inhibitors in monotherapy usually leads to the development of resistance and the subsequent recurrence of the cancer, despite the initial effectiveness of the therapy. A complete understanding of the mechanisms by which IDH mutations influence the development of leukemia, as well as the processes that enable resistance to mIDH inhibitors, may significantly improve the efficacy of this therapy through the use of an appropriate synergistic approach. The aim of this literature review is to present the role of IDH1/IDH2 mutations in the pathogenesis of AML and the results of clinical trials using mIDH1/IDH2 inhibitors in AML and to discuss the challenges related to the use of mIDH1/IDH2 inhibitors in practice and future prospects related to the potential methods of overcoming resistance to these agents.
Assuntos
Isocitrato Desidrogenase , Leucemia Mieloide Aguda , Mutação , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/antagonistas & inibidores , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Terapia de Alvo Molecular , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
The advent of comprehensive genomic profiling using next-generation sequencing (NGS) has unveiled an abundance of potentially actionable genetic aberrations that have shaped our understanding of the cancer biology landscape. Isocitrate dehydrogenase (IDH) is an enzyme present in the cytosol (IDH1) and mitochondria (IDH2 and IDH3). In the mitochondrion, it catalyzes the irreversible oxidative decarboxylation of isocitrate, yielding the production of α-ketoglutarate and nicotinamide adenine dinucleotide phosphate (NADPH) as well as carbon dioxide (CO2). In the cytosol, IDH catalyzes the decarboxylation of isocitrate to α-ketoglutarate as well as the reverse reductive carboxylation of α-ketoglutarate to isocitrate. These rate-limiting steps in the tricarboxylic acid cycle, as well as the cytoplasmic response to oxidative stress, play key roles in gene regulation, cell differentiation, and tissue homeostasis. Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy.
Assuntos
Isocitrato Desidrogenase , Terapia de Alvo Molecular , Neoplasias , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/metabolismo , Humanos , Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Mutação , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
Mutant isocitrate dehydrogenase (IDH) 2 "IDH2m" acquires a neo-enzymatic activity reducing α-ketoglutarate to an oncometabolite, D-2-hydroxyglutarate (2-HG). Three s-triazine series were designed and synthesised using enasidenib as a lead compound. In vitro anticancer screening via National Cancer Institute "NCI" revealed that analogues 6a, 6c, 6d, 7g, and 7l were most potent, with mean growth inhibition percentage "GI%" = 66.07, 66.00, 53.70, 35.10, and 81.15, respectively, followed by five-dose screening. Compounds 6c, 6e, and 7c were established as the best IDH2R140Q inhibitors compared to enasidenib, reporting IC50 = 101.70, 67.01, 88.93, and 75.51 nM, respectively. More importantly, 6c, 6e, and 7c displayed poor activity against the wild-type IDH2, IC50 = 2928, 2295, and 3128 nM, respectively, which implementing high selectivity and accordingly safety. Furthermore, 6c was screened for cell cycle arrest, apoptosis induction, and western blot analysis. Finally, computational tools were applied to predict physicochemical properties and binding poses in IDH2R140Q allosteric site.
Assuntos
Antineoplásicos , Isocitrato Desidrogenase , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Mutação , Antineoplásicos/farmacologia , Triazinas/farmacologia , Triazinas/químicaRESUMO
PURPOSE OF REVIEW: Treatment of elderly patients with acute myeloid leukemia is a known challenge for hematologists due to patient diversity, heterogeneous disease biology, and a rapidly evolving treatment landscape. Here, we highlight the importance of determining fitness, review the latest therapeutic developments, and discuss clinical scenarios to provide guidance on individualized treatment for older AML patients. RECENT FINDINGS: Several factors, like age, performance status, and comorbidities, play a role in fitness and are associated with outcome. Comorbidity scoring systems and geriatric assessments are tools to help physicians select the most appropriate treatment for each patient. The addition of venetoclax, targeted therapy with IDH1/2 and FLT3 inhibitors, and enhanced formulas of existing drugs like CPX-351 and oral azacitidine have improved responses and outcomes. New drugs and combination therapies have increased the therapeutic options for elderly AML patients but determination of fitness and disease biology is essential to select patient-tailored treatments.
Assuntos
Leucemia Mieloide Aguda , Humanos , Idoso , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Azacitidina/uso terapêuticoRESUMO
Targeting mutations that trigger acute myeloid leukaemia (AML) has emerged as a refined therapeutic approach in recent years. Enasidenib (Idhifa) is the first selective inhibitor of mutated forms of isocitrate dehydrogenase 2 (IDH2) approved against relapsed/refractory AML. In addition to its use as monotherapy, a combination trial of enasidenib with standard intensive induction therapy (daunorubicin + cytarabine) is being evaluated. This study aimed to decipher enasidenib off-target molecular mechanisms involved in anthracycline resistance, such as reduction by carbonyl reducing enzymes (CREs) and drug efflux by ATP-binding cassette (ABC) transporters. We analysed the effect of enasidenib on daunorubicin (Daun) reduction by several recombinant CREs and different human cell lines expressing aldo-keto reductase 1C3 (AKR1C3) exogenously (HCT116) or endogenously (A549 and KG1a). Additionally, A431 cell models overexpressing ABCB1, ABCG2, or ABCC1 were employed to evaluate enasidenib modulation of Daun efflux. Furthermore, the potential synergism of enasidenib over Daun cytotoxicity was quantified amongst all the cell models. Enasidenib selectively inhibited AKR1C3-mediated inactivation of Daun in vitro and in cell lines expressing AKR1C3, as well as its extrusion by ABCB1, ABCG2, and ABCC1 transporters, thus synergizing Daun cytotoxicity to overcome resistance. This work provides in vitro evidence on enasidenib-mediated targeting of the anthracycline resistance actors AKR1C3 and ABC transporters under clinically achievable concentrations. Our findings may encourage its combination with intensive chemotherapy and even suggest that the effectiveness of enasidenib as monotherapy against AML could lie beyond the targeting of mIDH2.
Assuntos
Daunorrubicina , Leucemia Mieloide Aguda , Humanos , Daunorrubicina/farmacologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Isocitrato Desidrogenase/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Antraciclinas , Antibióticos Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Trifosfato de AdenosinaRESUMO
Many conditions present with periorbital edema and erythema, mimicking preseptal cellulitis. We report the unique case of a patient with relapsed monoblastic mutant isocitrate dehydrogenase-2 (IDH2) acute myeloid leukemia (AML) who presented with periorbital edema and erythema, unresponsive to antibiotics. Histopathology from punch biopsy was consistent with leukemia cutis. The patient responded rapidly to the initiation of enasidenib, a novel targeted inhibitor of mutant IDH2 enzymes. Our case highlights the importance of considering leukemia cutis in patients with a history of leukemia presenting with periorbital edema and erythema.
Assuntos
Leucemia Mieloide Aguda , Neoplasias Cutâneas , Celulite (Flegmão)/diagnóstico , Celulite (Flegmão)/tratamento farmacológico , Celulite (Flegmão)/patologia , Edema , Eritema , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
OBJECTIVES: The presence of targeted therapy, Enasidenib, for IDH2-mutated AML underscores the importance of understanding the clonal dynamics of IDH2 mutations, which has not been elucidated. In the largest study of IDH2 clonal dynamics, we detail the IDH2-evolutionary patterns and their clinical significance. METHODS: We analyzed ~6000 patients with NGS results to identify 120 AML patients with IDH2 mutations and longitudinal NGS testing. IDH2 mutation status was recorded at diagnosis, remission, relapse, and persistent disease. RESULTS: One hundred and five patients were IDH2-positive at the initial diagnosis, and 15 acquired the mutation later. Of those 15 patients, 7 patients gained the mutation during persistent disease, 6 during relapse, and 2 at remission. Twenty-one patients (18%) who were IDH2-positive in a prior test remained IDH2-positive in remission. Twenty-four patients with IDH2-positive AML were IDH2-positive at relapse. IDH2-positive at diagnosis had better survival than IDH2 mutation acquired later in disease (P = .024). Patients who were IDH2-negative in remission had significantly improved survival (P = .002). Also, loss-of-IDH2 mutation with persistent disease had better OS (P = .035). CONCLUSIONS: There are 70% that clear IDH2 in disease remission. 12% gain IDH2 mutation later, usually in the setting of refractory/relapsed AML. These patients fared worse. Longitudinal IDH2 testing may be helpful in prognostic stratification.
Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Indução de RemissãoRESUMO
PURPOSE OF REVIEW: Until recently, improvement in terms of survival for patients with acute myeloid leukemia (AML) was achieved mostly in younger patients with dose intensification of conventional chemotherapy and a broadening use of allogeneic hematopoietic cell transplantation (allo-HCT) whereas the results remained dismal and very stable in patients older than 60 years. The current review highlights the recent developments in standard intensive post-remission chemotherapy, evidence for the use of recently approved agents, and discusses the relevance of measurable residual disease (MRD) measurement in treatment adaptation. RECENT FINDINGS: Current approvals of midostaurin, venetoclax, gemtuzumab ozogamicin, VYXEOS, ivosidenib, enasidenib, glasdegib, and CC-486 have changed the structure, aim, and schedule of consolidation therapy, and new, well-tolerated agents are being evaluated as maintenance therapies. Furthermore, MRD assessment has been implemented to guide the duration and type of consolidation and maintenance therapy as well as indicate the optimal timing of allo-HCT. Novel therapies have changed the structure and perspective of post-remission therapy in AML for both young and elderly patients. In addition, MRD assessment could guide the type, duration, and intensity of consolidation and maintenance therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide/terapia , Neoplasia Residual/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Indução de Remissão , Análise de Sobrevida , Transplante HomólogoRESUMO
Several small molecule inhibitors (SMIs) have been recently approved for AML patients. These targeted therapies could be more tolerable than classical antineoplastics, but potential drug-drug interactions (DDI) are relatively frequent. Underestimation or lack of appropriate awareness and management of DDIs with SMIs can jeopardize therapeutic success in AML patients, which often require multiple concomitant medications in the context of prior comorbidities or for the prevention and treatment of infectious and other complications. In this systematic review, we analyze DDIs of glasdegib, venetoclax, midostaurin, quizartinib, gilteritinib, enasidenib, and ivosidenib. CYP3A4 is the main enzyme responsible for SMIs metabolism, and strong CYP3A4 inhibitors, such azoles, could increase drug exposure and toxicity; therefore dose adjustments (venetoclax, quizartinib, and ivosidenib) or alternative therapies or close monitoring (glasdegib, midostaurin, and gilteritinib) are recommended. Besides, coadministration of strong CYP3A4 inducers with SMIs should be avoided due to potential decrease of efficacy. Regarding tolerability, QTc prolongation is frequently observed for most of approved SMIs, and drugs with a potential to prolong the QTc interval and CYP3A4 inhibitors should be avoided and replaced by alternative treatments. In this study, we critically assess the DDIs of SMIs, and we summarize best management options for these new drugs and concomitant medications.
Assuntos
Antineoplásicos/sangue , Inibidores do Citocromo P-450 CYP3A/sangue , Aprovação de Drogas , Interações Medicamentosas/fisiologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Antineoplásicos/efeitos adversos , Benzimidazóis/efeitos adversos , Benzimidazóis/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/metabolismo , Humanos , Síndrome do QT Longo/sangue , Síndrome do QT Longo/induzido quimicamente , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/sangue , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Estaurosporina/efeitos adversos , Estaurosporina/análogos & derivados , Estaurosporina/sangue , Sulfonamidas/efeitos adversos , Sulfonamidas/sangueRESUMO
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.
Assuntos
Leucemia Mieloide Aguda/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/etiologia , Resultado do TratamentoRESUMO
1. The present study investigated inhibitory effects of enasidenib and its metabolite AGI-16903 on (a) recombinant human nucleoside transporters (hNTs) in hNT-producing Xenopus laevis oocytes, and (b) azacitidine uptake in a normal B-lymphoblast peripheral blood cell line (PBC) and acute myeloid leukemia (AML) cell lines. 2. Enasidenib inhibited hENT1, hENT2, hENT3, and hENT4 in oocytes with IC50 values of 7, 63, 27, and 76 µM, respectively, but exhibited little inhibition of hCNT1-3. AGI-16903 exhibited little inhibition of any hNT produced in oocytes. 3. Azacitidine uptake was more than 2-fold higher in AML cells than in PBC. Enasidenib inhibited azacitidine uptake into OCI-AML2, TF-1 and PBC cells in a concentration-dependent manner with IC50 values of 0.27, 1.7, and 1.0 µM in sodium-containing transport medium, respectively. 4. IC50 values shifted approximately 100-fold higher when human plasma was used as the incubation medium (27 µM in OCI-AML2, 162 µM in TF-1, and 129 µM in PBC), likely due to high human plasma protein binding of enasidenib (98.5% bound). 5. Although enasidenib inhibits hENTs and azacitidine uptake in vitro, plasma proteins attenuate this inhibitory effect, likely resulting in no meaningful in vivo effects in humans.
Assuntos
Aminopiridinas , Azacitidina , Isocitrato Desidrogenase/antagonistas & inibidores , Proteínas de Transporte de Nucleosídeos/metabolismo , Triazinas , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Azacitidina/farmacocinética , Azacitidina/farmacologia , Linhagem Celular , Humanos , Proteínas de Transporte de Nucleosídeos/genética , Triazinas/farmacocinética , Triazinas/farmacologia , Xenopus laevisRESUMO
Isocitrate dehydrogenase (IDH) inhibitors comprise a novel class of anticancer drugs, which are approved to treat acute myeloid leukemia patients having mutations on IDH1/2. We report the development and validation of a high-performance liquid chromatography (HPLC) method for the simultaneous quantitation of IDH inhibitors, namely enasidenib (EDB), ivosidenib (IDB) and vorasidenib (VDB), in mouse plasma as per the US Food and Drug Administration regulatory guidelines. The method involves extraction of EDB, IDB and VDB along with internal standard (IS; phenacetin) from mouse plasma (100 µl) using a simple protein precipitation process. The chromatographic analysis was performed on an HPLC system using a gradient mobile phase (comprising 10 mm ammonium acetate and acetonitrile in a flow-gradient) and an X-Terra Phenyl column. The UV detection wave length was set at λmax 265 nm. EDB, IDB, VDB and the IS eluted at 7.36, 8.60, 9.50 and 5.12 min, respectively, with a total run time of 10 min. The calibration curve was linear over a concentration range of 0.20-12.5 µg/ml for EDB and 0.50-12.5 µg/ml for IDB and VDB (r2 = ≥0.998 for all of the analytes). Validation results met the acceptance criteria. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.
Assuntos
Aminopiridinas/sangue , Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Diaminas/sangue , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/sangue , Triazinas/sangue , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Diaminas/química , Diaminas/farmacocinética , Estabilidade de Medicamentos , Glicina/sangue , Glicina/química , Glicina/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Piridinas/química , Piridinas/farmacocinética , Reprodutibilidade dos Testes , Triazinas/química , Triazinas/farmacocinéticaRESUMO
A simple, sensitive and rapid assay method has been developed and validated as per regulatory guidelines for the estimation of enasidenib on mouse dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The method employs liquid extraction of enasidenib from DBS disks of mouse whole blood followed by chromatographic separation using 0.2% formic acid-acetonitrile (25:75, v/v) at a flow rate of 1.0 mL/min on an Atlantis dC18 column with a total run time of 2.0 min. The MS/MS ion transitions monitored were m/z 474.0 â 267.1 for enasidenib and m/z 309.2 â 251.3 for the internal standard (warfarin). The assay was linear in the range of 1.01-3044 ng/mL. The within-run and between-run precisions were in the range of 3.18-9.06 and 4.66-8.69%, respectively. Stability studies showed that enasidenib was stable on DBS cards for 1 month. This novel method has been applied to analyze the DBS samples of enasidenib obtained from a pharmacokinetic study in mice.
Assuntos
Aminopiridinas/sangue , Aminopiridinas/farmacocinética , Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco/métodos , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Triazinas/farmacocinética , Aminopiridinas/química , Animais , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Reprodutibilidade dos Testes , Triazinas/químicaRESUMO
Mutations in IDH2 genes (mIDH2) occur in approximately 12% of patients with acute myeloid leukemia. Enasidenib is an oral, small-molecule inhibitor of mIDH2 proteins. Enasidenib is shown to suppress the oncometabolite, 2-hydroxyglutarate, and promote differentiation of leukemic bone marrow blasts. In a Phase I dose-escalation and expansion study, 40.3% of patients with relapsed/refractory acute myeloid leukemia responded to enasidenib monotherapy, including 19.3% who achieved complete remission and 11% who proceeded to transplant. Median overall survival was 9.3 months. 2-hydroxyglutarate suppression did not predict response and mIDH2 clearance was possible, but not required for response. Patients with ≥6 co-mutations or NRAS co-mutations were less likely to attain a response. Enasidenib was safe and well tolerated with low rates of treatment-related adverse events. [Formula: see text].
Assuntos
Aminopiridinas/administração & dosagem , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Mutantes/genética , Triazinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Células da Medula Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Mutantes/antagonistas & inibidores , Mutação , Recidiva , Triazinas/efeitos adversos , Triazinas/farmacocinéticaRESUMO
The mainstay of therapeutic modalities of acute myeloid leukemia (AML) includes intensive chemotherapies and allogeneic hematopoietic cell transplantation. The gold standard of the induction treatment is a regular dose of cytarabine plus anthracycline, and several courses of consolidation therapy are administered. Allogeneic hematopoietic cell transplantation is employed in patients with intermediate-poor risks. No new drugs have been introduced to the treatment of AML for nearly 30 years. However, in 2017, the US Food and Drug Administration approved four novel drugs for treating AML: FLT3 inhibitor midostaurin, IDH2 inhibitor enasidenib, liposomal cytarabine-daunorubicin CPX-351, and revived antibody-drug conjugate gemtuzumab ozogamicin. In Japan, several new agents are also undergoing clinical trials, including Bcl-2 inhibitor venetoclax, CDK9 inhibitor alvocidib, smoothened (SMO) inhibitor glasdegib, hypomethylating agents guadecitabine and azacitidine, NEDD8 inhibitor pevonedistat, and FLT3 inhibitors quizartinib and gilteritinib. These agents will be incorporated into the conventional 7+3 regimen or combined with hypomethylating agents or low-dose cytarabine to improve the therapeutic outcomes of AML.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Antraciclinas/uso terapêutico , Citarabina/uso terapêutico , Humanos , Japão , Inibidores de Proteínas Quinases/uso terapêutico , Estados Unidos , United States Food and Drug AdministrationRESUMO
For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases. Inhibition of various classes of αKG-dependent dioxygenases results in dramatic epigenetic changes in hematopoietic cells, which has been found to directly impair differentiation. In addition to a global dysregulation of gene expression, other mechanisms have been described through which R2-HG promotes leukemic transformation including the induction of B cell lymphoma 2 dependency and stimulation of the EglN family of prolyl 4-hydroxylases (EglN). Due to the fact that mutations in IDH1 and IDH2 are acquired early during AML clonal evolution as well as because these mutations tend to remain stable during AML progression, the pharmaceutical industry has prompted the development of specific mutant IDH enzyme inhibitors. More recently, the FDA approved the first mutant IDH2 inhibitor, enasidenib (AG-221), for patients with relapsed or refractory IDH2-mutated AML (RR-AML). This has brought a lot of excitement to researchers, clinicians, and patients, especially because the treatment of AML remains challenging and is still associated with a high mortality.
Assuntos
Aminopiridinas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Triazinas/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoAssuntos
Aminopiridinas/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Isocitrato Desidrogenase/antagonistas & inibidores , Cetose/induzido quimicamente , Leucemia Mieloide Aguda/tratamento farmacológico , Triazinas/efeitos adversos , Idoso , Aminopiridinas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Masculino , Triazinas/uso terapêuticoRESUMO
As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.
Assuntos
Dextrometorfano , Interações Medicamentosas , Leucemia Mieloide Aguda , Midazolam , Síndromes Mielodisplásicas , Pioglitazona , Piridinas , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia Mieloide Aguda/tratamento farmacológico , Feminino , Idoso , Síndromes Mielodisplásicas/tratamento farmacológico , Midazolam/farmacocinética , Pioglitazona/farmacocinética , Pioglitazona/farmacologia , Dextrometorfano/farmacocinética , Dextrometorfano/administração & dosagem , Piridinas/farmacocinética , Piridinas/administração & dosagem , Flurbiprofeno/farmacocinética , Flurbiprofeno/administração & dosagem , Flurbiprofeno/análogos & derivados , Triazinas/farmacocinética , Triazinas/uso terapêutico , Triazinas/administração & dosagem , Adulto , Omeprazol/farmacocinética , Omeprazol/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Recidiva , Idoso de 80 Anos ou mais , AminopiridinasRESUMO
BACKGROUND: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. METHODS: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). FINDINGS: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. INTERPRETATION: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. FUNDING: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027).