RESUMEN
Decitabine is a DNA methyltransferase inhibitor used in the treatment of acute myeloid leukemia and myelodysplastic syndrome. The notion that ongoing trials are presently exploring the combined use of decitabine, with or without the cytidine deaminase inhibitor cedazuridine, and other antileukemic drugs necessitates a comprehensive understanding of pharmacokinetic properties and an evaluation of drug-drug interaction liabilities. We report here the development and validation of a sensitive UHPLC-MS/MS method for quantifying decitabine in mouse plasma, which should be useful for such studies. The method involved a one-step protein precipitation extraction, and chromatographic separation on an XBridge HILIC column using gradient elution. The method was found to be robust, accurate, precise, and sufficiently sensitive (lower limit of quantitation, 0.4 ng/mL) to determine decitabine concentrations in microvolumes of plasma from mice receiving the agent orally or intravenously in the presence or absence of cedazuridine.
Asunto(s)
Decitabina , Espectrometría de Masas en Tándem , Animales , Espectrometría de Masas en Tándem/métodos , Decitabina/farmacocinética , Decitabina/sangre , Decitabina/administración & dosificación , Ratones , Cromatografía Líquida de Alta Presión/métodos , Reproducibilidad de los Resultados , Azacitidina/farmacocinética , Azacitidina/sangre , Azacitidina/análogos & derivados , Azacitidina/administración & dosificación , Azacitidina/química , Modelos Lineales , Uridina/farmacocinética , Uridina/sangre , Uridina/análogos & derivados , Sensibilidad y Especificidad , Límite de DetecciónRESUMEN
OBJECTIVE: To review the pharmacokinetic (PK)-pharmacodynamic (PD) profiles, disease setting, dosing, and safety of oral and parenteral hypomethylating agents (HMAs) for the treatment of myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML), and to provide a multidisciplinary perspective on treatment selection and educational needs relating to HMA use. DATA SOURCES: Clinical and real-world data for parenteral decitabine and azacitidine and two oral HMAs: decitabine-cedazuridine (DEC-C) for MDS and azacitidine (CC-486) for AML maintenance therapy. DATA SUMMARY: Differences in the PK-PD profiles of oral and parenteral HMA formulations have implications for their potential toxicities and planned use. Oral DEC-C (decitabine 35â mg and cedazuridine 100â mg) has demonstrated equivalent systemic area under the concentration-time curve (AUC) exposure to a 5-day regimen of intravenous (IV) decitabine 20â mg/m2 and showed no significant difference in PD. The AUC equivalence of oral DEC-C and IV decitabine means that these regimens can be treated interchangeably (but must not be substituted within a cycle). Oral azacitidine has a distinct PK-PD profile versus IV or subcutaneous azacitidine, and the formulations are not bioequivalent or interchangeable owing to differences in plasma time-course kinetics and exposures. Clinical trials are ongoing to evaluate oral HMA combinations and novel oral HMAs, such as NTX-301 and ASTX030. CONCLUSIONS: Treatment with oral HMAs has the potential to improve quality of life, treatment adherence, and disease outcomes versus parenteral HMAs. Better education of multidisciplinary teams on the factors affecting HMA treatment selection may help to improve treatment outcomes in patients with MDS or AML.
Asunto(s)
Azacitidina , Decitabina , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Administración Oral , Azacitidina/farmacocinética , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Azacitidina/uso terapéutico , Decitabina/farmacocinética , Decitabina/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Uridina/farmacocinética , Uridina/análogos & derivados , Uridina/administración & dosificación , Uridina/uso terapéutico , Uridina/farmacologíaRESUMEN
Oral hypomethylating agents (HMAs) represent a substantial potential boon for patients with myelodysplastic syndrome (MDS) who have previously required between 5 and 7 visits per month to an infusion clinic to receive therapy. For patients who respond to treatment, ongoing monthly maintenance visits represent a considerable burden to quality of life, and for those who are early in therapy, these sequential visits may tax transportation and financial resources that would be optimally distributed over the treatment cycle to facilitate transfusion support. The availability of oral HMAs may support the optimal application of these agents by contributing to adherence and lessening the burden of therapy, potentially encouraging patients to stay on longer-term treatment. Distinct pharmacokinetic profiles for the recently approved oral HMAs (oral azacitidine and decitabine-cedazuridine) result in differential toxicity profiles and have prompted their clinical trial development in lower- and higher-risk MDS, respectively.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Decitabina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Uridina/análogos & derivados , Administración Oral , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Azacitidina/administración & dosificación , Azacitidina/farmacocinética , Decitabina/administración & dosificación , Decitabina/farmacocinética , Femenino , Humanos , Calidad de Vida , Uridina/administración & dosificación , Uridina/farmacocinética , Uridina/uso terapéuticoRESUMEN
Two oral hypomethylating agents, oral azacitidine (CC-486) and decitabine/cedazuridine (ASTX727), have recently entered the clinical domain. CC-486 has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia in complete remission, whereas the combination of decitabine with cedazuridine, a cytidine deaminase inhibitor, is indicated for the treatment of adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia with intermediate-1, or higher, International Prognostic Scoring System risk. This article briefly summarizes the clinical development of both drugs, the pivotal studies that led to their approval and some of the issues faced in extending the use of these drugs to other indications.
Lay abstract One of the key challenges in treating acute myeloid leukemia is to prevent relapse after remission has been achieved. This means that developing an effective maintenance treatment is very important. Maintenance treatment is given for a prolonged period and so it needs to be easy to give and well tolerated. Oral azacitidine is an example of this type of treatment and is the first drug that has been shown to improve survival as maintenance therapy for acute myeloid leukemia patients. This article describes the key studies that led to the approval of this important therapy.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Decitabina/administración & dosificación , Aprobación de Drogas , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Uridina/análogos & derivados , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/farmacocinética , Disponibilidad Biológica , Ensayos Clínicos Fase III como Asunto , Metilación de ADN/efectos de los fármacos , Decitabina/efectos adversos , Decitabina/farmacocinética , Combinación de Medicamentos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión/métodos , Uridina/administración & dosificación , Uridina/efectos adversos , Uridina/farmacocinéticaRESUMEN
Polo-like kinase 1 (PLK1) regulates mitotic checkpoints and cell division. PLK1 overexpression is reported in numerous cancers, including acute myeloid leukemia (AML), and is associated with poor prognosis. Volasertib is a selective, potent cell-cycle kinase inhibitor that targets PLK to induce mitotic arrest and apoptosis. This phase 1 trial investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of volasertib in combination with decitabine in AML patients aged ≥ 65 years. Thirteen patients were treated with escalating volasertib doses (3 + 3 design; 300 mg, 350 mg, and 400 mg) plus standard-dose decitabine. Dose-limiting toxicity was reported in one patient in cycle 1; the MTD of volasertib in combination with decitabine was determined as 400 mg. The most common treatment-emergent adverse events were febrile neutropenia, pneumonia, and decreased appetite. Objective response rate was 23%. The combination was well tolerated, and the adverse event profile was in line with previous findings.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Ciclo Celular , Decitabina/administración & dosificación , Expresión Génica , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Pteridinas/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/fisiología , Decitabina/efectos adversos , Decitabina/farmacocinética , Relación Dosis-Respuesta a Droga , Neutropenia Febril/inducido químicamente , Trastornos de Alimentación y de la Ingestión de Alimentos/inducido químicamente , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Terapia Molecular Dirigida , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/fisiología , Pteridinas/efectos adversos , Pteridinas/farmacocinética , Resultado del Tratamiento , Quinasa Tipo Polo 1RESUMEN
Talacotuzumab, a humanized anti-CD123 monoclonal antibody, was evaluated in combination with decitabine in elderly patients with acute myeloid leukemia (AML) not eligible for intensive chemotherapy. A multicenter, phase 2/3 study was initiated to determine the recommended phase 2 dose (RP2D) of talacotuzumab (Part A) followed by an open-label, randomized comparison of talacotuzumab in combination with decitabine versus decitabine alone to assess achievement of complete response (CR) and overall survival (OS) in Part B. Ten patients were enrolled in Part A and 316 in Part B; the results presented here are based on a database lock on January 25, 2018. Part A confirmed the RP2D of talacotuzumab to be 9 mg/kg. In Part B, CR was achieved in 12/80 (15%) patients receiving combination therapy and in 9/82 (11%) patients receiving decitabine alone (odds ratio: 1.4; 95% confidence interval [CI]: 0.6-3.6; p = 0.44). Median (95% CI) OS was 5.36 (4.27-7.95) months for combination therapy versus 7.26 (6.47-8.64) months for decitabine alone (hazard ratio: 1.04; 95% CI: 0.79-1.37; p = 0.78). Combination therapy showed no improvement in efficacy versus decitabine alone, resulting in the Independent Data Monitoring Committee's recommendation of early termination of enrollment and discontinuation of talacotuzumab treatment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Decitabina/uso terapéutico , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Decitabina/administración & dosificación , Decitabina/efectos adversos , Decitabina/farmacocinética , Monitoreo de Drogas , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Proyectos de Investigación , Resultado del TratamientoRESUMEN
This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Cápsulas , Estudios Cruzados , Metilación de ADN/efectos de los fármacos , ADN-Citosina Metilasas/antagonistas & inhibidores , Decitabina/administración & dosificación , Decitabina/efectos adversos , Decitabina/farmacocinética , Decitabina/farmacología , Progresión de la Enfermedad , Combinación de Medicamentos , Monitoreo de Drogas , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Estimación de Kaplan-Meier , Análisis de los Mínimos Cuadrados , Leucemia Mieloide Aguda/prevención & control , Elementos de Nucleótido Esparcido Largo/efectos de los fármacos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Comprimidos , Uridina/administración & dosificación , Uridina/efectos adversos , Uridina/análogos & derivados , Uridina/farmacocinética , Uridina/farmacologíaRESUMEN
Decitabine (DAC), a DNA methylation inhibitor, is transported into cancer cells mainly via equilibrative nucleoside transporter 1 (ENT1) and subsequently phosphorylated by deoxycytidine kinase (dCK). We previously reported that apparent DAC uptake into cells may be described using a simple compartment model with clearance for facilitated diffusion (PS) and subsequent phosphorylation (CLmet). In the present study, time course of apparent intracellular [3H]-DAC uptake was analyzed numerically, and PS and CLmet values were calculated using the compartment model in human colon cancer HCT116 cells. PS at 0.1 µM [3H]-DAC was markedly decreased in the presence of 100 µM irinotecan or etoposide, while CLmet was markedly decreased in the presence of 100 µM cytarabine or gemcitabine. CLmet at 0.1-10 µM [3H]-DAC varied in a concentration-dependent manner and was described by Michaelis-Menten parameters Km,met and Vmax,met. In conclusion, DAC uptake mainly via ENT1 may be described by a bidirectional first-order kinetic parameter, while phosphorylation by dCK may be described by Michaelis-Menten parameters.
Asunto(s)
Antimetabolitos Antineoplásicos/metabolismo , Antimetabolitos Antineoplásicos/farmacocinética , Decitabina/metabolismo , Decitabina/farmacocinética , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Dinámicas no Lineales , Células HCT116 , Humanos , Cinética , Fosforilación , Tritio/químicaRESUMEN
BACKGROUND: Acute myeloid leukemia mainly affects adult patients. Complete remission for patients younger than 60 years, who are candidates for standard induction therapy, is achieved in 60%-80% of cases. However, the prognosis is still poor for older patients, who are unfit for intensive chemotherapy, and only a few therapies are available. Hypomethylating agents, such as decitabine, are approved for such patients. The current dosing regimen consists of one administration per day, for 5 days, each 4 weeks. METHODS: Here, we present the synthesis of a decitabine prodrug, combined with its encapsulation into a lipid-based nanocapsule formulation. Decitabine (C12)2 was synthetized, then loaded into nanocapsules. Its stability in phosphate buffer ans human plasma was checked. Its activity was evaluated by Cell proliferation assays and cell-cycle analysis on human erythroleukemia cells. Then its pharmacokinetics was determined on a rat model. RESULTS: Decitabine (C12)2 was obtained with a yield of 50%. Drug loading into nanocarriers of 27.45±0.05 nm was 5.8±0.5 mg/mL. The stability of decitabine was improved and its activity on leukemia cells was not altered. Finally, pharmacokinetics studies showed a prolonged mean residence time of the drug. CONCLUSION: Decitabine (C12)2 as a prodrug showed high encapsulation efficiency, a good stability in plasma with no impact on its activity on leukemia cells and improved pharmacokinetics.
Asunto(s)
Decitabina/administración & dosificación , Decitabina/química , Leucemia Eritroblástica Aguda/tratamiento farmacológico , Lípidos/química , Nanocápsulas/administración & dosificación , Plasma/metabolismo , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/química , Antimetabolitos Antineoplásicos/farmacocinética , Ciclo Celular , Proliferación Celular , Decitabina/farmacocinética , Estabilidad de Medicamentos , Humanos , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patología , Masculino , Ratas , Ratas Wistar , Distribución Tisular , Células Tumorales CultivadasAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Citarabina/administración & dosificación , Citarabina/efectos adversos , Citarabina/farmacocinética , Decitabina/administración & dosificación , Decitabina/efectos adversos , Decitabina/farmacocinética , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/patología , Masculino , Recurrencia Local de Neoplasia , Resultado del TratamientoRESUMEN
The plasticity of cancer epigenetics makes them plausible candidates for therapeutic intervention. We took advantage of elevated expression of lysophosphatidic acid receptor 1 (LPAR1) in triple negative breast cancer (TNBC) tissues to target decitabine (DAC) and panobinostat (PAN) to breast cancer cells. DAC and PAN were shown to reverse abnormal methylation of DNA and altered chromatin structure, respectively, leading to increased expression of tumor suppressor genes and decreased expression of oncogenes. Although DAC and PAN have therapeutic benefits, they are limited by chemical instability and systemic toxicity. Herein, we present LPAR1-targeted, lipid nanoemulsions (LNEs) encapsulating both DAC and PAN. Our results demonstrated that the cell uptake and in vivo biodistribution of LNEs was dependent on LPAR1 expression in TNBCs. DAC/PAN-LNEs were effective in inhibiting the growth of mesenchymal breast cancer cells by restoring CDH1/E-cadherin and suppressing forkhead box M1 (FOXM1) expression. Epithelial breast cancer cells that inherently express low FOXM1 and high CDH1 were unaffected by DAC/PAN-LNEs. Overall, we successfully designed LPAR1-targeted LNEs that selectively act on CDH1(low)/FOXM1(high) TNBC cell lines.
Asunto(s)
Antígenos CD/metabolismo , Antimetabolitos Antineoplásicos/farmacocinética , Cadherinas/metabolismo , Decitabina/farmacocinética , Proteína Forkhead Box M1/metabolismo , Lípidos/química , Nanocápsulas/química , Panobinostat/farmacocinética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antimetabolitos Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Decitabina/uso terapéutico , Diseño de Fármacos , Liberación de Fármacos , Estabilidad de Medicamentos , Femenino , Xenoinjertos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Panobinostat/uso terapéutico , Receptores del Ácido Lisofosfatídico/metabolismo , Transducción de Señal/efectos de los fármacos , Distribución Tisular , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Guadecitabine (SGI-110), a dinucleotide of ßdecitabine and deoxyguanosine, is currently being evaluated in phase II/III clinical trials for the treatment of hematological malignancies and solid tumors. This article describes the development and validation of bioanalytical assays to quantify guadecitabine and its active metabolite ßdecitabine in human plasma, whole blood and urine using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Since ßdecitabine is rapidly metabolized further by cytidine deaminase, plasma and whole blood samples were kept on ice-water after collection and stabilized with tetrahydrouridine (THU) directly upon sample collection. Sample preparation consisted of protein precipitation for plasma and whole blood and dilution for urine samples and was further optimized for each matrix and analyte separately. Final extracts were injected onto a C6-phenyl column for guadecitabine analysis, or a Nova-Pak Silica column for ßdecitabine analysis. Gradient elution was applied for both analytes using the same eluents for each assay and detection was performed on triple quadrupole mass spectrometers operating in the positive ion mode (Sciex QTRAP 5500 and QTRAP 6500). The assay for guadecitabine was linear over a range of 1.0-200â¯ng/mL (plasma, whole blood) and 10-2000â¯ng/mL (urine). For ßdecitabine the assay was linear over a range of 0.5-100â¯ng/mL (plasma, whole blood) and 5-1000â¯ng/mL (urine). The presented methods were successfully validated according to the latest FDA and EMA guidelines for bioanalytical method validation and applied in a guadecitabine clinical mass balance trial in patients with advanced cancer.
Asunto(s)
Antineoplásicos/sangre , Azacitidina/análogos & derivados , Cromatografía Liquida/métodos , Decitabina/sangre , Espectrometría de Masas en Tándem/métodos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/orina , Azacitidina/sangre , Azacitidina/química , Azacitidina/farmacocinética , Azacitidina/orina , Decitabina/química , Decitabina/farmacocinética , Decitabina/orina , Humanos , Modelos Lineales , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Dacogen, the formulated product of the pharmaceutically active agent decitabine (5 aza-2'-deoxycytidine), is approved for treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). The current analysis was performed to characterize the pharmacokinetics of decitabine in pediatric patients with AML and evaluate their consistency with the PK in adult patients. A population pharmacokinetic model was developed by pooling decitabine concentration-time data from 5 adult (AML and MDS) and 2 pediatric (AML) studies. A total of 840 concentration-time data points obtained from 71 adults and 28 pediatric subjects (1 to 16 years old) were available for analysis. A 2-compartment linear pharmacokinetic (PK) model with allometric scaling using body surface area accounting for body size adequately described the PK of decitabine. After accounting for body size, decitabine pharmacokinetics were not affected by age, sex, race, dosing regimen, renal function (creatinine clearance), bilirubin, or disease type (AML or MDS) and all PK parameters (including clearance, steady-state volume of distribution, maximum concentration, time to reach maximal concentration, and terminal half-life) were comparable between adult and pediatric patients. Simulated concentration-time profiles using the final population PK model suggested that decitabine exposure at steady state was similar in adults and pediatrics for a 20 mg/m2 decitabine dose administered as a 1-hour infusion once daily. The current analysis suggests that decitabine PK is similar in pediatric AML patients and a combined adult AML and MDS population.
Asunto(s)
Decitabina/farmacocinética , Leucemia Mieloide Aguda/metabolismo , Adolescente , Adulto , Niño , Preescolar , Simulación por Computador , Esquema de Medicación , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Modelos BiológicosRESUMEN
Myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to evolve into accelerated and blast-phase disease (MPN-AP/BP), carrying a dismal prognosis. Conventional antileukemia therapy has limited efficacy in this setting. Thus, MPN-AP/BP is an urgent unmet clinical need. Modest responses to hypomethylating agents and single-agent ruxolitinib have been reported. More recently, combination of ruxolitinib and decitabine has demonstrated synergistic in vitro activity in human and murine systems. These observations led us to conduct a phase 1 study to explore the safety of combined decitabine and dose-escalated ruxolitinib in patients with MPN-AP/BP. A total of 21 patients were accrued to this multicenter study. Ruxolitinib was administered at doses of 10, 15, 25, or 50 mg twice daily in combination with decitabine (20 mg/m2 per day for 5 days) in 28-day cycles. The maximum tolerated dose was not reached. The most common reasons for study discontinuation were toxicity/adverse events (37%) and disease progression (21%). Fourteen patients died during study treatment period or follow-up. The median overall survival for patients on study was 7.9 months (95% confidence interval, 4.1-not reached). Among evaluable patients, the overall response rate by protocol-defined criteria (complete remission with incomplete count recovery + partial remission) was 9/17 (53%) and by intention-to-treat analysis was 9/21 (42.9%). The combination of decitabine and ruxolitinib was generally well tolerated by patients with MPN-AP/BP and demonstrates potentially promising clinical activity. A phase 2 trial evaluating the efficacy of this combination regimen is ongoing within the Myeloproliferative Disorder Research Consortium.
Asunto(s)
Antineoplásicos/uso terapéutico , Decitabina/uso terapéutico , Trastornos Mieloproliferativos/tratamiento farmacológico , Pirazoles/uso terapéutico , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Crisis Blástica , Decitabina/efectos adversos , Decitabina/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Semivida , Enfermedades Hematológicas/etiología , Humanos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/patología , Nitrilos , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Pirimidinas , Resultado del TratamientoRESUMEN
Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 µg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.