RESUMEN
OBJECTIVE: To investigate the efficacy of decitabine combined with preexcitation regimen in the treatment of newly diagnosed acute myeloid leukemia (AML) patients who have not been relieved by the first standard induction chemotherapy and its influence on the relative content of regulatory T lymphocytes (Tregs). METHODS: The clinical data of 102 newly diagnosed AML patients (except acute promyelocytic leukemia) who did not relieve after initial standard induction chemotherapy in Shaanxi Provincial People's Hospital from March 2013 to March 2019 were retrospectively analyzed. Fifty-one patients who accepted pre-excitation regimen were divided into regular group, while another 51 patients treated with decitabine combined with pre-excitation regimen were divided into combination group. The efficacy, incidence of toxic and side effects, Core Scale of Quality of Life (QLQ-C30) score before and after treatment, T lymphocyte subsets (CD3+, CD4+, CD4+/CD8+, Tregs) and 3-year overall survival (OS) rate were compared between the two groups. RESULTS: The total effective rate of combination group was 80.39%, which was significantly higher than 62.75% of regular group (P < 0.05). After treatment, the QLQ-C30 score of combination group was 60.27±6.96, which was significantly lower than 65.73±7.96 of regular group (P < 0.001). There was no statistical difference in the incidence of toxic and side effects between the two groups (P >0.05). After treatment, the levels of CD3+, CD4+, CD4+/CD8+ in the combination group were higher than those in the regular group (all P < 0.001), while Treg was lower (P < 0.001). The 3-year OS rate in the combination group was 72.55%, which was significantly higher than 52.94% in the regular group (P < 0.001). CONCLUSION: Decitabine combined with preexcitation regimen has a significant effect on AML patients who have not been alleviated by standard induction chemotherapy in the first course of treatment. It can reduce anti-tumor immune suppression and improve immune function by regulating the relative content of Tregs, thus prolongs survival time and improves life quality of patients without increasing adverse reactions.
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Decitabina , Quimioterapia de Inducción , Leucemia Mieloide Aguda , Humanos , Decitabina/administración & dosificación , Estudios Retrospectivos , Leucemia Mieloide Aguda/tratamiento farmacológico , Linfocitos T Reguladores , Calidad de Vida , Masculino , Femenino , Resultado del Tratamiento , Tasa de SupervivenciaRESUMEN
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.
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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
BACKGROUND: Outcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. METHODS: We conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021 to 2024. RESULTS: The cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle. CONCLUSIONS: This report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.
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Decitabina , Janus Quinasa 2 , Mielofibrosis Primaria , Humanos , Anciano , Masculino , Femenino , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/mortalidad , Decitabina/uso terapéutico , Decitabina/farmacología , Decitabina/administración & dosificación , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Anciano de 80 o más Años , Persona de Mediana Edad , Estudios Retrospectivos , Uridina/análogos & derivados , Uridina/uso terapéutico , Uridina/farmacología , Uridina/administración & dosificación , Administración Oral , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologíaRESUMEN
ABSTRACT: We hypothesized that fit older patients with acute myeloid leukemia (AML) treated with decitabine (DEC) would report better health-related quality of life (HRQoL) outcomes than those receiving intensive chemotherapy (IC). We conducted a phase 3 randomized trial to compare DEC (10-day schedule) with IC (3+7) in older fit patients with AML. HRQoL was a secondary end point, and it was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in conjunction with its elderly module (EORTC QLQ-ELD14). The following scales were a priori selected for defining the primary end point: physical and role functioning, fatigue, pain, and burden of illness. HRQoL was assessed at baseline, at regeneration from cycle 2, and at 6 and 12 months after randomization, and also before allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 100 days after transplantation. Overall, 606 patients underwent randomization. At 2 months, the risk of HRQoL deterioration was lower in the DEC arm than in the 3+7 arm; 76% (95% confidence interval [CI], 69-82) vs 88% (95% CI, 82-93); odds ratio, 0.43 (95% CI, 0.24-0.76; P = .003). No statistically significant HRQoL differences were observed between treatment arms at the long-term evaluation combining assessments at 6 and 12 months. HRQoL deteriorations between baseline and after allo-HSCT were observed in both arms. However, these deteriorations were not clinically meaningful in patients randomized to DEC, whereas this was the case for those in the 3+7 arm, in 4 of 5 primary HRQoL scales. Our HRQoL findings suggest that lower-intensity treatment with DEC may be preferable to current standard IC (3+7) in fit older patients with AML. This trial was registered at www.clinicaltrials.gov as #NCT02172872.
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Antimetabolitos Antineoplásicos , Decitabina , Leucemia Mieloide Aguda , Calidad de Vida , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Masculino , Femenino , Decitabina/uso terapéutico , Decitabina/administración & dosificación , Persona de Mediana Edad , Antimetabolitos Antineoplásicos/uso terapéutico , Anciano de 80 o más Años , Trasplante de Células Madre Hematopoyéticas , Azacitidina/uso terapéutico , Encuestas y Cuestionarios , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.
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Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compuestos Bicíclicos Heterocíclicos con Puentes , Decitabina , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/efectos adversos , Azacitidina/administración & dosificación , Azacitidina/uso terapéutico , Azacitidina/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Decitabina/administración & dosificación , Decitabina/uso terapéutico , Decitabina/efectos adversos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más Años , Adulto , Pacientes AmbulatoriosRESUMEN
BACKGROUND: Decitabine (DAC), a DNA methyltransferase inhibitor, has shown efficacy combined with chemotherapy for relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults, but less is known about its efficacy in children. Accordingly, we conducted a study which involved a priming regimen consisting of DAC with cladribine, cytarabine, and granulocyte-stimulating factor (DAC-CLAG) and compared the efficacy and safety of this regimen with CLAG alone. METHODS: A total of 39 R/R AML children who received the CLAG or DAC-CLAG regimen in Shanghai Children's Hospital were retrospectively enrolled in this non-randomized study. These regimens were studied sequentially over time. Twenty-two patients received CLAG from 2015, while 17 patients were administered epigenetic priming with DAC before CLAG from 2020. Patients were subsequently bridged to stem cell transplantation (SCT) or consolidation chemotherapy. Complete remission (CR) and adverse effects were analyzed by Fisher's exact test, and survival was analyzed by the Kaplan-Meier method. RESULTS: DAC-CLAG conferred a numerically higher CR compared to CLAG (70.59% vs 63.64%; P = 0.740). High CR rates occurred in patients with good cytogenetics (P = 0.029) and prior induction without cladribine (P = 0.099). The 1-year event-free survival (EFS) was 64.71% ± 11.59% and 63.31% ± 10.35% in the DAC-CLAG and CLAG group (P = 0.595), and 1-year overall survival (OS) was 81.45% ± 9.72% and 77.01% ± 9.04%, respectively (P = 0.265). The 1-year OS and EFS after SCT were higher in the DAC-CLAG than in the CLAG cohort (100% vs 92.31% ± 7.39%, P = 0.072; 92.31% ± 7.39% vs 85.71% ± 9.35%, P = 0.158). Univariate analysis revealed that a good prognosis included good cytogenetics (P = 0.002), non-complex karyotype (P = 0.056), CR on reinduction (P < 0.0001), and bridging to SCT (P = 0.0007). Use of a hypomethylating agent (P = 0.049) and bridging to SCT (P = 0.011) were independent prognostic factors. Grade 3/4 hematologic toxicity and infection were the main adverse events. CONCLUSIONS: DAC prior to the CLAG regimen improved remission in pediatric R/R AML, and was feasible and well tolerated. CLAG ± DAC as a salvage therapy prior to SCT induced improved survival.
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Protocolos de Quimioterapia Combinada Antineoplásica , Cladribina , Citarabina , Decitabina , Epigénesis Genética , Leucemia Mieloide Aguda , Humanos , Decitabina/uso terapéutico , Decitabina/administración & dosificación , Decitabina/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Femenino , Niño , Preescolar , Cladribina/uso terapéutico , Cladribina/administración & dosificación , Estudios Retrospectivos , Citarabina/uso terapéutico , Citarabina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adolescente , Epigénesis Genética/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Lactante , Resultado del Tratamiento , Inducción de Remisión/métodosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Decitabina , Quimioterapia de Inducción , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Quimioterapia de Inducción/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Decitabina/uso terapéutico , Decitabina/administración & dosificación , Uridina/análogos & derivados , Uridina/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéuticoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina , Síndrome de Down , Leucemia Mieloide Aguda , Humanos , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/complicaciones , Citarabina/uso terapéutico , Citarabina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Masculino , Lactante , Decitabina/farmacología , Decitabina/uso terapéutico , Decitabina/administración & dosificación , Azacitidina/uso terapéutico , Azacitidina/administración & dosificación , Preescolar , Antimetabolitos Antineoplásicos/uso terapéuticoRESUMEN
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.
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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/farmacologíaAsunto(s)
Azacitidina , Busulfano , Ciclofosfamida , Decitabina , Idarrubicina , Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/tratamiento farmacológico , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Decitabina/uso terapéutico , Decitabina/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Adulto , Azacitidina/uso terapéutico , Azacitidina/administración & dosificación , Estudios Prospectivos , Idarrubicina/uso terapéutico , Idarrubicina/administración & dosificación , Adulto Joven , Anciano , Acondicionamiento Pretrasplante/métodos , AdolescenteRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with decitabine (Dec)-conditioning regimen in the treatment of myelodysplastic syndrome (MDS) and MDS transformed acute myeloid leukemia (MDS-AML). METHODS: The characteristics and efficacy data of 93 patients with MDS and MDS-AML who received allo-HSCT in our center from April 2013 to November 2021 were retrospectively analyzed. All patients were administered by myeloablative conditioning regimen containing Dec (25 mg/m2 /d×3 d). RESULTS: Among the 93 patients, 63 males and 30 females, were diagnosed as MDSï¼n ï¼77ï¼, MDS-AMLï¼n ï¼16ï¼. The incidence of I/II grade regimen-related toxicity (RRT) was 39.8%, and III grade RRT was only found in 1 patient (1%). Neutrophil engraftment was successful in 91 (97.8%) patients after a median neutrophil engraftment time of 14 (9-27) days; Successful platelet engraftment was achieved in 87 (93.5%) patients, with a median engraftment time of 18 (9-290) days. The incidence of acute graft versus host diseaseï¼aGVHDï¼ and grade III-IV aGVHD was 44.2% and 16.2%, respectively. The incidence of chronic graft versus host diseaseï¼cGVHDï¼ and moderate-to-severe cGVHD was 59.5% and 37.1%, respectively. Of the 93 patients, 54 (58%) developed posttransplant infections, among which lung infection (32.3%) and bloodstream infection (12.9%) were the most common. The median follow-up after transplantation was 45 (0.1-108) months. The 5-year overall survival (OS) rate, disease-free survival (DFS) rate, treatment-related mortality, and cumulative incidence of relapse were 72.7%, 68.4%, 25.1%, and 6.5%, respectively. And the 1-year graft-versus-host disease/relapse-free survival rate was 49.3%. The patients in different group of relative high-risk prognostic scoring or low-risk prognostic scoring, with or without poor-risk mutation(s), with mutations number ≥3 or <3 had similar 5-year OS rate (more than 70%). Multivariate analysis showed that the incidence of grade III-IV aGVHD was the independent risk factor affecting OSï¼P =0.008ï¼and DFS (P =0.019). CONCLUSION: Allo-HSCT with Dec-conditioning regimen is feasible and effective in the treatment of patients with MDS and MDS-AML, especially those in high prognostic risk and with poor-risk mutations.
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Antimetabolitos Antineoplásicos , Decitabina , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Acondicionamiento Pretrasplante , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Femenino , Trasplante Homólogo , Síndromes Mielodisplásicos/terapia , Leucemia Mieloide Aguda/terapia , Decitabina/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Neutrófilos/inmunología , Enfermedad Injerto contra Huésped/epidemiología , Síndrome de Bronquiolitis Obliterante/epidemiología , Resultado del Tratamiento , IncidenciaRESUMEN
BACKGROUND: DNA methylation regulates gene expression by inhibiting transcription factor binding to promoter and regulatory regions. Acute hypoxia during altitude exposure is associated with decreased natural anticoagulants and morbid thrombotic events. Thrombomodulin (TM) is a high affinity thrombin binding receptor protein, vital for vascular homeostasis. The purpose of this study is to determine gene expression regulation via methylation of TM gene in high altitude hypoxia induced deep vein thrombosis (DVT) patients. MATERIALS AND RESULTS: Percent 5-methyl cytosine analysis showed increased methylation in high altitude DVT patients (HAP) as compared to high altitude control (HAC) and seal level control (Control) subjects, while TM protein and mRNA levels were decreased in high altitude DVT patients as compared to other two groups. Bisulfite sequencing analysis indicated increased methylation in TM promoter in high altitude DVT patients compared to high altitude controls. Flow cytometry analysis showed decreased TM expression in hypoxia induced primary human umbilical vein endothelial cells (HUVECs). Treatment with specific DNA methyltransferase (DNMT) inhibitor-decitabine during hypoxia, restored TM expression. in vitro global methylation assay showed increased methylation in hypoxia group. Specific concentration of decitabine in hypoxia decreased global methylation showing a direct correlation between DNMTs and methylation. Selective dose of decitabine restored TM levels in HUVECs. DNMT1 and DNMT3B proteins showed to mediate the overall expression of TM. CONCLUSION: TM emerged as a potential candidate for methylation in high altitude DVT patients, regulated by hypoxia-induced epigenetic mechanism. Hypoxia culminates in methylation of DNA sequences in the promoter region of TM gene and increased the expression of DNMT1 and DNMT3B per se in primary HUVECs. Critical DNA methylation events were found to be compromised in high altitude DVT patients.
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Metilación de ADN , Trombomodulina/genética , Trombosis de la Vena , Altitud , Decitabina/administración & dosificación , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hipoxia/metabolismo , Regiones Promotoras Genéticas , Trombosis de la Vena/genéticaRESUMEN
OBJECTIVE: Although the effect of decitabine on myelodysplastic syndrome (MDS) has been demonstrated, merely a proportion of patients respond to therapy, and no well-recognized predictors have been identified. This study was conducted to investigate the effectiveness of decitabine in real-world clinical practice, and determine the predictive factors of response and overall survival (OS) in MDS patients. METHODS: Clinical and pathological data were collected from 94 patients and analyzed. These patients were reclassified according to the 2016 World Health Organization classification criteria, and restratified by International Prognostic Scoring System prognostic scores. The response evaluation was performed according to the 2006 modified International Working Group response criteria. RESULTS: In this study, 62% of patients responded to decitabine. Among these patients, 15 patients (16%) obtained complete remission (CR), 15 patients (16%) obtained marrow CR with hematologic improvement (HI), 20 patients (21%) obtained marrow CR without HI, and 8 patients (9%) only obtained HI, and no patient botained partial remission. The OS of the responders was significantly longer than that of non-responders (67 months vs. 7 months, P<0.001). The OS in patients with and without platelet doubling was significantly different in both the low/intermediate and high/very high risk groups (P=0.0398 and P=0.0330). The multivariate analysis revealed that platelet doubling after the first decitabine cycle is an independent predictor of response and OS in MDS patients (P=0.002 and P=0.008). CONCLUSION: Decitabine is effective for treating MDS patients in real-world clinical practice. Furthermore, platelet doubling after the first decitabine cycle can be used as a predictor of response and survival in MDS patients.
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Antimetabolitos Antineoplásicos/farmacología , Plaquetas/efectos de los fármacos , Decitabina/farmacología , Síndromes Mielodisplásicos/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Decitabina/administración & dosificación , Femenino , Humanos , Masculino , PronósticoRESUMEN
A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide/tratamiento farmacológico , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Decitabina/administración & dosificación , Decitabina/efectos adversos , Supervivencia sin Enfermedad , Fatiga/inducido químicamente , Neutropenia Febril/inducido químicamente , Femenino , Humanos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Inducción de Remisión , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Resultado del TratamientoRESUMEN
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 terapéuticoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea/mortalidad , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/patología , Mutación , Recurrencia Local de Neoplasia/patología , Azacitidina/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Terapia Combinada , Decitabina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Retrospectivos , Sulfonamidas/administración & dosificación , Tasa de SupervivenciaRESUMEN
Oncofetal protein SALL4 is critical for cancer cell survival. Targeting SALL4, however, is only applicable in a fraction of cancer patients who are positive for this gene. To overcome this limitation, we propose to induce a cancer vulnerability by engineering a partial dependency upon SALL4. Following exogenous expression of SALL4, SALL4-negative cancer cells became partially dependent on SALL4. Treatment of SALL4-negative cells with the FDA-approved hypomethylating agent 5-aza-2'-deoxycytidine (DAC) resulted in transient upregulation of SALL4. DAC pretreatment sensitized SALL4-negative cancer cells to entinostat, which negatively affected SALL4 expression through a microRNA, miRNA-205, both in culture and in vivo. Moreover, SALL4 was essential for the efficiency of sequential treatment of DAC and entinostat. Overall, this proof-of-concept study provides a framework whereby the targeting pathways such as SALL4-centered therapy can be expanded, sensitizing cancer cells to treatment by transient target induction and engineering a dependency. SIGNIFICANCE: These findings provide a therapeutic approach for patients harboring no suitable target by induction of a SALL4-mediated vulnerability.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Metilación de ADN , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Factores de Transcripción/antagonistas & inhibidores , Animales , Apoptosis , Benzamidas/administración & dosificación , Proliferación Celular , Decitabina/administración & dosificación , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias/metabolismo , Neoplasias/patología , Piridinas/administración & dosificación , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Head and neck cancer squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 600,000 new diagnoses annually. Traditionally, HNCC has been related to tobacco and alcohol exposure; however, over the past decade, a growing number of head and neck cancers are attributed to human papillomavirus (HPV) infection. 5-Aza-2'-deoxycytidine (5-AzaD) was demonstrated as an effective chemotherapeutic agent for acute myelogenous leukaemia. Preclinical data revealed that 5-aza inhibits growth and increases cell death of HPV(+) cancer cells. These effects are associated with reduced expression of HPV genes, stabilization of TP53, and activation of TP53-dependent apoptosis. The aim of the present study is to test the effect of 5-AzaD on growth of human squamous cell carcinoma (FaDu), a HPV(-) and p53 mutated cells, in vitro and in vivo. The effect of 5-AzaD on cell viability, cell cycle progression and induction of apoptosis was tested in vitro. The effect of 5-AzaD on tumour growth in vivo was tested using xenograft mice inoculated with FaDu cells. The results indicated that 5-AzaD reduced cell viability and induced apoptosis in FaDu cells in vitro. In vivo studies revealed that 5-AzaD suppresses the growth of tumours in xenograft mice inoculated with FaDu cells through inhibition of proliferation and induction of apoptosis. These findings may emphasis that 5-AzaD is effective in treatment of HPV(-) HNSCC tumours through TP53 independent pathway. Future studies are needed in order to clarify the molecular mechanism of action of 5-AzaD in HPV(-) cancer cells.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Decitabina/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Proteína p53 Supresora de Tumor/genética , Animales , Antimetabolitos Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Decitabina/farmacología , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/genética , Humanos , Masculino , Ratones , Mutación , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Decitabine (DAC), a DNA methyltransferase (DNMT) inhibitor is a novel anti-cancer drug regulating epigenetic mechanisms. Similar to conventional anti-cancer drugs, drug resistance to DAC also has been reported, resulting in tumor recurrence. Our previous study using colorectal cancer HCT116 cells found the decrease in deoxycytidine kinase (dCK) (activation enzyme of DAC) and the increase in cytidine deaminase (inactivation enzyme of DAC) in acquired DAC-resistant HCT116 (HCT116/DAC) cells. The aim of our study was to clarify the involvement of dCK and CDA in DAC resistance. In order to tackle DAC resistance, it was also examined whether other DNMT inhibitors such as azacytidine (AC) and polyphenols are effective in DAC-resistant cancer cells. When dCK siRNA was transfected into HCT116 cells, IC50 value of DAC increased by about 74-fold and reached that of HCT116/DAC cells with attenuated dCK. dCK siRNA to HCT116 cells also abolished DNA demethylation effects of DAC. In contrast, CDA siRNA to HCT116 cells did not influence the efficacy of DAC. In addition, CDA siRNA to HCT116/DAC cells with increased CDA did not restore the compromised effects of DAC. These results suggested that attenuated dCK but not increased CDA mainly contributed to DAC resistance. Regarding dCK in HCT116/DAC cells, a point mutation with amino acid substitution was observed while the product size and expression of mRNA coding region did not change, suggesting that dCK protein was decreased by post-transcriptional regulation. AC and polyphenols showed no cross-resistance in HCT116/DAC cells. AC but not polyphenols exerted DNA demethylation effect. Among polyphenols, curcumin (Cur) showed the most synergistic cytotoxicity in combination with AC while DNA demethylation effect of AC was partly maintained. Taken together, combination of AC and Cur would be a promising alternative to tackle DAC resistance mainly due to attenuated dCK.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Azacitidina/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Curcumina/farmacología , Decitabina/farmacología , Desoxicitidina Quinasa/deficiencia , Antiinflamatorios no Esteroideos/farmacología , Antimetabolitos Antineoplásicos/farmacología , Azacitidina/administración & dosificación , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Curcumina/administración & dosificación , Citidina Desaminasa/metabolismo , Metilación de ADN , Decitabina/administración & dosificación , Resistencia a Antineoplásicos , Sinergismo Farmacológico , HumanosRESUMEN
Active cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment, which promote carcinogenesis and modulate response to therapy. Therefore, targeting these cells or reducing their paracrine pro-carcinogenic effects could be of great therapeutic value. To this end, we sought to investigate the effect of eugenol, a natural phenolic molecule, on active breast CAFs. We have shown that decitabine (5-Aza-2'-deoxycytidine, DAC) and eugenol inhibit the expression of the DNA methyltransferase genes DNMT1 and DNMT3A at both the protein and mRNA levels in breast CAF cells. While the effect of eugenol was persistent, DAC had only a transient inhibitory effect on the mRNA level of both DNMT genes. Furthermore, eugenol and DAC suppressed the invasive/migratory and proliferative potential of CAF cells as well as their paracrine pro-carcinogenic effects both in vitro and in humanized orthotopic tumor xenografts. Interestingly, these inhibitory effects of decitabine and eugenol were mediated through E2F1 downregulation. Indeed, ectopic expression of E2F1 upregulated both genes and attenuated the effects of eugenol. Additionally, we provide clear evidence that eugenol, like DAC, strongly modulates the methylation pattern in active CAF cells, through methylating several oncogenes and demethylating various important tumor suppressor genes, which affected their mRNA expression levels. Importantly, the E2F1 promoter was also hypermethylated and the gene downregulated in response to eugenol. Together, these findings show that the active features of breast CAF cells can be normalized through eugenol-dependent targeting of DNMT1/DNMT3A and the consequent modulation in gene methylation.