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1.
Indian J Gastroenterol ; 39(2): 153-160, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32468382

RESUMO

BACKGROUND: The development of anti-drug antibodies (ADA) to tumor necrosis factor (TNF-α) inhibitors is a significant result contributing to the loss of clinical response in inflammatory bowel disease (IBD). AIMS: We performed a systematic review and meta-analysis to assess whether the addition of immunomodulators to TNF-α inhibitors lead to reversal of antibody formation in TNF-α inhibitor-treated IBD patients. METHODS: We conducted a comprehensive search of electronic databases from inception through October 2018 in order to identify specific studies describing clinical response in IBD patients following the addition of immunomodulators (methotrexate or thiopurines) to TNF-α inhibitors. Clinical response was expressed as an improvement of symptoms, with a noted decrease or complete elimination of ADA against TNF-α inhibitors. The meta-analysis was performed using the DerSimonian and Laird random-effect model. RESULTS: Four studies were included in our final meta-analysis, which reported outcomes in 72 patients receiving TNF-α inhibitors. Forty-nine of the seventy-two (68%) patients received either methotrexate (19) or thiopurines (30). The average follow up period was 13.5 months. The overall pooled clinical response was 73.86% (95% confidence interval [CI] = 47.36-94.38, I2 = 60.77%). CONCLUSION: In our meta-analysis, addition of immunomodulators to TNF-α inhibitors was shown to restore the clinical response in 74% of the patients by either decreasing or completely eliminating anti-drug antibody levels. Further long-term multicenter studies are needed to validate these findings.


Assuntos
Anticorpos/sangue , Formação de Anticorpos/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Mercaptopurina/análogos & derivados , Metotrexato/administração & dosagem , Metotrexato/farmacologia , Inibidores do Fator de Necrose Tumoral/imunologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacologia , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Fator de Necrose Tumoral alfa
2.
Proc Natl Acad Sci U S A ; 117(10): 5394-5401, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32094176

RESUMO

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.


Assuntos
Antimetabólitos/administração & dosagem , Antimetabólitos/toxicidade , Mercaptopurina/administração & dosagem , Mercaptopurina/toxicidade , Variantes Farmacogenômicos , Pirofosfatases/genética , Alelos , Substituição de Aminoácidos , Relação Dose-Resposta a Droga , Determinação de Ponto Final , Estabilidade Enzimática , Células HEK293 , Humanos , Mutação de Sentido Incorreto , Medicina de Precisão , Conformação Proteica em alfa-Hélice/genética , Pirofosfatases/química , Risco
3.
Ann Hematol ; 99(4): 809-818, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32078009

RESUMO

Risk-adapted therapy has significantly contributed to improved survival rates in pediatric acute lymphoblastic leukemia (ALL) and reliable detection of chromosomal aberrations is mandatory for risk group stratification. This study evaluated the applicability of panel-based RNA sequencing and array CGH within the diagnostic workflow of the German study group of the international AIEOP-BFM ALL 2017 trial. In a consecutive cohort of 117 children with B cell precursor (BCP) ALL, array analysis identified twelve cases with an IKZF1plus profile of gene deletions and one case of masked hypodiploidy. Genetic markers BCR-ABL1 (n = 1), ETV6-RUNX1 (n = 25), and rearrangements involving KMT2A (n = 3) or TCF3 (n = 3) were assessed by established conventional techniques such as karyotyping, FISH, and RT-PCR. Comparison of these results with RNA sequencing analysis revealed overall consistency in n=115/117 cases, albeit with one undetected AFF1-KMT2A fusion in RNA sequencing and one undetected ETV6-RUNX1 fusion in conventional analyses. The combined application of RNA sequencing, FISH, and CGH+SNP array reliably detected all genetic markers necessary for risk stratification and will be used as the diagnostic standard workflow for BCP-ALL patients enrolled in the AIEOP-BFM ALL 2017 study. Prospectively, consistent collection of genome-wide CGH+SNP array as well as RNA sequencing data will be a valuable source to elucidate new prognostic lesions beyond established markers of pediatric ALL. In this respect, RNA sequencing identified various gene fusions in up to half of the IKZF1plus (n = 6/12) and B-other (n = 19/36) cases but not in cases with hyperdiploid karyotypes (n = 35). Among these fusions, this study reports several previously undescribed in frame PAX5 fusions, including PAX5-MYO1G and PAX5-NCOA6.


Assuntos
Hibridização Genômica Comparativa , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , RNA Mensageiro/análise , RNA Neoplásico/análise , Análise de Sequência de RNA , Cariótipo Anormal , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Genes Neoplásicos , Humanos , Fator de Transcrição Ikaros/genética , Hibridização in Situ Fluorescente , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prednisona/administração & dosagem , Estudos Prospectivos , Fatores de Risco , Transcriptoma , Vincristina/administração & dosagem , Fluxo de Trabalho
4.
Pediatr Hematol Oncol ; 37(3): 245-247, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31984843

RESUMO

Acute lymphoblastic leukemia maintenance chemotherapy includes mercaptopurine, a purine analog with uncommon side effects, that can be life-threatening. We describe a 7-year-old female patient with ALL that presented with altered state of consciousness after maintenance chemotherapy with methotrexate and 6-mercaptopurine, due to severe hypoglycemia with metabolic acidosis. She initiated metabolic corrections with rapid resolution of symptoms. Hypoglycemia secondary to 6-mercaptopurine is a rare and transient side effect. The cause effect relation is difficult to establish, leading to underdiagnosis. Hypoglycemia is preventable without compromising maintenance therapy efficacy.


Assuntos
Acidose , Hipoglicemia , Mercaptopurina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Acidose/sangue , Acidose/induzido quimicamente , Acidose/diagnóstico , Criança , Feminino , Humanos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Hipoglicemia/diagnóstico , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Índice de Gravidade de Doença
5.
Asian Pac J Cancer Prev ; 21(1): 147-155, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31983177

RESUMO

BACKGROUND: Management of unfit AML patients is a therapeutic challenge. Most hematologists tend to avoid aggressive treatment leaving patients with a choice of best supportive care. We hypothesized that metronomic chemotherapy could be an alternative treatment for unfit AML patients. METHODS: A multi-center randomized controlled trial was conducted in seven university-affiliated hospitals in Thailand. Unfit AML patients were recruited and followed up from December 2014 to December 2017. Patients were randomly assigned to receive either metronomic chemotherapy or palliative hydroxyurea. Overall survival rates were compared using Cox's proportional hazard survival analysis. RESULTS: A total of 81 eligible patients were randomly allocated and included for ITT analysis. The OS rate was higher in group receiving metronomic chemotherapy than in group receiving palliative treatment at 6 and 12 months with borderline significance (6 months HR 0.60; 95%CI 0.36, 1.02; p-value 0.060; 12 months: HR 0.66; 95%CI 0.41, 1.08; p-value 0.097). CONCLUSION: Metronomic chemotherapy could prolong survival time of unfit AML patients, especially in the first 12 months after diagnosis without increasing treatment-associated adverse events.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Hidroxiureia/administração & dosagem , Leucemia Mieloide Aguda/patologia , Masculino , Mercaptopurina/administração & dosagem , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Prognóstico , Taxa de Sobrevida
6.
J Pediatr Hematol Oncol ; 42(2): e94-e97, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31895215

RESUMO

6-mercaptopurine (6-MP) is the mainstay in pediatric acute lymphoblastic leukemia (ALL) maintenance treatment. Variants in genes coding for thiopurine S-methyl transferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are known to influence 6-MP metabolism. We determined TPMT and ITPA genotype and enzyme activity and the mean 6-MP doses during maintenance treatment in 40 children treated for ALL according to the Dutch Childhood Oncology Group (DCOG)-ALL11 protocol in the Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands. Patients with genetic variants in TPMT (N=3) had significantly lower TPMT enzyme activity (mean 0.46 vs. 0.72 µmol/mmol hemoglobin/h, P=0.005). Although the difference was not statistically significant, they were treated with lower mean 6-MP doses (28.1 mg/m [SD 25.5 mg/m] vs. 41.3 mg/m [SD 17.2 mg/m], P=0.375). In patients with genetic ITPA variants (N=21), ITPA enzyme activity was significantly lowered (mean 3.67 vs. 6.84 mmol/mmol hemoglobin/h, P<0.0005). The mean 6-MP doses did not differ between patients with and without variants in ITPA (40.0 mg/m [SD 20.3 mg/m] vs. 40.6 mg/m [SD 14.9 mg/m], P=0.663). The TPMT genotype, but not the ITPA genotype, should be considered as part of standard evaluation before starting ALL maintenance treatment.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Mercaptopurina/administração & dosagem , Metiltransferases/genética , Polimorfismo Genético , Medicina de Precisão , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirofosfatases/genética , Biomarcadores Tumorais/genética , Criança , Grupos Étnicos , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Retrospectivos
7.
Support Care Cancer ; 28(5): 2157-2161, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31410599

RESUMO

A 5-year-old patient treated for acute lymphoblastic leukaemia (ALL) developed proven pulmonary invasive fungal disease (IFD) due to Actinomucor elegans. While completing ALL treatment according to AIEOP ALL protocol 2009 for further 15 months, antifungal treatment with liposomal amphotericin B and intermittent additional posaconazole was continued until immune reconstitution 7 months after the end of ALL treatment. Repeated imaging guided treatment decisions. Twenty-six and 19 months after the end of ALL treatment and antifungal treatment, respectively, the patient is still in the first complete remission and shows no signs of active invasive fungal disease (IFD).


Assuntos
Anfotericina B/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Pneumopatias Fúngicas/tratamento farmacológico , Mucormicose/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antifúngicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Asparaginase/administração & dosagem , Pré-Escolar , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Humanos , Pneumopatias Fúngicas/microbiologia , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Mucorales/isolamento & purificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/microbiologia , Prednisona/administração & dosagem , Indução de Remissão , Triazóis/uso terapêutico , Vincristina/administração & dosagem
8.
Biochem Pharmacol ; 172: 113770, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31862449

RESUMO

The antimetabolite 6-mercaptopurine (6-MP) is an important component in the treatment of specific cancer subtypes, however, the development of drug resistance and dose-limiting toxicities can limit its effectiveness. The therapeutic activity of 6-MP requires cellular uptake, enzymatic conversion to thio-GMP and incorporation of thio-GTP into RNA and DNA, as well as inhibition of de novo purine synthesis by methyl-thio-IMP. Mechanisms that prevent 6-MP entry into the cell, prevent 6-MP metabolism or deplete thiopurine intermediates, can all lead to 6-MP resistance. We previously conducted a high-throughput screen for inhibitors of the multidrug transporter MRP4 using 6-MP sensitivity as the readout. In addition to MRP4-specific inhibitors, we identified a compound, CCI52, that sensitized cell lines to 6-MP independent of this transporter. CCI52 and its more stable analogue CCI52-14 also function as effective chemosensitizers in vivo, substantially extending survival in a transgenic mouse cancer model treated with 6-MP. Chemosensitization was associated with an increase in thio-IMP, suggesting that CCI52 functions directly on 6-MP uptake or metabolism. In addition to its chemosensitizing effects, CCI52 and CCI52-14 inhibited the growth of MYCN-amplified high-risk neuroblastoma cell lines and delayed tumor progression in a MYCN-driven, transgenic mouse model of neuroblastoma. These multifunctional inhibitors may be useful for the further development of anticancer agents and as tools to better understand 6-MP metabolism.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacologia , Neuroblastoma/tratamento farmacológico , Tiazóis/farmacologia , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neuroblastoma/patologia , Tiazóis/efeitos adversos , Tiazóis/química
9.
Ann Hematol ; 99(2): 391-393, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31858188
11.
Br J Cancer ; 122(4): 483-490, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31813938

RESUMO

BACKGROUND: Tumour cells with BRCA1/2 gene mutations demonstrate increased sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. 6-mercaptopurine (6MP) was found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AG014699, even after these cells acquired resistance to a PARP inhibitor or cisplatin. METHODS: This phase II single-arm trial investigated the activity of 6MP 55-75 mg/m2 per day, and methotrexate 15-20 mg/m2 per week in advanced breast or platinum-resistant ovarian cancer patients with a BRCA1/2 germline mutation, who had progressed after ≥1 previous line of chemotherapy. The primary outcome was objective response including stable disease (SD) as an assessment of clinical benefit rate (CBR), at 8 weeks, by RECIST v1.1. Secondary outcomes included overall survival (OS) and progression-free survival (PFS). RESULTS: In total, 67 evaluable patients were recruited; 55 ovarian and 11 breast cancer patients. In total, 21 patients had SD (31%), one had a partial response (1.5%); CBR was 33% at 8 weeks. In total, 12/67 patients (18%) had SD at 16 weeks. In total, five ovarian cancer patients had SD for over 200 days. Median OS was 10.3 months (95% CI 6.9-14.5), median PFS 1.9 months (1.7-2.8). CONCLUSIONS: The overall activity of 6MP and methotrexate in these patients was low; however, there was a small group of patients who appeared to derive longer-term clinical benefit. TRIAL REGISTRATION: NCT01432145 http://www.ClinicalTrials.gov.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Intervalo Livre de Progressão , Terapia de Salvação/métodos
12.
Clin Cancer Res ; 26(1): 256-264, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31573954

RESUMO

PURPOSE: Treatment outcomes for childhood acute lymphoblastic leukemia (ALL) have improved steadily, but a significant proportion of patients still experience relapse due to drug resistance, which is partly explained by inherited and/or somatic genetic alternations. Recently, we and others have identified genetic variants in the ARID5B gene associated with susceptibility to ALL and also with relapse. In this study, we sought to characterize the molecular pathway by which ARID5B affects antileukemic drug response in patients with ALL. EXPERIMENTAL DESIGN: We analyzed association of ARID5B expression in primary human ALL blasts with molecular subtypes and treatment outcome. Subsequent mechanistic studies were performed in ALL cell lines by manipulating ARID5B expression isogenically, in which we evaluated drug sensitivity, metabolism, and molecular signaling events. RESULTS: ARID5B expression varied substantially by ALL subtype, with the highest level being observed in hyperdiploid ALL. Lower ARID5B expression at diagnosis was associated with the risk of ALL relapse, and further reduction was noted at ALL relapse. In isogenic ALL cell models in vitro, ARID5B knockdown led to resistance specific to antimetabolite drugs (i.e., 6-mercaptopurine and methotrexate), without significantly affecting sensitivity to other antileukemic agents. ARID5B downregulation significantly inhibited ALL cell proliferation and caused partial cell-cycle arrest. At the molecular level, the cell-cycle checkpoint regulator p21 (encoded by CDKN1A) was most consistently modulated by ARID5B, plausibly as its direct transcription regulation target. CONCLUSIONS: Our data indicate that ARID5B is an important molecular determinant of antimetabolite drug sensitivity in ALL, in part, through p21-mediated effects on cell-cycle progression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Fatores de Transcrição/genética , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Fatores de Transcrição/metabolismo , Resultado do Tratamento , Células Tumorais Cultivadas
13.
Rev. bras. cancerol ; 66(2): 1-9, 20200402.
Artigo em Português | LILACS | ID: biblio-1095547

RESUMO

Introdução: A manipulação de antineoplásicos para ajuste de dose, como partição de comprimidos, é comum no tratamento de leucemias agudas de crianças e adolescentes. Objetivo: Identificar a frequência e descrever a prática da partição domiciliar de comprimidos antineoplásicos utilizados no tratamento oral de crianças e adolescentes com leucemias agudas na fase de manutenção. Método: Trata-se de um estudo transversal descritivo, realizado em um hospital pertencente à rede de saúde pública do Distrito Federal com assistência especializada em pediatria. Foram incluídos no estudo crianças e adolescentes entre 1 e 18 anos, diagnosticados com leucemias agudas e em fase de manutenção do tratamento no período de estudo. Foi aplicado um questionário semiestruturado ao responsável principal pela administração dos medicamentos quimioterápicos via oral, podendo ser o cuidador ou a própria criança/adolescente. Foram coletadas variáveis sociodemográficas dos pacientes e cuidadores e variáveis sobre a prática de partição de medicamentos antineoplásicos no domicílio. Resultados: Todos os 48 entrevistados no período do estudo relataram ter partido comprimidos antineoplásicos ao longo do tratamento de leucemias agudas, sendo estes mercaptopurina (n=45 [93,75%]) e tioguanina (n=3 [6,25%]). Conclusão: A partição de comprimidos antineoplásicos foi uma prática unânime em virtude da necessidade referida de ajuste de dose individual para o tratamento de leucemias agudas de crianças e adolescentes, considerando a indisponibilidade de formulações adequadas. Os resultados reforçam a necessidade de a partição ser uniformizada e realizada de maneira a minimizar os riscos e a garantir a segurança para as crianças e adolescentes e seus cuidadores.


Introduction: Antineoplastic drug manipulation for dose adjustment, such as tablet splitting, is standard in acute leukemia treatment for children and adolescents. Objective: To identify the frequency and describe the practice of household splitting of antineoplastic tablet for oral treatment of children and adolescents with acute leukemias in the maintenance phase. Method: Cross-sectional descriptive study performed in a public health system hospital from Distrito Federal (Brazil) with specialized pediatric assistance. Children and teenagers between 1 and 18 years old, diagnosed with acute leukemia and in treatment maintenance phase during the study period were included. A semi-structured questionnaire was applied to the main responsible for administering oral chemotherapy drugs, which could be the caregiver or the child/adolescent themselves. Sociodemographic variables of patients and caregivers and variables on the practice of splitting antineoplastic drugs at home were collected. Results: All 48 interviewees in the study period reported having split antineoplastic tablets during the treatment for acute leukemias, such as mercaptopurine (n = 45 [93.75%]) and thioguanine (n = 3 [6.25%]). Conclusion: The splitting of antineoplastic tablets was a unanimous practice due to the reported need to adjust the individual dose for acute leukemia treatment in children and adolescents, considering the unavailability of adequate formulations. The results reinforce the need for splitting to be standardized and performed in a way that minimizes risks and ensures safety for patients and their caregivers


Introducción: La manipulación de fármacos antineoplásicos para el ajuste de dosis, como las particiones de comprimidos, es frecuente en el tratamiento de las leucemias agudas en niños y jóvenes. Objetivo: Identificar la frecuencia y describir la práctica de la división domiciliaria de medicamentos antineoplásicos utilizados en el tratamiento oral de niños y adolescentes con leucemias agudas en la fase de mantenimiento. Método: Se trata de un estudio transversal descriptivo realizado en un hospital de la red de salud pública del Distrito Federal (Brasil) con asistencia especializada en pediatría. El estudio incluyó a niños y jóvenes de entre 1 y 18 años de edad diagnosticados con leucemia aguda y en fase de mantenimiento del tratamiento en el período del estudio. Se aplicó un cuestionario semiestructurado a la persona principal responsable de la administración de fármacos quimioterapéuticos por vía oral, que puede ser el cuidador o el propio niño/joven. Fueron colectadas variables sociodemográficas de los pacientes y cuidadores y variables sobre la práctica de la división de los medicamentos antineoplásicos en domicílios. Resultados: Los 48 entrevistados en el período de estudio informaron haber roto las pastillas antineoplásicas durante el tratamiento de la leucemia aguda, siendo éstas mercaptopurina (n=45 [93,75%]) y tioguanina (n=3 [6,25%]). Conclusión: La partición de comprimidos antineoplásicos fue una práctica unánime debido a la necesidad mencionada de ajustar la dosis individual para el tratamiento de las leucemias agudas de niños y adolescentes, considerando la falta de formulaciones apropiadas. Los resultados refuerzan la necesidad de estandarizar y realizar la partición para minimizar los riesgos y garantizar la seguridad de los niños, jóvenes y sus cuidadores.


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Comprimidos/administração & dosagem , Leucemia/tratamento farmacológico , Antineoplásicos/administração & dosagem , Fatores Socioeconômicos , Comprimidos/efeitos adversos , Tioguanina/administração & dosagem , Tioguanina/efeitos adversos , Doença Aguda , Estudos Transversais , Administração Oral , Cuidadores , Conduta do Tratamento Medicamentoso , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Antineoplásicos/efeitos adversos
14.
Sci Rep ; 9(1): 18076, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792398

RESUMO

Maintenance chemotherapy with oral 6-mercaptopurine and methotrexate remains a cornerstone of modern therapy for acute lymphoblastic leukaemia. The dosage and intensity of therapy are based on surrogate markers such as peripheral blood leukocyte and neutrophil counts. Dosage based leukocyte count predictions could provide support for dosage decisions clinicians face trying to find and maintain an appropriate dosage for the individual patient. We present two Bayesian nonlinear state space models for predicting patient leukocyte counts during the maintenance therapy. The models simplify some aspects of previously proposed models but allow for some extra flexibility. Our second model is an extension which accounts for extra variation in the leukocyte count due to a treatment adversity, infections, using C-reactive protein as a surrogate. The predictive performances of our models are compared against a model from the literature using time series cross-validation with patient data. In our experiments, our simplified models appear more robust and deliver competitive results with the model from the literature.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia de Manutenção/métodos , Modelos Biológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Teorema de Bayes , Criança , Pré-Escolar , Conjuntos de Dados como Assunto , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Lactente , Contagem de Leucócitos , Leucócitos/efeitos dos fármacos , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Neutrófilos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Processos Estocásticos
15.
J BUON ; 24(5): 2075-2083, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31786878

RESUMO

PURPOSE: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). METHODS: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). RESULTS: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680, -675, -556, -464, -317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. CONCLUSIONS: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteína Carregadora de Folato Reduzido/genética , Tetra-Hidrofolato Desidrogenase/genética , Timidilato Sintase/genética , Adolescente , Alelos , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Biomarcadores Tumorais/genética , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/imunologia , Criança , Pré-Escolar , Feminino , Ácido Fólico/metabolismo , Variação Genética/genética , Humanos , Imunofenotipagem , Lactente , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
16.
Cells ; 8(10)2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658693

RESUMO

Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease for a subset of such patients. We performed untargeted serum metabolomic profiling for 44 AML patients receiving treatment based on ATRA and valproic acid combined with low-dose cytotoxic drugs (cytarabine, hydroxyurea, 6-mercaptopurin) which identified 886 metabolites. When comparing pretreatment samples from responders and non-responders, metabolites mainly belonging to amino acid and lipid (i.e., fatty acid) pathways were altered. Furthermore, patients with rapidly progressive disease showed an extensively altered lipid metabolism. Both ATRA and valproic acid monotherapy also altered the amino acid and lipid metabolite profiles; however, these changes were only highly significant for valproic acid treatment. Twenty-three metabolites were significantly altered by seven-day valproic acid treatment (p < 0.05, q < 0.05), where the majority of altered metabolites belonged to lipid (especially fatty acid metabolism) and amino acid pathways, including several carnitines. These metabolomic effects, and especially the effects on lipid metabolism, may be important for the antileukemic and epigenetic effects of this treatment.


Assuntos
Tratamento Farmacológico/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Metabolômica/métodos , Tretinoína/administração & dosagem , Ácido Valproico/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/metabolismo , Citarabina/administração & dosagem , Citarabina/farmacologia , Feminino , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/farmacologia , Leucemia Mieloide Aguda/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacologia , Pessoa de Meia-Idade , Resultado do Tratamento , Tretinoína/farmacologia , Ácido Valproico/farmacologia
17.
Eur J Clin Pharmacol ; 75(12): 1669-1674, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31587102

RESUMO

PURPOSE: Many patients with Crohn's disease (CD) and ulcerative colitis (UC) who have a high 6-methylmercaptopurine/6-thioguanine (6-MMP/6-TGN) ratio receive allopurinol 100 mg in addition to thiopurines to optimize metabolite concentrations. However, some patients do not tolerate allopurinol at this dosage. The aim of this study was to determine the intra-patient effect of reducing the allopurinol dosage from 100 to 50 mg, in terms of metabolite concentrations, enzyme activities, efficacy, and tolerability. METHODS: A prospective non-inferiority one-way crossover study was performed. CD and UC patients with stable disease using a thiopurine and allopurinol 100 mg were switched to 50 mg for 1 month. Primary outcomes were thiopurine metabolite concentrations. Secondary outcomes were enzyme activities of xanthine oxidase, thiopurine methyltransferase and hypoxanthine-guanine phosphoribosyltransferase, disease activity, and tolerability. RESULTS: Twenty-two patients were included. Treatment with allopurinol 50 mg compared with 100 mg resulted in a significant decrease in mean 6-TGN levels (761 to 625 pmol/8 × 108 RBC; p = 0.005) and a significant increase in mean 6-MMP levels (451 to 665 pmol/8 × 108 RBC; p = 0.01). However, the mean metabolite concentrations were still therapeutic. Enzyme activities, disease activity scores, and patient experiences did not alter significantly. Generally, UC patients were more positive about their improved treatment than CD patients. CONCLUSION: Combination therapy with 50 mg allopurinol led to a decrease of 6-TGN levels compared with 100 mg allopurinol. Disease activity, side effects, and patient experience, however, were similar between allopurinol 100 and 50 mg. UC patients seem to benefit and prefer lower doses whereas the contrary is seen in CD patients. TRIAL REGISTRATION: EudraCT trial registry - number 2016-001638-84.


Assuntos
Alopurinol/administração & dosagem , Azatioprina/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Mercaptopurina/análogos & derivados , Adulto , Idoso , Alopurinol/efeitos adversos , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/metabolismo , Metiltransferases/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , Tioguanina/metabolismo
18.
J Pediatr Gastroenterol Nutr ; 69(4): e105-e110, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31568041

RESUMO

OBJECTIVES: Therapeutic drug monitoring of thiopurine erythrocyte levels is not available in all centers and it usually requires quite a long time to obtain the results. The aims of this study were to build a model predicting low levels of 6-thioguanine and 6-methylmercaptopurine in pediatric inflammatory bowel disease (IBD) patients and to build a model to predict nonadherence in patients treated with azathioprine (AZA). METHODS: The study consisted of 332 observations in 88 pediatric IBD patients. Low AZA dosing was defined as 6-thioguanine levels <125 pmol/8 × 10 erythrocytes and 6-methylmercaptopurine levels <5700 pmol/8 × 10 erythrocytes. Nonadherence was defined as undetectable levels of 6-thioguanine and 6-methylmercaptopurine <240 pmol/8 × 10 erythrocytes. Data were divided into training and testing part. To construct the model predicting low 6-thioguanine levels, nonadherence, and the level of 6-thioguanine, the modification of random forest method with cross-validation and resampling was used. RESULTS: The final models predicting low 6-thioguanine levels and nonadherence had area under the curve, 0.87 and 0.94; sensitivity, 0.81 and 0.82; specificity, 0.80 and 86; and distance, 0.31 and 0.21, respectively, when applied on the testing part of the dataset. When the final model for prediction of 6-thioguanine values was applied on testing dataset, a root-mean-square error of 110 was obtained. CONCLUSIONS: Using easily obtained laboratory parameters, we constructed a model with sufficient accuracy to predict patients with low 6-thioguanine levels and a model for prediction of AZA treatment nonadherence (web applications: https://hradskyo.shinyapps.io/6TG_prediction/ and https://hradskyo.shinyapps.io/Non_adherence/).


Assuntos
Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Adesão à Medicação , Mercaptopurina/análogos & derivados , Adolescente , Área Sob a Curva , Criança , Monitoramento de Medicamentos , Eritrócitos/metabolismo , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacocinética , Mercaptopurina/uso terapêutico , Modelos Biológicos , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Tioguanina/metabolismo
19.
Aliment Pharmacol Ther ; 50(7): 780-788, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31429097

RESUMO

BACKGROUND: Thiopurines are the most widely used immunosuppressants in IBD although drug-related adverse events (AE) occur in 20%-30% of cases. AIM: To evaluate the safety of thiopurines in elderly IBD patients METHODS: Cohort study including all adult patients in the ENEIDA registry who received thiopurines. Patients were grouped in terms of age at the beginning of thiopurine treatment, specifically in those who started thiopurines over 60 years or between 18 and 50 years of age. Thiopurine-related AEs registered in the ENEIDA database were compared. RESULTS: Out of 48 752 patients, 1888 started thiopurines when over 60 years of age and 15 477 under 50 years of age. Median treatment duration was significantly shorter for those who started thiopurines >60 years (13 [IQR 2-55] vs 32 [IQR 5-82] months; P < .001). Patients starting >60 years had higher rates of all types of myelotoxicity, digestive intolerance and hepatotoxicity. Thiopurines were discontinued due to AEs (excluding malignancies and infections) in more patients starting >60 years (67.2% vs 63.1%; P < .001). Elderly age and female sex were independent risk factors for most AEs. CONCLUSION: In elderly IBD patients, thiopurines are associated with an increased risk of non-infectious, non-neoplastic, AEs.


Assuntos
Azatioprina/efeitos adversos , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mercaptopurina/efeitos adversos , Adulto , Idoso , Azatioprina/administração & dosagem , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Mercaptopurina/administração & dosagem , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco
20.
Aliment Pharmacol Ther ; 50(4): 407-415, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31359480

RESUMO

BACKGROUND: Low-dose thiopurine-allopurinol (LDTA) combination therapy is a commonly applied optimisation strategy in IBD patients with a skewed thiopurine metabolism. AIM: To assess continued LDTA maintenance treatment at annual intervals and explore risk factors for treatment cessation METHODS: Adult IBD patients treated with LDTA between 2009 and 2016 were retrospectively included. Data on the incidence of clinical and laboratory adverse events (AEs), including hepatotoxicity and myelotoxicity resulting in imposing LDTA therapy cessation and associated risk factors were collected. RESULTS: In total, 221 IBD patients (46% male, median age 42 years) were included. Maintenance LDTA treatment was continued in 78% of patients at 1 year (n = 145), 66% at 2 years (n = 83), 57% at 3 years (n = 52) and 52% at 4 years (n = 33). Treatment in patients receiving LDTA therapy for AEs during thiopurine monotherapy was more often continued than in patients initiating LDTA for other indications (eg, ineffectiveness of thiopurine monotherapy, routinely discovered skewed metabolism) (P = 0.016). Myelotoxicity during thiopurine monotherapy resolved in 87% and hepatotoxicity in 86% after median of 1.2 and 1.4 months after LDTA initiation. Cumulative incidence of AEs during LDTA resulting in therapy cessation within total follow-up of 449 treatment-years was 7% for clinical AEs, 4% for myelotoxicity and 1% for hepatotoxicity. CONCLUSION: LDTA therapy is a safe and beneficial optimisation strategy in IBD patients. Continued maintenance LDTA treatment is 52% after 4 years of treatment and most commonly affected by ineffectiveness of LDTA rather than LDTA-attributed toxicity. LDTA optimisation strategy is most advantageous in patients failing thiopurine monotherapy due to AEs.


Assuntos
Alopurinol/efeitos adversos , Doenças da Medula Óssea/induzido quimicamente , Doenças da Medula Óssea/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mercaptopurina/efeitos adversos , Suspensão de Tratamento/estatística & dados numéricos , Adulto , Alopurinol/administração & dosagem , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/epidemiologia , Masculino , Adesão à Medicação/estatística & dados numéricos , Mercaptopurina/administração & dosagem , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos Retrospectivos
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