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1.
Ann Oncol ; 28(2): 386-392, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28426102

RESUMO

Background: Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking. Patients and methods: We evaluated infection-related complications that were grade ≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period. Results: Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n = 389), followed by ear (n = 151), bloodstream (n = 147), and gastrointestinal tract (n = 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n = 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1-9.9 years at diagnosis was associated with febrile neutropenia (P = 0.002) during induction and febrile neutropenia and documented infection (both P < 0.001) during later continuation. White race was associated with documented infection (P = 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P < 0.001) and documented infections (P = 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P < 0.001). Conclusions: The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/mortalidade , Neutropenia Febril Induzida por Quimioterapia/terapia , Criança , Pré-Escolar , Dexametasona/administração & dosagem , Feminino , Humanos , Lactente , Contagem de Leucócitos , Masculino , Neutrófilos/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Infecções Respiratórias/induzido quimicamente , Infecções Respiratórias/mortalidade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Vincristina/administração & dosagem
2.
Pharmacogenomics J ; 17(2): 180-185, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-26856247

RESUMO

Treatment with glucocorticoids is associated with lower bone mineral density (BMD). We performed a genome-wide association study to analyze interactive effects between genotypes and cumulative dose of prednisone (PD) over 4.3 years of follow-up period on the final BMD Z-scores in 461 white children from the Childhood Asthma Management Program. No variants met the conventional criteria for genome-wide significance, and thus we looked for evidence of replication. The top 100-ranked single-nucleotide polymorphisms (SNPs) were then carried forward replication in 59 children with acute lymphoblastic leukemia (ALL) exposed to large fixed doses of PD as part of their chemotherapeutic regimen. Among them, rs6461639 (interaction P=1.88 × 10-5 in the CAMP population) showed a significant association with the final BMD Z-scores in the ALL population (P=0.016). The association of the ALL population was only present after correction for the anti-metabolite treatment arm (high vs low dose). We have identified a novel SNP, rs6461639, showing a significant effect on the final BMD Z-scores in two independent pediatric populations after long-term high-dose PD treatment.


Assuntos
Antiasmáticos/efeitos adversos , Antineoplásicos/efeitos adversos , Asma/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Glucocorticoides/efeitos adversos , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prednisona/efeitos adversos , Absorciometria de Fóton , Fatores Etários , Antiasmáticos/administração & dosagem , Antineoplásicos/administração & dosagem , Criança , Esquema de Medicação , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Glucocorticoides/administração & dosagem , Humanos , Masculino , Farmacogenética , Fenótipo , Prednisona/administração & dosagem , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada Espiral , Resultado do Tratamento , Estados Unidos
3.
Pediatr Blood Cancer ; 61(5): 885-93, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24395288

RESUMO

BACKGROUND: We sought to improve lumbar spine bone mineral density (LS-BMD) in long-term survivors of childhood acute lymphoblastic leukemia (ALL) using calcium and cholecalciferol supplementation. PROCEDURE: This double-blind, placebo-controlled trial randomized 275 participants (median age, 17 [9-36.1] years) with age- and gender-specific LS-BMD Z-scores <0 to receive nutritional counseling with supplementation of 1,000 mg/day calcium and 800 International Unit cholecalciferol or placebo for 2 years. The primary outcome was change in LS-BMD assessed by quantitative computerized tomography (QCT) at 24 months. Linear regression models were employed to identify the baseline risk factors for low LS-BMD and to compare LS-BMD outcomes. RESULTS: Pre-randomization LS-BMD below the mean was associated with male gender (P = 0.0024), White race (P = 0.0003), lower body mass index (P < 0.0001), and cumulative glucocorticoid doses of ≥ 5,000 mg (P = 0.0012). One hundred eighty-eight (68%) participants completed the study; 77% adhered to the intervention. Mean LS-BMD change did not differ between survivors randomized to supplements (0.33 ± 0.57) or placebo (0.28 ± 0.56). Participants aged 9-13 years and those 22-35 years had the greatest mean increases in LS-BMD (0.50 ± 0.66 and 0.37 ± 0.23, respectively). Vitamin D insufficiency (serum 25[OH]D <30 ng/ml) found in 296 (75%), was not associated with LS-BMD outcomes (P = 0.78). CONCLUSION: Cholecalciferol and calcium supplementation provides no added benefit to nutritional counseling for improving LS-BMD among adolescent and young adult survivors of ALL (93% of whom had LS-BMD Z-scores above the mean at study entry).


Assuntos
Densidade Óssea , Cálcio da Dieta/administração & dosagem , Colecalciferol/administração & dosagem , Aconselhamento , Suplementos Nutricionais , Leucemia-Linfoma Linfoblástico de Células Precursoras/dietoterapia , Sobreviventes , Adolescente , Adulto , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Lactente , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/fisiopatologia , Masculino , Terapia Nutricional , Tomografia Computadorizada por Raios X , Adulto Jovem
4.
Pharmacogenomics J ; 13(5): 396-402, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22664480

RESUMO

Multidrug resistance protein 2 (MRP2, ABCC2) is an efflux membrane transporter highly expressed in liver, kidney and intestine with important physiological and pharmacological roles. The goal of this study was to investigate the functional significance of promoter region polymorphisms in ABCC2 and potential allele-specific expression. Twelve polymorphisms in the 1.6 kb region upstream of the translation start site were identified by resequencing 247 DNA samples from ethnically diverse individuals. Luciferase reporter gene assays showed that ABCC2 -24C>T both alone and as part of a common haplotype (-24C>T/-1019A>G/-1549G>A) increased promoter function 35% compared with the reference sequence (P<0.0001). No other common variants or haplotypes affected ABCC2 promoter activity. Allele-specific expression was also investigated as a mechanism to explain reported associations of the synonymous ABCC2 3972C>T variant with pharmacokinetic phenotypes. In Caucasian liver samples (n=41) heterozygous for the 3972C>T polymorphism, the 3972C allele was preferentially transcribed relative to the 3972T allele (P<0.0001). This allelic imbalance was particularly apparent in samples with haplotypes containing two or three promoter/untranslated region variants (-1549G>A, -1019A>G and -24C>T). The observed allelic imbalance was not associated with hepatic or renal ABCC2 mRNA expression. Additional mechanisms will need to be explored to account for the interindividual variation in ABCC2 expression and MRP2 function.


Assuntos
Alelos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Linhagem Celular Tumoral , Haplótipos , Células Hep G2 , Humanos , Fígado/metabolismo , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
5.
Nat Rev Cancer ; 1(2): 99-108, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11905809

RESUMO

Pharmacogenetics is the study of how genetic variations affect drug response. These variations can affect a patient's response to cancer drugs, for which there is usually a fine line between a dosage that has a therapeutic effect and one that produces toxicity. Gaining better insight into the genetic elements of both the patient and the tumour that affect drug efficacy will eventually allow for individualized dosage determination and fewer adverse effects.


Assuntos
Neoplasias/tratamento farmacológico , Farmacogenética , Transportadores de Cassetes de Ligação de ATP/genética , Antimetabólitos Antineoplásicos/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/classificação , Antineoplásicos/farmacocinética , Biotransformação/genética , Sistema Enzimático do Citocromo P-450/genética , Inibidores Enzimáticos/farmacocinética , Antagonistas do Ácido Fólico/farmacocinética , Previsões , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Hipoxantina Fosforribosiltransferase/genética , Metiltransferases/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Receptores de Droga/genética , Transferases/genética
6.
Science ; 286(5439): 487-91, 1999 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-10521338

RESUMO

Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications. Pharmacogenomic studies are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby enhancing drug discovery and providing a stronger scientific basis for optimizing drug therapy on the basis of each patient's genetic constitution.


Assuntos
Tratamento Farmacológico , Preparações Farmacêuticas/metabolismo , Farmacogenética , Polimorfismo Genético , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Química Farmacêutica , Desenho de Fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Farmacocinética , Fenótipo , Receptores de Droga/genética , Receptores de Droga/metabolismo
7.
Leukemia ; 21(10): 2128-36, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17673902

RESUMO

The genetic risk factors for etoposide-induced leukemia with MLL translocations remain largely unknown. To identify genetic risk factors for and novel characteristics of secondary leukemia, we profiled 116,204 single nucleotide polymorphisms (SNPs) in germline and paired leukemic cell DNA from 13 secondary leukemia/myelodysplasia cases and germline DNA from 13 matched and 156 unmatched controls, all with acute lymphoblastic leukemia treated with etoposide. We analyzed global gene expression from a partially overlapping cohort. No single locus was altered in most cases. We discovered 81 regions of loss of heterozygosity (LOH) in leukemic blasts and 309 SNPs whose allele frequencies differed in cases vs controls. Candidate genes were prioritized on the basis of genes whose SNPs or expression differentiated cases from controls or showed LOH or copy number change in germline vs paired blast DNA from the 13 cases. Three biological pathways were altered: adhesion, Wnt signaling and regulation of actin. Validation experiments using a genome scan for etoposide-induced leukemogenic MLL chimeric fusions in 15 HapMap cell lines also implicated genes involved in adhesion, a process linked to de novo leukemogenesis. Independent clinical epidemiologic and in vitro genome-wide approaches converged to identify novel pathways that may contribute to therapy-induced leukemia.


Assuntos
Genoma Humano , Leucemia/induzido quimicamente , Leucemia/genética , Leucemia/patologia , Adolescente , Estudos de Casos e Controles , Adesão Celular , Criança , Pré-Escolar , Estudos de Coortes , Etoposídeo/efeitos adversos , Etoposídeo/farmacologia , Feminino , Frequência do Gene , Humanos , Lactente , Perda de Heterozigosidade , Masculino , Polimorfismo de Nucleotídeo Único , Translocação Genética
8.
Clin Pharmacol Ther ; 103(4): 599-618, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28994452

RESUMO

Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group provide therapeutic recommendations for well-known gene-drug pairs. Published recommendations show a high rate of concordance. However, as a result of different guideline development methods used by these two consortia, differences between the published guidelines exist. The aim of this paper is to compare both initiatives and explore these differences, with the objective to achieve harmonization.


Assuntos
Farmacogenética , Guias de Prática Clínica como Assunto , Medicina de Precisão , Testes Genéticos/métodos , Humanos , Países Baixos , Farmacogenética/métodos , Farmacogenética/normas , Padrões de Prática Médica , Medicina de Precisão/métodos , Medicina de Precisão/normas , Pesquisa Translacional Biomédica/métodos , Pesquisa Translacional Biomédica/normas , Estados Unidos
9.
Clin Pharmacol Ther ; 81(3): 425-8, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17339872

RESUMO

The field of pharmacogenetics has existed since the 1950s, when it was demonstrated that some drug effects could differ substantially among race and ethnic groups, and that some drug metabolizing enzyme activities were inherited. During the 1990s, application of molecular biology to the study of inherited drug-related phenotypes proved the genetic basis of several genetic polymorphisms. Genomic technology has now demonstrated that germline genetic variability among humans is extremely common. The combined weight of proven examples whereby pharmacogenetics affects drugs, and the possibility of even more examples being elucidated in the coming decades, dictates that pharmacogenetics be incorporated into the drug approval process. It is our contention that minimal pharmacogenetic testing should be required for all new drug applications to the Food and Drug Administration (FDA). This would include a requirement for germline DNA to be prospectively collected from all subjects participating in preapproval clinical trials. For drugs that are metabolized by enzymes whose genes have clearly inactivating polymorphisms, clinical trial participants should be genotyped for those polymorphisms.


Assuntos
Aprovação de Drogas/legislação & jurisprudência , Farmacogenética/legislação & jurisprudência , Farmacogenética/tendências , DNA/genética , Genótipo , Humanos , Fenótipo , Manejo de Espécimes , Estados Unidos , United States Food and Drug Administration
10.
Clin Pharmacol Ther ; 81(5): 729-34, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17329987

RESUMO

One purpose of the International HapMap Project is to provide a genome-wide resource to discover pharmacogenetic determinants of drug response. The thiopurine methyltransferase (TPMT) 719A>G single-nucleotide polymorphism (SNP) causes decreased TPMT activity, increased intracellular thiopurines, and drug toxicities. Using HapMap cell lines and 3.3 million SNPs, we tested whether the TPMT 719A>G SNP could be identified as predicting TPMT phenotype. Assuming TPMT was a candidate gene, five SNPs and four haplotypes predicted TPMT phenotype, two of which were in complete linkage disequilibrium with the functional 719A>G SNP. We also used a genome-wide approach to rank all 17,542 genes as predictors of TPMT activity. A TPMT haplotype, HAP1, significantly predicted TPMT phenotype; however, haplotypes of 96 genes ranked higher than TPMT. Our findings show that HapMap resources are useful for pharmacogenetic discovery when the candidate gene is known, but challenges remain for definitive gene identification when a genome-wide agnostic approach is employed.


Assuntos
Metiltransferases/genética , Farmacogenética , Linhagem Celular , Mapeamento Cromossômico , Haplótipos , Isoenzimas/genética , Fenótipo , Polimorfismo de Nucleotídeo Único
11.
Clin Pharmacol Ther ; 81(3): 328-45, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17339863

RESUMO

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.


Assuntos
Tratamento Farmacológico , Farmacogenética , Polimorfismo de Nucleotídeo Único , Animais , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/genética , Humanos , Informática , Pneumopatias/tratamento farmacológico , Pneumopatias/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Preparações Farmacêuticas/metabolismo , Inibidores da Agregação Plaquetária/uso terapêutico , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/reabilitação
12.
J Clin Invest ; 91(5): 2150-4, 1993 May.
Artigo em Inglês | MEDLINE | ID: mdl-8098046

RESUMO

Debrisoquin hydroxylase (CYP2D6) is a cytochrome P450 enzyme that catalyzes the metabolism of > 30 commonly prescribed medications. Deficiency in CYP2D6 activity, inherited as an autosomal recessive trait, was found to be significantly less common in American blacks (1.9%) than whites (7.7%). To determine the genetic basis for this difference, inactivating CYP2D6 mutations were assessed by allele-specific PCR amplification and RFLP analyses of genomic DNA from 126 unrelated whites and 127 unrelated blacks. Blacks had a twofold lower frequency (8.5 versus 23%, P = 0.001) of the CYP2D6(B) mutation (point mutation at intron 3/exon 4 splice site), while complete deletion of the CYP2D6 gene (5.5% blacks, 2.4% whites), and the CYP2D6(A) mutation (single nucleotide deletion in exon 5; 0.24% blacks, 1.4% whites) were not different between the two groups. The prevalence of heterozygous genotypes was significantly lower in blacks (25 versus 42% of extensive metabolizers, P = 0.009), consistent with the observed prevalence of the deficient trait in blacks and whites. We conclude that the same CYP2D6 mutations lead to a loss of functional expression in blacks and whites, but American blacks have a lower prevalence of the deficient trait due to a lower frequency of the CYP2D6(B) mutation. This could explain racial differences in drug effects and disease risk.


Assuntos
População Negra/genética , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Deleção de Genes , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Polimorfismo de Fragmento de Restrição , Sequência de Bases , Citocromo P-450 CYP2D6 , Sistema Enzimático do Citocromo P-450/deficiência , DNA/sangue , DNA/genética , DNA/isolamento & purificação , Genótipo , Humanos , Leucócitos/enzimologia , Oxigenases de Função Mista/deficiência , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Fenótipo , Reação em Cadeia da Polimerase/métodos , Estados Unidos
13.
J Clin Invest ; 97(1): 73-80, 1996 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-8550853

RESUMO

Methotrexate (MTX) is one of the most widely used drugs for the treatment of childhood acute lymphoblastic leukemia (ALL) and is commonly given in high doses. However, the rationale for high-dose MTX (HDMTX) has been challenged recently. To determine whether higher MTX polyglutamate (MTXPG) concentrations in ALL blasts translate into greater antileukemic effects, 150 children with newly diagnosed ALL were randomized to initial treatment with either HDMTX (1,000 mg/m2 intravenously over 24 h) or lower-dose MTX (30 mg/m2 by mouth every 6 h x 6). ALL blasts accumulated higher concentrations of MTXPG and long-chain MTXPG (MTXPGLC) after HDMTX (P < 0.00001). Of 101 patients evaluable for peripheral blast cytoreduction, MTXPG concentrations were higher in patients whose blast count decreased within 24 h (P = 0.005) and in those who had no detectable circulating blasts within 4 days (P = 0.004). The extent of inhibition of de novo purine synthesis in ALL blasts was significantly related to the blast concentration of MTXPGLC (IC95% = 483 pmol/10(9) blasts). The percentage of patients with 44-h MTXPGLC exceeding the IC95% was greater after HDMTX (81%) than LDMTX (46%, P < 0.0001). These data indicate that higher blast concentrations of MTXPG are associated with greater antileukemic effects, establishing a strong rationale for HD-MTX in the treatment of childhood ALL.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Metotrexato/análogos & derivados , Metotrexato/administração & dosagem , Ácido Poliglutâmico/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Medula Óssea/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Metotrexato/efeitos adversos , Metotrexato/metabolismo , Metotrexato/farmacocinética , Ácido Poliglutâmico/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Purinas/biossíntese , Estomatite/induzido quimicamente
14.
J Clin Invest ; 94(5): 1996-2001, 1994 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7525652

RESUMO

High-dose methotrexate (HDMTX) is a component of most treatment protocols for childhood acute lymphoblastic leukemia (ALL), yet recent studies of receptor-mediated transport and saturable polyglutamylation have questioned its rationale. To investigate this in vivo, methotrexate and its active polyglutamated metabolites (MTX-PG) were measured in bone marrow blasts obtained from 101 children randomized to single-agent therapy with either HDMTX (1 g/m2 per 24 h i.v., n = 47) or low-dose MTX (LDMTX, 30 mg/m2 by mouth every 6 h x 6, n = 54), before remission induction therapy. Blast concentrations of total MTX-PGs (median 460 vs 1380 pmol/10(9) cells) and of long-chain MTX-glu4-6 were both significantly higher after HDMTX (P < 0.001). With either treatment, MTX-PGs were significantly higher in B-lineage blasts than in T-lineage blasts (LDMTX P = 0.001, HDMTX P = 0.03). In a multiple regression analysis of B-lineage ALL, blast MTX-PG was significantly related to MTX dose (or plasma MTX concentration), lymphoblast ploidy (hyperdiploid > nonhyperdiploid), and percentage S-phase. This is the first evidence that HDMTX achieves higher MTX-PG concentrations in ALL blasts in vivo, establishing a rationale for HDMTX in the treatment of childhood ALL, especially T-lineage or nonhyperdiploid B-lineage ALL, disease characteristics associated with a poor prognosis on conventional therapy.


Assuntos
Metotrexato/análogos & derivados , Ácido Poliglutâmico/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Metotrexato/administração & dosagem , Metotrexato/metabolismo , Metotrexato/farmacocinética , Ploidias , Ácido Poliglutâmico/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
15.
Leukemia ; 20(2): 239-46, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16341039

RESUMO

Using a target gene approach, only a few host genetic risk factors for treatment-related myeloid leukemia (t-ML) have been defined. Gene expression microarrays allow for a more genome-wide approach to assess possible genetic risk factors for t-ML. We assessed gene expression profiles (n=12 625 probe sets) in diagnostic acute lymphoblastic leukemic cells from 228 children treated on protocols that included leukemogenic agents such as etoposide, 13 of whom developed t-ML. Expression of 68 probes, corresponding to 63 genes, was significantly related to risk of t-ML. Hierarchical clustering of these probe sets clustered patients into three groups with 94, 122 and 12 patients, respectively; 12 of the 13 patients who went on to develop t-ML were overrepresented in the latter group (P<0.0001). A permutation test indicated a low likelihood that these probe sets and clusters were obtained by chance (P<0.001). Distinguishing genes included transcription-related oncogenes (v-Myb, Pax-5), cyclins (CCNG1, CCNG2 and CCND1) and histone HIST1H4C. Common transcription factor recognition elements among similarly up- or downregulated genes included several involved in hematopoietic differentiation or leukemogenesis (Maz, PU.1, ARNT). This approach has identified several genes whose expression distinguishes patients at risk of t-ML, and suggests targets for assessing germline predisposition to leukemogenesis.


Assuntos
Perfilação da Expressão Gênica , Leucemia Mieloide/genética , Segunda Neoplasia Primária/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Análise por Conglomerados , Estudos de Coortes , Seguimentos , Genótipo , Humanos , Leucemia Mieloide/etiologia , Segunda Neoplasia Primária/etiologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , RNA Neoplásico/genética , Análise de Regressão , Fatores de Risco
16.
Blood Cancer J ; 7(2): e531, 2017 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-28212374

RESUMO

The impact of body mass index (BMI) at diagnosis on treatment outcome in children with acute lymphoblastic leukemia (ALL) is controversial. We studied 373 children with ALL enrolled on the Total XV study, which prospectively used minimal residual disease (MRD) for risk assignment. MRD on day 19 and at the end of remission induction (day 46), cumulative incidence of relapse/refractory disease (CIR), event-free survival (EFS) and overall survival (OS) were evaluated using sets of four, three and two subgroups based on BMI at diagnosis, along with BMI percentile change during remission induction. Higher BMI was associated with older age and higher treatment risk. There was no association between MRD on days 19 or 46 and BMI for four, three or two BMI subgroups (P>0.1 in all cases), nor was BMI associated with CIR or EFS. Obese patients had worse OS compared with non-obese (P=0.031) due to treatment-related mortality and less salvage after refractory disease or bone marrow relapse. No association between BMI change during remission induction and MRD, CIR, EFS or OS was seen. BMI at diagnosis does not predict poorer response or relapse in a contemporary MRD-directed ALL regimen. Improvements in supportive care and innovative, less-toxic frontline/salvage therapies are needed, especially for obese patients.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Resultado do Tratamento
17.
Clin Pharmacol Ther ; 102(6): 897-902, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28795399

RESUMO

The goal of pharmacogenomics research is to discover genetic polymorphisms that underlie variation in drug response. Increasingly, pharmacogenomics research involves large numbers of patients and the application of new technologies and methodologies to enable discovery. The Pharmacogenomics Research Network (PGRN) has become a community-driven network of investigators spanning scientific and clinical disciplines. Here, we highlight the activities and types of resources that enable PGRN members to enhance and drive basic and translational research in pharmacogenomics.


Assuntos
Pesquisa Biomédica/organização & administração , Farmacogenética/organização & administração , Medicina de Precisão/métodos , Pesquisa Translacional Biomédica/organização & administração , Humanos
18.
Leukemia ; 31(2): 333-339, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27560110

RESUMO

To determine the clinical significance of minimal residual disease (MRD) in patients with prognostically relevant subtypes of childhood acute lymphoblastic leukemia (ALL), we analyzed data from 488 patients treated in St Jude Total Therapy Study XV with treatment intensity based mainly on MRD levels measured during remission induction. MRD levels on day 19 predicted treatment outcome for patients with hyperdiploid >50 ALL, National Cancer Institute (NCI) standard-risk B-ALL or T-cell ALL, while MRD levels on day 46 were prognostic for patients with NCI standard-risk or high-risk B-ALL. Patients with t(12;21)/(ETV6-RUNX1) or hyperdiploidy >50 ALL had the best prognosis; those with a negative MRD on day 19 had a particularly low risk of relapse: 1.9% and 3.8%, respectively. Patients with NCI high-risk B-ALL or T-cell ALL had an inferior outcome; even with undetectable MRD on day 46, cumulative risk of relapse was 12.7% and 15.5%, respectively. Among patients with NCI standard-risk B-ALL, the outcome was intermediate overall but was poor if MRD was ⩾1% on day 19 or MRD was detectable at any level on day 46. Our results indicate that the clinical impact of MRD on treatment outcome in childhood ALL varies considerably according to leukemia subtype and time of measurement.


Assuntos
Neoplasia Residual/patologia , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Recidiva , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento
19.
Clin Pharmacol Ther ; 101(3): 373-381, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27564568

RESUMO

We performed a genomewide association study (GWAS) of primary erythrocyte thiopurine S-methyltransferase (TPMT) activity in children with leukemia (n = 1,026). Adjusting for age and ancestry, TPMT was the only gene that reached genomewide significance (top hit rs1142345 or 719A>G; P = 8.6 × 10-61 ). Additional genetic variants (in addition to the three single-nucleotide polymorphisms [SNPs], rs1800462, rs1800460, and rs1142345, defining TPMT clinical genotype) did not significantly improve classification accuracy for TPMT phenotype. Clinical mercaptopurine tolerability in 839 patients was related to TPMT clinical genotype (P = 2.4 × 10-11 ). Using 177 lymphoblastoid cell lines (LCLs), there were 251 SNPs ranked higher than the top TPMT SNP (rs1142345; P = 6.8 × 10-5 ), revealing a limitation of LCLs for pharmacogenomic discovery. In a GWAS, TPMT activity in patients behaves as a monogenic trait, further bolstering the utility of TPMT genetic testing in the clinic.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Leucemia/tratamento farmacológico , Mercaptopurina/farmacocinética , Metiltransferases/genética , Antimetabólitos Antineoplásicos/administração & dosagem , Criança , Relação Dose-Resposta a Droga , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Mercaptopurina/administração & dosagem , Farmacogenética , Polimorfismo de Nucleotídeo Único
20.
Leukemia ; 31(6): 1325-1332, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28096535

RESUMO

The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 × 10-4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 × 10-5, model with SNPs HR=1.31, P=0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.


Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Recidiva Local de Neoplasia/diagnóstico , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Recidiva Local de Neoplasia/etiologia , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco
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