RESUMO
Human cytomegalovirus (CMV) reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Despite routine screening for CMV reactivation and early antiviral treatment, the rates of CMV-related complications after HCT remain high. Genetic variants in both the donor and recipient have been associated with the risk of CMV reactivation and disease after HCT, but these associations have not been validated, and their clinical importance remains unclear. In this study, we assessed 117 candidate variants previously associated with CMV-related phenotypes for association with CMV reactivation and disease in a cohort of 2169 CMV-seropositive HCT recipients. We also carried out a genome-wide association study (GWAS) for CMV reactivation and disease in the same cohort. Both analyses used a prespecified discovery and replication approach to control the risk of false-positive results. Among the 117 candidate variants, our analysis implicates only the donor ABCB1 rs1045642 genotype as a risk factor for CMV reactivation. This synonymous variant in P-glycoprotein may influence the risk of CMV reactivation by altering the efflux of cyclosporine and tacrolimus from donor lymphocytes. In the GWAS analysis, the donor CDC42EP3 rs11686168 genotype approached the significance threshold for association with CMV reactivation, although we could not identify a mechanism to explain this association. The results of this study suggest that most genomic variants previously associated with CMV phenotypes do not significantly alter the risk for CMV reactivation or disease after HCT.
Assuntos
Infecções por Citomegalovirus/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Citomegalovirus/isolamento & purificação , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/etiologia , Feminino , Reguladores de Proteínas de Ligação ao GTP/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Transplante Homólogo/efeitos adversos , Ativação Viral , Adulto JovemRESUMO
Acute graft-versus-host-disease (aGVHD) is a major complication following hematopoietic cell transplantations (HCTs). We have shown that HCT recipients in whom either the donor or patient had inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) have a higher incidence of developing more severe aGVHD. Previous studies established that increased proinflammatory cytokines are associated with increased risk for aGVHD and nonrelapse mortality post-HCT. We hypothesized that HCT recipients with donor or recipient iciHHV-6 (iciHHV-6pos HCT cases) will have higher cytokine levels compared with HCT recipients without iciHHV-6 (iciHHV-6neg HCT controls). We identified 64 iciHHV-6pos HCT cases with plasma from days 7, 14, and/or 21 post-HCT and before aGVHD onset in patients who developed aGVHD. We identified 64 iciHHV-6neg HCT controls matched for aGVHD risk factors. We also identified 28 donors with iciHHV-6 and 56 matched donors without iciHHV-6. We measured plasma cytokine concentrations for IL-6, suppression of tumorigenicity 2, T cell immunoglobulin and mucin-domain containing 3, TNFα, soluble TNF receptor 1 (TNFRp55), and C-reactive protein (CRP). We used Mann-Whitney tests and repeated-measures models to compare cytokine levels. iciHHV-6pos HCT cases had higher CRP levels on day 7 and day 21 and higher TNFRp55 levels on day 14 and day 21 compared with iciHHV-6neg HCT controls. These findings were recapitulated in a repeated-measures model. The differences were most evident among patients who subsequently developed aGVHD grades 2 to 4. Additionally, iciHHV-6pos HCT cases had earlier-onset aGVHD (median, 20 versus 27 days post-HCT; Pâ¯=â¯.02). There were no differences in cytokine levels among healthy donors with or without iciHHV-6. This study demonstrates that HCT recipients with iciHHV-6 have higher proinflammatory cytokines that may be associated with increased risk for aGVHD.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 6 , Doença Aguda , Citocinas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 6/genética , Humanos , Doadores de TecidosRESUMO
The risk of acute graft-versus-host disease (GVHD) is higher after allogeneic hematopoietic cell transplantation (HCT) from unrelated donors as compared with related donors. This difference has been explained by increased recipient mismatching for major histocompatibility antigens or minor histocompatibility antigens. In the current study, we used genome-wide arrays to enumerate single nucleotide polymorphisms (SNPs) that produce graft-versus-host (GVH) amino acid coding differences between recipients and donors. We then tested the hypothesis that higher degrees of genome-wide recipient GVH mismatching correlate with higher risks of GVHD after allogeneic HCT. In HLA-genotypically matched sibling recipients, the average recipient mismatching of coding SNPs was 9.35%. Each 1% increase in genome-wide recipient mismatching was associated with an estimated 20% increase in the hazard of grades III-IV GVHD (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.05-1.37; P = .007) and an estimated 22% increase in the hazard of stage 2-4 acute gut GVHD (HR, 1.22; 95% CI, 1.02-1.45; P = .03). In HLA-A, B, C, DRB1, DQA1, DQB1, DPA1, DPB1-phenotypically matched unrelated recipients, the average recipient mismatching of coding SNPs was 17.3%. The estimated risks of GVHD-related outcomes in HLA-phenotypically matched unrelated recipients were low, relative to the large difference in genome-wide mismatching between the 2 groups. In contrast, the risks of GVHD-related outcomes were higher in HLA-DP GVH-mismatched unrelated recipients than in HLA-matched sibling recipients. Taken together, these results suggest that the increased GVHD risk after unrelated HCT is predominantly an effect of HLA-mismatching.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor/imunologia , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/genética , Antígenos HLA/genética , Teste de Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Masculino , Antígenos de Histocompatibilidade Menor/genética , Modelos de Riscos Proporcionais , Risco , Irmãos , Transplantados , Transplante Homólogo , Doadores não RelacionadosRESUMO
Invasive aspergillosis (IA) is a significant cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Previous studies have reported an association between IA development and single nucleotide polymorphisms (SNPs), but many SNPs have not been replicated in a separate cohort. The presence of a positive serum galactomannan assay (SGM+) has also been associated with a worse prognosis in patients with IA, and genetic determinants in this subset of patients have not been systematically studied. The study cohort included 2609 HCT recipients and their donor pairs: 483 with proven/probable IA (183 SGM+) and 2126 with no IA by standard criteria. Of 25 SNPs previously published, we analyzed 20 in 14 genes that passed quality control. Samples were genotyped via microarray, and SNPs that could not be genotyped were imputed. The primary aim was to replicate SNPs associated with proven/probable IA at 2 years; secondary goals were to explore the associations using an end point of SGM+ IA or proven/probable IA using a different genetic model or time to IA (3 months vs 2 years) compared with the original study. Two SNPs in 2 genes (PTX3, CLEC7a) were replicated. Thirteen SNPs in 9 genes had an association at P ≤ .05 using the secondary aims (PTX3, CLEC7a, CD209, CXCL10, TLR6, S100B, IFNG, PLG, TNFR1), with hazard ratios ranging from 1.2 to 3.29. Underlying genetic differences can influence development of IA following HCT. Identification of genetic predispositions to IA could have important implications in donor screening, risk stratification of recipients, monitoring, and prophylaxis.
Assuntos
Aspergilose/etiologia , Aspergilose/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Polimorfismo de Nucleotídeo Único , Adulto , Proteína C-Reativa/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lectinas Tipo C/genética , Masculino , Pessoa de Meia-Idade , Componente Amiloide P Sérico/genéticaRESUMO
Human herpesvirus 6 (HHV-6) species have a unique ability to integrate into chromosomal telomeres. Mendelian inheritance via gametocyte integration results in HHV-6 in every nucleated cell. The epidemiology and clinical effect of inherited chromosomally integrated HHV-6 (iciHHV-6) in hematopoietic cell transplant (HCT) recipients is unclear. We identified 4319 HCT donor-recipient pairs (8638 subjects) who received an allogeneic HCT and had archived pre-HCT peripheral blood mononuclear cell samples. We screened these samples for iciHHV-6 and compared characteristics of HCT recipients and donors with iciHHV-6 with those of recipients and donors without iciHHV-6, respectively. We calculated Kaplan-Meier probability estimates and Cox proportional hazards models for post-HCT outcomes based on recipient and donor iciHHV-6 status. We identified 60 HCT recipients (1.4%) and 40 donors (0.9%) with iciHHV-6; both recipient and donor harbored iciHHV-6 in 13 HCTs. Thus, there were 87 HCTs (2%) in which the recipient, donor, or both harbored iciHHV-6. Acute graft-versus-host disease (GVHD) grades 2-4 was more frequent when recipients or donors had iciHHV-6 (adjusted hazard ratios, 1.7-1.9; P = .004-.001). Cytomegalovirus viremia (any and high-level) was more frequent among recipients with iciHHV-6 (adjusted HRs, 1.7-3.1; P = .001-.040). Inherited ciHHV-6 status did not significantly affect risk for chronic GVHD, hematopoietic cell engraftment, overall mortality, or nonrelapse mortality. Screening for iciHHV-6 could guide donor selection and post-HCT risk stratification and treatment. Further study is needed to replicate these findings and identify potential mechanisms.
Assuntos
Cromossomos Humanos/genética , Cromossomos Humanos/virologia , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 6/genética , Padrões de Herança/genética , Doadores de Tecidos , Doença Aguda , Adulto , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/genética , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Probabilidade , Modelos de Riscos Proporcionais , Fatores de Risco , Resultado do TratamentoRESUMO
Sclerotic graft-versus-host disease (GVHD) is a distinctive phenotype of chronic GVHD after allogeneic hematopoietic cell transplantation, characterized by fibrosis of skin or fascia. Sclerotic GVHD has clinical and histopathological similarities with systemic sclerosis, an autoimmune disease whose risk is influenced by genetic polymorphisms. We examined 13 candidate single-nucleotide polymorphisms (SNPs) that have a well-documented association with systemic sclerosis to determine whether these SNPs are also associated with the risk of sclerotic GVHD. The study cohort included 847 consecutive patients who were diagnosed with chronic GVHD. Genotyping was performed using microarrays, followed by imputation of unobserved SNPs. The donor rs10516487 (BANK1: B-cell scaffold protein with ankyrin repeats 1) TT genotype was associated with lower risk of sclerotic GVHD (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.21-0.87; P = .02). Donor and recipient rs2056626 (CD247: T-cell receptor ζ subunit) GG or GT genotypes were associated with higher risk of sclerotic GVHD (HR, 1.57; 95% CI, 1.13-2.18; P = .007 and HR, 1.66; 95% CI, 1.19-2.32; P = .003, respectively). Donor and recipient rs987870 (5'-flanking region of HLA-DPA1) CC genotypes were associated with higher risk of sclerotic GVHD (HR, 2.50; 95% CI, 1.22-5.11; P = .01 and HR, 2.13; 95% CI, 1.00-4.54; P = .05, respectively). In further analyses, the recipient DPA1*01:03â¼DPB1*04:01 haplotype and certain amino acid substitutions in the recipient P1 peptide-binding pocket of the HLA-DP heterodimer were associated with risk of sclerotic GVHD. Genetic components associated with systemic sclerosis are also associated with sclerotic GVHD. HLA-DP-mediated antigen presentation, T-cell response, and B-cell activation have important roles in the pathogenic mechanisms of both diseases.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos CD/genética , Antígenos de Neoplasias/genética , Doença Enxerto-Hospedeiro/diagnóstico , Cadeias alfa de HLA-DP/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Esclerose/diagnóstico , Dermatopatias/diagnóstico , Adolescente , Adulto , Idoso , Linfócitos B/metabolismo , Linfócitos B/patologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Genótipo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Cadeias alfa de HLA-DP/química , Haplótipos , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Conformação Proteica , Esclerose/etiologia , Esclerose/patologia , Dermatopatias/etiologia , Dermatopatias/patologia , Transplante Homólogo , Adulto JovemRESUMO
Previous studies have identified single-nucleotide polymorphisms (SNPs) associated with the risk of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. The current study determined whether these associations could be replicated in large cohorts of donors and recipients. Each SNP was tested with cohorts of patients having the same donor type (HLA-matched related, unrelated, or both) reported in the original publication, and testing was limited to the same genome (recipient or donor) and genetic model (dominant, recessive, or allelic) reported in the original study. The 21 SNPs reported in this study represent 19 genes, and the analysis encompassed 22 SNP association tests. The hazard ratio (HR) point estimates and risk ratio point estimates corresponding to odds ratios in previous studies consistently fall outside the 95% confidence intervals of HR estimates in the current study. Despite the large size of the cohorts available for the current study, the 95% confidence intervals for most HRs did not exclude 1.0. Three SNPs representing CTLA4, HPSE, and IL1R1 showed evidence of association with the risk of chronic GVHD in unrelated donor-recipient pairs from 1 cohort, but none of these associations was replicated when tested in unrelated donor-recipient pairs from an independent cohort. Two SNPs representing CCR6 and FGFR1OP showed possible associations with the risk of chronic GVHD in related donor-recipient pairs but not in unrelated donor-recipient pairs. These results remain to be tested for replication in other cohorts of related donor-recipient pairs.
Assuntos
Doença Enxerto-Hospedeiro/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença Crônica , Estudos de Coortes , Feminino , Estudos de Associação Genética , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Doadores não Relacionados , Adulto JovemRESUMO
We examined the hypothesis that plasma biomarkers and concomitant clinical findings after initial glucocorticoid therapy can accurately predict failure of graft-versus-host-disease (GVHD) treatment and mortality. We analyzed plasma samples and clinical data in 165 patients after 14 days of glucocorticoid therapy and used logistic regression and areas under receiver-operating characteristic curves (AUC) to evaluate associations with treatment failure and nonrelapse mortality (NRM). Initial treatment of GVHD was unsuccessful in 49 patients (30%). For predicting GVHD treatment failure, the best clinical combination (total serum bilirubin and skin GVHD stage: AUC, .70) was competitive with the best biomarker combination (T cell immunoglobulin and mucin domain 3 [TIM3] and [interleukin 1 receptor family encoded by the IL1RL1 gene, ST2]: AUC, .73). The combination of clinical features and biomarker results offered only a slight improvement (AUC, .75). For predicting NRM at 1 year, the best clinical predictor (total serum bilirubin: AUC, .81) was competitive with the best biomarker combination (TIM3 and soluble tumor necrosis factor receptor-1 [sTNFR1]: AUC, .85). The combination offered no improvement (AUC, .85). Infection was the proximate cause of death in virtually all patients. We conclude that after 14 days of glucocorticoid therapy, clinical findings (serum bilirubin, skin GVHD) and plasma biomarkers (TIM3, ST2, sTNFR1) can predict failure of GVHD treatment and NRM. These biomarkers reflect counter-regulatory mechanisms and provide insight into the pathophysiology of GVHD reactions after glucocorticoid treatment. The best predictive models, however, exhibit inadequate positive predictive values for identifying high-risk GVHD cohorts for investigational trials, as only a minority of patients with high-risk GVHD would be identified and most patients would be falsely predicted to have adverse outcomes.
Assuntos
Bilirrubina/sangue , Doença Enxerto-Hospedeiro , Receptor Celular 2 do Vírus da Hepatite A/sangue , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Prednisolona/administração & dosagem , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Criança , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de TempoRESUMO
Chronic graft-versus-host disease (GVHD) is the leading cause of long-term morbidity and mortality after allogeneic hematopoietic cell transplantation. To identify prognostic plasma proteins associated with de novo- or quiescent-onset chronic GVHD (cGVHD), we performed a discovery and validation proteomic study. The total study cohort included 167 consecutive patients who had no clinical evidence of GVHD under minimum glucocorticoid administration and had available plasma samples obtained at 80 ± 14 days after transplantation. We first used high-throughput mass spectrometry to screen pooled plasma using 20 cases with subsequent cGVHD and 20 controls without it, and we identified 20 candidate proteins. We then measured 12 of the 20 candidate proteins by ELISA on the same individual samples and identified 4 proteins for further verification (LGALS3BP, CD5L, CD163, and TXN for de novo onset, and LGALS3BP and CD5L for quiescent onset). The verification cohort included 127 remaining patients. The cumulative incidence of de novo-onset cGVHD was higher in patients with higher plasma soluble CD163 concentrations at day 80 than those with lower concentrations (75% versus 40%, P = .018). The cumulative incidence of de novo- or quiescent-onset cGVHD did not differ statistically according to concentrations of the 3 other proteins at day 80. CD163 is a macrophage scavenger receptor and is elevated in oxidative conditions. These results suggest that monocyte or macrophage activation or increased oxidative stress may contribute to the pathogenesis of cGVHD.
Assuntos
Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas , Receptores de Superfície Celular/sangue , Adulto , Idoso , Aloenxertos , Biomarcadores/sangue , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Incidência , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismoRESUMO
Chronic graft-versus-host disease (GVHD) is the leading cause of late, nonrelapse mortality and disability in allogeneic hematopoietic cell transplantation recipients and a major obstacle to improving outcomes. The biology of chronic GVHD remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD.
Assuntos
Ensaios Clínicos como Assunto/normas , Doença Enxerto-Hospedeiro , Aloenxertos , Animais , Biomarcadores , Doença Crônica , Citocinas/metabolismo , Endotélio Vascular/patologia , Fibrose , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Inflamação , Interferon gama/fisiologia , Camundongos , Modelos Animais , Modelos Imunológicos , Especificidade de Órgãos , Subpopulações de Linfócitos T/imunologia , Terminologia como Assunto , Imunologia de Transplantes , CicatrizaçãoRESUMO
We identified plasma biomarkers that presaged outcomes in patients with gastrointestinal graft-versus-host disease (GVHD) by measuring 23 biomarkers in samples collected before initiation of treatment. Six analytes with the greatest accuracy in predicting grade 3-4 GVHD in the first cohort (74 patients) were then tested in a second cohort (76 patients). The same 6 analytes were also tested in samples collected at day 14 ± 3 from 167 patients free of GVHD at the time. Logistic regression and calculation of an area under a receiver-operating characteristic (ROC) curve for each analyte were used to determine associations with outcome. Best models in the GVHD onset and landmark analyses were determined by forward selection. In samples from the second cohort, collected a median of 4 days before start of treatment, levels of TIM3, IL6, and sTNFR1 had utility in predicting development of peak grade 3-4 GVHD (area under ROC curve, 0.88). Plasma ST2 and sTNFR1 predicted nonrelapse mortality within 1 year after transplantation (area under ROC curve, 0.90). In the landmark analysis, plasma TIM3 predicted subsequent grade 3-4 GVHD (area under ROC curve, 0.76). We conclude that plasma levels of TIM3, sTNFR1, ST2, and IL6 are informative in predicting more severe GVHD and nonrelapse mortality.
Assuntos
Biomarcadores/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doença Aguda , Adulto , Idoso , Feminino , Gastroenteropatias/sangue , Gastroenteropatias/diagnóstico , Gastroenteropatias/etiologia , Gastroenteropatias/mortalidade , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Estudos Retrospectivos , Fatores de Tempo , Transplante Homólogo , Adulto JovemRESUMO
Cardiomyopathy has been recognized as a complication after hematopoietic cell transplantation (HCT). Using a nested case-cohort design, we examined the relationships between demographic, therapeutic, and selected cardiovascular disease risk factors among ≥1-year HCT survivors who developed cardiomyopathy before (n = 43) or after (n = 89) 1 year from HCT as compared to a randomly selected subcohort of survivors without cardiomyopathy (n = 444). Genomic data were available for 79 cases and 267 noncases. Clinical and genetic covariates were examined for association with the risk of early or late cardiomyopathy. Clinical risk factors associated with both early- and late-onset cardiomyopathy included anthracycline exposure ≥250 mg/m(2) and pre-existing hypertension. Among late-onset cardiomyopathy cases, the development of diabetes and ischemic heart disease further increased risk. We replicated several previously reported genetic associations among early-onset cardiomyopathy cases, including rs1786814 in CELF4, rs2232228 in HAS3, and rs17863783 in UGT1A6. None of these markers were associated with risk of late-onset cardiomyopathy. A combination of demographic, treatment, and clinical covariates predicted early-onset cardiomyopathy with reasonable accuracy (area under the curve [AUC], .76; 95% confidence interval [CI], .68 to .83), but prediction of late cardiomyopathy was poor (AUC, .59; 95% CI .53 to .67). The addition of genetic polymorphisms with marginal associations (odds ratios ≥1.3) did not enhance prediction for either early- or late-onset cardiomyopathy. Conventional cardiovascular risk factors influence the risk of both early- and late-onset cardiomyopathy in HCT survivors. Although certain genetic markers may influence the risk of early-onset disease, further work is required to validate previously reported findings and to determine how genetic information should be incorporated into clinically useful risk prediction models.
Assuntos
Cardiomiopatias/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Medição de Risco , Sobreviventes , Adulto , Antraciclinas/uso terapêutico , Cardiomiopatias/genética , Estudos de Casos e Controles , Diabetes Mellitus , Predisposição Genética para Doença , Humanos , Hipertensão , Pessoa de Meia-Idade , Isquemia Miocárdica , Valor Preditivo dos Testes , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
α1-Antitrypsin (AAT) is a serine protease inhibitor with anti-inflammatory, antiapoptotic, and immunomodulatory properties. It has therapeutic efficacy in animal models of autoimmune diseases, inflammatory disorders, and transplantation. In a phase I/II open-label single-center study, we administered AAT (Glassia; Baxalta/Kamada, New Ziona, Israel) as salvage therapy to 12 patients with steroid-refractory acute graft-versus-host disease (GVHD). AAT was given i.v. at 2 dose levels over a 15-day course. All patients had grades III or IV GVHD with stage 4 gut involvement. After treatment, plasma AAT levels increased in both cohorts and remained within 2 to 4 mg/mL for the duration of treatment. No clinically relevant toxicities attributable to AAT were observed. GVHD manifestations improved in 8 of 12 patients, and 4 responses were complete. Six patients (50%) were alive at last follow-up (>104 to >820 days). These findings show that AAT is well tolerated and has efficacy in the treatment of steroid-refractory severe acute GVHD. Further studies are warranted.
Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , alfa 1-Antitripsina/farmacologia , Doença Aguda , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Enteropatias/etiologia , Masculino , Pessoa de Meia-Idade , Terapia de Salvação/métodos , Inibidores de Serina Proteinase/farmacologia , Inibidores de Serina Proteinase/uso terapêutico , Esteroides/farmacologia , Esteroides/uso terapêutico , Transplante Homólogo , Resultado do Tratamento , alfa 1-Antitripsina/administração & dosagem , alfa 1-Antitripsina/sangue , alfa 1-Antitripsina/uso terapêuticoRESUMO
There are no validated biomarkers for chronic GVHD (cGVHD). We used a protein microarray and subsequent sequential enzyme-linked immunosorbent assay to compare 17 patients with treatment-refractory de novo-onset cGVHD and 18 time-matched control patients without acute or chronic GVHD to identify 5 candidate proteins that distinguished cGVHD from no cGVHD: CXCL9, IL2Rα, elafin, CD13, and BAFF. We then assessed the discriminatory value of each protein individually and in composite panels in a validation cohort (n = 109). CXCL9 was found to have the highest discriminatory value with an area under the receiver operating characteristic curve of 0.83 (95% confidence interval, 0.74-0.91). CXCL9 plasma concentrations above the median were associated with a higher frequency of cGVHD even after adjustment for other factors related to developing cGVHD including age, diagnosis, donor source, and degree of HLA matching (71% vs 20%; P < .001). A separate validation cohort from a different transplant center (n = 211) confirmed that CXCL9 plasma concentrations above the median were associated with more frequent newly diagnosed cGVHD after adjusting for the aforementioned factors (84% vs 60%; P = .001). Our results confirm that CXCL9 is elevated in patients with newly diagnosed cGVHD.
Assuntos
Quimiocina CXCL9/sangue , Doença Enxerto-Hospedeiro/sangue , Adulto , Doença Crônica , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Terapia de Imunossupressão , Pessoa de Meia-IdadeRESUMO
Clinical trials commonly use adjudication committees to refine endpoints, but observational research or genome-wide association studies rarely do. Our goals were to establish definitions of cause-specific death after unrelated-donor allogeneic hematopoietic cell transplantation (URD-HCT), to estimate discordance between reported and adjudicated cause-specific death, and to identify factors contributing to inconsistency in cause-specific death determination. A consensus panel adjudicated cause-specific death in 1484 patients who died within 1 year after HCT, derived from 3532 acute leukemia or myelodysplasia patients after URD-HCT from 2000 to 2011 reported by 151 US transplant centers to the Center for International Blood and Marrow Transplant Research. Deaths were classified as disease-related or transplant-related. The panel agreed with >99% of deaths reported by centers as disease-related and 80% reported as transplant-related. Year of transplant (cohort effect) and disease status significantly influenced agreement between the panel and centers. Sensitivity analysis of deaths < 100 days post-transplant yielded the lowest agreement between the panel and centers for myelodysplastic syndrome patients. Standard predefined criteria for adjudicating cause-specific death led to consistent application to similar clinical scenarios and clearer delineation of cause-specific death categories. Other studies of competing events such as cancer-specific versus treatment-related mortality would benefit from our results. Our detailed algorithm should result in more consistent reporting of cause-specific death by centers.
Assuntos
Algoritmos , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doadores não Relacionados , Adulto , Idoso , Aloenxertos , Feminino , Seguimentos , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Sclerotic chronic graft-versus-host disease (GVHD) can result in disability after allogeneic hematopoietic cell transplantation. We assessed the incidence and risk factors of sclerosis and its association with transplant outcomes among 977 consecutive patients treated with systemic immunosuppression for chronic GVHD. Sclerosis was defined when cutaneous sclerosis, fasciitis, or joint contracture was first documented in the medical record. Seventy (7%) patients presented with sclerosis at the time of initial systemic treatment for chronic GVHD, and the cumulative incidence of sclerosis increased to 20% at 3 years. Factors associated with an increased risk of sclerosis included the use of a mobilized blood cell graft and a conditioning regimen with > 450 cGy total body irradiation. Factors associated with a decreased risk of sclerosis included the use of an HLA-mismatched donor and a major ABO-mismatched donor. Development of sclerosis was associated with longer time to withdrawal of immunosuppressive treatment but not with risks of overall mortality, nonrelapse mortality, or recurrent malignancy. We found a substantial incidence of sclerosis in patients with chronic GVHD. Development of sclerosis can cause disability but does not affect mortality or recurrent malignancy in patients with chronic GVHD.
Assuntos
Doença Enxerto-Hospedeiro/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença Crônica , Feminino , Antígenos HLA , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Terapia de Imunossupressão/efeitos adversos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Esclerose/epidemiologia , Condicionamento Pré-Transplante/efeitos adversos , Adulto JovemRESUMO
The outcome of allogeneic hematopoietic cell transplantation is influenced by donor/recipient genetic disparity at loci both inside and outside the MHC on chromosome 6p. Although disparity at loci within the MHC is the most important risk factor for the development of severe GVHD, disparity at loci outside the MHC that encode minor histocompatibility (H) antigens can elicit GVHD and GVL activity in donor/recipient pairs who are otherwise genetically identical across the MHC. Minor H antigens are created by sequence and structural variations within the genome. The enormous variation that characterizes the human genome suggests that the total number of minor H loci is probably large and ensures that all donor/recipient pairs, despite selection for identity at the MHC, will be mismatched for many minor H antigens. In addition to mismatch at minor H loci, unrelated donor/recipient pairs exhibit genetic disparity at numerous loci within the MHC, particularly HLA-DP, despite selection for identity at HLA-A, -B, -C, and -DRB1. Disparity at HLA-DP exists in 80% of unrelated pairs and clearly influences the outcome of unrelated hematopoietic cell transplantation; the magnitude of this effect probably exceeds that associated with disparity at any locus outside the MHC.
Assuntos
Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Doadores de Tecidos , Humanos , Prognóstico , Transplante HomólogoRESUMO
Candidate genetic associations with acute GVHD (aGVHD) were evaluated with the use of genotyped and imputed single-nucleotide polymorphism data from genome-wide scans of 1298 allogeneic hematopoietic cell transplantation (HCT) donors and recipients. Of 40 previously reported candidate SNPs, 6 were successfully genotyped, and 10 were imputed and passed criteria for analysis. Patient and donor genotypes were assessed for association with grades IIb-IV and III-IV aGVHD, stratified by donor type, in univariate and multivariate allelic, recessive and dominant models. Use of imputed genotypes to replicate previous IL10 associations was validated. Similar to previous publications, the IL6 donor genotype for rs1800795 was associated with a 20%-50% increased risk for grade IIb-IV aGVHD after unrelated HCT in the allelic (adjusted P = .011) and recessive (adjusted P = .0013) models. The donor genotype was associated with a 60% increase in risk for grade III-IV aGVHD after related HCT (adjusted P = .028). Other associations were found for IL2, CTLA4, HPSE, and MTHFR but were inconsistent with original publications. These results illustrate the advantages of using imputed single-nucleotide polymorphism data in genetic analyses and demonstrate the importance of validation in genetic association studies.
Assuntos
Predisposição Genética para Doença , Glucuronidase/genética , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas , Interleucina-10/genética , Interleucina-2/genética , Interleucina-6/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Doença Aguda , Adulto , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
Unraveling the nature of genetic interactions is crucial to obtaining a more complete picture of complex diseases. It is thought that gene-gene interactions play an important role in the etiology of cancer, cardiovascular, and immune-mediated disease. Interactions among genes are defined as phenotypic effects that differ from those observed for independent contributions of each gene, usually detected by univariate logistic regression methods. Using a multivariate extension of linkage disequilibrium (LD), we have developed a new method, based on distances between sample covariance matrices for groups of single nucleotide polymorphisms (SNPs), to test for interaction effects of two groups of genes associated with a disease phenotype. Since a disease-associated interacting locus will often be in LD with more than one marker in the region, a method that examines a set of markers in a region collectively can offer greater power than traditional methods. Our method effectively identifies interaction effects in simulated data, as well as in data on the genetic contributions to the risk for graft-versus-host disease following hematopoietic stem cell transplantation.
Assuntos
Epistasia Genética , Predisposição Genética para Doença , Desequilíbrio de Ligação , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Simulação por Computador , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Modelos Logísticos , Modelos Estatísticos , Análise MultivariadaRESUMO
The T cell Ig and mucin domain 3 (Tim-3) receptor has been implicated as a negative regulator of adaptive immune responses. We have utilized a proteomic strategy to identify novel proteins associated with graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Mass spectrometry analysis of plasma from subjects with mid-gut and upper-gut GVHD compared with those without GVHD identified increased levels of a protein identified with high confidence as Tim-3. A follow-up validation study using an immunoassay to measure Tim-3 levels in individual plasma samples from 127 patients demonstrated significantly higher plasma Tim-3 concentrations in patients with the more severe mid-gut GVHD, compared with those with upper-gut GVHD (P = .005), patients without GVHD (P = .002), and normal controls (P < .0001). Surface expression of Tim-3 was increased on CD8(+) T cells from patients with grade 2 to 4 acute GVHD (P = .01). Mass spectrometry-based profiling of plasma from multiple subjects diagnosed with common diseases provided evidence for restricted release of soluble Tim-3 in the context of GVHD. These findings have mechanistic implications for the development of novel strategies for targeting the Tim-3 immune regulatory pathway as an approach to improving control of GVHD.