RESUMO
Treatment of chronic graft-versus-host disease is intended to produce a sustainable benefit by reducing symptom burden, controlling objective manifestations of disease activity, preventing damage and impairment, and improving overall survival without causing disproportionate harms related to the treatment itself. Successful management can control the disease until systemic treatment is no longer needed. The complexity of the disease, the extended duration of follow-up needed to observe disease resolution and withdrawal of immunosuppressive treatment, and the lack of fully developed shorter term endpoints impede progress in the field. Identification and characterization of primary endpoints demonstrating clinical benefit without requiring years of follow-up is urgently needed, with the understanding that clinical benefit encompasses not only the self-evident benefit of the primary endpoint but also any other associated benefits. This report discusses regulatory considerations, eligibility criteria, the value of controlled trial designs, the merits of proposed primary endpoints, and key considerations elaborated from experience and progress during the past decade. The report concludes by mapping an overall approach that could support and lead to maximally informative clinical trials, especially those that seek to demonstrate clinical benefit along a pathway to regulatory review and approval.
Assuntos
Ensaios Clínicos como Assunto/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , História do Século XXI , Humanos , National Institutes of Health (U.S.) , Estados UnidosRESUMO
The 2005 National Institute of Health (NIH) Consensus Conference outlined histopathological diagnostic criteria for the major organ systems affected by both acute and chronic graft-versus-host disease (GVHD). The 2014 Consensus Conference led to this updated document with new information from histopathological studies of GVHD in the gut, liver, skin, and oral mucosa and an expanded discussion of GVHD in the lungs and kidneys. The recommendations for final histological diagnostic categories have been simplified from 4 categories to 3: no GVHD, possible GVHD, and likely GVHD, based on better reproducibility achieved by combining the previous categories of "consistent with GVHD" and "definite GVHD" into the single category of "likely GVHD." Issues remain in the histopathological characterization of GVHD, particularly with respect to the threshold of histological changes required for diagnostic certainty. Guidance is provided for the incorporation of biopsy information into prospective clinical studies of GVHD, particularly with respect to biomarker validation.
Assuntos
Ensaios Clínicos como Assunto , Doença Enxerto-Hospedeiro , Enteropatias , Hepatopatias , Doenças da Boca , Dermatopatias , Biomarcadores/metabolismo , Feminino , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Humanos , Enteropatias/metabolismo , Enteropatias/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Doenças da Boca/metabolismo , Doenças da Boca/patologia , Dermatopatias/metabolismo , Dermatopatias/patologiaRESUMO
The 2006 National Institutes of Health (NIH) Consensus paper presented recommendations by the Ancillary Therapy and Supportive Care Working Group to support clinical research trials in chronic graft-versus-host disease (GVHD). Topics covered in that inaugural effort included the prevention and management of infections and common complications of chronic GVHD, as well as recommendations for patient education and appropriate follow-up. Given the new literature that has emerged during the past 8 years, we made further organ-specific refinements to these guidelines. Minimum frequencies are suggested for monitoring key parameters relevant to chronic GVHD during systemic immunosuppressive therapy and, thereafter, referral to existing late effects consensus guidelines is advised. Using the framework of the prior consensus, the 2014 NIH recommendations are organized by organ or other relevant systems and graded according to the strength and quality of supporting evidence.
Assuntos
Antineoplásicos/uso terapêutico , Doença Enxerto-Hospedeiro/terapia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/uso terapêutico , Transplante de Medula Óssea , Doença Crônica , Consenso , Contraindicações , Gerenciamento Clínico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Humanos , Fármacos Fotossensibilizantes , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante HomólogoRESUMO
The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.
Assuntos
Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Doença Enxerto-Hospedeiro/diagnóstico , Biomarcadores , Doença Crônica , Consenso , Conferências para Desenvolvimento de Consenso de NIH como Assunto , Feminino , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/terapia , Humanos , Masculino , Especificidade de Órgãos , Guias de Prática Clínica como Assunto , Estados UnidosRESUMO
The 2005 National Institutes of Health (NIH) Consensus Conference recommended assessment of lung function in patients with chronic graft-versus-host disease (GVHD) by both pulmonary function tests (PFTs) and assessment of pulmonary symptoms. We tested whether pulmonary measures were associated with nonrelapse mortality (NRM), overall survival (OS), and patient-reported outcomes (PRO). Clinician and patient-reported data were collected serially in a prospective, multicenter, observational study. Available PFT data were abstracted. Cox regression models were fit for outcomes using a time-varying covariate model for lung function measures and adjusting for patient and transplantation characteristics and nonlung chronic GVHD severity. A total of 1591 visits (496 patients) were used in this analysis. The NIH symptom-based lung score was associated with NRM (P = .02), OS (P = .02), patient-reported symptoms (P < .001) and functional status (P < .001). Worsening of NIH symptom-based lung score over time was associated with higher NRM and lower survival. All other measures were not associated with OS or NRM; although, some were associated with patient-reported lung symptoms. In conclusion, the NIH symptom-based lung symptom score of 0 to 3 is associated with NRM, OS, and PRO measures in patients with chronic GVHD. Worsening of the NIH symptom-based lung score was associated with increased mortality.
Assuntos
Doença Enxerto-Hospedeiro/fisiopatologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Pulmão/fisiopatologia , Avaliação de Resultados da Assistência ao Paciente , Adolescente , Adulto , Criança , Pré-Escolar , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Humanos , Pulmão/imunologia , Masculino , National Institutes of Health (U.S.) , Modelos de Riscos Proporcionais , Estudos Prospectivos , Projetos de Pesquisa , Testes de Função Respiratória , Índice de Gravidade de Doença , Análise de Sobrevida , Transplante Homólogo , Estados UnidosRESUMO
The National Institutes of Health global score for chronic graft-versus-host disease was devised by experts but was not based on empirical data. We hypothesized that analysis of prospectively collected data would enable derivation of a more accurate model for estimating mortality risk. We analyzed 574 adult patients with chronic graft-versus-host disease enrolled in a multicenter, observational study, using multivariate time-varying analysis accounting for serial changes in severity of involvement of eight individual organ sites over time. In the training set, severity of skin, mouth, gastrointestinal tract, liver and lung involvement were independently associated with the risk of non-relapse mortality. Weighted mortality points were assigned to individual organs based on the hazard ratios and were summed. The population was divided into three risk groups based on the total mortality points. The three new risk groups were validated in an independent validation set, but did not show better discriminative performance than the National Institutes of Health global score. As compared to a moderate or mild global score, a severe global score was associated with increased risks of non-relapse and overall mortality across time but not with a decreased risk of recurrent malignancy. The National Institutes of Health global score predicts patients' mortality risk throughout the course of their chronic graft-versus-host disease. Further research is required in order to improve outcomes in patients with severe chronic graft-versus-host disease, since their risk of mortality remains elevated.
Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Recidiva Local de Neoplasia , Neoplasias/mortalidade , Neoplasias/patologia , Adulto , Idoso , Doença Crônica , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Neoplasias/complicações , Neoplasias/diagnóstico , Neoplasias/terapia , Índice de Gravidade de Doença , Adulto JovemRESUMO
In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2-year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689.
Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/fisiopatologia , Transplante de Células-Tronco Hematopoéticas , Índice de Gravidade de Doença , Adulto , Idoso , Doença Crônica , Conferências para Desenvolvimento de Consenso de NIH como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo , Estados UnidosRESUMO
To determine whether changes in objective response measures proposed by the National Institutes of Health correlate with clinical benefit, such as symptom burden, quality of life, and survival outcomes, we analyzed data from a multicenter prospective cohort of 283 patients with chronic graft-versus-host disease requiring systemic treatment. The median follow-up time of survivors was 25.1 months (range, 5.4-47.7 months) after enrollment. Symptom measures included the Lee symptom scale and 10-point patient-reported symptoms. Quality-of-life measures included the Short Form-36, Functional Assessment of Cancer Therapy-Bone Marrow Transplantation, and Human Activities Profile. Overall and organ-specific responses were calculated by comparing manifestations at the 6-month visit and those at the enrollment visit using a provisional algorithm. Complete or partial responses were considered "response," and stable or progressive disease was considered "no response." Overall response rate at 6 months was 32%. Organ-specific response rates were 45% for skin, 23% for eyes, 32% for mouth, and 51% for gastrointestinal tract. Response at 6 months, as calculated according to the provisional response algorithm, was correlated with changes in symptom burden in patients with newly diagnosed chronic graft-versus-host disease, but not with changes in quality of life or survival outcomes. Modification of the algorithm or validation of other more meaningful clinical endpoints is warranted for future clinical trials of treatment for chronic graft-versus-host disease.
Assuntos
Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/patologia , Adolescente , Adulto , Idoso , Algoritmos , Criança , Pré-Escolar , Doença Crônica , Olho/imunologia , Olho/patologia , Feminino , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/patologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Boca/imunologia , Boca/patologia , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Pele/imunologia , Pele/patologia , Inquéritos e Questionários , Análise de SobrevidaRESUMO
PURPOSE: To validate measurement scales for rating ocular chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. Candidate scales were recommended for use in clinical trials by the National Institutes of Health (NIH) Chronic GVHD Consensus Conference or have been previously validated in dry eye syndromes. DESIGN: Prospective follow-up study. PARTICIPANTS: Between August 2007 and June 2010, the study enrolled 387 patients with chronic GVHD in a multicenter, prospective, observational cohort. METHODS: Using anchor-based methods, we compared clinician or patient-reported changes in eye symptoms (8-point scale) with calculated changes in 5 candidate scales: The NIH eye score, patient-reported global rating of eye symptoms, Lee eye subscale, Ocular Surface Disease Index, and Schirmer test. Change was examined for 333 follow-up visits where both clinician and patient reported eye involvement at the previous visit. Linear mixed models were used to account for within-patient correlation. MAIN OUTCOME MEASURES: An 8-point scale of clinician or patient-reported symptom change was used as an anchor to measure symptom changes at the follow-up visits. RESULTS: In serial evaluations, agreement regarding improvement, stability, or worsening between the clinician and patient was fair (weighted kappa = 0.34). Despite only fair agreement between evaluators, all scales except the Schirmer test correlated with both clinician-reported and patient-reported changes in ocular GVHD activity. Among all scales, changes in the NIH eye scores showed the greatest sensitivity to symptom change reported by clinicians or patients. CONCLUSIONS: Our results support the use of the NIH eye score as a sensitive measure of eye symptom changes in clinical trials assessing treatment of chronic GVHD.
Assuntos
Técnicas de Diagnóstico Oftalmológico , Síndromes do Olho Seco/diagnóstico , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Perfil de Impacto da Doença , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença Crônica , Conferências para Desenvolvimento de Consenso de NIH como Assunto , Síndromes do Olho Seco/etiologia , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Transplante Homólogo , Estados Unidos , Adulto JovemRESUMO
Steroid refractory chronic graft-versus-host disease (cGVHD) is associated with a significant morbidity and mortality. Although first-line treatment of cGVHD is based on controlled trials, second-line treatment is almost solely based on phase II trials or retrospective analyses. The consensus conference on clinical practice in cGVHD held in Regensburg aimed to achieve a consensus on the current evidence of treatment options as well as to provide guidelines for daily clinical practice. Treatment modalities are the use of steroids and calcineurin inhibitors as well as immunomodulating modalities (photopheresis, mTOR-inhibitors, thalidomide, hydroxychloroquine, vitamin A analogs, clofazimine), and cytostatic agents (mycophenolate mofetil, methotrexate, cyclophosphamide, pentostatin). Recent reports showed some efficacy of rituximab, alemtuzumab, and etanercept in selected patients. Moreover, tyrosine kinase inihibitors such as imatinib came into the field because of their ability to interfere with the platelet-derived growth factor (PDGF-R) pathway involved in fibrosis. An other treatment option is low-dose thoracoabdominal irradiation. Although different treatment options are available, the "trial-and-error system" remains the only way to identify the drug effective in the individual patient, and valid biomarkers are eagerly needed to identify the likelihood of response to a drug in advance. Moreover, the sparse evidence for most treatment entities indicates the urgent need for systematic evaluation of second-line treatment options in cGVHD.
Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Crônica , Tratamento Farmacológico/métodos , Tratamento Farmacológico/tendências , Fibrose/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Humanos , Medicina de Precisão/métodos , Terapia de SalvaçãoRESUMO
The lack of standardized criteria for measuring therapeutic response is a major obstacle to the development of new therapeutic agents for chronic graft-versus-host disease (cGVHD). National Institutes of Health (NIH) consensus criteria for evaluating therapeutic response were published in 2006. We report the results of 4 consecutive pilot trials evaluating the feasibility and estimating the interrater reliability and minimum detectable change of these response criteria. Hematology-oncology clinicians with limited experience in applying the NIH cGVHD response criteria (n = 34) participated in a 2.5-hour training session on response evaluation in cGVHD. Feasibility and interrater reliability between subspecialty cGVHD experts and this panel of clinician raters were examined in a sample of 25 children and adults with cGVHD. The minimum detectable change was calculated using the standard error of measurement. Clinicians' impressions of the brief training session, the photo atlas, and the response criteria documentation tools were generally favorable. Performing and documenting the full set of response evaluations required a median of 21 minutes (range: 12-60 minutes) per rater. The Schirmer tear test required the greatest time of any single test (median: 9 minutes). Overall, interrater agreement for skin and oral manifestations was modest; however, in the third and fourth trials, the agreement between clinicians and experts for all dimensions except movable sclerosis approached satisfactory values. In the final 2 trials, the threshold for defining change exceeding measurement error was 19% to 22% body surface area (BSA) for erythema, 18% to 26% BSA for movable sclerosis, 17% to 21% BSA for nonmovable sclerosis, and 2.1 to 2.6 points on the 15-point NIH Oral cGHVD scale. Agreement between clinician-expert pairs was moderate to substantial for the measures of functional capacity and for the gastrointestinal and global cGVHD rating scales. These results suggest that the NIH response criteria are feasible for use, and these reliability estimates are encouraging, because they were observed following a single 2.5-hour training session given at multiple transplant centers, with no opportunity for iterative training and calibration. Research is needed to evaluate inter- and intrarater reliability in larger samples, and to evaluate these response criteria as predictors of outcomes in clinical trials.
Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença Crônica , Feminino , Hematologia/educação , Humanos , Leucemia/cirurgia , Linfoma/cirurgia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/cirurgia , National Institutes of Health (U.S.) , Projetos Piloto , Estudos Prospectivos , Transplante de Células-Tronco/efeitos adversos , Estados Unidos , Adulto JovemRESUMO
In this issue of Blood, Oliveri and colleagues and Magro and colleagues report pilot trials using imatinib for steroid refractory sclerotic cGVHD,showing response rates of 79%and 50%.
RESUMO
There is no standard therapy for steroid-refractory chronic graft-versus-host disease (GVHD). This problem is particularly daunting in children with chronic GVHD, whereby the effects of the disease and its treatment may impair normal growth and development. Children are also particularly vulnerable to failure and/or toxicity of therapy; for example, joint contractures or joint damage may result in life-long disability. The Pediatric Blood and Marrow Transplant Consortium performed a phase 2 trial of pentostatin for steroid-refractory chronic GVHD in 51 children (median age, 9.8 years) from 24 institutions. Overall response was 53% (95% confidence interval, 40%-64%), with a response of 59% (95% confidence interval, 42%-75%) in sclerosis. Thirteen subjects (25%) had toxicity requiring them to stop pentostatin. The drug had a significant steroid-sparing effect in those that responded. A trend was also observed toward increased survival at 3 years in responders versus nonresponders (69% vs 50%; P = .06). The intravenous administration of the drug ensures compliance in a patient group in which oral therapy is difficult to monitor. Pentostatin has activity in refractory chronic GVHD in children, and future studies, including treatment of children newly diagnosed with high-risk chronic GVHD, are warranted. The trial was registered at www.Clinicaltrials.gov as #NCT00144430.
Assuntos
Antineoplásicos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Pentostatina/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Lactente , Masculino , Neoplasias/cirurgia , Transplante de Células-Tronco/efeitos adversos , Adulto JovemRESUMO
Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation is still associated with significant morbidity and mortality. First-line treatment of cGVHD is based on steroids of 1 mg/kg/day of prednisone. The role of calcineurin inhibitors remains controversial, especially in patients with low risk for mortality (normal platelets counts), whereas patients with low platelets at diagnosis and/or high risk for steroid toxicity may be treated upfront with the combination of prednisone and a calcineurin inhibitor. Additional systemic immunosuppressive agents, like thalidomide, mycophenolic acid, and azathioprine, failed to improve treatment results in the primary treatment of cGVHD and are in part associated with higher morbidity, and in the case of azathioprine, with higher mortality. Despite advances in diagnosis of cGVHD as well as supportive care, half of the patients fail to achieve a long-lasting response to first-line treatment, and infectious morbidity continues to be significant. Therefore, immunomodulatory interventions with low infectious morbidity and mortality such as photopheresis need urgent evaluation in clinical trials. Beside systemic immunosuppression, the use of topical immunosuppressive interventions may improve local response rates and may be used as the only treatment in mild localized organ manifestations of cGVHD.
Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Crônica , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Prednisona/uso terapêuticoRESUMO
Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.
Assuntos
Fibrinolíticos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Polidesoxirribonucleotídeos/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Fibrinolíticos/efeitos adversos , Fibrinolíticos/farmacocinética , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/metabolismo , Hepatopatia Veno-Oclusiva/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/metabolismo , Polidesoxirribonucleotídeos/efeitos adversos , Polidesoxirribonucleotídeos/farmacocinética , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Implementation of the 2014 National Institutes of Health (NIH) response algorithm for joint/fascia graft-versus-host disease (GVHD) has identified real-world limits to its application. To refine the 2014 NIH response algorithm, we analyzed multicenter prospective observational data from the Chronic GVHD Consortium. The training cohort included 209 patients and the replication cohort included 191 patients with joint/fascia involvement during their course of chronic GVHD. Linear mixed models with random patient effect were used to evaluate correlations between response categories and clinician- or patient-perceived changes in joint status as an anchor of response. Analysis of the training cohort showed that a 2-point change in total photographic range of motion (P-ROM) score was clinically meaningful. The results also suggested that a change from 0 to 1 on the NIH joint/fascia score should not be considered as worsening and suggested that both the NIH joint/fascia score and total P-ROM score, but not individual P-ROM scores, should be used for response assessment. On the basis of these results, we developed an evidence-based refined algorithm, the utility of which was examined in an independent replication cohort. Using the refined algorithm, â¼40% of responses were reclassified, largely mitigating most divergent responses among individual joints and changes from 0 to 1 on the NIH joint/fascia score. The refined algorithm showed robust point estimates and tighter 95% confidence intervals associated with clinician- or patient-perceived changes, compared with the 2014 NIH algorithm. The refined algorithm provides a superior, evidence-based method for measuring therapeutic response in joint/fascia chronic GVHD.