A high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease

AbstractCorticosteroids remain essential for controlling active chronic graft-versus-host disease (cGVHD). However, the optimum dose and administration schedule is unknown. We have reviewed our results in 61 patients with severe refractory cGVHD who were treated with a high-dose pulse steroid regimen (PS) consisting of methylprednisolone at 10 mg/kg per day for 4 consecutive days, with subsequent tapering doses. After 4 days, all patients received a course of additional immunosuppressive therapy. The median age of the 56 patients who were evaluable for response was 32 years (range, 0.2-57 years). Patients had failed a median of 2 (range, 1-5) treatments prior to the PS. The median follow-up for 45 surviving patients after PS was 1.5 years. The probability of survival at 1 year and 2 years after PS was 88% (95% confidence interval [CI], 76%-95%) and 81% (95% CI, 65%-91%), respectively. Twenty-seven patients (48%) showed a major response to PS with substantial improvement of cGVHD manifestations, including softening of the skin, increased range of motion, and improved performance status; 15 patients (27%) showed a minor response, defined as improvement in some but not all symptoms of cGVHD. Of the 42 responders, 21 (50%) had progression of their cGVHD afterwards. The median time to progression was 1.9 years. The probability of progression at 1 and 2 years after PS was 36% (95% CI, 23%-53%) and 54% (95% CI, 38%-71%), respectively. The probability of progression at 1 year was 25% (95% CI, 12%-47%) and 55% (95% CI, 32%-81%) for patients who had major and minor response, respectively (hazard ratio, 2.13). Ten of the 42 responders (24%) were able to discontinue all systemic immunosuppressive treatments. The probability of discontinuation at 1 and 2 years after PS was 9% (95% CI, 3%-25%) and 27% (95% CI, 15%-48%), respectively. The treatment was well tolerated with no serious adverse events. Our results suggest that PS is a well-tolerated regimen for achieving rapid clinical response in the majority of patients with cGVHD who failed on multiple previous therapies. Further studies are warranted to maintain the efficacy of this regimen by combining with new active agents in cGVHD.Biol Blood Marrow Transplant 2001;7(9):495-502

Gastrointestinal involvement in chronic graft-versus-host disease: A clinicopathologic study

AbstractThe original histopathologic description of chronic graft-versus-host disease (CGVHD) of the gastrointestinal (GI) tract was from autopsy series. There is little information on the evaluation of living patients with CGVHD and GI symptoms. We reviewed data on 40 consecutive patients with CGVHD and persistent GI symptoms who underwent endoscopic examinations. The diagnosis of CGVHD in these 40 patients was made on the basis of clinical criteria and confirmed by histology of other involved organs in 70%. Patients had progressive (in 19 patients, or 48%), quiescent (in 11, or 27%) or de novo–type (in 10, or 25%) onset of their CGVHD. Four groups were defined based on the following histologic criteria: (1) consistent with acute GI GVHD if there was marked apoptosis with or without cryptitis, (2) suggestive of acute GI GVHD if there was scattered apoptosis with or without cryptitis, (3) suggestive of chronic GI GVHD if there were at least 2 histologic indicators of chronicity such as fibrosis and significant crypt distortion, and (4) no histologic evidence of GVHD. Results of microbiologic, radiologic, and malabsorption studies, if performed, were also retrieved. Median time from diagnosis of CGVHD to GI endoscopy was 4.5 months (0-109 months). The major GI symptoms at the time of endoscopy were diarrhea, abdominal pain/cramping, nausea/vomiting, weight loss, dysphagia, and early satiety. The endoscopic examination was nonspecific for the diagnosis of GI GVHD except for diffuse mucosal sloughing. Based on the histologic criteria in 22 patients with biopsies, 13 cases (59%) were considered to have acute GI GVHD, and 3 cases (14%) were felt to show possible chronic GI GVHD; changes of both acute and chronic GVHD were seen in 6 (27%) cases. GI dysmotility was diagnosed in 7 (18%) patients, including 2 of the patients who had histologic changes suggestive of chronic GVHD. Other causes of the GI symptoms included infection, drug side effect, and malabsorption. In conclusion, GI involvement by acute GVHD appears to be a major cause of persistent GI symptoms in patients with chronic GVHD. An isolated form of chronic GI GVHD confirmed by histology is an uncommon phenomenon in the actual clinical setting. © 2003 American Society for Blood and Marrow TransplantationBiology of Blood and Marrow Transplantation 9:46-51 (2003

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

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: • Summarize the current state of the science regarding pathogenic mechanisms of chronic GVHD and critical knowledge gaps. • Develop working hypotheses/overriding concepts for chronic GVHD development. • Define the usefulness of current preclinical models to test working hypotheses and ultimately discover and develop new therapeutic strategies. • Identify shortcomings of preclinical models, and define criteria for the creation of additional models to address these limitations. 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

Ancillary Therapy and Supportive Care of Chronic Graft-versus-Host Disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. Ancillary Therapy and Supportive Care Working Group Report

AbstractThe Ancillary Therapy and Supportive Care Working Group had 3 goals: (1) to establish guidelines for ancillary therapy and supportive care in chronic graft-versus-host disease (GVHD), including treatment for symptoms and recommendations for patient education, preventive measures, and appropriate follow-up; (2) to provide guidelines for the prevention and management of infections and other common complications of treatment for chronic GVHD; and (3) to highlight the areas with the greatest need for clinical research. The definition of “ancillary therapy and supportive care” embraces the most frequent immunosuppressive or anti-inflammatory interventions used with topical intent and any other interventions directed at organ-specific control of symptoms or complications resulting from GVHD and its therapy. Also included in the definition are educational, preventive, and psychosocial interventions with this same objective. Recommendations are organized according to the strength and quality of evidence supporting them and cover the most commonly involved organs, including the skin, mouth, female genital tract, eyes, gastrointestinal tract, and lungs. Recommendations are provided for prevention of infections, osteoporosis, and steroid myopathy and management of neurocognitive and psychosocial adverse effects related to chronic GVHD. Optimal care of patients with chronic GVHD often requires a multidisciplinary approach

Pulmonary Symptoms Measured by the National Institutes of Health Lung Score Predict Overall Survival, Nonrelapse Mortality, and Patient-Reported Outcomes In Chronic Graft-Versus-Host Disease

The 2005 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 non-relapse 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 transplant characteristics and non-lung 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=0.02), overall survival (p=0.02), patient-reported symptoms (p<0.001) and functional status (p<0.001). 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 0–3 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

Acute graft versus host disease

Acute graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues. Activated donor T cells damage host epithelial cells after an inflammatory cascade that begins with the preparative regimen. About 35%–50% of hematopoietic stem cell transplant (HSCT) recipients will develop acute GVHD. The exact risk is dependent on the stem cell source, age of the patient, conditioning, and GVHD prophylaxis used. Given the number of transplants performed, we can expect about 5500 patients/year to develop acute GVHD. Patients can have involvement of three organs: skin (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). One or more organs may be involved. GVHD is a clinical diagnosis that may be supported with appropriate biopsies. The reason to pursue a tissue biopsy is to help differentiate from other diagnoses which may mimic GVHD, such as viral infection (hepatitis, colitis) or drug reaction (causing skin rash). Acute GVHD is staged and graded (grade 0-IV) by the number and extent of organ involvement. Patients with grade III/IV acute GVHD tend to have a poor outcome. Generally the patient is treated by optimizing their immunosuppression and adding methylprednisolone. About 50% of patients will have a solid response to methylprednisolone. If patients progress after 3 days or are not improved after 7 days, they will get salvage (second-line) immunosuppressive therapy for which there is currently no standard-of-care. Well-organized clinical trials are imperative to better define second-line therapies for this disease. Additional management issues are attention to wound infections in skin GVHD and fluid/nutrition management in gastrointestinal GVHD. About 50% of patients with acute GVHD will eventually have manifestations of chronic GVHD

A Multicenter Pilot Evaluation of the National Institutes of Health Chronic Graft-versus-Host Disease (cGVHD) Therapeutic Response Measures: Feasibility, Interrater Reliability, and Minimum Detectable Change

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 four consecutive pilot trials evaluating the feasibility and estimating the inter-rater reliability and minimum detectable change of these response criteria