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Chronic graft versus host disease (GVHD) is the most common complication of allogenic bone marrow transplantation. Because of the protracted clinical course of chronic GVHD, transplant centers and hematology/oncology offices are inadequately equipped to manage these immuno-incompetent patients with a multi-system disorder. Practitioners need to be able to recognize and effectively manage chronic GVHD as a late effect of more than half of allogenic transplantations. The text is oriented for the clinician, with chapters covering staging, organ site and system-specific manifestations, treatment options, and supportive care. Drs Georgia B. Vogelsang and Steven Z. Pavletic have been pioneers in the recognition of the multi-organ complexity of this disease and have gathered the input of a variety of subspecialist physicians for this book. This book fills the gap in practical literature on chronic GVHD, providing a comprehensive, up-to-date, and clinically relevant resource for anyone who deals with cancer patients post-transplant.
Chronic graft versus host disease (cGVHD) is an alloreactive phenomenon that often complicates allogeneic stem cell transplantation (SCT). Significant progress has been made in acute graft versus host disease (aGVHD) prophylaxis and management. Similar progress in cGVHD has been elusive due to multiple factors, including lack of well defined and prognostically validated classification. This in turn leads to enrollment of a heterogeneous spectrum of cGVHD patients on clinical trials and confounds accurate interpretation of the outcome. Lack of appropriate animal models and the true pathogenesis of this clinical entity with protean manifestations have limited the progress in this field.
The spectrum of allogeneic SCT has increased to include elderly patients and alternative stem cell sources. Advances in critical care, better understanding of infectious disease post SCT and the advent of reduced-intensity and nonmyeloablative conditioning regimens has decreased early mortality after SCT. Thus, the combination of these factors, over time, has lead to an increasing number of patients post SCT at risk for developing cGVHD. Thus it is important to revisit and reaccess cGVHD in the current milleau of SCT.
Chronic graft versus host disease (GVHD) is one of the major barriers to successful outcomes in allogeneic hematopoietic stem cell transplantation (HSCT). Undoubtedly, one of the key problems has been the lack of well-designed prospective clinical trials that test agents in chronic GVHD. Accepted endpoints for chronic GVHD studies are overall survival or permanent discontinuation of immunosuppression. While these endpoints may work for a large phase III trial, they are not acceptable for early phase trials. Moreover, they are endpoints that require one to control for significant confounding variables, thus necessitating larger sample sizes typically only achievable in multisite studies. Patients, investigators, and clinicians need results from smaller early phase studies that may indicate the potential efficacy of a specific agent for treatment of chronic GVHD. Unfortunately, few such early phase trials have been conducted, and the relative absence of clinically meaningful short, intermediate, and longer-term endpoints that can be feasibly and reliably measured may deter investigators from pursuing such drug development trials (Table 14.1).
The imperative to define response criteria that are reliable, valid, and sensitive to clinically important therapeutic change is clear. Chronic GVHD problem is increasing because of the decrease in early transplant-related mortality, more frequent use of donor-lymphocyte infusions, peripheral blood stem cells, increasing age of transplant recipients, and use of more alternative donors.
Bone marrow transplantation has changed remarkably from its earliest days. Patients were transplanted with bone marrow as a last resort for refractory leukemia or aplastic anemia. The transplant procedure required prolonged hospital stays – often months - with significant uncontrolled toxicities from the preparative regimen, limited antimicrobial success, and even more limited ability to prevent or treat acute graft versus host disease (GVHD). The lucky survivors now marvel at how different the experience is for patients receiving allografts as outpatients.
Unfortunately, the same level of improvement has not been seen in chronic GVHD. The reasons for this lack of success are varied – including the latency of chronic GVHD, lack of accepted readily reproducible animal models, and complex underlying immuno-pathology. It is no wonder that patients with this affliction felt like abandoned stepchildren.
Over the last 5 years, there has been both a resurgence of interest and progress in chronic GVHD. To a significant degree, the NIH-sponsored Consensus Conference on Chronic GVHD is responsible for this change. This conference suggested working definitions, standardized staging and response criteria, recommended supportive care measures, and suggested areas for future study. Although the indolent nature of the disease means that clinical progress is going to be time consuming, there has been remarkable progress since the initial NIH-sponsored meeting. One of the main lessons learned is that it is imperative to have transplant centers cooperate in studying this disorder.