A B S T R A C T PurposeAllogeneic hematopoietic cell transplantation (HCT) is curative but is associated with lifethreatening complications. Most deaths occur within the first 2 years after transplantation. In this report, we examine long-term survival in 2-year survivors in the largest cohort ever studied. Patients and MethodsRecords of 10,632 patients worldwide reported to the Center for International Blood and Marrow Transplant Research who were alive and disease free 2 years after receiving a myeloablative allogeneic HCT before 2004 for acute myelogenous or lymphoblastic leukemia, myelodysplastic syndrome, lymphoma, or severe aplastic anemia were reviewed. ResultsMedian follow-up was 9 years, and 3,788 patients had been observed for 10 or more years. The probability of being alive 10 years after HCT was 85%. The chief risk factors for late death included older age and chronic graft-versus-host disease (GVHD). For patients who underwent transplantation for malignancy, relapse was the most common cause of death. The greatest risk factor for late relapse was advanced disease at transplantation. Principal risk factors for nonrelapse deaths were older age and GVHD. When compared with age, sex, and nationality-matched general population, late deaths remained higher than expected for each disease, with the possible exception of lymphoma, although the relative risk generally receded over time. ConclusionThe prospect for long-term survival is excellent for 2-year survivors of allogeneic HCT. However, life expectancy remains lower than expected. Performance of HCT earlier in the course of disease, control of GVHD, enhancement of immune reconstitution, less toxic regimens, and prevention and early treatment of late complications are needed.
During the past decade, progress in basic immunology has been impressive. In parallel, whereas our understanding of the pathophysiology of acute graft-versushost disease (GVHD) has greatly improved, so has our knowledge of the complexities of the immune system. Much of the immunobiology of acute GVHD has been gleaned from preclinical models and far less from correlations with clinical observations or therapeutic interventions. In this review, we summarize some of the major advances in GVHD pathophysiology, including the translation of these from the bench to the bedside, and discuss preclinical approaches that warrant further exploration in the clinic. IntroductionMuch of our understanding of the biology of graft-versus-host disease (GVHD) has developed from 2 preclinical animal models, the mouse and the dog (reviewed in Welniak et al, 1 Ferrara et al, 2 Shlomchik, 3 van den Brink and Burakoff, 4 Feinstein et al, 5 and Schleuning 6 ). Because the inbred mouse model has been used as the basis for much of our knowledge of the immunologic mechanisms of GVHD, this review will focus on murine models but also will highlight several aspects of the canine model. Because there are significant species differences between humans and mice, 5 points are important to consider when drawing conclusions from studies with animal models and before correlation to the clinical allogeneic hematopoietic stem cell transplantation (HSCT) scenario (Table 1).GVHD is a complex disease resulting from donor T-cell recognition of a genetically disparate recipient that is unable to reject donor cells after allogeneic HSCT. The classical scheme of GVHD 1,2,7 development includes 5 basic steps.Step 1: priming of the immune response. Cytoreductive conditioning induces tissue damage and the release of a storm of proinflammatory cytokines that promote the activation and maturation of antigen-presenting cells (APCs) and the rapid amplification of donor T cells. [8][9][10] Step 2: T-cell activation and costimulation. Activation occurs as the result of the recognition and interaction of the T-cell receptor (TCR) and costimulatory molecules with their cognate ligands expressed on the surface of the APC.Step 3: alloreactive T-cell expansion and differentiation.Step 4: activated T-cell trafficking. Activated T-cell migration to GVHD target tissues (gut, liver, skin, and lung) is followed by the recruitment of other effector leukocytes. 11 Step 5: destruction of the target tissues by effector T cells. Destruction occurs via exposure to cell surface and release of soluble immune effector molecules. Tissue damage then leads to increased inflammatory signals, perpetuating and augmenting the disease process by contributing to the cytokine storm that fuels GVHD. Previous reviews 1,2,7,8,11,12 have detailed these phases of GVHD initiation and tissue destruction. We will focus on recent advances in GVHD pathophysiology and their translation into clinical knowledge or therapies. In each section, we briefly summarize key experimental data and then provide a persp...
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