Acute GVHD

Acute GVHD is caused by the alloreactive, donor-derived T cells contained in the graft, which attack nonshared recipient’s antigens on target tissues. A 3-step process generates the clinical syndrome. First, conditioning-induced tissue damage activates recipient antigen-presenting cells (APC), which present recipient alloantigens to the donor T cells transferred with the graft and secrete cytokines, such as interleukin 12, favoring the polarization of T-cell response in the type 1 direction. Second, in response to recipient antigens, donor T cells become activated, proliferate, expand, and generate cytokines such as tumor necrosis factor-α (TNF-α), interleukin 2 (IL-2), and interferon-γ (IFN-γ). In the 3rd step of the process, these cytokines cause tissue damage and promote differentiation of cytotoxic CD8+ T cells, which together with macrophages kill recipient cells and further disrupt tissues.

Acute GVHD usually develops from 2-5 wk post-transplantation. The primary manifestations are an erythematous maculopapular rash, persistent anorexia, vomiting and/or diarrhea, and liver disease with increased serum levels of bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase (Table 131-1). Diagnosis may benefit from skin, liver, or endoscopic biopsy for confirmation. Endothelial damage and lymphocytic infiltrates are seen in all affected organs. The epidermis and hair follicles of the skin are damaged, the hepatic small bile ducts show segmental disruption, and there is destruction of the crypts and mucosal ulceration of the gastrointestinal tract. Grade I acute GVHD (skin rash alone) has a favorable prognosis and often does not require treatment (Fig. 131-1). Grade II GVHD is a moderately severe multiorgan disease requiring therapy. Grade III GVHD is a severe multiorgan disease, and grade IV GVHD is a life-threatening, often fatal condition. The standard prophylaxis of GVHD relies mainly on post-transplant administration of immunosuppressive drugs such as cyclosporine or tacrolimus, often in combination with methotrexate or prednisone, anti–T-cell antibodies, mycophenolate mofetil, or other immunosuppressive agents. An alternative approach that has been widely used in clinical practice is the removal of T lymphocytes from the graft (T-cell depletion). Any form of GVHD prophylaxis in itself may impair post-transplant immunologic reconstitution, increasing the risk of infection-related deaths. T-cell depletion of the graft has also been associated with an increased risk of leukemia recurrence in patients transplanted from an HLA-identical sibling or an unrelated volunteer.

Figure 131-1 Acute graft versus host disease of the skin with ear, arm, shoulder, and trunk involvement.

(Courtesy of Evan Farmer, MD.)

Despite prophylaxis, significant acute GVHD develops in ≈30% of recipients of HSCT from matched siblings and in as many as 60% of HSCT recipients from unrelated donors. The risk of acute GVHD is increased by factors such as diagnosis of malignant disease, older donor and recipient ages, and, in patients given an unmanipulated allograft, GVHD prophylaxis with only 1 drug. However, the most important risk factor for acute GVHD is the present of disparities for HLA-molecules in the donor/recipient pair. Acute GVHD is usually treated with glucocorticoids; about 40-50% of patients show a complete response to steroids. The risk of transplantation-related mortality is much higher in patients who did not respond to steroids than in those showing a complete response. Antithymocyte globulin, mycophenolate mofetil, pentostatin, extracorporeal photopheresis, or monoclonal antibodies targeting molecules expressed on T cells or cytokines during the inflammatory cascade, which underlies the physiopathology of GVHD, have been used in patients with steroid-resistant acute GVHD. There are no clear data showing the superiority of 1 of these approaches over the others. Promising results in children with steroid-resistant acute GVHD have been recently obtained using mesenchymal stromal cells (MSCs).

Chronic GVHD

Chronic GVHD develops or persists >3 mo post-transplant and is the most frequent late complication of allogeneic HSCT, with an incidence of ≈25% in pediatric patients. Chronic GVHD is the major cause of nonrelapse mortality and morbidity in long-term HSCT survivors. Acute GVHD has been recognized as the most important factor predicting the development of the chronic form of the disease. The use of matched unrelated volunteers as donors, and of peripheral blood as the stem cell source, has increased the incidence and severity of chronic GVHD. Other factors that predict occurrence of chronic GVHD include older donor and recipient ages, female donor for male recipient, diagnosis of malignancy, and use of total body irradiation (TBI) as part of the preparative regimen.

Chronic GVHD is a disorder of immune regulation characterized by autoantibody production, increased collagen deposition and fibrosis, and clinical symptoms similar to those seen in patients with autoimmune diseases. The predominant cytokines involved in the pathophysiology of chronic GVHD are usually type II cytokines such as IL-4, IL-5, and IL-13. IL-4 and IL-5 contribute to eosinophilia and B-cell hyperactivity with elevated IgM, IgG, and IgE titers. Associated monoclonal gammopathies indicate clonal dysregulation. Chronic GVHD is dependent on the development and persistence of donor T cells that are not tolerant to the recipient. They could well derive from the original donor inoculum and/or the recipient thymus that has been damaged by acute GVHD. Maturation of transplanted stem cells within a damaged thymus could lead to errors in negative selection and production of cells that have not been tolerized to recipient antigens and are therefore autoreactive or, more accurately, recipient reactive. This ongoing immune reactivity results in clinical features resembling a systemic autoimmune disease with lichenoid and sclerodermatous skin lesions, malar rash, sicca syndrome, arthritis, joint contractures, obliterative bronchiolitis, and bile duct degeneration with cholestasis.

Patients with chronic GVHD involving only the skin and liver have a favorable course (Fig. 131-2). Extensive multiorgan disease may be associated with a very poor quality of life, recurrent infections associated with prolonged immunosuppressive regimens to control GVHD, and a high mortality rate. Morbidity and mortality are highest in patients with a progressive onset of chronic GVHD that directly follows acute GVHD, intermediate in those with a quiescent onset after resolution of acute GVHD, and lowest in patients with de novo onset in the absence of acute GVHD. Single-agent prednisone is standard treatment at present, although other agents, including extracorporeal photopheresis, mycophenolate mofetil, anti-CD20 monoclonal antibody, and pentostatin, have been employed with variable success. Treatment with imatinib mesylate, which inhibits the synthesis of collagen, has been effective in patients with chronic GVHD and sclerotic features. As a consequence of prolonged immunosuppression, patients with chronic GVHD are particularly susceptible to infections and should receive appropriate antibiotic prophylaxis, including trimethoprim-sulfamethoxazole. Chronic GVHD resolves in most patients but may require 1-3 yr of immunosuppressive therapy before the drugs can be withdrawn without the disease recurring. Chronic GVHD also promotes the development of secondary neoplasms.

Figure 131-2 Chronic graft versus host disease of the skin with sclerodermoid changes. See also color plates.

(Courtesy of Evan Farmer, MD.)

Graft failure is a serious complication exposing patients to a high risk of fatal infection. Primary graft failure is defined as failure to achieve a neutrophil count of 0.2 × 10⁹/L by 21 days post-transplant. Secondary graft failure is loss of peripheral blood counts following initial transient engraftment of donor cells. Causes of graft failure after autologous and allogeneic transplantation include transplant of an inadequate stem cell dose (more frequently observed in children given cord blood transplantation), and viral infections such as with cytomegalovirus (CMV) or human herpesvirus type 6 (HHV6), which are often associated with activation of recipient macrophages. However, graft failure after allogeneic transplantation is mainly caused by immunologically mediated rejection of the graft by residual recipient-type T cells that survive the conditioning regimen. Diagnosis of graft failure resulting from immunologic mechanisms is based on examination of peripheral blood and marrow aspirate and biopsy, along with molecular analysis of chimerism status. Persistence of lymphocytes of host origin in allogeneic transplant recipients with graft failure indicates immunologic rejection. The risk of immune-mediated graft rejection is higher in patients given HLA-disparate, T-cell–depleted grafts, reduced-intensity conditioning regimens, and transplantation of low numbers of stem cells, and in recipients who are sensitized toward HLA antigens or, less frequently, minor histocompatibility antigens. Allosensitization develops as a consequence of preceding blood product transfusions and is observed particularly in recipients with aplastic anemia, sickle cell disease, and thalassemia. In HSCT for nonmalignant diseases, such as mucopolysaccharidoses, graft failure is also facilitated by the absence of previous treatment with cytotoxic and immunosuppressive drugs. In thalassemia, graft failure is promoted by expansion of hematopoietic cells. GVHD prophylaxis with methotrexate, an antimetabolite, and anti-infective prophylaxis with trimethoprim-sulfamethoxazole or ganciclovir may also delay engraftment.

Treatment of graft failure usually requires removing all potentially myelotoxic agents from the treatment regimen and attempting a short trial of hematopoietic growth factors, such as G-CSF. A second transplant, usually preceded by a highly immune-suppressive regimen, has to be frequently employed to rescue patients experiencing graft failure. High-intensity regimens are generally tolerated poorly if administered within 100 days of a 1st transplant because of cumulative toxicities.