Chapter 108. Hematopoietic Cell Transplantation (Part 5)

Graft-versus-Host Disease GVHD is the result of allogeneic T cells that were either transferred with the donors stem cell inoculum or develop from it, reacting with antigenic targets on host cells. GVHD developing within the first 3 months posttransplant is termed acute GVHD, while GVHD developing or persisting beyond 3 months posttransplant is termed chronic GVHD. Acute GVHD most often first becomes apparent 2–4 weeks posttransplant and is characterized by an erythematous maculopapular rash; persistent anorexia or diarrhea, or both; and by liver disease with increased serum levels of bilirubin, alanine and aspartate aminotransferase, and alkaline phosphatase. ...
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Chapter 108. Hematopoietic Cell Transplantation (Part 5) Chapter 108. Hematopoietic Cell Transplantation (Part 5) Graft-versus-Host Disease GVHD is the result of allogeneic T cells that were either transferred withthe donors stem cell inoculum or develop from it, reacting with antigenic targetson host cells. GVHD developing within the first 3 months posttransplant is termedacute GVHD, while GVHD developing or persisting beyond 3 monthsposttransplant is termed chronic GVHD. Acute GVHD most often first becomesapparent 2–4 weeks posttransplant and is characterized by an erythematousmaculopapular rash; persistent anorexia or diarrhea, or both; and by liver diseasewith increased serum levels of bilirubin, alanine and aspartate aminotransferase,and alkaline phosphatase. Since many conditions can mimic acute GVHD,diagnosis usually requires skin, liver, or endoscopic biopsy for confirmation. In allthese organs, endothelial damage and lymphocytic infiltrates are seen. In skin, theepidermis and hair follicles are damaged; in liver, the small bile ducts showsegmental disruption; and in intestines, destruction of the crypts and mucosalulceration may be noted. A commonly used rating system for acute GVHD isshown in Table 108-1. Grade I acute GVHD is of little clinical significance, doesnot affect the likelihood of survival, and does not require treatment. In contrast,grades II to IV GVHD are associated with significant symptoms and a poorerprobability of survival, and they require aggressive therapy. The incidence ofacute GVHD is higher in recipients of stem cells from mismatched or unrelateddonors, in older patients, and in patients unable to receive full doses of drugs usedto prevent the disease. Table 108-1 Clinical Staging and Grading of Acute Graft-versus-HostDisease Clinical Skin Liver— GutStage Bilirubin, µmol/L (mg/dL) 1 Rash body surface 500–1000 mL/d 2 Rash 25–50% 51–103 (3–6) Diarrhea body surface 1000–1500 mL/d 3 Generalized 103–257 (6– Diarrhea erythroderma 15) >1500 mL/d 4 Desquamation >257 (> 15) Ileus and bullae Overall Skin Stage Liver Stage Gut StageClinical Grade I 1–2 0 0 II 1–3 1 1 III 1–3 2–3 2–3 IV 2–4 2–4 2–4 One general approach to the prevention of GVHD is the administration ofimmunosuppressive drugs early after transplant. Combinations of methotrexateand either cyclosporine or tacrolimus are among the most effective and widelyused regimens. Prednisone, anti–T cell antibodies, mycophenolate mofetil, andother immunosuppressive agents have also been or are being studied in variouscombinations. A second general approach to GVHD prevention is removal of Tcells from the stem cell inoculum. While effective in preventing GVHD, T celldepletion is associated with an increased incidence of graft failure and of tumorrecurrence posttransplant; as yet, little evidence suggests that T-cell depletionimproves cure rates in any specific setting. Despite prophylaxis, significant acute GVHD will develop in ~30% ofrecipients of stem cells from matched siblings and in as many as 60% of thosereceiving stem cells from unrelated donors. The disease is usually treated withglucocorticoids, antithymocyte globulin, or monoclonal antibodies targeted againstT cells or T cell subsets. Between 20 and 50% of patients surviving >6 months after allogeneictransplantation will develop chronic GVHD. The disease is more common in olderpatients, in recipients of mismatched or unrelated stem cells, and in those with apreceding episode of acute GVHD. The disease resembles an autoimmunedisorder with malar rash, sicca syndrome, arthritis, obliterative bronchiolitis, andbile duct degeneration and cholestasis. Single-agent prednisone or cyclosporine isstandard treatment at present, although trials of other agents are under way. Inmost patients, chronic GVHD resolves, but it may require 1–3 years ofimmunosuppressive treatment before these agents can be withdrawn without thedisease recurring. Because patients with chronic GVHD are susceptible tosignificant ...