Summary:Chronic graft-versus-host disease (GVHD) is a common late complication of allogeneic bone marrow transplantation (BMT) and is the principal cause of morbidity and non-relapse mortality. The improved management of acute GVHD has not translated into lower rates of chronic GVHD as older patients undergo allogeneic BMT, more patients receive unrelated or related mismatched allogeneic BMT, and donor lymphocyte infusion is increasingly used for treatment of post-BMT relapses. Patients with high risk chronic GVHD or those who fail on standard therapy have a bad prognosis. Salvage therapies have produced disappointing results. Here, we present a retrospective analysis of 26 patients where a steroid sparing synergistic combination of mycophenolate mofetil (MMF) and tacrolimus was used in refractory chronic GVHD. 46% patients showed an objective response, 11.5% had stable disease, 34.6% had progression and 7.7% were not evaluable. The combination was well tolerated. This promising preliminary result has prompted a trial to assess the safety and efficacy of this regimen in patients with chronic GVHD who have failed prior therapy and to determine if it would improve survival as well as quality of life in such patients. Keywords: chronic graft-versus-host disease; allogeneic bone marrow transplantation; salvage therapy; mycophenolate mofetil; tacrolimus Chronic graft-versus-host disease (GVHD) is the most common late complication of allogeneic bone marrow transplantation (BMT) and is the principal cause of morbidity and non-relapse mortality. In patients diagnosed with chronic GVHD some have a particularly poor prognosis. These patients have certain risk factors such as progressive presentation from acute GVHD, lichenoid histology, hepatic disease (bilirubin Ͼ1.2) or thrombocytopenia. response and a 52% partial response to a combination of alternate day cyclosporine and prednisone in patients with steroid refractory disease. Other forms of treatment including thalidomide, tacrolimus, ultraviolet irradiation and psoralen (PUVA), total lymphoid irradiation, photopheresis, etretinate and clofazimine have been tried with varying degrees of success.
4-12MMF is an ester prodrug of the active immunosuppressant mycophenolic acid that is a noncompetitive reversible inhibitor of inosine monophosphate dehydrogenase. This inhibition blocks the de novo synthesis of guanosine nucleotides that are necessary substrates for DNA and RNA synthesis. Lymphocytes are dependent on this pathway and unlike other cells do not possess salvage pathways. 13 This drug has been shown to be efficacious in several animal models of transplantation in preventing rejection or in reversing ongoing rejection of allogeneic donor organs. 14 Moreover, its clinical efficacy has been successfully tested in multicenter randomized trials for preventing renal transplant rejection. [15][16][17][18] In canine models MMF has been shown to increase the duration of chimerism after DLA identical BMT with suboptimal preparative radiotherapy.19 Tacrolimus (FK-506, Progr...
GVHD can be safely induced by treatment with CSA in women with advanced breast cancer who are receiving high-dose alkylating agents and autologous bone marrow transplantation. The toxicity of this approach is acceptable. Evidence of antitumor efficacy awaits further investigation.
CSA-induced GVHD can be safely augmented by IFN-gamma in women treated with high-dose alkylating agents and autologous bone marrow transplantation. There is little evidence of increased toxicity. Evidence of antitumor efficacy awaits further investigation.
Our results support an association of bleeding with acute GVHD, suggesting that GVHD is a risk factor for bleeding after BMT. The occurrence of bleeding clearly identified poor outcome subgroup within GVHD, suggesting further evaluation for clinical application of bleeding in the assessment of GVHD severity.
Chronic graft-versus-host disease (GVHD) is the most common late complication of allogeneic bone marrow transplantation (BMT). The sclerodermatous form of the disease is often refractory to standard treatment modalities. Based on reports of response to etretinate, a synthetic retinoid, among patients with scleroderma, we have added etretinate to the treatment regimen of 32 patients with refractory sclerodermatous chronic GVHD. This case series is comprised mainly of patients who had chronic GVHD of long duration (median of 30 months before the initiation of etretinate). Most had failed to respond to three or more agents before etretinate treatment was started. Clinical response was assessed after 3 months of therapy. Five patients did not complete a 3-month trial. Among the 27 patients evaluable for response, 20 showed improvement including softening of the skin, flattening of cutaneous lesions, increased range of motion, and improved performance status. Four showed no response after 3 months of therapy and 3 had progression of their sclerosis. Overall, etretinate has been fairly well tolerated in our patients, with skin breakdown and/or ulceration leading to its discontinuation in 6 patients. We believe the results in our patients are encouraging and suggest that further evaluation of etretinate in the treatment of sclerodermatous chronic GVHD is warranted.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.