Salvage therapy for refractory chronic graft-versus-host disease with mycophenolate mofetil and tacrolimus

Abstract

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...

Targeting mycophenolate mofetil for graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation

“…Although not officially licensed, many investigators have used the compound to treat acute and chronic GVHD. 20,21 In addition, MMF was shown to be synergistic with CYA in inducing a stable mixed chimerism after nonmyeloablative conditioning in a large animal model and in subsequent clinical studies. 22,23 Studies on the use of MMF as part of GVHD prophylaxis have been limited in size and mostly inconclusive, as most investigators reported insufficient plasma levels of the active metabolite MPA.…”

Optimal management of chronic graft‐versus‐host disease in children

“…This drug is commonly used for prophylaxis of acute GVHD, in combination with a calcineurin inhibitor, both after cord blood transplantation and reduced intensity regimens (Parikh et al, 2009;Sabry et al, 2009). Single-arm retrospective studies have shown some benefit in terms of improvement of symptoms and steroid reduction in patients receiving MMF as second-line therapy in chronic GVHD (Mookerjee et al, 1999;Lopez et al, 2005). Interestingly, in a double-blind placebo controlled study, when MMF was added to standard therapy to newlydiagnosed patients with chronic GVHD, there was no evidence of benefit from adding MMF .…”

Mycophenolate mofetil for the treatment of acute and chronic GVHD is effective and well tolerated but induces a high risk of infectious complications: a series of 21 BM or PBSC transplant patients

“…18 This immunosuppressive agent might also be useful in the treatment of auto-immune diseases, such as diffuse proliferative lupus nephritis, in combination with prednisolone. 19 Preliminary clinical studies suggest that MMF might be an effective agent for prophylaxis of aGVHD 1,20,21 and/or treatment of acute 22,23 or chronic 14,22 GVHD after allogeneic BMT or PBSCT in adult patients or in children, 24 when administered alone or in combination with other immunosuppressive agents (CsA Ϯ prednisolone, 21,22 tacrolimus 14 ). However, few data are available.…”

“…In the largest series of patients reported by Basara et al, 22 MMF was administered in combination with CsA and prednisolone in 30 patients with acute (21 patients) or chronic (9 patients) GVHD; overall grade improvement of aGVHD was found in 71% of patients and MMF therapy led to moderate improvment in 50% of patients with limited cGVHD. Used as a salvage therapy for refractory GVHD, MMF induced 46% objective response in a series of 26 adult patients, 14 while an overall response rate of 60% (complete and partial response) has been reported in a series of 15 children. 24 The bioavailability of the oral formulation of MMF, especially in patients with GVHD of the bowel, might be an important factor influencing the efficacy of MMF and the use of an i.v.…”

“…However, therapeutic options are limited in cases of resistance to first-line therapy, and alternative treatments including thalidomide, tacrolimus, ultraviolet irradiation and psoralen (PUVA), total lymphoid irradiation, photopheresis, etretinate and clofazimine do not always control GVHD. [12][13][14][15] Mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF, CellCept), selectively suppresses proliferation of T and B lymphocytes, formation of antibodies, and glycosylation of adhesion molecules by inhibiting purine nucleotide synthesis and depleting lymphocytes and monocytes of guanosine triphosphate. 16 MMF is successfully used in the prevention of acute rejection of renal allografts, 17 demonstrating even more efficacy than azathioprine.…”