A mismatch of minor histocompatibility antigen HA-1 can cause GVHD in adult recipients of allogeneic bone marrow from HLA-identical donors. Prospective HA-1 typing may improve donor selection and identify recipients who are at high risk for GVHD.

Cyclophosphamide (Cy) is a potent immunosuppressive agent that is selectively toxic to lymphocytes proliferating in response to recent antigen stimulation. In animal models, both graft rejection and GVHD after histoincompatible BMT can be inhibited by the posttransplantation administration of high-dose Cy. Therefore, a phase I clinical trial was undertaken to determine the minimal conditioning, including posttransplantation Cy, that permits the stable engraftment of partially HLA-mismatched marrow (up to 3 HLA antigens) from first-degree relatives. Thirteen patients (median age, 53 years) with high-risk hematologic malignancies received conditioning with fludarabine, 30 mg/m2 per day from days -6 to -2, and TBI, 2 Gy on day -1. All patients received Cy, 50 mg/kg on day 3, mycophenolate mofetil from day 4 to day 35, and tacrolimus from day 4 to day > or = 50. Three patients in cohort 1 received no additional conditioning, and 2 experienced graft rejection. Ten patients in cohort 2 received identical conditioning with the addition of Cy 14.5 mg/kg on days -6 and -5. Sustained donor cell engraftment occurred in 8 of these patients, with a median time to absolute neutrophil count > 500/microL of 15 days (range, 13-16 days) and to unsupported platelet count > 20,000/microL of 14 days (range, 0-26 days). All patients with engraftment achieved > or = 95% donor chimerism within 60 days of transplantation. Two patients with myelodysplastic syndrome rejected their grafts but experienced autologous neutrophil recovery at 24 and 44 days. Histologic acute GVHD developed in 6 patients (grade II in 3 patients, grade III in 3 patients) at a median of 99 days (range, 38-143 days) after transplantation and was fatal in 1 patient. At a median follow-up of 191 days (range, 124-423 days), 6 of 10 patients in cohort 2 were alive, and 5 were in complete remission of their disease, including both patients with graft rejection. These data demonstrate that partially HLA-mismatched bone marrow can engraft rapidly and stably after nonmyeloablative conditioning that includes posttransplantation Cy. Clinically significant antitumor responses occur, even among patients who reject their donor grafts.

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...

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