Efficacy and Safety of Early Administration of Mycophenolate Mofetil to Steroid-Resistant Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation: A Single Institution Study.

Introduction: Acute graft-versus-host disease (aGVHD) remains a major problem following allogeneic hematopoietic stem cell transplantation (HSCT), and is associated with significant morbidity and mortality. Mycophenolate mofetil (MMF) has been known as a key drug, with which aGVHD and chronic GVHD are treated in Western countries, but it remains unclear when and how MMF is administered to GVHD in Japan. We evaluated the efficacy of treatment with MMF to steroid-resistant aGVHD.

Patients and Methods: For eligibility, thirteen patients were ten men and three women after eighty-eight HSCT in our center from 2001 to 2007, retrospectively. Among them, 6 acute myelogenous leukemia, 2 acute lymphoblastic leukemia, 2 chronic myelogenous leukemia, 2 lymphoblastic lymphoma, and 1 adult T-cell leukemia were diagnosed. Four peripheral bloods, 8 bone marrows and 1 cord blood were transplanted from 2 mothers, 4 siblings and 7 unrelated donors with the conditioning treatments, including 9 total-body irradiation-based regimen, 2 busulfan plus cyclophosphamide and 2 reduced-intensity regimen. The numbers of HLA-mismatch locus were serologically one at 4/6, four at 5/6, and genetically one at 2/6, three at 4/6 and three at 5/6. GVHD prophylaxis included FK506 plus methotrexate (MTX) and/or antithymocyte globulin for 9 patients, and cyclosporine and MTX for 4 patients. Steroid at a dose of 1∼2 mg/kg per day firstly was administered for the treatment of aGVHD of grade II to IV. Then, all of refractory or steroid-tapering-failure cases were treated with the second-line MMF as the steroid-refractory aGVHD, including methylprednisolone pulse therapy in eight.

Results: Max doses of MMF at 1g of three patients, 2g of nine patients and 3g of one patient were required in our cases, but less than in Western countries as reported. Onsets of MMF starting day were from 27 days to 139 days after HSCT, and less than 53 days among them except for one. Target organs were skin (more than stage 3) in seven, skin+gastrointestinal tracts (GI) in four, and skin+GI+liver in two. Acute GVHD grades were II–IV in all and III–IV in six, even though 12 patients were improved and successfully tapered the amounts of steroid. The adverse events were diagnosed as cytopenia in 2 patients (15%) and infectious events in 7 patients (54%) including CMV antigenemia in 5 patients, though were tolerable to all patients except for one, which discontinued MMF due to grade 3 neutropenia. GI tract disorder was not complicated in all patients. As a consequence, relapse mortality was 31% (4/13), but non-relapse mortality was zero percent.

Conclusion: We consider that MMF is more beneficial and well tolerated for the treatment of steroid-refractory aGVHD, and the early administration of MMF as a second-line therapy is more important.