Mycophenolate mofetil combined with tacrolimus and minidose methotrexate after unrelated donor bone marrow transplantation with reduced-intensity conditioning

Abstract

We evaluated the efficacy of a post-grafting immunosuppressive regimen consisting of tacrolimus, methotrexate, and mycophenolate mofetil (MMF) in 21 adults (median age, 55 years) with poor-risk hematologic malignancy who underwent unrelated bone marrow transplantation after fludarabine-based reduced-intensity conditioning (RIC). In combination with intravenous tacrolimus and minidose methotrexate (5 mg/m2 on days 1, 3, and 6), MMF was orally administered at 30 mg/kg daily in three divided doses between days 7 and 27. All patients achieved neutrophil recovery with donor-type chimerism at a median of 19 days (range, 13-35). Cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 33% (95% CI, 15-53%) and 5% (95% CI, 0.3-20%), respectively. Five of 20 evaluable patients developed extensive chronic GVHD. Toxicities associated with the use of MMF were acceptable, although one patient experienced intractable GVHD immediately after the cessation of MMF. With a median follow-up of 24 months, overall survival at 3 years was 38% (95% CI, 14-63%). No late graft failure was observed. In conclusion, post-transplant MMF combined with tacrolimus and methotrexate was well tolerated and conferred stable donor cell engraftment, low risk of severe acute GVHD, and encouraging overall survival in unrelated donor marrow transplantation after RIC regimens.

Clinical significance of subcategory and severity of chronic graft-versus-host disease evaluated by National Institutes of Health consensus criteria

“…Patients with malignant hematologic neoplasms received myeloablative or fludarabine-based reduced-intensity conditioning regimens with or without total-body irradiation (TBI) as described elsewhere [27,28]. Patients with aplastic anemia received conditioning regimens consisting of high-dose cyclophosphamide and horse or rabbit antilymphocyte globulin with or without 2-4 Gy TBI.…”

Reduced-intensity conditioning by fludarabine/busulfan without additional irradiation or T-cell depletion leads to low non-relapse mortality in unrelated bone marrow transplantation

“…In RIST using ATG, alemtuzumab, or TBI, the reported incidence of acute GVHD was 19-47% [1][2][3][4][5][6][7], 16-36% [5,[8][9][10], and 3-77% [11][12][13][14][15][16][17][18], respectively. In RIST with TBI, the incidence of acute GVHD tended to be higher than in RIST with T-cell depletion.…”

“…These patients included eleven individuals with acute myeloid leukemia, nine with acute lymphoblastic leukemia (ALL) (including seven Ph-positive ALL), two with refractory anemia with excess blasts II [RAEB II, a variant of myelodysplastic syndrome (MDS)], six with non-Hodgkin's lymphoma, and three with the lymphomatous type of adult T-cell leukemia/lymphoma. All patients had experienced chemotherapy prior to transplantation with a median of six courses of prior chemotherapy (range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Reduced-intensity conditioning was chosen because of age above 50 years (n = 17), cardiac dysfunction (n = 7), prior allogeneic hematopoietic stem cell transplantation (n = 4), prior intense chemotherapy (n = 2), or the patient's choice (n = 1).…”

“…In u-RIST, high rates of graft-versus-host disease (GVHD), graft failure, and nonrelapse mortality (NRM) remain major problems, contributed by the elderly population and/or co-morbidity. Most of the reported conditioning regimens for u-RIST include T-cell depletion with anti-thymocyte globulin (ATG) [1][2][3][4][5][6][7] or alemtuzumab [5,[8][9][10], or low-dose total body irradiation (TBI) [11][12][13][14][15][16][17][18]. Recently, it was reported that the addition of ATG to GVHD prophylaxis resulted in a decreased incidence of acute and chronic GVHD without an increase in relapse or NRM, in a large, prospective, randomized phase 3 trial of myeloablative allogeneic hematopoietic stem cell transplantation with matched, unrelated grafts derived from peripheral blood [19].…”

Prophylactic and therapeutic treatment of graft-versus-host disease in Japan

“…Three retrospective studies [49][50][51] suggested the safety and efficacy of MMF together with Tac or CsA as GVHD prophylaxis. Wakahashi et al [51] reported that the blood concentration of MMF at 2 h after the start of infusion could be a surrogate marker of the area under the curve and helpful for predicting acute GVHD development.…”