title: Comparison of Tacrolimus and Sirolimus (Tac/Sir) versus Tacrolimus, Sirolimus, and mini-methotrexate (Tac/Sir/MTX) as acute graft-versus-host disease prophylaxis after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation.
abstract: Previous studies have shown that adding sirolimus to a tacrolimus/mini-methotrexate regimen (Tac/Sir/MTX) as graft-versus-host disease (GVHD) prophylaxis produces low rates of acute GVHD (aGVHD) after reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). To assess whether posttransplantation methotrexate MTX can be safely eliminated altogether, we conducted a prospective clinical trial testing the combination of T and Sir alone (tac/sir) as GVHD prophylaxis after RIC SCT from matched related donors. We compared the results with patients who received (Tac/Sir/MTX) as GVHD prophylaxis after RIC SCT from matched related donors in a previous prospective study. Patients in both groups received i.v. fludarabine (Flu) 30 mg/m(2)/day and i.v. busulfan (Bu) 0.8 mg/kg/day on days -5 to -2 as conditioning, followed by transplantation of unmanipulated filgrastim-mobilized peripheral blood stem cells (PBSCS). After transplantation, patients in both groups received Tac and Sir orally starting on day -3, with doses adjusted to achieve trough serum levels of 5 to 10 ng/mL and 3 to 12 ng/mL, respectively. The patients in the Tac/Sir/MTX group also received mini-MTX therapy (5 mg/m(2) i.v.) on days +1, +3, and +6. Filgrastim 5 microg/kg/day s.c. was started on day +1 and continued until neutrophil engraftment. Twenty-nine patients received the Tac/Sir regimen, and 46 patients received the Tac/Sir/MTX regimen. The 2 groups were balanced in terms of age, sex, and disease characteristics. Engraftment was brisk and donor chimerism after transplantation robust in both groups. The cumulative incidence of grade II-IV aGVHD was similar in the 2 groups (17% for Tac/Sir versus 11% for Tac/Sir/MTX; P = .46). There also were no differences between the 2 groups in cumulative incidence of extensive chronic GVHD (cGVHD), treatment-related mortality (TRM), disease relapse, or survival. The Tac/Sir combination for GVHD prophylaxis is well tolerated and associated with a low incidence of aGVHD in matched related donor RIC SCT. The omission of mini-MTX from the Tac/Sir GVHD prophylaxis regimen appears to have no adverse effect on the development of aGVHD.
authors.affiliation: Center for Hematologic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Vincent_Ho@DFCI.Harvard.edu
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.forename: Julie
authors.initials: J
authors.lastname: Aldridge
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000401:mortality / Q000628:therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D011446:Prospective Studies; D012737:Sex Factors; D020123:Sirolimus / Q000008:administration & dosage*; D016559:Tacrolimus / Q000008:administration & dosage*; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus; D008727:Methotrexate