Tacrolimus, Mini-Methotrexate and Mycophenolate Mofetil Is Safe and Effective as Acute Gvhd Prophylaxis for Non-Myeloablative Unrelated Donor Allogeneic Stem Cell Transplantation.

Acute and chronic graft versus host disease (aGVHD and cGVHD, respectively) cause significant morbidity and mortality following nonmyeloablative unrelated donor transplantation (NMUDT). The incidence of severe aGVHD (grades II-IV) following non-myeloablative transplant and standard GVHD prophylaxis (cyclosporine or tacrolimus plus mini-methotrexate or mycophenolate mofetil (i.e. two drug prophylaxis)) ranges between 40-70%. The incidence of cGVHD ranges between 50-70%. In order to decrease the incidence and severity of acute and chronic GVHD following NMUDT, consecutive patients were given triple prophylaxis therapy with tacrolimus (TAC), mycophenolate mofetil (MMF) and mini-methotrexate (MTX). In addition, patients were given anti-thymocyte globulin (ATG, thymoglobulin 10 mg/kg) as part of preparative therapy.

Thirty-five consecutive patients meeting eligibility criteria for NMUDT were prospectively enrolled. The majority of patients had advanced disease; 9AML, 4 MDS, 2CML, 2MPD, 4 MM, 3CLL, 9 Lymphoma and 2 with aplastic anemia. The mean age was 53 years (26-68); 18 males and 17 females. Preparative therapy consisted of Fludarabine (F) 150mg/m2, Busulfan (Bu) 6.4mg/kg IV and ATG. All patients received stem cells from allele-matched unrelated donors; 9/10 (n= 13) or 10/10 (n= 22) at HLA A, B, C, DR and DQ. Thirteen patients received bone marrow and 22 patients received G-CSF mobilized blood stem cells. All patients received TAC (target 5-10 ug/L), MTX (5mg/m2 d1,3,6,11) and MMF (15mg/kg bid day 0 to 60) for GVHD prophylaxis. Infectious disease prophylaxis included; G-CSF, acyclovir, anti-bacterials, voriconazole, and CMV pre-emptive therapy.

The F/Bu/ATG non-myeloablative regimen was well tolerated. On average, patients experienced little or no mucositis (15% > grade 1), enteritis (3%> grade 1), skin toxicity (3% >grade 1) or liver toxicity (29% > grade 1). No VOD was seen. The median total bilirubin, alkaline phosphatase, ALT, and AST values post-transplant were 1.4 mg/dL, 153 U/L, 91 U/L and 77 U/L, respectively. The incidence of Grades II-IV and III-IV aGVHD were 26% and 6% respectively. No difference in aGVHD for 9/10 vs. 10/10 allele matched donors or those receiving stem cells vs. bone marrow was detected. The 100 day non-relapse mortality (NRM) was 11% (2 GVHD, 1 infection, 1 neurotoxicity). The incidence of cGVHD was 52% (80% extensive cGVHD). The majority of these patients required immunosuppression for >1 year. The 1 year NRM was 20% (2 GVHD, 2 infection, 2 neurotoxicity). Disease relapse was the most common cause of mortality; 37% overall and 17% within the first year of transplantation. The overall survival at 4 years is 41%.

In this prospective study of 35 patients undergoing matched unrelated donor transplantation, the GVHD prophylaxis regimen of TAC/MTX/MMF is safe and effective. The low incidence of aGVHD (26%) compares favorably to published results. Only two patients experienced Grade IV aGVHD within 100 days of transplantation. Chronic GVHD and disease relapse remain problematic. Better strategies to prevent and treat cGVHD and disease relapse are needed.

No relevant conflicts of interest to declare.