Comparison of Tacrolimus Versus Cyclosporine with Methotrexate for Immunosuppression after Allogeneic Hematopoietic Cell Transplantation for Severe Aplastic Anemia: A CIBMTR Analysis

Background: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for patients with severe aplastic anemia (SAA), but graft-versus-host disease (GVHD) has been a major impediment to success. Cyclosporine (CSP) has been widely used as GVHD prophylaxis after HCT for SAA, while both CSP and tacrolimus (TAC) have been used after HCT for hematological malignancies. The aim of this study was to compare transplant outcomes according to TAC+methotrexate (MTX) vs. CSP+MTX as GVHD prophylaxis after HCT for SAA using large registry data. Patients and methods:The retrospective cohort included 949 patients who had a first allogeneic bone marrow or growth factor-mobilized peripheral blood cell transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) for treatment of SAA using GVHD prophylaxis with MTX in combination with either TAC or CSP from 2001 to 2011. Patients who had ex-vivo T cell depletion were excluded. Study endpoints included grades II-IV acute GVHD, grades III-IV acute GVHD, chronic GVHD, overall mortality, hematopoietic recovery and graft failure. Multivariate Cox regression models were used to evaluate hazard ratios for endpoints with TAC+MTX as compared with CSP+MTX. A stepwise procedure was used in developing models for each outcome, using a P value threshold of 0.05, with GVHD prophylaxis and year of HCT forced in all models. Analyses were performed separately in SIB (n=631) and URD (n=318) recipients. Results: The median age of patients was 19 (range, 0.5 to 70) years. TAC+MTX was used in 62 SIB recipients (10%) and in 120 (38%) URD recipients, and was used more frequently in older patents than in younger patients in both groups. Multivariate analysis showed a decreased risk of overall mortality with TAC+MTX in URD group and an increased probability of neutrophil recovery with TAC+MTX in SIB group, but other outcomes did not differ statistically between TAC and CSP prophylaxis (Table). Center effect was not statistically associated with overall mortality, and results were similar even after adjustment for center effect. Causes of death were similar between CSP and TAC prophylaxis in both SIB and URD recipients. Conclusion: Based on adjusted multivariate analyses, the use of TAC+MTX was associated with a decreased risk of mortality among URD recipients and with earlier neutrophil recovery among SIB recipients. Results showed no statistically significant differences in other outcomes with the 2 prophylaxis regimens, although power was limited by the number of patients treated with TAC. Our results support the use of either prophylaxis regimen for SIB recipients. TAC+MTX may be favored for URD recipients, but the interpretation of the survival difference remains uncertain, since TAC was not associated with a reduction in the risk of GVHD, causes of death were similar between the 2 prophylaxis regimens, and the actual difference in survival was small between the 2 prophylaxis regimens.

*Adjusted for other covariates.