Clinical Effects of Tacrolimus Blood Concentrations Early after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (p=0.03) and lower non-relapse mortality (p=0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (p=0.04) and high (p<0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (p=0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (p=0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (p=0.05) and significantly lower (p=0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (p=0.03 and p<0.01, respectively), not treated with anti-thymocyte globulin (p=0.02 and p=0.02, respectively), and receiving three stMTX doses (p=0.03 and p=0.02, respectively). The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.