Time in therapeutic range of tacrolimus in allogeneic hematopoietic stem cell transplant recipients is associated with acute graft-versus-host disease prophylaxis

Abstract

Intra-patient variability in immunosuppressive blood drug concentrations is a potential biomarker in managing organ transplant patients. However, the association between the time in therapeutic range of tacrolimus blood concentrations and its efficacy in preventing graft-versus-host disease remains unknown. In this study, we analyzed the relationship between the time in therapeutic range of tacrolimus blood concentrations and its efficacy in acute graft-versus-host disease prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation. Eligible patients administered tacrolimus were categorized into two groups based on the grade of acute graft-versus-host disease, and propensity score matching was performed using graft-versus-host disease prophylaxis protocols and days to the disease onset to compare time in therapeutic range. In patients with tacrolimus blood concentration therapeutic range ≥ 10 ng/mL, time in therapeutic range during the first 4 weeks post-transplantation was significantly lower in the Grade II-III than in the Grade 0-I group. Among propensity score matching-extracted patients, the Grade II-III group had significantly lower time in therapeutic range during the first 2 and 4 weeks post-transplantation. Our results suggest that high time in therapeutic range early post-transplantation, particularly within 4 weeks, may avert the severity of acute graft-versus-host disease.

Keywords: Graft-versus-host disease; Hematopoietic stem cell transplantation; Tacrolimus; Therapeutic drug monitoring; Time in therapeutic range.

Fig. 1

Receiver operating characteristic curve (A) for determining the cut-off value of TTR10 during the first 4 weeks post-transplantation associated with acute GVHD (Grade II–III) development in all transplant episodes. Acute GVHD (Grade II–III) frequency (B) in two groups was categorized based on the TTR10 cut-off value from all transplant episodes. GVHD, graft-versus-host disease; TTR10, time in the therapeutic range at a tacrolimus concentration of ≥ 10 ng/mL.

Fig. 2

TTR10 during the first 4 weeks post-transplantation-based comparison of cumulative incidence of acute GVHD (Grade II–III) during the observation period in all transplant episodes. Solid (n = 14) and dotted lines (n = 66) indicate the Kaplan–Meier curve of the TTR10 ≦ 75.9% and 75.9%< TTR10 groups, respectively. GVHD, graft-versus-host disease; TTR10, time in the therapeutic range at a tacrolimus concentration of ≥ 10 ng/mL.

Fig. 3

Receiver operating characteristic curve (A) for determining the cut-off value of TTR10 during the first 2 weeks post-transplantation associated with acute GVHD (Grade II–III) development in PSM episodes. Acute GVHD (Grade II–III) frequency (B) in two groups classified based on the TTR10 cut-off value from PSM episodes. GVHD, graft-versus-host disease; TTR10, time in the therapeutic range at a tacrolimus concentration of ≥ 10 ng/mL; PSM, propensity score matching.

Fig. 4

Receiver operating characteristic curve (A) for determining the cut-off value of TTR10 during the first 4 weeks post-transplantation associated with acute GVHD (Grade II–III) development in PSM episodes. Acute GVHD (Grade II–III) frequency (B) in two groups classified based on the TTR10 cut-off value from PSM episodes. GVHD, graft-versus-host disease; TTR10, time in the therapeutic range at a tacrolimus concentration of ≥ 10 ng/mL; PSM, propensity score matching.