Relationship of Tacrolimus Concentration and Incidence of Acute Graft-Versus-Host Disease after Allogenic Stem Cell Transplantation

Abstract

<h3>Introduction</h3> Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Preventing GVHD without impairing the graft-versus-tumor effect remains an important goal for successful allo-HSCT. Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as aGVHD prophylaxis. The influence of TAC has proved effective for preventing aGVHD after allo-HSCT. There is also variability in the serum concentrations of TAC and very little is known on the impact of early (first 4 weeks) TAC levels on aGVHD incidence. <h3>Methods</h3> Data were analyzed for 707 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002- 2016. All patients received standard prophylaxis with TAC daily and methotrexate on days +1, +3, +6, and +11 post allo-HSCT. Tacrolimus dose was adjusted to achieve a target serum level of 5-12 ng/ml. Fine and Gray's proportional hazard models accounting for competing risks were used to evaluate the association between TAC levels and outcome of aGVHD, cGVHD, GVHD-free/relapse-free survival (GRFS),and relapse. Cox proportional hazard models were used for the association with OS. <h3>Results</h3> The mean weekly TAC concentrations at weeks 1, 2, 3 and 4 were 8.0, 9.7, 11.3 and 10.5 ng/mL, respectively. The cumulative incidence of grades II–IV aGVHD was 40% at day 100 and 45% at day 180 post HSCT. In univariable analysis, high TAC level at week 1 was associated with lower grade II-IV aGVHD (Hazard ratio (HR), 0.96; p = 0.006). We examined the effect of week 1 TAC levels categorized into tertiles (< 5.85, 5.85-8.95 and >8.95 ng/ml). Higher level of TAC (>8.95 ng/ml) was associated with lower risk of aGVHD (Figure 1a). In multivariable analysis, week 1 TAC levels > 5.85 ng/ml remained associated with a lower risk of grade II-IV aGVHD. However, only levels of 5.85-8.95 ng/ml were associated with statistically significant lower risk with HR=0.75, p=0.04 compared to the lower group (<5.85 ng/ml), adjusting for conditioning, related donors, HLA match and comorbidity index (CI). Week 1 TAC was also associated with reduced risk of cGVHD at TAC levels >7.2 ng/ml (HR: 0.78, p=0.03). The CI of cGVHD was 41% at 1 year post-allo-HSCT. Week 2 TAC level >10.6 ng/ml was associated with an increased risk of relapse (HR, 1.37, p=0.043) (Figure 1b). The cumulative incidence of relapse at 1, 3 and 5 year post allo-HSCT was 33%, 38% and 40%, respectively. TAC levels at weeks 1, 2, 3 and 4 were not associated with OS. The 1, 3 and 5 year GRFS was 21%, 14% and 12%.TAC levels at any week were not associated with GRFS. <h3>Conclusion</h3> Achieving mean whole-blood level of tacrolimus between 6.0-9.0 ng/ml within the first week post-allogenic bone marrow transplantation may reduce the risk of aGVHD.