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Background: Tacrolimus (TAC) remains the backbone of graft-versus-host disease (GVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT). There is significant variability in the serum concentrations of TAC attained early post-transplant due to drug interactions and genomic variation. Whether a relationship exists between early TAC concentrations and acute GVHD in reduced-intensity conditioning (RIC) HSCT remains poorly characterized.
Methods: We aimed to retrospectively evaluate whether mean weekly TAC concentrations correlate with incidence of acute GVHD in 120 consecutive patients (pts) undergoing first allogeneic HSCT at the University of Pennsylvania between January 2009 and January 2014. All pts received a uniform RIC regimen of fludarabine (120 mg/m2) and busulfan (6.4 mg/kg), followed by infusion of peripheral-blood stem cells from either a related (n=53) or unrelated (n=67) donor. All pts received standard GVHD prophylaxis with oral TAC (0.06 mg/kg/day) beginning day -3 and intravenous methotrexate (15 mg/m2 day +1, 10 mg/m2 days +3, +6, +11). The dose of TAC was adjusted to a target trough of 5 – 15 ng/mL. The primary endpoint was the incidence of acute grade 2 – 4 GVHD. We analyzed mean weekly TAC concentrations as continuous variables up to 4 weeks post-HSCT and then classified pts in tertiles (e.g., week 1: ≤8.5, 8.5 – 12; >12 ng/mL). Univariate analyses were performed using cumulative incidence and Cox regression models. Multivariate models were constructed using the backward elimination method.
Results: The mean TAC concentrations (ranges) at 1, 2, 3, and 4 weeks after RIC HSCT were 10.2 (2.8 – 19.4), 10.6 (3.9 – 23.9), 12.7 (4.2 – 24.1), and 11.9 (2.9 – 29.2) ng/mL, respectively. The day-180 cumulative incidence of acute grade 2 – 4 GVHD was 42.5%. In multivariate analysis, week 1 TAC concentration was an independent predictor of acute grade 2 – 4 GVHD (HR 0.91; 0.84 – 0.97; P=.008). Interestingly, this association was driven by a lower risk of acute grade 2 – 4 GVHD in pts with week 1 TAC concentrations in the upper tertile (>12 ng/mL) (HR 0.47; 0.25 – 0.88; P=.02), as shown in Figure 1. Week 1 TAC concentrations were not predictive of relapse, chronic GVHD, overall survival or non-relapse mortality. In this cohort, 9 pts (7.5%) developed acute kidney injury (AKI) by day 14. Week 1 TAC concentrations were higher in pts who developed AKI compared to those who did not (13.0 vs. 10.0 ng/mL; P=.01). We did not observe an association between TAC concentrations at weeks 2, 3, and 4 and clinical outcomes.
Conclusion: Higher TAC concentrations during the first week after RIC HSCT were associated with significantly reduced risk of acute grade 2 – 4 GVHD without increasing risk of relapse. These data highlight the importance of optimizing initial dosing of TAC in RIC HSCT recipients.
