Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation

Abstract

There is significant variability in the serum concentrations of tacrolimus attained early post transplant due to drug interactions and genomic variation. We evaluated whether tacrolimus concentrations early post transplant correlated with incidence of acute GvHD in 120 consecutive patients allografted with a uniform reduced-intensity conditioning regimen. All patients received standard prophylaxis with oral tacrolimus and IV methotrexate. The primary variable of interest was mean weekly tacrolimus concentrations in the initial 4 weeks post transplant. In multivariate analysis, week 1 tacrolimus concentration was an independent predictor of acute grade 2-4 GvHD (hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.84-0.97; P<0.01). This association was driven by a lower risk of acute grade 2-4 GvHD in patients with week 1 tacrolimus concentrations >12 ng/mL (HR, 0.47; 95% CI, 0.25-0.88; P=0.02). Week 1 tacrolimus concentrations were not associated with chronic GvHD, relapse or overall survival. Lower tacrolimus concentrations at weeks 2, 3 and 4 were not associated with a higher incidence of GvHD. In summary, we found that higher tacrolimus concentrations during the first week after allografting with a reduced-intensity conditioning regimen were associated with significantly reduced risk of acute grade 2-4 GvHD without increasing risk of relapse.

Figure 1

Significant variability in TAC concentrations attained early after RIC HSCT. Box-and-whisker plot showing the distribution of mean weekly TAC concentrations during the first 4 weeks after transplantation.

Figure 2

Significant association between week 1 TAC concentrations and acute grade 2 – 4 GVHD. Multivariable analysis showing adjusted hazard ratios (aHRs) for acute grade 2 – 4 GVHD based on mean TAC concentrations at weeks 1, 2, 3 and 4 after RIC HSCT. The aHRs reflect the increased or decreased risk of acute grade 2 – 4 GVHD for each 1 ng/mL of difference in mean TAC concentration.

Figure 3

Lower risk of acute grade 2 – 4 GVHD in patients with mean week 1 TAC > 12 ng/mL. Cumulative incidence plots showing acute grade 2 – 4 GVHD according to mean week 1 TAC concentrations. Patients in the lower tertile (< 8.5 ng/mL), middle tertile (8.5 – 12 ng/mL), and upper tertile (> 12 ng/mL) are represented by the blue, red and green solid lines, respectively.