Higher Peak Tacrolimus Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation Increase the Risk of Endothelial Cell Damage Complications

Noninfectious transplantation-related complications (TRCs) such as graft-versus-host disease (GVHD) and endothelial cell damage (TRC-EC) are critical after allogeneic hematopoietic stem cell transplantation. Tacrolimus (TAC) is used to control GVHD. Hypertension and renal failure are common adverse events after TAC treatment. Higher blood concentrations of TAC would be expected to reduce the risk of GVHD but may increase TRC-EC. TRC-EC often develops in patients with GVHD; thus, it is difficult to clinically determine the proper intensity of immunosuppression. We therefore evaluated the impact of weekly mean/peak TAC blood concentrations (PTCs) on TRC-EC occurrence and prognosis. Patients (N = 295) who received TAC as a GVHD prophylaxis at our institute from 2009 to 2016 were eligible for this retrospective study. Forty-three patients were diagnosed with TRC-EC: 8 with sinusoidal obstructive syndrome, 28 with transplant-associated microangiopathy, and 7 with idiopathic pneumonia syndrome. The cumulative incidence of TRC-EC at 12 months was 13.8% (95% confidence interval [CI] 10.1% to 18.1%). After multivariate analysis high PTCs during days 22 to 28 (hazard ratio [HR] 2.47; 95% CI, 1.37 to 4.45; P < .01) and grades II to IV acute GVHD (HR, 5.61; 95% CI, 2.99 to 10.53; P < .01) were associated with TRC-EC occurrence. The probability of overall survival (OS) at 12 months was 67.7% (95% CI, 61.7% to 73.0%). After multivariate analysis TRC-EC diagnosis (HR, 2.47, 95% CI, 1.59 to 3.83; P < .01) and high-risk disease (HR, 1.75; 95% CI, 1.17 to 2.61; P < .01) were significantly associated with poor OS. In conclusion, higher PTC during days 22 to 28 increased the risk of TRC-EC. TRC-EC development was associated with poor OS.