PF768 THE INTRAPATIENT VARIABILITY OF BLOOD LEVEL OF TACROLIMUS PREDICTS TRANSPLANT‐ASSOCIATED THROMBOTIC MICROANGIOPATHY
Authors: K. Sagou, S. Ukai, Y. Adachi, N. Fukushima, K. Ozeki, A. Kohno
Journal: HemaSphere (2019)

Background: Tacrolimus (TAC) is a calcineurin inhibitor essential for prophylaxis of acute graft versus host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo‐HSCT). Mean TAC concentration was reported to be associated with the incidence of grade II to IV aGVHD, renal dysfunction, and neurotoxicity. However, most studies were done in the retrospective settings, and TAC was not intentionally controlled in higher or lower concentration in many cases without complications related to TAC. The difference of TAC concentration between patients with and without complications might reflect rapid change of TAC concentration per dose (C/D) affected by complications. On the other hand, we sometimes experience big fluctuation of TAC concentration at early phase after allo‐HSCT. However, the association between variability of concentration or C/D of TAC and clinical complications in allo‐HSCT settings were still ambiguous. Aims: The aim of this study is to clarify the relationship between various parameters of TAC and early complications such as pre‐engraftment immune reactions/engraftment syndrome (PIR/ES), aGVHD, and transplant‐associated thrombotic microangiopathy (TA‐TMA). Methods: Total 149 patients, who underwent first allo‐HSCT and used TAC for GVHD prophylaxis between July 2008 and July 2018 at the Konan Kosei Hospital, were included in our single‐center retrospective analysis. TAC was initiated by intravenous continuous infusion at a starting dose of 0.02 mg/kg/day, and the target concentration was set between 10 and 13 ng/ml. Concentration of TAC was measured three times a week until day 28. Intrapatient variabilities of concentration and C/D of TAC were estimated by coefficient of variance (CV) weekly and throughout the measurement period (day 0–28). Onsets of PIR/ES, aGVHD, and TA‐TMA were assessed from the day of TAC initiation to day 100 after allo‐HSCT. The severest grade of aGVHD was also assessed. Results: The median follow‐up duration from allo‐HSCT was 532 days (range, 7–3309 days), and 54 patients died. Mean concentration and C/D of TAC were not significantly different between patients with and without early post‐transplant complications. CVs for concentration and C/D of TAC during the measurement period were higher in cases developing PIR/ES and those developing TA‐TMA. In weekly analysis, CVs for both concentration and C/D of TAC from day15 to 21 were significantly higher in cases developing PIR/ES and TA‐TMA only in the period from day15 to 21. Especially strong association was observed between higher CV for TAC C/D from day15 to 21 and development of TA‐TMA (P = 0.002). By a receiver operator characteristic curve analysis, the best value of CV for TAC C/D predicting TA‐TMA was 11.8. In the univariate and multivariate analysis for TA‐TMA, CV for TAC C/D ≥ 11.8 and hematopoietic cell transplant‐comorbidity index ≥ 3 were extracted as significant risk factors. Summary/Conclusion: This study showed that intrapatient variability of C/D of TAC was strongly associated with the incidence of TA‐TMA. The usefulness of CV of TAC and the best cutoff point for predicting TA‐TMA need to be verified by multicenter studies. image