Impact of tacrolimus time in therapeutic range (TTR) on early post transplantation outcomes

Tacrolimus is a backbone for immunosuppression after allogeneic stem cell transplantation (AlloSCT). There is no sufficient kinetic data demonstrating the consistency of maintaining therapeutic levels. Herein, we measured the kinetic of therapeutic range (TTR) and its impact on outcomes of AlloSCT. Our local observational cohort included 186 adult AlloSCT performed at Hospital Austral between January 2012 and December 2019. An additional external cohort included 307 adult patients with AlloSCT from the University of Utah. We defined adequate TTR as >75 % of the measurements between 5.0 and 15.0 ng/mL during the first 30 days post-transplantation. In our local cohort, 55 % of patients had adequate TTR values. Primary graft failure was significantly lower in patients with adequate TTR (2 %, 95 % CI 0.5-7.7 % vs. 10 %, 95 % CI 5-18 %, p = 0.01). Non relapse mortality (NRM) was significantly lower with adequate TTR (17 %, 95 % CI 11-26 % vs. 33 %, 95 % CI 24-43 %; p < 0.01). Similarly, the external cohort had an NRM value significantly reduced in patients with adequate TTR values. In the pooled data analysis of local and external groups (n = 493), the TTR value below minimal range (≥25 % of measurements <5 ng/mL) was an independent risk factor for graft failure, as well as for NRM rate (44 %, 95 % CI 30-57 % vs. 18 %, 95 % CI 15-22 %) (p < 0.001) and lower OS at 3 years (47 %, 95 % CI 26-55 % vs. 56 %, 95 % CI 49-59 %, p < 0.001). These findings showed the importance of adequate TTRs during the first month after AlloSCTs. Sub-therapeutic TTR values were associated with worse survival outcomes.