Moiseev Ivan Sergeevich, Burmina Ekaterina Andreevna, Muslimov Albert Radikovich, Pirogova Olga Vladislavovna, Bondarenko Sergey Nikolaevich, Darskaya Elena Igorevna, Tarakanova Yuliya Alexandrovna, Senina Nadegda Georgievna, Afanasyev Boris Vladimirovich
R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia.
Ann Hematol. 2017 Jun;96(6):935-942. doi: 10.1007/s00277-017-2975-0. Epub 2017 Mar 25.
A number of studies were published with contradictory results comparing tacrolimus (Tac) and cyclosporine A (CsA) for graft-versus-host disease (GVHD) prophylaxis, but there are only few that accounted for pharmacokinetic (PK) parameters. In this study, we created a model based on median concentrations, variability of concentrations, and failures to maintain target levels that distinguished patients with low, intermediate, and high risks of acute GVHD (hazard ratios (HR) 1.77, 95%CI 1.36-2.32, p < 0.0001). This model was used to compare 95 patients with CsA and 239 with Tac GVHD prophylaxis. In the multivariate analysis, incorporating PK risk, no differences were observed for grade II-IV acute GVHD (HR 0.73, 95%CI 0.48-1.10, p = 0.13), but grade III-IV acute GVHD was lower in the Tac group (HR 0.47, 95%CI 0.28-0.78, p = 0.004). The observed difference was due to patients with high PK risk (HR 0.377, 95%CI 0.19-0.75, p = 0.005), but not with low and intermediate PK risk (p > 0.05). Patients in the Tac group had better GVHD relapse-free survival (HR = 0.659, p = 0.01) and comparable overall survival (p > 0.05). In conclusion, PK risk should be accounted for in comparisons of GVHD prophylaxis regimens with calcineurin inhibitors, and Tac was superior to CsA in patients with high, but not intermediate and low PK risk.
发表了多项比较他克莫司（Tac）和环孢素A（CsA）预防移植物抗宿主病（GVHD）的研究，结果相互矛盾，但只有少数研究考虑了药代动力学（PK）参数。在本研究中，我们基于中位浓度、浓度变异性以及未能维持目标水平创建了一个模型，该模型区分了急性GVHD低、中、高风险患者（风险比（HR）1.77，95%置信区间1.36 - 2.32，p < 0.0001）。该模型用于比较95例接受CsA预防GVHD的患者和239例接受Tac预防GVHD的患者。在多变量分析中，纳入PK风险后，II - IV级急性GVHD未观察到差异（HR 0.73，95%置信区间0.48 - 1.10，p = 0.13），但Tac组III - IV级急性GVHD较低（HR 0.47，95%置信区间0.28 - 0.78，p = 0.004）。观察到的差异归因于高PK风险患者（HR 0.377，95%置信区间0.19 - 0.75，p = 0.005），而低和中等PK风险患者则无差异（p > 0.05）。Tac组患者的GVHD无复发生存率更好（HR = 0.659，p = 0.01），总生存率相当（p > 0.05）。总之，在比较使用钙调神经磷酸酶抑制剂的GVHD预防方案时应考虑PK风险，Tac在高PK风险患者中优于CsA，但在中等和低PK风险患者中并非如此。
