异基因造血干细胞移植术后严重并发症的高危可疑因素：环孢素A与三唑类抗真菌药物的相互作用

Life-threatening complications suspected due to clinical pharmacokinetic interaction between cyclosporine A （CsA） and triazole antifungal agents in allogeneic Hematopoietic Stem Cell Transplantation （allo-HSCT） recipients

目的探讨异基因造血干细胞移植（allo-HSCT）术后三唑类抗真菌药物的应用对免疫抑制剂环孢素A（CsA）的疗效、药物安全性以及患者生存预后的影响。方法回顾性调查2005年以来我所104例接受异基因造血干细胞移植的恶性血液病患者资料,其中12例（11.54﹪）同时应用了三唑类抗真菌药和CsA治疗,并且发生了移植排斥或严重危及生命的并发症。在此,总结分析了此12例中三唑类抗真菌药物对CsA的全血谷浓度、并发症以及患者生存预后可能产生的影响。结果 12例中共分为伊曲康唑预防组5例、伏立康唑治疗组3例和伊曲康唑预防序贯伏立康唑治疗组4例三组。伊曲康唑预防组2例（16.67﹪）患者CsA的剂量和血药浓度均未受伊曲康唑影响,发生急性移植排斥后至今已分别存活46个月和34个月。其余10例（83.33﹪）均获稳定植入;并在应用三唑类抗真菌药物同时下调CsA的剂量,但在不同治疗时期分别出现CsA谷浓度的急剧升高,虽经继续下调CsA的剂量,其全血谷浓度仍高于安全范围;10例中4例（33.33﹪）发生急性移植物抗宿主病（aGVHD）及特发性肺炎综合征（IPS）,2例（16.67﹪）发生aGVHD及弥漫性肺泡出血（DAH）,3例（25﹪）发生进行性多灶性脑白质病（PML）,1例（8.33﹪）发生PML合并急性肝肾功能不全;此10例患者存活时间为46.5（27～105）d,主要死亡原因为非感染性肺部并发症（IPS,DAH）及PML。结论我所这12例病例资料提示CsA与三唑类抗真菌药物的相互作用是allo-HSCT术后严重并发症的发生的高危可疑因素。CsA的全血谷浓度可能无法准确反映CsA的体内代谢情况及临床疗效。临床实践中同时应用三唑类抗真药物和CsA时,除了同时下调CsA的剂量及严密监测血药浓度之外,还应充分认识到二类药物代谢在个体间和个体内所存在的差异性,以实现CsA的个体化合理用药,有效降低造血干细胞移植术后并发症,改善移植患者的生存预后。

Objectives To evaluate the tolerability, toxicity and clinical outcome of the co-administration of CSA and triazole antifungal agents in allo-HSCT recipients. Methods A retrospective review of the medical records of 104 consecutive patients undergoing allo-HSCT for hematologic malignancies at our transplant center over past 5 years was conducted. The causality of administration of CsA in combination with triazole in 12 cases （11.54﹪）with graft rejection or life-threatening complications experiencing supratherapeutic trough levels of CsA were identified and analyzed. Results Out of 12 patients, 5 patients received itraconazole prophylaxis, 3 voriconazole treatment, 4 itraconazole prophylaxis sequenced with voriconazole treatment. 2 cases developed acute graft rejection but still alive, in which CsA dosage and trough levels were not influnenced by the presence of itraconazole prophylaxis. That indicates the trough plasma concentration might be inadequately re？ ect CsA absorption profile. In other 10 patients, the CsA trough levels remained highly than therapeutic range even after gradual tapering of CsA dosage. Shortly after the engraftment, 6 patients （50﹪） developed acute graft-versus-host disease （aGVHD） and, either idiopathic pneumonia syndrome （IPS）or diffuse alveolar hemorrhage （DAH）;Whereas, 3 （25﹪） patients were evaluated with Progressive multi-focal leukoencephalopathy （PML）, 1 （8.33﹪） PML accompanied by acute renal failure and liver dysfunction, that might be ascribed to CsA-related adverse effects. These 10 patients eventually died. The median survival time was 46.5 days and the major causes of death were non-infectious pulmonary complication or PML. Conclusion Although preemptive CsA dosage reduction and the close monitoring of its whole blood trough levels may minimize the drug-toxicity when co-administration with triazole antifungal agents, the different clinical spectrum and different disease evolution post transplant in this group warn that in the setting of hematopoietic cell transplantation with CsA as immunosuppression agent the individual variables influence the drug-exposure and drug-toxicity. Therefore, as clinicians we should not be misleaded by trough plasma concentrations as a routine therapeutic drug monitoring in terms of CsA exposure related efficacy or toxicity, especially when CsA in combination with triazole.