慢性髓系白血病患者尼洛替尼血药浓度与临床疗效相关性的研究

Correlation of Serum Concentration of Nilotinib with Clinical Efficacy in Patients with Chronic Myeloid Leukemia

目的:通过监测慢性髓系白血病慢性期(CML-CP)患者尼洛替尼(NIL)血清谷浓度水平,探讨其与临床疗效及不良反应的关系。方法:根据患者服用NIL剂量将其分为A组(44例),600-800 mg/d;B组(10例),400mg/d。通过液相色谱-单联质谱法分析服用不同剂量NIL治疗的CML-CP患者的血清药物谷浓度,探讨其与患者治疗反应的相关性。结果:54例患者中位NIL血清药物谷浓度为1.71(0.52-5.93)μg/ml,其中A组和B组NIL血清药物谷浓度分别为2.09±1.21μg/ml和0.94±0.27μg/ml,A组非常显著高于B组(P=0.001)。A组中服用NIL治疗12月累计达主要分子学缓解(MMR)者24例,未达MMR者20例;血清药物谷浓度分别为1.70±0.75μg/ml和2.03±0.82μg/ml(P=0.154)。发生Ⅲ-Ⅳ级重度不良反应患者13例,0-Ⅱ级轻度不良反应患者31例;血清药物谷浓度分别为3.09±1.76μg/ml和1.76±0.68μg/ml(P=0.018)。B组服用NIL治疗12月累计达MMR者4例,未达MMR者6例;血清药物谷浓度分别为1.15±0.27μg/ml和0.83±0.24μg/ml(P=0.051)。服用NIL治疗12月累计达MMR比率在A组、B组分别为24/44(54.5%)和4/10(40%),(P=0.494);但Ⅲ-Ⅳ级不良反应发生率在A组、B组分别为13/44(29.5%)、0/10(0%),B组不良反应发生率显著低于A组。结论:CML患者NIL血药浓度个体差异较大,与患者服药剂量及不良反应密切相关,低剂量服用NIL治疗可维持较好的治疗效果且可以明显减少不良反应的发生。

Objective： To investigate the correlation of the serum minimal concentrations（ Cmins） of nilotinib（ NIL）with the clinical efficacy and adverse events（ AEs） in CML patients. Methods： A total of 54 patients were divided into two groups according to the dosage of nilotinib. 44 cases received dose of 600-800 mg/d were classified as group A;while 10 cases received dose of 400 mg/d as group B. The Cmins of nilotinib were determmined by liquid chromatography-tandem mass spectrometry. Results： Median Cmins of nilotinib in 54 patients was 1. 71（ 0. 52-5. 93）μg/ml. Cmins of nilotinib in group A and group B were 2. 09 ± 1. 21 μg/ml and 0. 94 ± 0. 27 μg/ml respectively,Cmins of group A was significantly higher than that of group B（ P = 0. 001）. In group A,24 out of 44 cases obtained major molecular response（ MMR） in 12 months,while 20 cases did not reach MMR in 12 months; the serum drug concentrations were 1. 70 ± 0. 75 μg/ml and 2. 03 ± 0. 82 μg/ml respectively,without statistically significant differences between these 2 subgroups（ P = 0. 154）. However,Cmins of nilotinib in patients with Ⅲ-Ⅳ grade of adverse events were significantly higher than those in patients with 0-Ⅱ grade of adverse events（ 3. 09 ± 1. 76 μg/ml vs 1. 76 ± 0. 68μg/ml）（ P = 0. 018）. There was no statistic diffence in Cmins of nilotinib with MMR in 12 months of group A MMR1. 15 ± 0. 27 μg/ml vs no MMR 0. 83 ± 0. 24 μg/ml（ P = 0. 051）. The MMR rate at 12 months in group A was 54. 5%（ 24/44） and that in group B was 40%（ 4/10）（ P = 0. 494）. But the incidence of grade Ⅲ-Ⅳ adverse events in group A was 29. 5%（ 13/44）,which was significantly higher than that of group B[0/10（ 0%） ]. Conclusion： Cmins of nilotinib shows significant individual differences. The Cmins of nilotinib relate with the dosage and grade Ⅲ-Ⅳ of adverse events. The lower dose of nilotinib may maintain a good therapeutic effect and significantly reduce the adverse events.