以门冬酰胺酶为基础化疗方案治疗ⅠE和ⅡE期ENKTL的疗效分析及其与门冬酰胺合成酶表达的关系

The efficacy of asparaginase-based chemotherapy combined with radiotherapy among stage ⅠE/ⅡE ENKTL patients and its relationship to asparagine synthetase expression

目的探讨以左旋门冬酰胺酶(L-ASP)为基础的化疗方案联合放疗治疗ⅠE和ⅡE期结外鼻型NK/T细胞淋巴瘤(ENKTL)患者的疗效,及门冬酰胺合成酶(ASNS)的表达水平与L-ASP治疗ENKTL疗效之间的关系。方法回顾性分析2008年5月至2013年5月ⅠE期和ⅡE期ENKTL患者119例,按治疗方式分为单纯放疗(RT)组(n=27)、CHOP或CHOP样化疗方案联合放疗(RT+CHOP)组(n=33)和以L-ASP为基础的化疗方案联合放疗(RT+L-ASP)组(n=59)。放疗总剂量DT 50~60 Gy,L-ASP 6000 U/m^2静滴,d1~d7。比较RT组、RT+CHOP组和RT+L-ASP组ENKTL患者的疗效;采用RTPCR和免疫组化法分别检测ASNS m RNA和蛋白表达水平,并分析其与疗效之间的关系。结果 RT+L-ASP组的有效率(RR)为91.5%,显著优于RT组的74.1%和RT+CHOP组的69.7%(P=0.007,P=0.030)。RT+L-ASP组的中位总生存时间(OS)为49个月,高于RT组的28个月(P=0.017),但与RT+CHOP组(31个月)的差异无统计学意义(P=0.077);RT+L-ASP组的中位无进展生存时间(PFS)为47个月,高于RT组的25个月和RT+CHOP组的17个月,差异均有统计学意义(P=0.018,P<0.001)。Cox比例风险回归分析显示,Ann Arbor分期和β2微球蛋白是影响OS的独立预后因素;治疗方案和近期疗效是影响PFS的独立因素。3组最常见的不良反应为骨髓抑制和肝肾功能损伤,RT+L-ASP组有8例患者出现过敏反应。近期疗效好的患者的ASNS m RNA和蛋白表达水平明显低于疗效较差的患者。ASNS m RNA表达分别与OS和PFS呈负相关(r=-0.60,P=0.01;r=-0.65,P=0.004);ASNS蛋白表达与OS和PFS亦呈负相关(r=-0.77,P<0.001;r=-0.71,P<0.001)。结论对于ⅠE期和ⅡE期ENKTL患者,以L-ASP为基础的化疗方案联合放疗的疗效优于单纯放疗和CHOP或CHOP样化疗方案联合放疗。ASNS的表达,尤其是蛋白表达水平,可作为L-ASP治疗ⅠE期和ⅡE期ENKTL疗效的预测指标。

Objective To explore the efficacy of L-asparaginase （ L-ASP）-based chemotherapy combined with radiotherapy （RT） treating stage I E/Ⅱ E extranodal NK/T-cell lymphoma, nasal type（ENKTL） and the correlation between efficacy and the ex- pression of asparagine synthetase （ASNS）. Methods We retrospectively reviewed 119 patients with stage [ E/Ⅱ E ENKTL from May 2008 to July 2013. The efficacy of RT group （n = 27 ） , CHOP chemotherapy combined with RT （RT＋CHOP） group （n = 33 ） and L- ASP-based chemotherapy combined with RT（RT＋L-ASP） group （n = 59） were compared. The involved-field radiotherapy dose was be- tween 50 Gy to 60 Gy. L-ASP 6000 U/m2 was intravenously dropped from dI to dT.We also detected the mRNA and protein level of ASNS by RT-PCR and immunochemistry in RT＋L-ASP group. Results The results showed that response rate （RR） in RT＋L-ASP group was 91.5%, significantly higher than 74. 1% in RT group, and 69.7% in RT＋CHOP group（P=0. 007, P=0. 030）. The medi- an overall survival（OS） of RT＋L-ASP group was 49 months, higher than 28 months of RT group（P=0. 017） , and 31 months of RT＋CHOP group（P= 0. 077）. The median progression free survival（PFS） of RT＋L-ASP group was 47 months, higher than 25 months of RT group and 17 months of RT＋CHOP group with significant difference（ P = 0. 018, P〈0. 001 ）. Cox regression model showed that ther- apies and short term efficacy were independent factors influencing PFS of ENKTL. The most common side effects of the 3 groups were hepatic and renal dysfunction, and myelosuppression. Eight patients in RT＋L-ASP group showed anaphylactic reaction. The expression of both ASNS mRNA and protein were lower in patients with better responses. ASNS mRNA was negatively correlated with OS and PFS and protein were both highly negatively（ r=-0. 65, P=0. 01; r=-0. 60, P= 0. 004）, as well as ASNS protein（r=-0. 77, P〈0. 001; r= -0. 71 ,P〈0. 001 ）. Conclusion L-ASP-based chemotherapy combined with RT can improve efficacy of ENKTL patients with stage I E/Ⅱ E, better than RT alone or CHOP chemotherapy in combination with RT. And the expression of ASNS, especially in protein level can serve as a L-ASP efficacy predictor for stage I E/II E ENKTL.