单中心真性红细胞增多症816例生存现状及预后分析

Survival and prognosis of patients with polycythemia vera： a study of 816 patients in a single Chinese center

目的 分析中国真性红细胞增多症（PV）患者生存现状和不良预后的危险因素,以及治疗对预后的影响.方法 回顾性分析自1983年8月至2013年6月于中国医学科学院北京协和医学院血液病医院就诊的816例PV患者资料,其中诊断PV最早时间为1968年12月.与年龄、性别、年度匹配的健康中国人的生存情况对比,计算816例PV患者标准死亡比（SMR）;应用Cox多因素分析的方法对影响PV生存的危险因素进行研究,建立符合我国PV特点的预后模型;研究不同治疗对PV预后的影响;分析JAK2 V617F基因突变负荷（V617F％）与临床特征的相关性.结果 816例PV患者中位随访时间为6（1～42）年.其中预计的10、15和20年生存率分别为89.50％、76.70％和64.70％.与健康中国人对比,PV患者的SMR为17.40（95％ CI：13.71 ～21.78）.Cox多因素分析显示诊断PV时高白细胞（HR=3.10,95％ CI：1.47～6.53,P=0.003）、高年龄（HR=2.89,95％ CI：1.84 ～4.53,P＜0.001）、血栓栓塞史（HR=2.66,95％ CI：1.65 ～4.29,P＜0.001）是影响PV预后不良的危险因素.根据高年龄、高白细胞和血栓栓塞史的HR值权重分别为1分,将PV患者分为低危组（0分,中位生存时间未能得出）、中危1组[1分,中位生存时间为33.10（28.20 ～ 38.00）年]、中危2组[2分,中位生存时间为23.00（16.08 ～ 29.92）年]和高危组[3分,中位生存时间为13.00（10.58 ～15.42）年],高危组死亡的危险是低危组患者的5.37倍.不同治疗组的PV患者预计的10、20年无骨髓纤维化生存率分别为：干扰素α（IFN-α）治疗组89.50％、79.60％,羟基脲治疗组73.80％、43.50％,32P/烷化剂治疗组82.20％和71.40％,无降细胞治疗组80.00％、38.20％,Kaplan-Meier分析显示IFN-α治疗组的无骨髓纤维化生存率较高（Log-rank=9.79,P=0.020）.V617F％≥50％的PV患者发生骨髓纤维化的比率较高（P＜0.001）.结论 PV患者的生存明显差于健康中国人.高白细胞、高年龄、血栓栓塞是影响PV不良预后的危险因素.IFN-α可能通过降低V617F％,减低PV后骨髓纤维化发生的风险。

Objective To explore the survival and the risk factors of poor prognosis in Chinese patients with polycythemia vera （PV）.Methods A total of 816 patients with a definite diagnosis of PV were enrolled from August 1983 to June 2013 into this study.The standardized mortality ratio （SMR） was calculated by comparing the cumulative survival of 816 PV patients with age-and sex-and calendar year-matched healthy Chinese population from the national bureau of statistics of the People＆#39;s Republic of China.The clinical features of diagnosis and prognosis of PV patients were analyzed by Cox regression to identify risk factors for the poor prognosis of PV and to develop a dynamic prognostic model in Chinese patients.The effects of different treatments on the development of acute myelocytic leukemia （AML） and post-PV myelofibrosis （post-PV MF） were determined by Kaplan-Meier analysis.JAK2 V617F allele burden （V617F%） was determined by quantitative real-time PCR in 104 patients.Results The median follow-up time was 6（1-42） years.The 10-,15-and 20-year overall survival （OS） was 89.50%,76.70% and 64.70%,respectively.The SMR was 17.40（95% CI：13.71-21.78）.Cox regression analysis revealed that white blood cell（WBC） count 〉 10 × 109/L（HR =3.10,95% CI：1.47-6.53,P =0.003）,age 〉 60 years（HR =2.89,95% CI：1.84-4.53,P 〈 0.001） and prior thrombosis （HR =2.66,95% CI：1.65-4.29,P 〈0.001）were significant predictors for the poor prognosis of PV.Based on the hazard radio,816 patents were allocated into 4 categories with significantly different survival：low （sum of points =0;median survival no reached）,intermediate 1 （sum of points =1;median survival 33.10（28.20-38.00） years）,intermediate 2 （sum of points =2;median survival 23.00 （16.08-29.92） years）,high （sum of points =3;median survival 13.00（10.58-15.42） years）.The mortality of high risk group was 5.37 fold higher than low risk patients.The 10-and 20-year survival of no post-PV MF were 89.50% and 79.60%,respectively,for interferon α （IFN-α）;73.80% and 43.50%,respectively,for hydroxyurea treatment;82.20% and 71.40%,respectively,for alkylating agent treatment;and 80.00% and 38.20%,respectively,for no cytoreductive treatment.The treatment of exposure to IFN-α associated with a higher rate of no-post-PV MF survival （Log-rank =9.79,P =0.020）.There were more post-PV MF patients with V617F% ≥50% compared with those V617F% 〈 50% （P 〈 0.001）.Conclusions The mortality of PV patients is significantly higher than that of healthy Chinese population.The WBC count 〉 10 × 109/L,age 〉60 years,and prior thrombosis are identified as significant predictors for the prognosis of PV.The risk of post-PV MF transformation may be ameliorated by IFN-α via decreasing the burden of JAK2 V617F mutation.