真实世界中单中心慢性髓性白血病患者停药状况分析

Analysis on tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia in the real world： experience from single center

目的探讨真实世界中慢性髓性白血病慢性期（CML-CP）患者的酪氨酸激酶抑制剂（TKI）停药状况，分析停药原因及相关因素，以及目前中国CML患者追求无治疗缓解（TFR）的可能性。方法回顾性分析2013年1月至2016年8月在北京大学人民医院就诊的非临床试验的CML—CP患者病例资料。结果共收集662例服用TKI的CML-CP患者的临床资料，TKI治疗后中位随访时间为26（3—187）个月，187例（28．2％）患者曾中断TKI治疗／〉2周，原因包括：血液学不良反应108例（57．8％）、非血液学不良反应57例（30．4％）、经济困难47例（25．1％）和其他13例（7．0％）。多因素分析显示，女性、年龄I〉40岁、无共存疾病、诊断距TKI治疗间隔〉16个月、曾更换TKI和来自外院与因血液学不良反应停药显著相关；女性和来自外院与因非血液学不良反应停药显著相关；曾更换TKI、目前服用仿制品和来自外院与因经济困难而停药显著相关。因血液学、非血液学不良反应和经济困难停药的患者完全细胞遗传学反应率显著低于未停药患者（P值分别为〈0．001、0．025、〈0．001），因血液学不良反应和经济困难停药的患者完全分子学反应（CMR）率显著低于未停药患者（P值均〈0．001）。因血液学不良反应和经济困难停药的患者4年无疾病进展生存率显著低于未停药患者（P值分别为〈0．001、0．023）。7例持续获得CMR后停药的患者中，5例在停药后3（2～32）个月BCR．ABL融合基因转阳。来自外院的39例持续为BCR-ABL阴性的患者中，21例（53．8％）北京大学人民医院检测BCR—ABL为阳性。结论真实世界中，TKI治疗中停药的原因半数为TKI相关血液学不良反应，因非血液学不良反应和经济困难停药者各约占1／4。因血液学不良反应和经济困难停药与不良的治疗结果相关。中国CML患者的治疗现状，距离停药标准尚有很大差距。

Objective To explore status of tyrosine kinase inhibitor （TKI） discontinuation in patients with chronic myeloid leukemia （CML） in the chronic phase （CP） in the real world, to analyze causes, factors and outcomes associated with TKI discontinuation and the possibility of pursuit treatment- free remission （TFR） in China. Methods From January 2013 to August 2016, data of CML-CP patients in Peking University People＇ s Hospital which were not enrolled in clinical trials were retrospectively collected and analyzed. Results Data of 662 CML-CP patients were collected. With a median follow-up after TKI-therapy of 26 months （range, 3-187 months）, 187 patients （28.2%） experienced TKI cessation of at least 2 weeks. Causes of TKI discontinuation included hematologic adverse events 57.8% （n = 108）, non-hematologic adverse events 30.4% （n = 57）, financial burden 25.1% （n = 47）, and others 7.0% （n = 13 ）. Multivariate analyses showed female, ≥40 years, no co-morbidity, and interval from diagnosis to TKI initiation ≥6 months, TKI switch and patients from other hospitals were factors associated with TKI discontinuation because of hematologic adverse effects. Female and patients from other hospitals werefactors associated with TKI discontinuation because of non-hematologic adverse effect. TKI switch, generic TKI used and patients from other hospitals were factors associated with TKI discontinuation because of financial toxicity. Patients TKI discontinuation because of hematologic, non-hematologic or financial toxicity achieved a lower complete cytogenetic response or complete molecular response （CMR） than those with uninterrupted TKI-therapy. Patients with TKI discontinuation because of hematologic or financial toxicity had a shorter progression-free survival than those with uninterrupted TKI-therapy. 5 of 7 patients who obtained sustained CMR and discontinued TK/-therapy experienced disease recurrence with a median duration of 3 months （range, 2-32 months）. In 39 patients from other hospitals who aimed to confirm their optimal response of sustained CMR in Peking University People＇ s Hospital, 21 （53.8%） were BCR-ABL positive. Conclusion In the real world in China, half of CML-CP patients who discontinued TKI-therapy were incurred to TKI-related hematologic adverse effect, and both a quarter of them, TKI- related non-hematologic toxicities and financial toxicity, respectively. Discontinued TKI-therapy due to hematologic adverse events or financial toxicity was associated with lower TKI-therapy response rates. Nowadays, based on the Chinese situation, it is too early to talk about TFR.