尼洛替尼和达沙替尼作为二三线药物治疗慢性髓性白血病慢性期和加速期患者的疗效及影响因素分析

Analysis of the efficacy and influencing factors of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia in the chronic phase and accelerated phase

目的分析二代酪氨酸激酶抑制剂(TKI)尼洛替尼和达沙替尼作为二三线药物治疗慢性髓性白血病(CML)慢性期(CP)和加速期(AP)患者的治疗反应和预后,以及相关影响因素。方法回顾性分析2008年1月至2018年11月北京大学人民医院收治的一二线TKI治疗失败并接受尼洛替尼或达沙替尼作为二三线治疗的CML-CP和AP患者资料。结果共收集183例尼洛替尼和达沙替尼作为二线治疗和43例尼洛替尼和达沙替尼作为三线治疗的CML-CP或AP患者。二线TKI治疗患者中,中位随访21(1~135)个月,完全血液学反应(CHR)率为80.4%,完全细胞遗传学反应(CCyR)率为56.3%,主要分子学反应(MMR)率为38.3%,3年疾病无进展生存(PFS)和总生存(OS)率分别为78.7%和93.1%。二线TKI治疗中,Sokal积分为高危、女性、一线TKI治疗期间获得最佳反应<CHR、诊断CML距转换二线TKI治疗时间≥18个月、二线TKI治疗前为AP/血液学耐药、二线TKI治疗前未检测出BCR-ABL特殊突变、二线治疗中发生≥3级血液学不良反应是获得细胞遗传学或分子学反应或PFS的不利影响因素。三线TKI治疗患者中,中位随访6(3~129)个月,CHR率为95.7%,CCyR率为29.3%,MMR率为18.6%,2年PFS和OS率分别为66.8%和93.8%。三线TKI治疗中,诊断距一线TKI治疗时间≥6个月、二线TKI治疗期间未获得细胞遗传学反应、诊断距三线TKI治疗时间≥60个月或转换治疗前疾病分期为AP患者获得治疗反应的比例显著降低或预后不良。结论尼洛替尼和达沙替尼作为二三线药物可以有效治疗TKI耐药的CML-CP和AP患者,前次TKI治疗期间获得的最佳反应、换药前疾病分期和本次TKI治疗中是否发生≥3级血液学不良反应等因素影响治疗结果。

Objective To explore the efficacy and prognosis of nilotinib or dasatinib as second-or third-line treatment in patients with chronic myeloid leukemia(CML)in the chronic phase(CP)and accelerated phase(AP).Methods From January 2008 to November 2018,the data of CML patients who failed first-or second-line tyrosine kinase inhibitor(TKI)-therapy received nilotinib or dasatinib as second-line and third-line therapy were retrospectively reviewed.Results A total of 226 patients receiving nilotinib or dastinib as second-line(n=183)and third-line(n=43)therapy were included in this study.With a median follow-up of 21(range,1-135)months,the cumulative rates of complete hematological response(CHR),complete cytogenetic response(CCyR)and major molecular response(MMR)were 80.4%,56.3%and 38.3%,respectively in those receiving TKI as second-line TKI therapy.The 3-year progression-free survival(PFS)and overall survival(OS)rates were 78.7%and 93.1%,respectively.Multivariate analyses showed that Sokal high risk,female gender,the best response achieved<CHR on the first-line TKI-therapy,the interval from diagnosis to switching to second-line TKI≥18 months,AP or hematologic failure,or non-specific mutation of BCR-ABL kinase domain before second-line TKI therapy,developing severe hematologic toxicity during the second-line TKI therapy were variables associated with poor responses or outcomes on second-line TKI therapy.With a median follow-up of 6(range,3-129)months,the cumulative CHR,CCyR and MMR were 95.7%,29.3%,and 18.6%,respectively in those receiving the third-line TKI therapy.The 2-year PFS and OS rates were 66.8%and 93.8%,respectively.The patients with an interval from diagnosis to starting TKI≥6 months,achieving no cytogenetic response on the second-line TKI,the interval from diagnosis to starting second-line TKI≥60 months,and progression to AP before the third-line TKI therapy had lower probabilities of responses and unfavorable outcomes.Conclusions The efficacy of dasatinib and nilotinib as second-or third-line TKI-therapy were active in the CML patients with TKI-resistance.The best response achieved on previous TKI-therapy,the disease phase before switching TKI,and the severe hematologic toxicity developing on the current TKI-therapy were associated with the responses and outcomes.