慢性髓性白血病患者服用酪氨酸激酶抑制剂期间发生的严重血液学不良反应及其对治疗反应的影响  

Severe hematologic toxicity and its impact on treatment response in newly diagnosed patients with chronic myeloid leukemia receiving tyrosine kinase-inhibitor therapy

作　　者：于露[1] 秦亚溱[1] 赖悦云[1] 石红霞[1] 黄晓军[1] 江倩[1] Yu Lu;Qin Yazhen;Lai Yueyun;Shi Hongxia;Huang Xiaojun;Jiang Qian(Peking University People’s Hospital,Peking University Institute of Hematology,Beijing 100044,China)

机构地区：[1]北京大学人民医院、北京大学血液病研究所,100044

出　　处：《中华血液学杂志》2019年第4期281-287,共7页Chinese Journal of Hematology

摘　　要：目的评估慢性髓性白血病(CML)初诊患者酪氨酸激酶抑制剂(TKI)一线治疗中严重的白细胞和(或)血小板减少的发生率、相关因素及其对治疗反应及生存的影响。方法回顾性分析2001年1月至2018年1月诊治的初诊CML慢性期(CP)或加速期(AP)连续病例资料。结果共收集855例患者的数据,其中523例(61.2%)为男性,中位年龄39(14~87)岁。CP患者744例(87.0%),AP患者111例(13.0%)。一线服用伊马替尼749例(87.6%),尼洛替尼93例(10.9%),达沙替尼13例(1.5%)。137例(16.0%)在中位1.0(0.1~7.0)个月时发生≥3级白细胞和(或)血小板减少,持续0.6(0.3~6.5)个月。多因素分析显示,女性(OR=1.5,95%CI 1.0~2.2,P=0.033)、诊断时WBC ≥100×109/L(OR=1.9,95%CI 1.3~2.8,P=0.001)、CP-Sokal高危(OR=2.2,95%CI 1.2~3.9,P=0.005)和原始细胞增多型AP(OR=5.1,95%CI 1.9~13.3,P=0.001)与≥3级白细胞和(或)血小板减少的发生显著相关。与未发生≥3级白细胞和(或)血小板减少相比,发生≥3级白细胞和(或)血小板减少且停药>2周与较低的完全细胞遗传学反应率(OR=0.4,95%CI 0.3~0.6,P<0.001)显著相关;发生≥3级白细胞和(或)血小板减少,无论停药是否>2周,均与较低的主要分子学反应率(OR=0.3,95%CI 0.2~0.5,P<0.001;OR=0.7,95%CI 0.5~1.0,P=0.036)和MR4.5率(OR=0.2,95%CI 0.1~0.5,P=0.002;OR=0.7,95%CI 0.4~1.1,P=0.110)相关,但不影响疾病进展和生存。结论严重的白细胞和(或)血小板减少是TKI治疗中常见的不良反应,女性、诊断时WBC ≥100×10^9/L和CP-Sokal高危、原始细胞增多型AP是严重的白细胞和(或)血小板减少发生的高危人群。发生严重的白细胞和(或)血小板减少降低了TKI治疗中的细胞遗传学和分子学反应率。Objectives To explore the incidence and factors of severe leukopenia and/or thrombocytopenia in newly diagnosed patients with chronic myeloid leukemia (CML) to probe their impacts on cytogenetic and molecular responses, progression free survival (PFS) and overall survival (OS). Methods Data of newly diagnosed patients with CML in the chronic phase (CP) and/or accelerated phase (AP) were retrospectively collected and analyzed. Results 855 CML patients [including 744 (87%) in the CP and 111 (13.0%) in the AP] were included in this study. 523 (61.2%) patients were male with a median age of 39 years (range, 14-87 years). 749 (87.6%) patients received imatinib, 93 (10.9%) nilotinib, and 13 (1.5%) dasatinib, respectively as front-line therapy. At a median treatment of 1 month (range, 0.1-7.0 months), 137 (16.0%) developed ≥grade 3 leukopenia and/or thrombocytopenia and recovered 0.6 month (range, 0.3-6.5 months). Multivariate analysis showed that female gender (OR=1.5, 95%CI 1.0-2.2, P=0.033), WBC ≥100×109/L (OR=1.9, 95%CI 1.3-2.8, P=0.001), CP in Sokal high-risk (OR=2.2, 95%CI 1.2-3.9, P=0.005), AP with ≥15% blast cells in blood or bone marrow (OR=5.1, 95%CI 1.9-13.3, P=0.001) were factors associated with higher incidence of ≥grade 3 leukopenia and/or thrombocytopenia. Severe leukopenia and/or thrombocytopenia with time of drug discontinuance >2 weeks was associated with lower probabilities of achieving complete cytogenetic (OR=0.4, 95%CI 0.3-0.6, P<0.001), severe leukopenia and/or thrombocytopenia, no matter the time of drug discontinuance >2 weeks or ≤2 weeks, were associated with lower probabilities of achieving major molecular responses (OR=0.3, 95%CI 0.2-0.5, P<0.001;OR=0.7, 95%CI 0.5-1.0, P=0.036) and MR4.5 (OR=0.2, 95%CI 0.1-0.5, P=0.002;OR=0.7, 95%CI 0.4-1.1, P=0.110);however, those had no impacts on PFS and OS. Conclusions Severe leukopenia and/or thrombocytopenia were common adverse events during TKI therapy. Female patients, WBC ≥100×10^9/L at diagnosed, CP in Sokal high-risk, CML-AP with ≥1

关 键 词：白血病 髓系 慢性 BCR-ABL阳性 酪氨酸激酶抑制剂 血液学不良反应 

分 类 号：R733.72[医药卫生—肿瘤]