二代酪氨酸激酶抑制剂一线治疗慢性髓性白血病慢性期患者发生严重血细胞减少的相关因素及其对治疗反应和结局的影响

Factors influencing severe cytopenia in chronic phase chronic myeloid leukemia patients receiving initial second generation tyrosine kinase inhibitors and its impact on treatment responses and outcomes

目的探索二代酪氨酸激酶抑制剂(TKI)一线治疗慢性髓性白血病慢性期(CML-CP)患者发生严重血细胞减少的相关因素及其对治疗反应和结局的影响,并建立严重血细胞减少的预测模型。方法纳入2008年9月至2021年11月间在北京大学人民医院确诊并服用二代TKI作为一线治疗的成年CML-CP连续病例。采用二元Logistic模型、Fine-gray模型和Cox回归模型进行分析。结果共收集267例患者,中位年龄36(18~73)岁,男性156例(58.4%),服用尼洛替尼239例(89.5%),达沙替尼28例(10.5%)。43例(16.1%)患者在一线治疗开始后1.0(0.1~3.0)个月发生≥3级中性粒细胞和(或)血小板减少,持续1.0(0.1~24.6)个月。男性(OR=2.9,95%CI 1.2~6.8,P=0.018)、初诊年龄≥36岁(OR=3.2,95%CI 1.4~7.2,P=0.005)、脾脏肋缘下≥7 cm(OR=2.8,95%CI 1.2~6.6,P=0.020)以及HGB<100 g/L(OR=2.9,95%CI 1.3~6.8,P=0.012)与发生≥3级中性粒细胞和(或)血小板减少显著相关。根据回归系数,男性、初诊年龄≥36岁,脾脏肋缘下≥7 cm以及HGB<100 g/L各赋1分,可将患者分为低危、中危和高危3组,各组间血细胞减少发生率差异有统计学意义(P<0.001)。持续>2周的严重血液学不良反应与较低的完全细胞遗传学反应(HR=0.5,95%CI 0.3~0.7,P<0.001)和主要分子学反应(HR=0.4,95%CI 0.3~0.8,P=0.004)获得率显著相关,与二代TKI治疗失败、疾病进展和生存期无关。结论男性、初诊年龄≥36岁、脾脏肋缘下≥7 cm以及HGB<100 g/L与初发CML-CP患者服用二代TKI期间发生严重血细胞减少显著相关,联合四者建立的预测模型有助于识别严重血细胞减少的发生风险。严重血细胞减少持续>2周是细胞遗传学和分子学反应的不利因素。

Objective To explore the influencing covariates of severe neutrophils and/or thrombocytopenia and their effect on treatment response and outcome in patients with chronic-phase chronic myeloid leukemia(CP-CML)receiving initial second-generation tyrosine kinase inhibitors(2G-TKI).Methods Data from consecutive patients aged≥18 years with newly diagnosed CP-CML who received initial 2G-TKI at Peking University People's Hospital from September 2008 to November 2021 were interrogated.Binary logistic regression models and Fine-Gray and Cox regression models were applied.Results Data from 267 patients who received initial 2G-TKI,including nilotinib(n=239,89.5%)and dasatinib(n=28,10.5%),were interrogated.The median age was 36(range,18-73)years,and 156(58.4%)patients were male.At a median treatment period of 1.0(0.1-3.0)month,43(16.1%)patients developed grade≥3 neutrophils and/or thrombocytopenia and recovered within 1.0(0.1-24.6)month.Male(OR=2.9,95%CI 1.2-6.8;P=0.018),age of≥36 years(OR=3.2,95%CI 1.4-7.2,P=0.005),a spleen below a costal margin of≥7 cm(OR=2.8,95%CI 1.2-6.6,P=0.020),and a hemoglobin(HGB)level of<100 g/L(OR=2.9,95%CI 1.3-6.8,P=0.012)at diagnosis were significantly associated with grade≥3 neutrophils and/or thrombocytopenia.Based on their regression coefficients,male,age of≥36 years,a spleen below a costal margin of≥7 cm,and an HGB level of<100 g/L were given 1 point to form a predictive system.All patients were divided into three risk subgroups,and the incidence of severe cytopenia significantly differed among the three groups(P<0.001).Grade≥3 neutrophils and/or thrombocytopenia for>2 weeks was significantly associated with lower cumulative incidences of complete cytogenetic response(CCyR,HR=0.5,95%CI 0.3-0.7,P<0.001)and major molecular response(MMR,HR=0.4,95%CI 0.3-0.8,P=0.004)and was not significantly associated with failure,progression,and survival.Conclusion Male,advanced age,a large spleen,and a low HGB level were significantly associated with severe cytopenia.The four covariates were used to establish a prediction model,in which the incidence of severe cytopenia among different risk groups was significantly different.Severe cytopenia for>2 weeks was a negative factor for responses but not for outcomes.