Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib: Development and Validation of a Four-Factor Prognostic Model
Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib: Development and Validation of a Four-Factor Prognostic Model
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DOI：
10.1200/jco.20.00979
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发表时间：
2021-02-20
影响因子：
45.3
通讯作者：
Wiestner, Adrian
中科院分区：
文献类型：
--
作者：
Ahn, Inhye E.;Tian, Xin;Wiestner, Adrian
随机试验证实了在慢性淋巴细胞白血病中，以伊替尼为基础的治疗优于化学免疫治疗。伊鲁替尼的无进展生存期（PFS）的持久性可能因患者亚组而异。患者和方法在II期和III期试验中用伊曲替尼治疗的患者提供了发现数据集，并被细分为发现和内部验证队列。一个外部验证队列包括84名患者参加了我们的药物启动的II期试验。使用PFS和总生存期（OS）终点对18个治疗前参数进行单变量分析。多变量分析和机器学习算法确定了预后模型的四个因素，该模型在内部和外部cohols. Results中得到验证，与PFS和OS较差独立相关的因素如下：TP 53畸变，既往治疗，β 2微球蛋白>= 5 mg/L，乳酸脱氢酶> 250 U/L。这四个因素中的每一个都对预后模型贡献了一个点，该模型将患者分为三个风险组：三到四个点，高风险;两个点，中等风险;零到一个点，低风险。所有804例患者的3年PFS率在高、中、低风险组分别为47%、74%和87%（P <0.0001）。3年OS率分别为63%、83%和93%（P < .0001）。当单独应用于初治和复发/难治性队列时，该模型仍具有显著性。对于外部队列中的84例患者，在横断面和进展时检测BTK和PLCG 2突变。突变的累积发生率与模型密切相关。在外部队列中，里希特的转换发生在17%的高风险组，并在没有病人在低风险group.CONCLUSION患者在增加风险的伊鲁替尼失败可以确定在治疗开始，并考虑进行临床试验。(C)2020年美国临床肿瘤学会
PURPOSE Randomized trials established the superiority of ibrutinib-based therapy over chemoimmunotherapy in chronic lymphocytic leukemia. Durability of progression-free survival (PFS) with ibrutinib can vary by patient subgroup. Clinical tools for prognostication and risk-stratification are needed.PATIENTS AND METHODS Patients treated with ibrutinib in phase II and III trials provided the discovery data set and were subdivided into discovery and internal validation cohorts. An external validation cohort included 84 patients enrolled in our investigator-initiated phase II trial. Univariable analysis of 18 pretreatment parameters was performed using PFS and overall survival (OS) end-points. Multivariable analysis and machine-learning algorithms identified four factors for a prognostic model that was validated in internal and external cohorts.RESULTS Factors independently associated with inferior PFS and OS were as follows: TP53 aberration, prior treatment, beta-2 microglobulin >= 5 mg/L, and lactate dehydrogenase > 250 U/L. Each of these four factors contributed one point to a prognostic model that stratified patients into three risk groups: three to four points, high risk; two points, intermediate risk; zero to one point, low risk. The 3-year PFS rates for all 804 patients combined were 47%, 74%, and 87% for the high-, the intermediate-, and the low-risk group, respectively (P < .0001). The 3-year OS rates were 63%, 83%, and 93%, respectively (P < .0001). The model remained significant when applied to treatment-naive and relapsed/refractory cohorts individually. For 84 patients in the external cohort, BTK and PLCG2 mutations were tested cross-sectionally and at progression. The cumulative incidences of mutations were strongly correlated with the model. In the external cohort, Richter's transformation occurred in 17% of the high-risk group, and in no patient in the low-risk group.CONCLUSION Patients at increased risk of ibrutinib failure can be identified at treatment initiation and considered for clinical trials. (C) 2020 by American Society of Clinical Oncology