Background

Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies.

Methods

In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included. Eligible patients had CLL, were previously treated, were aged 18 years or older, had ECOG performance status 0–1, and required further treatment as per the international workshop on CLL 2008 criteria. There was heterogeneity in other eligibility criteria. We evaluated 28 candidate factors known to affect the overall survival of these patients and applied univariate and multivariate analyses to derive the risk score in a training dataset (n=727) of patients treated with ibrutinib or chemoimmunotherapy. We validated the score in an internal-validation dataset (n=242) of patients treated with ibrutinib or chemoimmunotherapy and three external-validation datasets (ibrutinib or chemoimmunotherapy dataset, n=897; venetoclax or chemoimmunotherapy dataset, n=389; and the MCCD [including patients treated with heterogeneous therapies], n=220), applying C-statistics as a measure of discrimination.

Findings

The derived model consisted of four factors (one point each; serum β₂-microglobulin ≥5 mg/dL, lactate dehydrogenase >upper limit of normal, haemoglobin <110 g/L for women or <120 g/L for men, and time from initiation of last therapy <24 months), separating patients into low (score 0–1), intermediate (score 2–3), and high risk (score 4) groups. The risk score was prognostic for overall survival in the training dataset (CS=0·74, 95% CI 0·60–0·85, log-rank p<0·0001), and in the internal-validation (CS=0·79, 0·56–0·97, log-rank p=0·0003), and all three external-validation cohorts (idelalisib or chemoimmunotherapy: CS=0·71, 0·59–0·81, log-rank p<0·0001; venetoclax or chemoimmunotherapy: CS =0·76, 0·66–0·85, log-rank p=0·014; MCCD cohort: CS=0·61, 0·56–0·66), log-rank p<0·0001). The risk score is available on Calculate by QxMD.

Interpretation

We present the first validated risk score to predict overall survival in patients with relapsed or refractory CLL treated with targeted therapy. The model is applicable to patients treated with all currently approved targeted therapies (ibrutinib, idelalisib, and venetoclax) and chemoimmunotherapy. This tool allows the identification of a well defined cohort of previously treated patients with CLL who are at high risk of death, and could be used in future prospective trials to test therapeutic options for these patients with an unmet clinical need.

Funding

Lymphoma Research Foundation, Lymphoma Research Fund (Andrew D Zelenetz), and National Institutes of Health/National Cancer Institute.

中文翻译：

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通过靶向疗法或化学免疫疗法治疗的复发性或难治性慢性淋巴细胞性白血病患者的预后风险评分：一项回顾性，汇总队列研究，并经过外部验证。

背景

对于接受靶向治疗的复发性或难治性慢性淋巴细胞性白血病（CLL）患者，尚无临床验证的总生存期预后模型。我们旨在创建一种预后模型，以识别无法通过可用靶向疗法获得良好结果的高风险个体。

方法

在这项回顾性汇总队列研究中，纳入了2 475例CLL患者，这些患者在2012年6月22日至2015年9月23日之间接受了ibrutinib，艾达拉西布和venetoclax的六项随机试验，或在Mayo Clinic CLL数据库（MCCD）中进行了治疗。符合条件的CLL患者，先前接受过治疗，年龄在18岁或以上，ECOG表现为0-1，并且需要根据国际CLL 2008标准研讨会进行进一步治疗。其他资格标准存在异质性。我们评估了已知会影响这些患者总体生存的28个候选因素，并应用单因素和多因素分析得出了接受依鲁替尼或化学免疫疗法治疗的患者的训练数据集（n = 727）中的风险评分。

发现

派生模型包括四个因子（一个点的每个;血清β ₂-微球蛋白≥5mg / dL，乳酸脱氢酶>正常上限，女性血红蛋白<110 g / L或男性<120 g / L，自上次治疗开始的时间<24个月），将患者分为低（得分0–1），中级（得分2–3）和高风险（得分4）组。在训练数据集中（CS = 0·74，95％CI 0·60-0·85，对数秩p <0·0001）和内部验证（CS = 0），该风险评分对总体生存具有预后性。 ·79，0·56–0·97，log-rank p = 0·0003），以及所有三个外部验证队列（伊德利西伯或化学免疫疗法：CS = 0·71，0·59–0·81，log-rank p <0·0001；静脉曲张或化学免疫疗法：CS = 0·76，0·66-0·85，对数秩p = 0·014； MCCD队列：CS = 0·61，0·56-0·66） ，对数秩p <0·0001）。风险评分可在QxMD的“计算”中获得。

解释

我们提出了第一个经过验证的风险评分，以预测接受靶向治疗的复发性或难治性CLL患者的总体生存率。该模型适用于接受所有当前批准的靶向疗法（依鲁替尼，依达拉西布和威尼托克）和化学免疫疗法治疗的患者。该工具可以识别出高风险死亡的先前治疗过的CLL患者的明确定义，并且可以在未来的前瞻性试验中用于测试这些未满足临床需求的患者的治疗选择。

资金

淋巴瘤研究基金会，淋巴瘤研究基金（Andrew D Zelenetz）和美国国立卫生研究院/国家癌症研究所。