Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index
Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index
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DOI：
10.1002/ajh.25831
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发表时间：
2020-05-07
影响因子：
12.8
通讯作者：
Braggio, Esteban
中科院分区：
文献类型：
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作者：
Kleinstern, Geffen;O'Brien, Daniel R.;Braggio, Esteban
下一代测序确定了慢性淋巴细胞白血病（CLL）中约60个复发突变的基因。我们检查了复发突变的CLL基因总数的加性预后价值（即，肿瘤突变负荷[TML]）或新诊断的CLL和高计数单克隆B细胞淋巴细胞增多症（HC MBL）中超过CLL国际预后指数（CLL-IPI）的单独突变基因。我们在多阶段设计中对557名个体（112名HC MBL/445名CLL）中的59个基因进行测序，以估计首次治疗时间（TTT）的风险比（HR）和95%置信区间（CI），并根据CLL-IPI和性别进行调整。在发现和验证队列中，TML与TTT较短相关，连续HR的综合估计值= 1.27（CI：1.17-1.39，P = 2.6 x 10（-8）; c-统计量= 0.76）。当按CLL-IPI分层时，TML与TTT的相关性更强，并在低/中等风险范围内得到验证（合并HR = 1.54，CI：1.37-1.72，P = 7.0 x 10（-14））。总体而言，80%具有两个或更多突变基因的低/中度CLL-IPI病例在5年内进展到需要治疗，而没有突变的病例为24%。在HC MBL队列中，TML也与TTT缩短相关（HR = 1.53，CI：1.12-2.07，P = 0.007; c-统计量= 0.71）。TML是TTT独立于CLL-IPI的强预后因子，特别是在低/中等CLL-IPI风险中，并且是比任何单个基因更好的预测因子。在早期阶段进行突变筛查可以改善危险分层，更好地预测TTT。
Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 x 10(-8); c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 x 10(-14)). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.