Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study.
Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study.
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DOI：
10.1016/s1470-2045(15)70106-3
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发表时间：
2015-05
期刊：
影响因子：
51.1
通讯作者：
Wilson, Wyndham H.
中科院分区：
文献类型：
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作者：
Roschewski, Mark;Dunleavy, Kieron;Pittaluga, Stefania;Moorhead, Martin;Pepin, Francois;Kong, Katherine;Shovlin, Margaret;Jaffe, Elaine S.;Staudt, Louis M.;Lai, Catherine;Steinberg, Seth M.;Chen, Clara C.;Zheng, Jianbiao;Willis, Thomas D.;Faham, Malek;Wilson, Wyndham H.
弥漫性大B细胞淋巴瘤（DLBCL）是可治愈的，但当治疗失败时，结果很差。成像扫描有助于识别有治疗失败风险的患者，但通常不精确，辐射暴露是一种潜在的健康风险。需要治疗失败的特异性、敏感性和容易获得的生物标志物。我们回顾性分析了无细胞循环肿瘤DNA（ctDNA）的患者治疗的3种治疗方案之一，使用定量下一代DNA测序。符合条件的患者患有DLBCL，没有惰性淋巴瘤的证据，并且先前未接受过治疗。在大多数治疗周期和5年随访期间的指定时间获得系列血清样本和同步计算机断层扫描。从治疗前标本中扩增重排免疫球蛋白受体基因的VDJ基因片段并测序，并定量编码VDJ重排的血清ctDNA。在126例患者的治疗前标本中确定了肿瘤克隆型，这些患者的中位（四分位距）随访时间为11年（6.8 - 14.2）。108例患者在2个治疗周期结束时的中期ctDNA监测显示，41.7%的患者的至进展时间（TTP）（95%置信区间（CI）：22.2%至60.1%）和80.2%（95%置信区间：69.6%至87.3%），5年时（p<0.0001），阳性和阴性预测值分别为（PPV和NPV）分别为63%和80%。对107例达到完全缓解的患者进行了ctDNA监测。考克斯比例风险模型显示，监测期间出现可检测ctDNA的患者的临床疾病进展风险比是未检测到ctDNA的患者的228倍（95% CI：51至1022）（p<0.0001）。监测ctDNA的PPV和NPV分别为88%和98%，并在临床疾病证据出现前3.5个月（0至200）的中位数（范围）内确定复发。在大多数患者中，监测ctDNA在疾病的临床证据之前识别处于复发风险的患者，并且在复发时导致较低的疾病负担。中期ctDNA是一种有前途的生物标志物，用于识别治疗失败风险高的患者。
Diffuse large-B-cell lymphoma (DLBCL) is curable but when treatment fails, outcome is poor. Imaging scans help identify patients at risk of treatment failure but are often imprecise, and the radiation exposure is a potential health risk. Specific, sensitive and readily available biomarkers of treatment failure are needed. We retrospectively analyzed cell-free circulating tumor DNA (ctDNA) in patients treated on one of 3 treatment protocols using quantitative next-generation DNA sequencing. Eligible patients had DLBCL, no evidence of indolent lymphoma and were previously untreated. Serial serum samples and concurrent computed tomography scans were obtained at specified times during most treatment cycles and 5-years of follow-up. VDJ gene segments of the rearranged immunoglobulin receptor genes were amplified and sequenced from pre-treatment specimens and serum ctDNA encoding the VDJ rearrangements was quantitated. Tumor clonotype(s) were identified in pretreatment specimens from 126 patients who were followed for a median (interquartile range) of 11 (6.8 to 14.2) years. Interim ctDNA monitoring at the end of 2 treatment cycles in 108 patients showed a time to progression (TTP) of 41.7% (95% Confidence Interval (CI): 22.2% to 60.1%) and 80.2% (95% CI: 69.6% to 87.3%), at 5-years (p<0.0001) in patients with and without detectable ctDNA, respectively, and a positive and negative predicative value (PPV and NPV) of 63% and 80%, respectively. Surveillance ctDNA monitoring was performed in 107 patients who achieved complete remission. A Cox proportional hazards model showed patients who developed detectable ctDNA during surveillance had a hazard ratio 228 times that of patients with undetectable ctDNA for clinical disease progression (95% CI: 51 to 1022) (p<0.0001). Surveillance ctDNA had a PPV and NPV of 88% and 98%, respectively, and identified recurrence a median (range) of 3.5 months (0 to 200) before evidence of clinical disease. Surveillance ctDNA identifies patients at risk of recurrence before clinical evidence of disease in most patients and results in lower disease burden at relapse. Interim ctDNA is a promising biomarker to identify patients at high risk of treatment failure.