A genomic approach to improve prognosis and predict therapeutic response in chronic lymphocytic leukemia.
A genomic approach to improve prognosis and predict therapeutic response in chronic lymphocytic leukemia.
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DOI：
10.1158/1078-0432.ccr-09-1132
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发表时间：
2009-11-15
期刊：
影响因子：
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通讯作者：
Nevins JR
中科院分区：
文献类型：
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作者：
Friedman DR;Weinberg JB;Barry WT;Goodman BK;Volkheimer AD;Bond KM;Chen Y;Jiang N;Moore JO;Gockerman JP;Diehl LF;Decastro CM;Potti A;Nevins JR
慢性淋巴细胞性白血病（CLL）是一种B细胞恶性肿瘤，其特征在于可变的临床过程。一些参数具有预后能力，但仅在一小部分患者中与治疗反应改变相关。我们使用基因表达谱方法来产生治疗反应和预后的预测因子。使用癌细胞系和患者白血病细胞样品产生反映进行性疾病和对化学疗法或化学免疫疗法的反应的基因组特征。我们验证并将这三个签名应用于来自四个队列的独立临床数据，共代表301例CLL患者。从患者白血病细胞基因表达数据结合临床参数创建的预后的基因组签名显著区分了训练数据集中具有稳定疾病的患者与具有进行性疾病的患者。在两个独立的数据集中验证了进展特征，证明了准确识别具有疾病进展风险的患者的能力。此外，产生了预测对苯丁酸氮芥或喷司他丁、环磷酰胺和利妥昔单抗的应答的基因组特征，并且可以准确区分应答和非应答CLL患者。因此，CLL淋巴细胞的微阵列分析可用于改善预后和预测对不同疗法的反应。这些结果对CLL患者的标准和研究性治疗有影响。
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients. We used gene expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemo-immunotherapy were created using cancer cell lines and patient leukemia cell samples. We validated and applied these three signatures to independent clinical data from four cohorts representing a total of 301 CLL patients. A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training dataset. The progression signature was validated in two independent datasets, demonstrating a capacity to accurately identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could accurately distinguish responding and non-responding CLL patients. Thus, microarray analysis of CLL lymphocytes can be used to refine prognosis and predict response to different therapies. These results have implications for standard and investigational therapeutics in CLL patients.