慢性淋巴细胞白血病的基因突变与治疗结果：CLL8 试验结果。

Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.

机构信息

Department of Internal Medicine III, Ulm University, Ulm, Germany;

Department of Internal Medicine III, Ulm University, Ulm, Germany; Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, and Department of Medicine V, University of Heidelberg, Heidelberg, Germany;

出版信息

Blood. 2014 May 22;123(21):3247-54. doi: 10.1182/blood-2014-01-546150. Epub 2014 Mar 20.

DOI:10.1182/blood-2014-01-546150

PMID:24652989

Abstract

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, β2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.

摘要

在 CLL8 研究中，分析了未经治疗的慢性淋巴细胞白血病（CLL）患者一线治疗中氟达拉滨和环磷酰胺（FC）或氟达拉滨和环磷酰胺加利妥昔单抗（FCR）的 TP53、NOTCH1 和 SF3B1 突变。分别有 11.5%、10.0%和 18.4%的患者存在 TP53、NOTCH1 和 SF3B1 突变。NOTCH1（mut）和 SF3B1（mut）几乎呈现相互排斥（6%的一致性），但在 NOTCH1（mut）（16.1%）和 SF3B1（mut）（14.0%）患者中经常发现 TP53（mut）。与临床和实验室特征几乎没有显著关联，但遗传标志物对反应和生存有很强的影响。在多变量分析中，FCR、胸苷激酶（TK）≥10U/L、未突变的 IGHV、11q 缺失、17p 缺失、TP53（mut）和 SF3B1（mut）对无进展生存期具有独立的预后影响；FCR、年龄≥65 岁、东部肿瘤协作组体能状态≥1、β2-微球蛋白≥3.5mg/L、TK≥10U/L、未突变的 IGHV、17p 缺失和 TP53（mut）对总生存期有影响。值得注意的是，预测标志物分析发现 NOTCH1 突变状态与治疗之间存在相互作用，即在 NOTCH1（mut）患者中，利妥昔单抗未能改善反应和生存。总之，TP53 和 SF3B1 突变是接受当前标准一线治疗的 CLL 患者中最强的预后标志物之一。NOTCH1（mut）被确定为利妥昔单抗联合 FC 治疗获益降低的预测标志物。这项研究在 www.clinicaltrials.gov 注册，编号为 #NCT00281918。