Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
Cologne Center for Genomics, and.
Blood. 2016 Jul 21;128(3):395-404. doi: 10.1182/blood-2016-01-691550. Epub 2016 May 25.
Genetic instability is a feature of chronic lymphocytic leukemia (CLL) with adverse prognosis. We hypothesized that chromosomal translocations or complex karyotypes and distinct somatic mutations may impact outcome after first-line chemoimmunotherapy of CLL patients. We performed metaphase karyotyping and next-generation sequencing (NGS) of 85 genes in pretreatment blood samples obtained from 161 patients registered for CLL11, a 3-arm phase 3 trial comparing frontline chlorambucil (Clb) vs Clb plus rituximab (Clb-R) or Clb plus obinutuzumab in CLL patients with significant comorbidity. Chromosomal aberrations as assessed by karyotyping were observed in 68.8% of 154 patients, 31.2% carried translocations, and 19.5% showed complex karyotypes. NGS revealed 198 missense/nonsense mutations and 76 small indels in 76.4% of patients. The most frequently mutated genes were NOTCH1, SF3B1, ATM, TP53, BIRC3, POT1, XPO1, and KRAS Sole chemotherapy, treatment with Clb-R, or genetic lesions in TP53 (9.9% of patients) and KRAS (6.2% of patients) were significantly associated with nonresponse to study therapy. In multivariate models, complex karyotypes and POT1 mutations (8.1% of patients) represented significant prognostic factors for an unfavorable survival, independently of IGHV mutation status, Binet stage, and serum β-2-microglobuline. Patients with the copresence of complex karyotypes and deletions/mutations involving TP53 demonstrated a particularly short survival. In summary, this is the first prospective, controlled study in CLL patients that shows a role of complex karyotype aberrations as an independent prognostic factor for survival after front-line therapy. Moreover, the study identifies mutations in KRAS and POT1 as novel determinants of outcome after chemoimmunotherapy using chlorambucil and anti-CD20 treatment.
遗传不稳定性是慢性淋巴细胞白血病（CLL）的一个特征，具有不良预后。我们假设染色体易位或复杂核型以及不同的体细胞突变可能会影响 CLL 患者一线化疗免疫治疗后的结果。我们对 161 名参加 CLL11 试验的患者的预处理血液样本进行了中期核型分析和 85 个基因的下一代测序（NGS），该试验是一项 3 臂 3 期临床试验，比较了氯丁酸（Clb）与 Clb 加利妥昔单抗（Clb-R）或 Clb 加奥滨尤妥珠单抗在伴有显著合并症的 CLL 患者中的一线治疗。在 154 名可评估核型的患者中，68.8%存在染色体异常，31.2%存在易位，19.5%显示复杂核型。在 76.4%的患者中，NGS 发现了 198 个错义/无义突变和 76 个小插入缺失。最常突变的基因是 NOTCH1、SF3B1、ATM、TP53、BIRC3、POT1、XPO1 和 KRAS。单纯化疗、Clb-R 治疗或 TP53（患者的 9.9%）和 KRAS（患者的 6.2%）的遗传病变与研究治疗的无反应显著相关。在多变量模型中，复杂核型和 POT1 突变（患者的 8.1%）是独立于 IGHV 突变状态、Binet 分期和血清β-2-微球蛋白的不利生存的显著预后因素。复杂核型和涉及 TP53 的缺失/突变共存在的患者的生存时间尤其短。总之，这是第一项针对 CLL 患者的前瞻性、对照研究，表明复杂核型异常是一线治疗后生存的独立预后因素。此外，该研究确定了 KRAS 和 POT1 突变是氯丁酸和抗 CD20 治疗后化疗免疫治疗结局的新决定因素。
