Department of Biological Hematology and Immunology, Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Mondor, Créteil, France; Institut Mondor de Recherche Biomédicale-INSERM U955, Equipe 9, Henri Mondor Hospital, Créteil, France; Université Paris-Est, Créteil, France;
Departments of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Kiel, Germany;
Blood. 2015 Jul 30;126(5):604-11. doi: 10.1182/blood-2015-02-628792. Epub 2015 May 28.
We revisited the prognostic value of frequently detected somatic gene copy number alterations (CNAs) in mantle cell lymphoma (MCL) patients treated first line with immunochemotherapy and autologous stem cell transplantation (ASCT), with or without high-dose cytarabine, in the randomized European MCL Younger trial. DNA extracted from tumor material of 135 patients (median age, 56 years) was analyzed by multiplex ligation-dependent probe amplification and/or quantitative multiplex polymerase chain reaction of short fluorescent fragments. As expected, MYC (18%) was the more frequently gained, whereas RB1 (26%), ATM (25%), CDKN2A (p16) (25%), and TP53 (22%) were the more frequently deleted. Whether adjusted for MCL International Prognostic Index (MIPI) or not, deletions of RB1, CDKN2A, TP53, and CDKN1B were associated with shorter overall survival (OS), similarly in both treatment arms, whereas CNAs in MYC, ATM, CDK2, CDK4, and MDM2 had no prognostic value. Additive effects were seen for CDKN2A (hazard ratio, 2.3; P = .007, MIPI-adjusted) and TP53 deletions (hazard ratio, 2.4; P = .007), reflected in a dismal outcome with simultaneous deletions (median OS, 1.8 years) compared with single deletions (median OS, 4.3 and 5.1 years) or without these deletions (median OS, 7 years), again similarly in both treatment arms. The additive prognostic effects of CDKN2A and TP53 deletions were independent of the Ki-67 index. Despite immunochemotherapy, high-dose cytarabine, and ASCT, younger MCL patients with deletions of CDKN2A (p16) and TP53 show an unfavorable prognosis and are candidates for alternative therapeutic strategies. This trial was registered at www.clinicaltrials.gov as #NCT00209222.
我们重新评估了在欧洲套细胞淋巴瘤年轻研究中，一线接受免疫化疗和自体干细胞移植（ASCT）治疗，联合或不联合大剂量阿糖胞苷治疗的患者中，频繁检测到的体细胞基因拷贝数改变（CNA）的预后价值。对 135 例患者（中位年龄 56 岁）的肿瘤组织提取的 DNA 进行了多重连接依赖性探针扩增和/或短荧光片段的定量多重聚合酶链反应分析。正如预期的那样，MYC（18%）是最常获得的，而 RB1（26%）、ATM（25%）、CDKN2A（p16）（25%）和 TP53（22%）是最常缺失的。无论是否调整套细胞淋巴瘤国际预后指数（MIPI），RB1、CDKN2A、TP53 和 CDKN1B 的缺失均与总生存期（OS）较短相关，且在两种治疗臂中均如此，而 MYC、ATM、CDK2、CDK4 和 MDM2 的 CNA 无预后价值。CDKN2A（危险比，2.3；P =.007，MIPI 调整）和 TP53 缺失（危险比，2.4；P =.007）的附加效应，反映了同时缺失（中位 OS，1.8 年）与单个缺失（中位 OS，4.3 和 5.1 年）或无这些缺失（中位 OS，7 年）相比，预后更差，且在两种治疗臂中均如此。CDKN2A 和 TP53 缺失的附加预后效应独立于 Ki-67 指数。尽管接受了免疫化疗、大剂量阿糖胞苷和 ASCT，CDKN2A（p16）和 TP53 缺失的年轻套细胞淋巴瘤患者仍预后不良，是替代治疗策略的候选者。这项研究在 www.clinicaltrials.gov 上注册为 #NCT00209222。
