Biallelic ATM Inactivation Significantly Reduces Survival in Patients Treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 Trial
Biallelic ATM Inactivation Significantly Reduces Survival in Patients Treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 Trial
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DOI：
10.1200/jco.2011.41.0852
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发表时间：
2012-12-20
影响因子：
45.3
通讯作者：
Stankovic, Tatjana
中科院分区：
文献类型：
--
作者：
Skowronska, Anna;Parker, Anton;Stankovic, Tatjana
目的 ATM 突变对慢性淋巴细胞白血病 (CLL) 的预后意义尚不清楚。我们在一项前瞻性随机试验的背景下评估了它们的影响。患者和方法我们分析了白血病研究基金慢性淋巴细胞白血病 4 (LRF-CLL4) 试验中接受苯丁酸氮芥或氟达拉滨联合或不联合环磷酰胺治疗的 224 名患者的 ATM 基因。通过变性高效液相色谱分析 ATM 状态，并与同一患者队列的治疗反应、生存率和 TP53 改变的影响相关。结果我们在 33 个肿瘤中发现了 36 个 ATM 突变，其中 16 个有 11q 缺失，17 个没有 11q 缺失。突变与晚期疾病阶段和多个淋巴部位受累有关。与 ATM 野生型（28.6 个月）、仅 11q 缺失（17.1 个月）或仅 ATM 突变（30.8 个月）的患者相比，同时具有 ATM 突变和 11q 缺失的患者的无进展生存期（中位 7.4 个月）显着缩短，但生存期与单等位基因（6.7 个月）或双等位基因（3.4 个月）TP53 改变的患者相似。这种效应与治疗、免疫球蛋白重链可变基因 (IGHV) 状态、年龄、性别或疾病阶段无关。与仅具有 ATM 野生型或 ATM 突变的患者相比，具有双等位基因 ATM 改变的患者的总生存期也显着降低（中位分别为 42.2 个月、85.5 个月和 77.6 个月）。 结论 CLL 中 11q 缺失和 ATM 突变的组合与烷化剂和嘌呤类似物一线治疗后的无进展生存期和总生存期显着缩短相关。 11q 缺失患者 ATM 突变状态的评估可能会影响后续治疗的选择。 J 临床肿瘤杂志 30：4524-4532。 (C) 2012 年美国临床肿瘤学会
PurposeThe prognostic significance of ATM mutations in chronic lymphocytic leukemia (CLL) is unclear. We assessed their impact in the context of a prospective randomized trial.Patients and MethodsWe analyzed the ATM gene in 224 patients treated on the Leukemia Research Fund Chronic Lymphocytic Leukemia 4 (LRF-CLL4) trial with chlorambucil or fludarabine with and without cyclophosphamide. ATM status was analyzed by denaturing high-performance liquid chromatography and was related to treatment response, survival, and the impact of TP53 alterations for the same patient cohort.ResultsWe identified 36 ATM mutations in 33 tumors, 16 with and 17 without 11q deletion. Mutations were associated with advanced disease stage and involvement of multiple lymphoid sites. Patients with both ATM mutation and 11q deletion showed significantly reduced progression-free survival (median, 7.4 months) compared with those with ATM wild type (28.6 months), 11q deletion alone (17.1 months), or ATM mutation alone (30.8 months), but survival was similar to that in patients with monoallelic (6.7 months) or biallelic (3.4 months) TP53 alterations. This effect was independent of treatment, immunoglobulin heavy chain variable gene (IGHV) status, age, sex, or disease stage. Overall survival for patients with biallelic ATM alterations was also significantly reduced compared with those with ATM wild type or ATM mutation alone (median, 42.2 v 85.5 v 77.6 months, respectively).ConclusionThe combination of 11q deletion and ATM mutation in CLL is associated with significantly shorter progression-free and overall survival following first-line treatment with alkylating agents and purine analogs. Assessment of ATM mutation status in patients with 11q deletion may influence the choice of subsequent therapy. J Clin Oncol 30:4524-4532. (C) 2012 by American Society of Clinical Oncology