儿童 B 细胞前体急性淋巴细胞白血病染色体异常的预后影响：来自英国医学研究理事会 ALL97/99 随机试验的结果。

Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial.

机构信息

Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.

出版信息

Lancet Oncol. 2010 May;11(5):429-38. doi: 10.1016/S1470-2045(10)70066-8. Epub 2010 Apr 19.

DOI:10.1016/S1470-2045(10)70066-8

PMID:20409752

Abstract

BACKGROUND

Chromosomal abnormalities in childhood acute lymphoblastic leukaemia are well established disease markers and indicators of outcomes. However, the long-term prognosis and independent prognostic effect of some abnormalities has been questioned. Also, little is known about the association between cytogenetics and the characteristics of relapse (eg, time and site of relapse) that are known to predict outcome after relapse.

METHODS

We analysed cytogenetic data from 1725 children with B-cell precursor acute lymphoblastic leukaemia who were included in the UK Medical Research Council ALL97/99 study and followed up for a median time of 8.2 years. Univariate and multivariate analysis were done to examine risk of relapse, event-free survival, and overall survival associated with 21 chromosomal abnormalities and three cytogenetic risk groups constructed from these data.

FINDINGS

Two chromosomal abnormalities were associated with a significantly better outcome (ETV6-RUNX1, hazard ratio [HR] 0.51, 95% CI 0.38-0.70 and high hyperdiploidy, 0.60, 0.47-0.78), whereas five abnormalities were associated with an increased risk of relapse (intrachromosomal amplification of chromosome 21 [iAMP21], 6.04, 3.90-9.35; t(9;22), 3.55, 2.21-5.72; MLL translocations, 2.98, 1.71-5.20; abnormal 17p, 2.09, 1.30-3.37; and loss of 13q, 1.87, 1.09-3.20). Multivariate analysis incorporating age, white-cell count, and treatment parameters showed that six cytogenetic abnormalities (ETV6-RUNX1, high hyperdiploidy, iAMP21, t(9;22), loss of 13q, and abnormal 17p) retained their significance for effect on relapse risk. Based on these data, patients were classified into good, intermediate, and poor cytogenetic risk groups. Slow early treatment response correlated with cytogenetic risk group: 34 of 460 (7%) in the good-risk group, 22 of 211 (10%) in the intermediate-risk group, and 27 of 95 (28%) in the poor-risk group had a slow response (p<0.0001). Additionally, the proportion of patients with a very early (<18 months) relapse varied by cytogenetic risk group: eight of 129 (6%) patients in the good-risk group had a very early relapse, compared with 24 of 98 (24%) in the intermediate-risk group, and 37 of 82 (45%) in the poor-risk group (p<0.0001). However, there was no difference in the site of relapse by cytogenetic risk group.

INTERPRETATION

Individual chromosomal abnormalities are strong independent indicators of outcome, especially risk of relapse. Diagnostic cytogenetics identifies patients with a higher rate of relapse and those who are likely to have a high-risk relapse.

FUNDING

Leukaemia and Lymphoma Research (LLR).

摘要

背景

儿童急性淋巴细胞白血病的染色体异常是公认的疾病标志物和预后指标。然而，一些异常的长期预后和独立预后作用一直存在争议。此外，人们对细胞遗传学与已知可预测复发后结局的复发特征（如复发时间和部位）之间的关联知之甚少。

方法

我们分析了 1725 例 B 细胞前体急性淋巴细胞白血病患儿的细胞遗传学数据，这些患儿均纳入英国医学研究理事会 ALL97/99 研究，并进行了中位数为 8.2 年的随访。我们采用单变量和多变量分析来研究与 21 种染色体异常和从这些数据构建的 3 种细胞遗传学风险组相关的复发风险、无事件生存和总生存情况。

结果

两种染色体异常与更好的结局显著相关（ETV6-RUNX1，风险比[HR]0.51，95%CI 0.38-0.70 和高倍体性，0.60，0.47-0.78），而五种异常与复发风险增加相关（21 号染色体的染色体内扩增[iAMP21]，6.04，3.90-9.35；t（9；22），3.55，2.21-5.72；MLL 易位，2.98，1.71-5.20；17p 异常，2.09，1.30-3.37；13q 缺失，1.87，1.09-3.20）。多变量分析纳入年龄、白细胞计数和治疗参数后，6 种细胞遗传学异常（ETV6-RUNX1、高倍体性、iAMP21、t（9；22）、13q 缺失和 17p 异常）在复发风险方面仍具有统计学意义。根据这些数据，患者被分为良好、中等和不良细胞遗传学风险组。早期治疗反应缓慢与细胞遗传学风险组相关：在良好风险组中，460 例中有 34 例（7%），在中等风险组中，211 例中有 22 例（10%），在不良风险组中，27 例（28%）治疗反应缓慢（p<0.0001）。此外，细胞遗传学风险组的极早期（<18 个月）复发比例不同：在良好风险组中，8 例（6%）患者极早期复发，而在中等风险组中，24 例（24%）患者极早期复发，在不良风险组中，37 例（45%）患者极早期复发（p<0.0001）。然而，细胞遗传学风险组之间的复发部位无差异。