BACKGROUND High hyperdiploidy is the most common genetic subtype of childhood acute lymphoblastic leukaemia and is associated with a good outcome. However, some patients relapse and, given its prevalence, patients with high hyperdiploidy account for a large proportion of all relapses. We aimed to evaluate putative risk factors and determine the optimal pattern of trisomies for predicting outcome. METHODS We used discovery and validation cohorts from consecutive trials-UKALL97/99 (n=456) and UKALL2003 (n=725)-to develop the prognostic profile. UKALL97/99 recruited patients aged 1-18 years between Jan 1, 1997, and June 15, 2002, and UKALL2003 recruited children and young adults aged 1-24 years between Oct 1, 2003, and June 30, 2001, from the UK and Ireland who were newly diagnosed with acute lymphoblastic leukaemia. Cytogenetic and fluorescence in-situ hybridisation testing was performed on pre-treatment bone marrow samples by regional UK National Health Service genetic laboratories or centrally by the Leukaemia Research Cytogenetics Group, and results were reported using established nomenclature and definitions. We examined the prognostic effect of previously proposed genetic and non-genetic risk factors among patients with high hyperdiploid acute lymphoblastic leukaemia treated on UKALL2003. We used Bayesian information criterion, targeted projection pursuit, and multivariate analysis to identify the optimal number of trisomies, and best subset regression and multivariate analysis to identify the optimal combination. Survival analysis considered three endpoints, as follows: event-free survival, defined as time to relapse, second tumour, or death, censored at last contact; relapse rate, defined as time to relapse for those reaching complete remission, censored at death in remission or last contact; and overall survival, defined as time to death, censored at last contact. FINDINGS The median follow-up time for UKALL97/99 was 10·59 years (IQR 9·25-12·06) and 9·40 years (8·00-11·55) for UKALL2003. UKALL97/99 included 208 female patients and 248 male patients, and UKALL2003 included 345 female patients and 380 male patients. We deduced that the trisomic status of four chromosomes provided the optimal information for predicting outcome. The good risk profile comprised karyotypes with +17 and +18 or +17 or +18 in the absence of +5 and +20. All remaining cases were classified in the poor risk profile. The ratio of patients with good risk and poor risk was 82:18 and 80:20 in the discovery and validation cohorts, respectively. In the validation cohort, patients with the high hyperdiploid good risk profile had an improved response to treatment compared with other patients with high hyperdiploidy at 10 years (relapse rate 5% [95% CI 3-7] vs 16% [10-23]; p<0·0001; event-free survival 92% [90-94] vs 81% [73-86]; p<0·0001; and overall survival 96% [94-97] vs 86% [79-91]; p<0·0001). The outcome for high hyperdiploid poor risk patients was similar to that of patients with an intermediate cytogenetic profile. The prognostic effect of the UKALL high hyperdiploid profile was independent of minimal residual disease and the profile outperformed other high hyperdiploid risk profiles. INTERPRETATION Future clinical trials and treatment protocols using high hyperdiploidy as a risk stratification factor should consider modifying the definition beyond chromosome count to incorporate this novel UKALL high hyperdiploid profile. FUNDING Blood Cancer UK.

中文翻译：

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定义小儿急性淋巴细胞白血病患者的低风险高超二倍体：对 UKALL97/99 和 UKALL2003 临床试验数据的回顾性分析。

背景高超二倍体是儿童急性淋巴细胞白血病最常见的遗传亚型，与良好的预后相关。然而，一些患者会复发，鉴于其患病率，高超二倍体患者在所有复发中占很大比例。我们旨在评估假定的风险因素并确定预测结果的最佳三体模式。方法我们使用来自连续试验——UKALL97/99（n=456）和UKALL2003（n=725）——的发现和验证队列来开发预后特征。UKALL97/99 在 1997 年 1 月 1 日至 2002 年 6 月 15 日期间招募了 1-18 岁的患者，UKALL2003 在 2003 年 10 月 1 日至 2001 年 6 月 30 日期间招募了来自英国和新诊断出患有急性淋巴细胞白血病的爱尔兰人。细胞遗传学和荧光原位杂交测试由英国国家卫生服务区域遗传实验室或白血病研究细胞遗传学小组集中对治疗前的骨髓样本进行，并使用既定的命名法和定义报告结果。我们检查了先前提出的遗传和非遗传危险因素对接受 UKALL2003 治疗的高超二倍体急性淋巴细胞白血病患者的预后影响。我们使用贝叶斯信息准则、目标投影追踪和多变量分析来确定最佳三体数，并使用最佳子集回归和多变量分析来确定最佳组合。生存分析考虑了三个终点，如下：无事件生存，定义为复发时间、第二个肿瘤或死亡，最后一次联系被审查；复发率，定义为达到完全缓解者的复发时间，在缓解期死亡或最后一次接触时截断；和总生存期，定义为死亡时间，在最后一次接触时进行审查。结果 UKALL97/99 的中位随访时间为 10·59 年（IQR 9·25-12·06）和 UKALL2003 的 9·40 年（8·00-11·55）。UKALL97/99包括208名女性患者和248名男性患者，UKALL2003包括345名女性患者和380名男性患者。我们推断四条染色体的三体状态提供了预测结果的最佳信息。良好的风险特征包括+17 和+18 或+17 或+18 的核型，而没有+5 和+20。所有剩余病例均归类为不良风险状况。良好风险和不良风险患者的比例为82:18和80：分别在发现和验证队列中排名 20。在验证队列中，与其他高超二倍体患者相比，具有高超二倍体良好风险特征的患者在 10 年时对治疗的反应有所改善（复发率 5% [95% CI 3-7] 与 16% [10-23] ；p<0·0001；无事件生存率 92% [90-94] 与 81% [73-86]；p<0·0001；总生存率 96% [94-97] 与 86% [79-91] ]；p<0·0001)。高超二倍体低危患者的结果与具有中等细胞遗传学特征的患者相似。UKALL 高超二倍体特征的预后效果与微小残留病无关，并且该特征优于其他高超二倍体风险特征。解释 使用高超二倍体作为风险分层因素的未来临床试验和治疗方案应考虑修改染色体计数以外的定义，以纳入这种新的 UKALL 高超二倍体特征。资助英国血癌。