儿童急性淋巴细胞白血病中超二倍体的预后和药代动力学异质性。
Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL.
机构信息
Department of Pharmacy and Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN.
Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
出版信息
J Clin Oncol. 2023 Dec 10;41(35):5422-5432. doi: 10.1200/JCO.23.00880. Epub 2023 Sep 20.
PURPOSE
High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain.
METHODS
We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs.
RESULTS
Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3% 86.8%; = .0003) and cumulative incidence of relapse (CIR; 10-year CIR, 1.4% 8.8%; = .002) compared with the remaining B-ALL. In multivariable analysis, accounting for patient numbers using the akaike information criterion (AIC), DI1.16-1.6 was the most favorable criterion, exhibiting the best AIC for both EFS (hazard ratio [HR], 0.45; 95% CI, 0.23 to 0.88) and CIR (HR, 0.45; 95% CI, 0.21 to 0.99). Hyperdiploidy and subgroups with favorable prognoses exhibited notable sensitivities to asparaginase and mercaptopurine. Specifically, asparaginase sensitivity was associated with trisomy of chromosomes 16 and 17, whereas mercaptopurine sensitivity was linked to gains of chromosomes 14 and 17.
CONCLUSION
Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations.
目的
高倍体性，即儿童急性淋巴细胞白血病（ALL）最大和最有利的亚型，表现出显著的生物学和预后异质性。然而，导致不同治疗反应和高倍体定义的最佳方法仍不确定。
方法
我们分析了在两个连续的一线 ALL 方案中治疗的患者的结果，使用了六种不同的高倍体定义：染色体数 51-67（Chr51-67）；DNA 指数（DI；DI1.16-1.6）；英国 ALL 研究组低危高倍体，即 17 号和 18 号染色体三体或 17 号和 18 号染色体单体缺失的情况下存在+5 和+20；18 号染色体单体三体；4 号和 10 号染色体双三体；以及 4 号、10 号和 17 号染色体三体（TT）。此外，我们对 8 种主要细胞毒性药物的 ALL 体外药物表型进行了特征描述。
结果
在分析的 1096 名患者中，915 名患有 B-ALL，634 名进行了药物表型分析。在单变量分析中，TT 是无事件生存（EFS；10 年 EFS，97.3% vs 86.8%；=0.0003）和累积复发率（CIR；10 年 CIR，1.4% vs 8.8%；=0.002）最有利的标准，与其余的 B-ALL 相比。在多变量分析中，为了使用赤池信息量准则（AIC）计算患者数量，DI1.16-1.6 是最有利的标准，在 EFS（风险比[HR]，0.45；95%CI，0.23 至 0.88）和 CIR（HR，0.45；95%CI，0.21 至 0.99）方面均表现出最佳的 AIC。高倍体性和预后较好的亚组对天冬酰胺酶和巯基嘌呤具有显著的敏感性。具体而言，天冬酰胺酶敏感性与 16 号和 17 号染色体三体有关，而巯基嘌呤敏感性与 14 号和 17 号染色体增益有关。
结论
在不同的高倍体 ALL 定义中，基于独立的预后影响和识别的低危患者比例，DI 是最佳的。高倍体 ALL 对天冬酰胺酶和巯基嘌呤具有特殊的敏感性，与染色体特异性有关。
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