Maxwell Rochelle R, Cole Peter D
The Children's Hospital at Montefiore, 3415 Bainbridge Avenue, Bronx, NY, 10467, USA.
Albert Einstein College of Medicine, 1225 Morris Park Avenue, Van Etten Building, Room VE 6A03, Bronx, NY, 10461, USA.
Curr Hematol Malig Rep. 2017 Jun;12(3):176-186. doi: 10.1007/s11899-017-0376-z.
The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL).
Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.
本综述旨在总结儿童急性淋巴细胞白血病（ALL）中与治疗相关毒性（TRT）最相关且最可靠的药物遗传学预测指标。
多项研究探讨了用于治疗儿童ALL的主要化疗药物的毒性与宿主遗传因素之间的关系。然而，很少有结果能被独立重复验证，这主要是由于不同队列在血统、化疗治疗方案以及毒性定义方面存在差异。迄今为止，基于基因状态进行剂量调整的临床指南仅有一项被广泛接受：即根据TPMT基因型调整硫嘌呤剂量。基于近期数据，该指南很可能会进行修订，纳入其他基因变异，如NUDT15。我们重点介绍了在各治疗组中均与TRT持续相关的基因变异，以及那些最能阐明TRT潜在病理生理学机制的基因变异。在未来十年，我们预计生存护理将常规性地根据遗传学制定筛查建议。此外，测试保护性干预措施的临床试验可能会根据基因确定的特定TRT风险修改纳入标准。
