Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia.
Leukemia. 2019 Aug;33(8):1835-1850. doi: 10.1038/s41375-019-0512-y. Epub 2019 Jun 17.
Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.
由于药物开发和合理治疗干预策略的进步，慢性髓性白血病（CML）患者的预后得到了极大改善。尽管取得了这些重大进展，但在患者管理方面仍存在一些悬而未决的问题，例如如何更可靠地预测诊断时的治疗失败，以及如何选择一线酪氨酸激酶抑制剂（TKI）治疗以获得最佳疗效。诊断时 BCR-ABL1 转录本水平尚无明确的预后影响，也无法指导一线 TKI 选择。约 50%的 TKI 耐药患者可检测到 BCR-ABL1 突变，但这些突变很少导致原发性耐药。其他耐药机制在很大程度上尚未得到阐明，也没有其他常规分子检测策略来帮助评估和进一步分层 TKI 耐药。下一代测序技术的进步有助于管理越来越多的其他恶性肿瘤，使体细胞突变谱能够纳入诊断、分类和预后。CML 研究中一个很大程度上尚未探索的领域是，在诊断、耐药和疾病转化时是否扩大基因组分析可以增强患者管理决策，就像其他癌症一样。本文的目的是回顾报道 CML 患者在不同疾病阶段的突变癌症相关基因的出版物。我们讨论了这些变体在初始诊断时以及在治疗失败和转化时的频率和类型。概述了当前评估突变体的局限性和对未来报告的建议。十多年来对突变研究的综合评估表明，确实有一组有限的癌症相关基因在 CML 中经常发生突变，有些基因的突变频率相对较高。基因组研究有可能为根据临床和基因组风险进行改进的诊断风险分类奠定基础，并能够更精确地早期识别 TKI 耐药。
