Lyndon B. Johnson General Hospital, Houston, Texas.
MD Anderson Cancer Center, Houston, Texas.
Pharmacotherapy. 2017 Sep;37(9):1052-1072. doi: 10.1002/phar.1977. Epub 2017 Jul 31.
Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not changed significantly over the last few decades. We present a nonexhaustive summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways. Some of these targets may be used as predictive biomarkers for the development of novel targeted therapies that depart significantly from conventional chemotherapy, the current mainstay for the treatment of acute leukemias. Established leukemia-specific predictive biomarkers for precision medicine include those genetic lesions such as BCR-ABL1 for Philadelphia-positive acute lymphoblastic leukemia and PML-RARα for acute promyelocytic leukemia. Evidence indicates that targeted therapy for FLT-ITD gene mutations with small-molecule tyrosine kinase inhibitors can extend its use from relapsed disease to up-front induction therapy. Core-binding factor acute myeloid leukemia in adults predicts benefit with high-dose cytarabine in the absence of KIT mutation. Although risk-adapted therapy based on genetic abnormalities in acute leukemias has allowed the beginning of personalized treatment and selective use of hematopoietic stem cell transplantation, the prognostic and/or predictive value of many novel mutations of the acute leukemic genome is yet to be elucidated. Many challenges lie ahead in targeted therapies due to overlapping of chromosomal and molecular lesions as well as other limiting factors. Future work should focus on the understanding of pathogenetic changes that lead to leukemogenesis, which may guide the rational design of new targeted therapies and make the drive toward precision medicine for acute leukemias one step closer.
尽管近年来人们对急性白血病的分子基础有了更深入的了解，但这些疾病的治疗选择在过去几十年中并没有显著改变。我们对目前与急性白血病相关的细胞遗传学和分子变化进行了非详尽的总结，这些变化与疾病预后和潜在的靶向治疗有关。一个新兴的观点是，许多遗传或分子改变靶向相似的信号转导、转录和表观遗传途径。其中一些靶点可能被用作预测生物标志物，用于开发与传统化疗有显著不同的新型靶向治疗，而传统化疗是治疗急性白血病的主要方法。用于精准医学的既定白血病特异性预测生物标志物包括 BCR-ABL1 等遗传病变，用于费城阳性急性淋巴细胞白血病，以及 PML-RARα 用于急性早幼粒细胞白血病。有证据表明，针对 FLT-ITD 基因突变的靶向治疗，使用小分子酪氨酸激酶抑制剂，可以将其从复发疾病扩展到一线诱导治疗。成人核心结合因子急性髓细胞白血病在没有 KIT 突变的情况下，高剂量阿糖胞苷预测获益。尽管基于急性白血病遗传异常的风险适应治疗允许开始个性化治疗和选择性使用造血干细胞移植，但急性白血病基因组中许多新突变的预后和/或预测价值仍有待阐明。由于染色体和分子病变以及其他限制因素的重叠，靶向治疗仍然面临许多挑战。未来的工作应集中于理解导致白血病发生的发病机制变化，这可能指导新的靶向治疗的合理设计，并使急性白血病的精准医学更进一 步。
