Children's Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Hematology Am Soc Hematol Educ Program. 2011;2011:361-5. doi: 10.1182/asheducation-2011.1.361.
Until recently, pediatric Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) was associated with an extremely poor outcome when treated with chemotherapy alone, and only modest survival benefits were obtained with the widespread use of hematopoietic stem cell transplantation (HSCT). The development of first-generation (imatinib) and second-generation (dasatinib and nilotinib) tyrosine kinase inhibitors (TKIs) that target the BCR-ABL1 fusion protein produced by the Ph chromosome revolutionized the treatment of chronic myelogenous leukemia (CML). The Children's Oncology Group (COG) AALL0031 trial showed that the addition of imatinib to intensive chemotherapy did not cause increased toxicity and resulted in 3-year event-free survival rates that were more than double those of historical control data from the pre-imatinib era. These findings create a new paradigm for integrating molecularly targeted agents with conventional chemotherapy and call for a reassessment of the routine use of HSCT for children and adolescents with Ph(+) ALL. Second-generation TKIs have theoretical advantages over imatinib, and are now being tested in Ph(+) ALL. The focus of contemporary trials is to define the optimal use of chemotherapy, HSCT, and TKI in Ph(+) ALL. In the coming years, it is anticipated that additional agents will become available to potentiate TKI therapy and/or circumvent TKI resistance in Ph(+) ALL. Recent genomic studies have identified a subtype of high-risk pediatric B-cell-precursor ALL with a gene-expression profile similar to that of Ph(+) ALL, suggestive of active kinase signaling. Many of these Ph-like ALL cases harbor chromosome rearrangements and mutations that dysregulate cytokine receptor and kinase signaling, and these leukemias may also be candidates for TKI therapy.
直到最近，单独接受化疗治疗的儿科费城染色体阳性（Ph(+））急性淋巴细胞白血病（ALL）的预后极差，而广泛应用造血干细胞移植（HSCT）仅能获得适度的生存获益。第一代（伊马替尼）和第二代（达沙替尼和尼洛替尼）酪氨酸激酶抑制剂（TKI）靶向 Ph 染色体产生的 BCR-ABL1 融合蛋白的发展彻底改变了慢性髓细胞白血病（CML）的治疗方法。儿童肿瘤学组（COG）AALL0031 试验表明，伊马替尼联合强化化疗不会增加毒性，并且导致 3 年无事件生存率是伊马替尼前时代历史对照数据的两倍多。这些发现为将分子靶向药物与常规化疗相结合创造了一个新的范例，并呼吁重新评估 HSCT 在 Ph(+)ALL 儿童和青少年中的常规应用。第二代 TKI 具有比伊马替尼更具理论优势，目前正在 Ph(+)ALL 中进行测试。当代试验的重点是确定化疗、HSCT 和 TKI 在 Ph(+)ALL 中的最佳应用。在未来几年，预计将有更多的药物可用于增强 TKI 治疗和/或规避 Ph(+)ALL 中的 TKI 耐药性。最近的基因组研究确定了一种具有与 Ph(+)ALL 相似基因表达谱的高危儿科 B 细胞前体 ALL 亚型，提示激酶信号活跃。许多这些 Ph 样 ALL 病例存在染色体重排和突变，导致细胞因子受体和激酶信号失调，这些白血病也可能是 TKI 治疗的候选者。
