Hematology/Oncology 'L. e A. Seràgnoli', Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
Division of Hematology, Ospedale dell'Angelo, Mestre, Venice, Italy.
J Hematol Oncol. 2019 Apr 23;12(1):39. doi: 10.1186/s13045-019-0729-2.
The Philadelphia (Ph) chromosome, resulting from the t(9;22)(q34;q11) translocation, can be found in chronic myeloid leukemia (CML) as well as in a subset of acute lymphoblastic leukemias (ALL). The deregulated BCR-ABL1 tyrosine kinase encoded by the fusion gene resulting from the translocation is considered the pathogenetic driver and can be therapeutically targeted. In both CML and Ph-positive (Ph+) ALL, tyrosine kinase inhibitors (TKIs) have significantly improved outcomes. In the TKI era, testing for BCR-ABL1 transcript levels by real-time quantitative polymerase chain reaction (RQ-PCR) has become the gold standard to monitor patient response, anticipate relapse, and guide therapeutic decisions. In CML, key molecular response milestones have been defined that draw the ideal trajectory towards optimal long-term outcomes. Treatment discontinuation (treatment-free remission, TFR) has proven feasible in a proportion of patients, and clinical efforts are now focused on how to increase this proportion and how to best select TFR candidates. In Ph+ ALL, results of trials with second- and third-generation TKIs are challenging the role of intensive chemotherapy and even that of allogeneic stem cell transplantation. Additional weapons are offered by the recently introduced monoclonal antibodies. In patients harboring mutations in the BCR-ABL1 kinase domain, prompt therapeutic reassessment and individualization based on mutation status are important to regain response and prevent disease progression. Next-generation sequencing is likely to become a precious tool for mutation testing because of the greater sensitivity and the possibility to discriminate between compound and polyclonal mutations. In this review, we discuss the latest advances in treatment and monitoring of CML and Ph+ ALL and the issues that still need to be addressed to make the best use of the therapeutic armamentarium and molecular testing technologies currently at our disposal.
费城（Ph）染色体源自 t（9；22）（q34；q11）易位，可在慢性髓细胞白血病（CML）以及部分急性淋巴细胞白血病（ALL）中发现。易位产生的融合基因编码的失调 BCR-ABL1 酪氨酸激酶被认为是致病驱动因素，可以进行治疗靶向。在 CML 和 Ph 阳性（Ph+）ALL 中，酪氨酸激酶抑制剂（TKI）都显著改善了结果。在 TKI 时代，通过实时定量聚合酶链反应（RQ-PCR）检测 BCR-ABL1 转录本水平已成为监测患者反应、预测复发和指导治疗决策的金标准。在 CML 中，已经定义了关键的分子反应里程碑，描绘了朝着最佳长期结果的理想轨迹。在一部分患者中，已经证明可以停止治疗（无治疗缓解，TFR），现在的临床工作重点是如何增加这一比例，以及如何最好地选择 TFR 候选者。在 Ph+ALL 中，第二代和第三代 TKI 试验的结果正在挑战强化化疗的作用，甚至是异基因干细胞移植的作用。最近推出的单克隆抗体提供了额外的武器。在携带 BCR-ABL1 激酶结构域突变的患者中，根据突变状态及时进行治疗重新评估和个体化治疗对于恢复反应和防止疾病进展非常重要。下一代测序很可能成为突变检测的宝贵工具，因为它具有更高的灵敏度和区分复合和多克隆突变的可能性。在这篇综述中，我们讨论了 CML 和 Ph+ALL 的最新治疗和监测进展，以及为了充分利用目前可获得的治疗武器和分子检测技术，仍需解决的问题。
