Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Institute of Statistical Science Academia Sinica, Taipei, Taiwan.
Cancer. 2023 Mar 1;129(5):790-802. doi: 10.1002/cncr.34606. Epub 2022 Dec 20.
This study analyzed data from two consecutive protocols for children newly diagnosed with acute lymphoblastic leukemia (ALL) to determine the clinical impact of minimal/measurable residual disease (MRD) and recently identified tumor genetic subtypes.
Genetic subtypes were determined by sequential approaches including DNA indexing, reverse transcriptase-polymerase chain reaction, multiplex ligation-dependent probe amplification, and RNA-sequencing. MRD was assessed by flow cytometry. The Taiwan Pediatric Oncology Group TPOG-ALL-2013 study enrolled patients who received MRD-directed therapy.
The 5-year event-free survival (EFS) and overall survival rates in the 2013 cohort were 77.8% and 86.9% compared to those of the 2002 cohort, which were 62.4% and 76.5%. Among patients treated with MRD-guided therapy, those with ETV6-RUNX1 fusion and high hyperdiploidy had the highest 5-year EFS (91.4% and 89.6%, respectively). The addition of dasatinib improved outcomes in patients with BCR-ABL1 ALL. Recently identified subtypes like DUX4-rearranged, ZNF384-rearranged, MEF2D-rearranged, and PAX5alt subtypes were frequently positive for MRD after remission induction, and these patients consequently received intensified chemotherapy. Treatment intensification according to the MRD improved the outcomes of patients presenting DUX4 rearrangements. In high-risk or very-high-risk subtypes, the TPOG-ALL-2013 regimen did not confer significant improvements compared to TPOG-ALL-2002, and the outcomes of BCR-ABL1-like, MEF2D-rearranged, and KMT2A-rearranged ALL subtypes (in addition to those of T-cell ALL) were not sufficiently good. Novel agents or approaches are needed to improve the outcomes for these patients.
The TPOG-ALL-2013 study yielded outcomes superior to those of patients treated in the preceding TPOG-ALL-2002 study. This study provides important data to inform the design of future clinical trials in Taiwan.
MRD-directed therapy improved the outcomes for pediatric ALL, especially standard-risk patients. Genomic analyses and MRD might be used together for risk-directed therapy of childhood ALL. Our work provides important data to inform the design of future clinical trials in Taiwan.
本研究分析了两项连续协议中儿童新发急性淋巴细胞白血病（ALL）的数据，以确定微小残留病（MRD）和最近鉴定的肿瘤遗传亚型的临床影响。
遗传亚型通过包括 DNA 索引、逆转录-聚合酶链反应、多重连接依赖性探针扩增和 RNA 测序的连续方法确定。MRD 通过流式细胞术评估。台湾儿科肿瘤学组 TPOG-ALL-2013 研究招募了接受 MRD 导向治疗的患者。
2013 年队列的 5 年无事件生存率（EFS）和总生存率分别为 77.8%和 86.9%，而 2002 年队列的分别为 62.4%和 76.5%。在接受 MRD 指导治疗的患者中，具有 ETV6-RUNX1 融合和高倍体性的患者 5 年 EFS 最高（分别为 91.4%和 89.6%）。添加达沙替尼可改善 BCR-ABL1 ALL 患者的预后。最近鉴定的亚型，如 DUX4 重排、ZNF384 重排、MEF2D 重排和 PAX5alt 亚型，在缓解诱导后经常呈 MRD 阳性，这些患者随后接受了强化化疗。根据 MRD 进行的治疗强化改善了 DUX4 重排患者的预后。在高危或极高危亚型中，与 TPOG-ALL-2002 相比，TPOG-ALL-2013 方案并未显著改善，BCR-ABL1 样、MEF2D 重排和 KMT2A 重排 ALL 亚型（以及 T 细胞 ALL）的预后并不理想。需要新的药物或方法来改善这些患者的预后。
TPOG-ALL-2013 研究的结果优于 TPOG-ALL-2002 研究中治疗的患者。这项研究为台湾未来临床试验的设计提供了重要数据。
