Department of Pediatric Oncology Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany; German Cancer Consortium, and German Cancer Research Center, Im Neuenheimer Feld, Heidelberg, Germany.
Children's Cancer Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, UK.
Eur J Cancer. 2021 Jul;151:175-189. doi: 10.1016/j.ejca.2021.03.034. Epub 2021 May 16.
Outcomes of children with high-risk (HR) relapsed acute lymphoblastic leukaemia (ALL) (N = 393), recruited to ALLR3 and ALL-REZ BFM 2002 trials, were analysed. Minimal residual disease (MRD) was assessed after induction and at predetermined time points until haematopoietic stem cell transplantation (SCT).
Genetic analyses included karyotype, copy-number alterations and mutation analyses. Ten-year survivals were analysed using Kaplan-Meier and Cox models for multivariable analyses.
Outcomes of patients were comparable in ALLR3 and ALL-REZ BFM 2002. The event-free survival of B-cell precursor (BCP) and T-cell ALL (T-ALL) was 22.6% and 26.2% (P = 0.94), respectively, and the overall survival (OS) was 32.6% and 28.2% (P = 0.11), respectively. Induction failures (38%) were associated with deletions of NR3C1 (P = 0.002) and BTG1 (P = 0.03) in BCP-ALL. The disease-free survival (DFS) and OS in patients with good vs poor MRD responses were 57.4% vs 22.6% (P < 0.0001) and 57.8% vs 32.0% (P = 0.0004), respectively. For BCP- and T-ALL, the post-SCT DFS and OS were 42.1% and 56.8% (P = 0.26) and 51.6% and 55.4% (P = 0.67), respectively. The cumulative incidences of post-SCT relapse for BCP- and T-ALL were 36.9% and 17.8% (P = 0.012) and of death were 10.7% and 25.5% (P = 0.013), respectively. Determinants of outcomes after SCT were acute graft versus host disease, pre-SCT MRD (≥10), HR cytogenetics and TP53 alterations in BCP-ALL.
Improvements in outcomes for HR ALL relapses require novel compounds in induction therapy to improve remission rates and immune targeted therapy after induction to maintain remission after SCT.
ALLR3: NCT00967057; ALL REZ-BFM 2002: NCT00114348.
分析入组 ALLR3 和 ALL-REZ BFM 2002 试验的 393 例高危（HR）复发急性淋巴细胞白血病（ALL）儿童的结局。在诱导后和预定时间点评估微小残留病（MRD），直至造血干细胞移植（SCT）。
遗传分析包括核型、拷贝数改变和突变分析。使用 Kaplan-Meier 和 Cox 模型进行多变量分析，分析 10 年生存率。
ALLR3 和 ALL-REZ BFM 2002 患者的结局相当。B 细胞前体（BCP）和 T 细胞 ALL（T-ALL）的无事件生存（EFS）分别为 22.6%和 26.2%（P=0.94），总生存（OS）分别为 32.6%和 28.2%（P=0.11）。诱导失败（38%）与 BCP-ALL 中 NR3C1（P=0.002）和 BTG1（P=0.03）缺失有关。MRD 反应良好与不良的患者疾病无进展生存（DFS）和 OS 分别为 57.4%和 22.6%（P<0.0001）和 57.8%和 32.0%（P=0.0004）。对于 BCP-ALL 和 T-ALL，SCT 后 DFS 和 OS 分别为 42.1%和 56.8%（P=0.26）和 51.6%和 55.4%（P=0.67）。BCP-ALL 和 T-ALL 的 SCT 后复发累积发生率分别为 36.9%和 17.8%（P=0.012），死亡累积发生率分别为 10.7%和 25.5%（P=0.013）。SCT 后结局的决定因素包括急性移植物抗宿主病、SCT 前 MRD（≥10）、HR 细胞遗传学和 BCP-ALL 中的 TP53 改变。
为改善 HR ALL 复发的结局，需要在诱导治疗中加入新型化合物以提高缓解率，并在诱导后进行免疫靶向治疗，以维持 SCT 后的缓解。
ALLR3：NCT00967057；ALL REZ-BFM 2002：NCT00114348。
