Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Viva-University Children's Cancer Centre, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore.
Br J Haematol. 2018 Jun;181(5):653-663. doi: 10.1111/bjh.15252.
Accurate risk assignment in childhood acute lymphoblastic leukaemia is essential to avoid under- or over-treatment. We hypothesized that time-series gene expression profiles (GEPs) of bone marrow samples during remission-induction therapy can measure the response and be used for relapse prediction. We computed the time-series changes from diagnosis to Day 8 of remission-induction, termed Effective Response Metric (ERM-D8) and tested its ability to predict relapse against contemporary risk assignment methods, including National Cancer Institutes (NCI) criteria, genetics and minimal residual disease (MRD). ERM-D8 was trained on a set of 131 patients and validated on an independent set of 79 patients. In the independent blinded test set, unfavourable ERM-D8 patients had >3-fold increased risk of relapse compared to favourable ERM-D8 (5-year cumulative incidence of relapse 38·1% vs. 10·6%; P = 2·5 × 10 ). ERM-D8 remained predictive of relapse [P = 0·05; Hazard ratio 4·09, 95% confidence interval (CI) 1·03-16·23] after adjusting for NCI criteria, genetics, Day 8 peripheral response and Day 33 MRD. ERM-D8 improved risk stratification in favourable genetics subgroups (P = 0·01) and Day 33 MRD positive patients (P = 1·7 × 10 ). We conclude that our novel metric - ERM-D8 - based on time-series GEP after 8 days of remission-induction therapy can independently predict relapse even after adjusting for NCI risk, genetics, Day 8 peripheral blood response and MRD.
准确的儿童急性淋巴细胞白血病风险分配对于避免过度或不足治疗至关重要。我们假设缓解诱导治疗期间骨髓样本的时间序列基因表达谱（GEP）可以衡量反应并用于预测复发。我们计算了从诊断到缓解诱导第 8 天的时间序列变化，称为有效反应度量（ERM-D8），并测试了其预测复发的能力，与当代风险分配方法（包括美国国立癌症研究所（NCI）标准、遗传学和微小残留病（MRD））进行了比较。ERM-D8 在一组 131 名患者中进行了训练，并在一组 79 名独立患者中进行了验证。在独立的盲法测试集中，不利的 ERM-D8 患者比有利的 ERM-D8 患者复发风险增加了 3 倍以上（5 年累积复发率为 38.1%对 10.6%；P=2.5×10）。ERM-D8 在调整 NCI 标准、遗传学、第 8 天外周反应和第 33 天 MRD 后，仍然具有预测复发的能力[P=0.05；危险比 4.09，95%置信区间（CI）1.03-16.23]。ERM-D8 改善了有利遗传学亚组（P=0.01）和第 33 天 MRD 阳性患者（P=1.7×10）的风险分层。我们得出结论，我们的新指标 - ERM-D8 - 基于缓解诱导治疗 8 天后的时间序列 GEP，即使在调整 NCI 风险、遗传学、第 8 天外周血反应和 MRD 后，也可以独立预测复发。
