Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia
Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia
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DOI：
10.1182/blood.v99.6.1952
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发表时间：
2002-03-15
期刊：
影响因子：
20.3
通讯作者：
Gadner, H
中科院分区：
文献类型：
--
作者：
Dworzak, MN;Fröschl, G;Gadner, H
急性淋巴细胞白血病（ALL）微小残留病（MRD）检测可预测预后以前的研究总是基于相对定量，没有研究影响测试准确性的样本固有参数，这使得比较和临床结论变得繁琐。因此，我们在108名连续招募的ALL儿童中进行了一项前瞻性、基于人群的MRD研究，这些儿童在奥地利接受了ALL-Berlin-Frankfurt-Munster（ALL-BFM）95方案的统一治疗（中位随访时间为40个月）。使用适用于97%患者的灵敏、有限抗体组流式细胞术，我们研究了4个治疗时间点的329份骨髓样本。通过有核细胞（NC）中的原始细胞百分比和绝对计数（每微升）定量MRD。还记录了协变量，如NC计数、正常B细胞和检测灵敏度估计值。在研究的每个时间点，MRD的存在和不同水平与早期复发的高概率相关。第33天和第12周的序贯监测对于独立于临床风险组预测结果最有用：持续性疾病（大于或等于1个原始细胞/穆尔）患者的复发概率为100%，而所有其他患者的复发概率为6%。由于样本间总NC计数存在相当大的差异，因此绝对MRD定量比相对MRD定量更合适。正常未成熟B细胞在治疗后休息一段时间后再生限制了试验灵敏度。总之，流式细胞术检测MRD是儿童ALL的一个强有力的独立结局指标。在连续治疗期间，基于NC和评估的绝对定量标准化有望提高该方法的准确性、简单性和成本效益。
Detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) predicts outcome. Previous studies were invariably based on relative quantification and did not investigate sample-inherent parameters that influence test accuracy, which makes comparisons and clinical conclusions cumbersome. Hence, we conducted a prospective, population-based MRD study in 108 sequentially recruited children with ALL uniformly treated with the ALL-Berlin-Frankfurt-Munster (ALL-BFM) 95 protocol in Austria (median follow-up of 40 months). Using sensitive, limited antibody panel flow cytometry applicable to 97% of patients, we investigated 329 bone marrow samples from 4 treatment time points. MRD was quantified by blast percentages among nucleated cells (NCs) and by absolute counts (per microliter). Covariables such as NC count, normal B cells, and an estimate of the test sensitivity were also recorded. Presence and distinct levels of MRD correlated with a high probability of early relapse at each of the time points studied. Sequential monitoring at day 33 and week 12 was most useful for predicting outcome independently from clinical risk groups: patients with persistent disease (greater than or equal to 1 blast/muL) had a 100% probability of relapse, compared to 6% in all others. Absolute MRD quantification was more appropriate than relative, due to considerable variations In total NC counts between samples. Regeneration of normal immature B cells after periods of rest from treatment limited the test sensitivity. In conclusion, MRD detection by flow cytometry Is a strong and Independent outcome indicator in childhood ALL. Standardization regarding absolute quantification on the basis of NCs and assessment during periods of continuous treatment promise to increase the accuracy, simplicity, and cost efficiency of the approach.