Biondi A, Valsecchi M G, Seriu T, D'Aniello E, Willemse M J, Fasching K, Pannunzio A, Gadner H, Schrappe M, Kamps W A, Bartram C R, van Dongen J J, Panzer-Grümayer E R
Clinica Pediatrica Università di Milano-Bicocca, Ospedale S Gerardo, Monza, Italy.
Leukemia. 2000 Nov;14(11):1939-43. doi: 10.1038/sj.leu.2401922.
The medium-risk B cell precursor acute lymphoblastic leukemia (ALL) accounts for 50-60% of total childhood ALL and comprises the largest number of relapses still unpredictable with diagnostic criteria. To evaluate the prognostic impact of minimal residual disease (MRD) in this specific group, a case control study was performed in patients classified and treated as medium (or intermediate)-risk according to the criteria of national studies (ALL-BFM 90, DCLSG protocol ALL-8, AIEOP-ALL 91), which includes a good day 7 treatment response. Standardized polymerase chain reaction (PCR) analysis of patient-specific immunoglobulin and T cell receptor gene (TCR) rearrangements were used as targets for semi-quantitative estimation of MRD levels: > or =10(-2), 10(-3), < or =10(-4). Twenty-nine relapsing ALL patients were matched with the same number of controls by using white blood cell count (WBC), age, sex, and time in first complete remission, as matching factors. MRD was evaluated at time-point 1 (end of protocol Ia of induction treatment, ie 6 weeks from diagnosis) and time-point 2 (before consolidation treatment, ie 3 months from diagnosis). MRD-based high risk patients (> or =10(-3) at both time-points) were more frequently present in the relapsed cases than in controls (14 vs 2), while MRD-based low risk patients (MRD negative at both time-points) (1 vs 18) showed the opposite distribution. MRD-based high risk cases experienced a significantly higher relapse rate than all other patients, according to the estimated seven-fold increase in the odds of failure, and a much higher rate than MRD-based low risk patients (OR = 35.7; P= 0.003). Using the Cox model, the prediction of the relapse-free interval at 4 years was 44.7%, 76.4% and 97.7% according to the different MRD categories. MRD-based risk group classification demonstrate their clinical relevance within the medium-risk B cell precursor ALL which account for the largest number of unpredictable relapses, despite the current knowledge about clinical and biological characteristics at diagnosis. Therefore, MRD detection during the first 3 months of follow-up can provide the tools to target more intensive therapy to those patients at true risk of relapse.
中危B细胞前体急性淋巴细胞白血病（ALL）占儿童ALL总数的50%-60%，是复发数最多且诊断标准仍无法预测复发情况的类型。为评估微小残留病（MRD）对这一特定组患者的预后影响，我们根据国家研究标准（ALL-BFM 90、DCLSG方案ALL-8、AIEOP-ALL 91）对归类为中（或中危）风险的患者进行了病例对照研究，其中包括第7天良好的治疗反应。以患者特异性免疫球蛋白和T细胞受体基因（TCR）重排的标准化聚合酶链反应（PCR）分析作为MRD水平半定量估计的靶点：≥10⁻²、10⁻³、≤10⁻⁴。29例复发ALL患者与相同数量的对照进行匹配，匹配因素包括白细胞计数（WBC）、年龄、性别和首次完全缓解时间。在时间点1（诱导治疗方案Ia结束时，即诊断后6周）和时间点2（巩固治疗前，即诊断后3个月）评估MRD。复发病例中基于MRD的高危患者（两个时间点均≥10⁻³）比对照组更常见（14例对2例），而基于MRD的低危患者（两个时间点MRD均为阴性）（1例对18例）则呈现相反的分布。根据估计失败几率增加7倍，基于MRD的高危病例的复发率显著高于所有其他患者，且比基于MRD的低危患者高得多（OR = 35.7；P = 0.003）。使用Cox模型，根据不同的MRD类别，4年无复发生存期的预测分别为44.7%、76.4%和97.7%。基于MRD的风险组分类显示了其在中危B细胞前体ALL中的临床相关性，尽管目前对诊断时的临床和生物学特征已有了解，但该类型是复发数最多且无法预测的。因此无法预测复发情况的类型。因此，在随访的前3个月内检测MRD可为针对真正有复发风险的患者进行更强化治疗提供依据。
