van Dongen J J, Seriu T, Panzer-Grümayer E R, Biondi A, Pongers-Willemse M J, Corral L, Stolz F, Schrappe M, Masera G, Kamps W A, Gadner H, van Wering E R, Ludwig W D, Basso G, de Bruijn M A, Cazzaniga G, Hettinger K, van der Does-van den Berg A, Hop W C, Riehm H, Bartram C R
Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, The Netherlands.
Lancet. 1998 Nov 28;352(9142):1731-8. doi: 10.1016/S0140-6736(98)04058-6.
Sensitive techniques for detection of minimal residual disease (MRD) at degrees of one leukaemic cell per 10(3)-10(6) cells (10(-3)-10(-6)) during follow-up of children with acute lymphoblastic leukaemia (ALL) can provide insight into the effectiveness of cytotoxic treatment. However, it is not yet clear how information on MRD can be applied to treatment protocols.
We monitored 240 patients with childhood ALL who were treated according to national protocols of the International BFM Study Group. 60 patients relapsed and the patients in continuous complete remission (CCR) had a median event-free follow-up of 48 months. Bone-marrow samples were collected at up to nine time points during and after treatment. Standardised PCR analysis of patient-specific immunoglobulin and T-cell receptor gene rearrangements and TAL1 deletions were used as targets for semiquantitative estimation of MRD. Amount of MRD was classed as 10(-2) or more, 10(-3), and 10(-4) or less.
MRD negativity at the various follow-up times was associated with low relapse rates (3-15% at 3 years), but five-fold to ten-fold higher relapse rates (39-86% at 3 years) were found in MRD-positive patients. The distinct degrees of MRD appeared to have independent prognostic value (p [trend]<0.001) at all separate time points, especially at the first two time points (at the end of induction treatment and before consolidation treatment). At these two time points a high degree of MRD (> or = 10(-2)) was associated with a three-fold higher relapse rate when compared with patients with a low degree of MRD (< or = 10(-4)). At later time points (including the end of treatment) even a low degree of MRD was associated with a poor outcome. Positivity in patients in CCR after treatment was rare (< 1%). With the combined MRD information from the first two follow-up time points, it was possible to recognise three different risk groups--55 (43%) were in a low-risk group and had a 3-year relapse rate of only 2% (95% CI 0.05-12%); 19 (15%) were in a high-risk group and had a relapse rate of 75% (55-95%); and 55 (43%) were in an intermediate-risk group and had a 3-year relapse rate of 23% (13-36%).
Our collaborative MRD study shows that monitoring patients with childhood ALL at consecutive time points gives clinically relevant insight into the effectiveness of treatment. Combined information on MRD from the first 3 months of treatment distinguishes patients with good prognoses from those with poor prognoses, and this helps in decisions whether and how to modify treatment.
在急性淋巴细胞白血病（ALL）患儿随访期间，检测微小残留病（MRD）的敏感技术可精确至每10³ - 10⁶个细胞中有一个白血病细胞（10⁻³ - 10⁻⁶），这有助于深入了解细胞毒性治疗的效果。然而，目前尚不清楚MRD信息如何应用于治疗方案。
我们监测了240例按照国际BFM研究组国家方案接受治疗的儿童ALL患者。60例患者复发，持续完全缓解（CCR）的患者无事件中位随访时间为48个月。在治疗期间和治疗后，最多在9个时间点采集骨髓样本。以患者特异性免疫球蛋白和T细胞受体基因重排以及TAL1缺失的标准化PCR分析作为MRD半定量估计的靶点。MRD量分为10⁻²及以上、10⁻³和10⁻⁴及以下。
不同随访时间的MRD阴性与低复发率相关（3年时为3% - 15%），但MRD阳性患者的复发率高5至10倍（3年时为39% - 86%）。在所有单独时间点，尤其是前两个时间点（诱导治疗结束时和巩固治疗前），不同程度的MRD似乎具有独立的预后价值（p[趋势]<0.001）。与MRD程度低（≤10⁻⁴）的患者相比，在这两个时间点，MRD程度高（≥10⁻²）的患者复发率高三倍。在后期时间点（包括治疗结束时），即使MRD程度低也与不良预后相关。治疗后处于CCR的患者中阳性情况罕见（<1%）。结合前两个随访时间点的MRD信息，可以识别出三个不同的风险组——55例（43%）为低风险组，3年复发率仅为2%（95%CI 0.05 - 12%）；19例（15%）为高风险组，复发率为75%（55 - 95%）；55例（43%）为中风险组，3年复发率为23%（13 - 36%）。
我们的合作MRD研究表明，连续时间点监测儿童ALL患者能为治疗效果提供具有临床相关性的见解。治疗前3个月的MRD综合信息可区分预后良好和预后不良的患者，这有助于决定是否以及如何调整治疗。
