University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
J Clin Oncol. 2012 Mar 20;30(9):980-8. doi: 10.1200/JCO.2011.36.9348. Epub 2012 Feb 13.
To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial.
MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (< 10(-4)), intermediate- (≥ 10(-4) to <10(-2)), and high-level (≥ 10(-2)) groups.
Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P < .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P < .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC.
MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.
除了治疗前的风险因素外，确定流式细胞术微小残留病（MRD）定量在慢性淋巴细胞白血病（CLL）中的临床意义，并比较德国 CLL 研究组 CLL8 试验中 MRD 在各治疗组之间的预后影响。
对 493 例随机接受氟达拉滨和环磷酰胺（FC）或 FC 加利妥昔单抗（FCR）治疗的患者的 1775 份血液和骨髓样本进行前瞻性 MRD 水平定量检测。根据 MRD 将患者分为低（<10⁻⁴）、中（≥10⁻⁴至<10⁻²）和高（≥10⁻²）水平组。
治疗期间和治疗后的低 MRD 水平与更长的无进展生存期（PFS）和总生存期（OS）相关（P<0.0001）。当在治疗后 2 个月评估时，低、中、高 MRD 水平患者的估计中位 PFS 分别为 68.7、40.5 和 15.4 个月。与低 MRD 患者相比，中、高 MRD 水平患者疾病进展的风险更高（风险比分别为 2.49 和 14.7，均 P<0.0001）。高 MRD 患者的中位 OS 为 48.4 个月，而低 MRD 水平患者的 OS 未达到。在包括 CLL 最重要的治疗前风险标志物的多变量分析中，MRD 仍然是 OS 和 PFS 的预测因素。在每个 MRD 类别中，治疗组之间的 PFS 和 OS 没有差异。然而，FCR 比 FC 更频繁地诱导低 MRD 水平。
MRD 水平独立预测 CLL 的 OS 和 PFS。因此，在可以评估临床终点之前，MRD 定量可能作为随机试验中评估治疗效果的替代标志物。
