Institute for Medical Informatics, Biometry, and Epidemiology (IBE), LMU Munich, Munich, Germany.
Department of Internal Medicine III, University Hospital LMU Munich, Munich, Germany.
J Clin Oncol. 2024 Feb 10;42(5):538-549. doi: 10.1200/JCO.23.00899. Epub 2023 Nov 22.
The outcome of older patients with mantle cell lymphoma (MCL) has improved by the introduction of immunochemotherapy, followed by rituximab (R)-maintenance. Assessment of minimal residual disease (MRD) represents a promising tool for individualized treatment decisions and was a prospectively planned part of the European MCL Elderly trial. We investigated how MRD status influenced the efficacy of R-maintenance and how MRD can enable tailored consolidation strategies.
Previously untreated patients with MCL age 60 years or older have been randomly assigned to R versus interferon-alpha maintenance after response to rituximab, fludarabine, cyclophosphamide (R-FC) versus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). MRD monitoring was performed by real-time quantitative polymerase chain reaction (qPCR) following EuroMRD guidelines.
A qPCR assay with a median sensitivity of 1 × 10 could be generated in 80% of 288 patients in an international, multicenter, multilaboratory setting. More extensive tumor dissemination facilitated the identification of a molecular marker. The efficacy of R-maintenance in clinical remission was confirmed for MRD-negative patients at the end of induction in terms of progression-free survival (PFS; hazard ratio [HR], 0.38 [95% CI, 0.21 to 0.63]) and overall survival (OS; HR, 0.37 [95% CI, 0.20 to 0.68]), particularly in R-CHOP-treated patients (PFS-HR, 0.23 [95% CI, 0.10 to 0.52]; OS-HR, 0.19 [95% CI, 0.07 to 0.52]). R-maintenance appeared less effective in MRD-positive patients (PFS-HR, 0.51 [95% CI, 0.26 to 1.02]) overall and after R-CHOP induction (PFS-HR, 0.59 [95% CI, 0.28 to 1.26]). R-FC achieved more frequent and faster MRD clearance compared with R-CHOP. MRD positivity in clinical remission after induction was associated with a short median time to clinical progression of approximately 1-1.7 years.
The results confirm the strong efficacy of R-maintenance in patients who are MRD-negative after induction. Treatment de-escalation for MRD-negative patients is discouraged by our results. More effective consolidation strategies should be explored in MRD-positive patients to improve their long-term prognosis.
随着免疫化疗的引入，尤其是在利妥昔单抗（R）维持治疗之后，套细胞淋巴瘤（MCL）老年患者的预后得到了改善。微小残留病（MRD）的评估代表了一种有前途的个体化治疗决策工具，也是欧洲 MCL 老年患者试验的一个前瞻性计划部分。我们研究了 MRD 状态如何影响 R 维持治疗的疗效，以及 MRD 如何能够实现定制的巩固策略。
先前未经治疗的年龄在 60 岁或以上的 MCL 患者被随机分配接受 R 维持治疗或干扰素-α维持治疗，后者用于利妥昔单抗、氟达拉滨、环磷酰胺（R-FC）治疗后缓解的患者，以及利妥昔单抗、环磷酰胺、多柔比星、长春新碱、泼尼松（R-CHOP）治疗后缓解的患者。采用实时定量聚合酶链反应（qPCR）按照 EuroMRD 指南进行 MRD 监测。
在国际多中心、多实验室环境中，80%的 288 例患者中可生成中位敏感性为 1×10 的 qPCR 检测方法。更广泛的肿瘤播散有助于识别分子标志物。在诱导治疗结束时，MRD 阴性患者的 R 维持治疗在无进展生存期（PFS；风险比 [HR]，0.38 [95%CI，0.21 至 0.63]）和总生存期（OS；HR，0.37 [95%CI，0.20 至 0.68]）方面证实了其疗效，尤其是在接受 R-CHOP 治疗的患者中（PFS-HR，0.23 [95%CI，0.10 至 0.52]；OS-HR，0.19 [95%CI，0.07 至 0.52]）。在 MRD 阳性患者中，R 维持治疗的效果似乎较差（PFS-HR，0.51 [95%CI，0.26 至 1.02]），总体而言，在接受 R-CHOP 诱导后也是如此（PFS-HR，0.59 [95%CI，0.28 至 1.26]）。与 R-CHOP 相比，R-FC 更能频繁且更快地清除 MRD。诱导后缓解期的 MRD 阳性与临床进展的中位时间约为 1-1.7 年有关。
这些结果证实了 R 维持治疗在诱导后 MRD 阴性患者中的强大疗效。我们的研究结果不鼓励对 MRD 阴性患者进行治疗降级。应探索更有效的巩固策略，以改善 MRD 阳性患者的长期预后。
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