Galimberti Sara, Genuardi Elisa, Mazziotta Francesco, Iovino Lorenzo, Morabito Fortunato, Grassi Susanna, Ciabatti Elena, Guerrini Francesca, Petrini Mario
Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Department of Molecular Biotechnologies and Health Sciences, University of Torino, Turin, Italy.
Front Oncol. 2019 Jun 26;9:528. doi: 10.3389/fonc.2019.00528. eCollection 2019.
Minimal residual disease (MRD) in non-Hodgkin's lymphomas (NHLs) still represents matter of interest and debate: indeed, the new available treatments offer higher rates of complete responses and MRD negativity than in the past, with a positive impact on the long-term survival. Furthermore, the introduction of more sensitive and accurate molecular techniques, such as digital PCR (ddPCR) and the next generation sequencing techniques (NGS), increased the possibility of identifying molecular targets to be followed after therapy (such as rearrangement of immunoglobulins, fusion genes, or mutations). This review focused on how molecular biology can help to detect MRD in different types of NHLs and how MRD can change the clinical practice in 2019. In follicular lymphoma (FL), contamination of the grafts and molecular disease persistence after transplantation represent a negative prognostic factors. The combination of Rituximab or Obinutuzumab with Bendamustine seems to be the most effective way to clear MRD in FL patients receiving chemo-immunotherapy (further studies are in progress), and also Yttrium-Ibritumomab-Tiuxetan offers a deep clearance of molecular disease. Finally, molecular MRD can further stratify PET-negative cases, with subjects both PET- and MRD-negative presenting the best outcome. In aggressive lymphomas, MRD has a relevant prognostic power and can represent the platform for immunotherapy (such as CAR-T). In diffuse large B-cell lymphoma (DLBCL), the assessment of MRD in the plasma (where cell-free DNA and exosomes circulate) seems to be more predictive than the bone marrow analysis or peripheral blood mononuclear cells. Finally, NGS technologies could be more useful than the classical "patient allele-specific PCR" because they can identify any possible clone emerging during the treatment or follow-up, even if different from that identified at diagnosis, thus predicting relapse. After all, the present available molecular approaches can move MRD from the bench side to the clinical practice.
非霍奇金淋巴瘤（NHL）中的微小残留病（MRD）仍是一个备受关注和争议的问题：事实上，现有的新疗法比过去提供了更高的完全缓解率和MRD阴性率，对长期生存产生了积极影响。此外，更灵敏和准确的分子技术的引入，如数字PCR（ddPCR）和下一代测序技术（NGS），增加了识别治疗后需追踪的分子靶点（如免疫球蛋白重排、融合基因或突变）的可能性。本综述聚焦于分子生物学如何有助于检测不同类型NHL中的MRD以及MRD如何在2019年改变临床实践。在滤泡性淋巴瘤（FL）中，移植时移植物的污染和移植后分子疾病的持续存在是不良预后因素。利妥昔单抗或奥妥珠单抗与苯达莫司汀联合使用似乎是清除接受化疗免疫治疗的FL患者MRD的最有效方法（进一步研究正在进行中），钇-伊布替膦酸钇也能深度清除分子疾病。最后，分子MRD可进一步对PET阴性病例进行分层，PET和MRD均为阴性的患者预后最佳。在侵袭性淋巴瘤中，MRD具有重要的预后价值，可作为免疫治疗（如CAR-T）的平台。在弥漫性大B细胞淋巴瘤（DLBCL）中，血浆中MRD的评估（其中存在游离DNA和外泌体循环）似乎比骨髓分析或外周血单个核细胞更具预测性。最后，NGS技术可能比传统的“患者等位基因特异性PCR”更有用，因为它们可以识别治疗或随访期间出现的任何可能的克隆，即使与诊断时识别的克隆不同，从而预测复发。毕竟，现有的分子方法可以将MRD从实验室研究推向临床实践。
