Kolstad Arne, Pedersen Lone Bredo, Eskelund Christian W, Husby Simon, Grønbæk Kirsten, Jerkeman Mats, Laurell Anna, Räty Riikka, Elonen Erkki, Andersen Niels Smedegaard, Brown Peter deNully, Kimby Eva, Bentzen Hans, Sundström Christer, Ehinger Mats, Karjalainen-Lindsberg Marja-Liisa, Delabie Jan, Ralfkiær Elisabeth, Fagerli Unn-Merete, Nilsson-Ehle Herman, Lauritzsen Grete Fossum, Kuittinen Outi, Niemann Carsten, Geisler Christian Hartman
Department of Oncology, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Biol Blood Marrow Transplant. 2017 Mar;23(3):428-435. doi: 10.1016/j.bbmt.2016.12.634. Epub 2016 Dec 27.
The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rearrangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P < .0001). OS was 75% at 10 years and median not reached in the MRD-negative group, compared with only 35 months in the MRD-positive group (P < .0001). Of the 86 patients (47%) who remained in continuous molecular remission, 73% were still in clinical remission after 10 years. For all patients, the median time from ASCT to first molecular relapse was 55 months, with a continuous occurrence of late molecular relapses. Fifty-eight patients who experienced MRD relapse received rituximab as preemptive treatment on 1 or more occasions, and in this group, the median time from first molecular relapse to clinical relapse was 55 months. In most cases, rituximab converted patients to MRD negativity (87%), but many patients became MRD-positive again later during follow-up (69%). By multivariate analysis, high-risk Mantle Cell Lymphoma International Prognostic Index score and positive MRD status pre-ASCT predicted early molecular relapse. In conclusion, preemptive rituximab treatment converts patients to MRD negativity and likely postpones clinical relapse. Molecular monitoring offers an opportunity to select some patients for therapeutic intervention and to avoid unnecessary treatment in others. MRD-positive patients in the first analysis post-ASCT have a dismal prognosis and thus are in need of novel strategies.
本研究的主要目的是监测套细胞淋巴瘤（MCL）患者骨髓中的微小残留病（MRD），以预测临床复发并指导利妥昔单抗的抢先治疗。在北欧淋巴瘤小组开展的2项前瞻性试验纳入的患者中，183例完成了自体干细胞移植（ASCT）且已获得MRD标志物的患者被纳入我们的分析。通过针对Bcl-1/免疫球蛋白重链基因（IgH）和克隆性IgH重排的标准巢式和定量实时聚合酶链反应联合检测法，对新鲜骨髓样本进行MRD分析。ASCT前MRD阳性的患者（54例）或ASCT后首次分析时MRD阳性的患者（23例），其无进展生存期（PFS）和总生存期（OS）显著缩短。ASCT后首个样本MRD阳性的患者，其PFS中位数仅为20个月，而MRD阴性组为142个月（P＜0.0001）。MRD阴性组10年OS率为75%，中位数未达到，而MRD阳性组仅为35个月（P＜0.0001）。在86例（47%）持续分子缓解的患者中，73%在10年后仍处于临床缓解状态。对于所有患者，从ASCT到首次分子复发的中位时间为55个月，晚期分子复发持续发生。58例发生MRD复发的患者接受了1次或多次利妥昔单抗抢先治疗，在该组中，从首次分子复发到临床复发的中位时间为55个月。在大多数情况下，利妥昔单抗使患者转为MRD阴性（87%），但许多患者在后续随访中后来又再次变为MRD阳性（69%）。通过多变量分析，高危套细胞淋巴瘤国际预后指数评分和ASCT前MRD阳性状态可预测早期分子复发。总之，抢先使用利妥昔单抗治疗可使患者转为MRD阴性，并可能推迟临床复发。分子监测为选择部分患者进行治疗干预以及避免其他患者接受不必要的治疗提供了机会。ASCT后首次分析时MRD阳性的患者预后不佳，因此需要新的策略。
