Soscia Roberta, Assanto Giovanni Manfredi, Starza Irene Della, Moia Riccardo, Talotta Donatella, Bellomarino Vittorio, Bellissimo Teresa, Antonacci Marco, Petrucci Luigi, Gaidano Gianluca, Guarini Anna, Martelli Maurizio, Di Rocco Alice, Foà Robin, Del Giudice Ilaria
Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome.
AIL Roma Odv, Rome.
Haematologica. 2025 Jul 1;110(7):1573-1583. doi: 10.3324/haematol.2024.286331. Epub 2024 Dec 19.
In diffuse large B-cell lymphoma (DLBCL) treatment response relies on imaging. We investigated the potential value of molecular measurable residual disease (MRD) on circulating tumor DNA (ctDNA) to predict the outcome of 73 DLBCL patients. At baseline, next-generation sequencing was used to detect clonal immunoglobulin (IG) gene rearrangements on tumor biopsies (N=57) and ctDNA (N=73). MRD monitoring was applied by tracking the IG clones in ctDNA samples collected during treatment (interim) and at the end of treatment (EOT). MRD results were correlated with clinical data and radiologic disease assessment. Before treatment, clonal IG were found in 91.2% (52/57) of tumor biopsies and in 93.2% (68/73) of ctDNA samples. In paired samples, the same clonotype was found in 69.2% (36/52) of cases. At the interim analysis, ctDNA MRD was negative in 32 of 45 evaluable patients and positive in 13 of 45, correlating significantly with progression-free survival (PFS) (78.1% MRD- vs. 30.8% MRD+; P<0.0001) after a median follow-up of 40 months. Moreover, ctDNA MRD could stratify prognosis of 27 patients in partial response (P=0.018). At EOT, ctDNA MRD was negative in 37 of 47 patients and positive in ten of 47 (PFS 83.8% MRD- vs. 0% MRD+; P<0.0001). All MRD+ patients in complete metabolic response relapsed (P<0.0001). At multivariate analysis, MRD at EOT independently predicted PFS and overall survival. Monitoring IG-based ctDNA MRD during and after treatment predicts DLBCL patients' outcome. This non-invasive method should be implemented in risk-adapted clinical trials and validated as a treatment decision-making tool.
在弥漫性大B细胞淋巴瘤（DLBCL）中，治疗反应依赖于影像学检查。我们研究了循环肿瘤DNA（ctDNA）上分子可测量残留病（MRD）预测73例DLBCL患者预后的潜在价值。在基线时，采用二代测序检测肿瘤活检样本（N = 57）和ctDNA样本（N = 73）中的克隆性免疫球蛋白（IG）基因重排。通过追踪治疗期间（中期）和治疗结束时（EOT）收集的ctDNA样本中的IG克隆进行MRD监测。MRD结果与临床数据和放射学疾病评估相关。治疗前，91.2%（52/57）的肿瘤活检样本和93.2%（68/73）的ctDNA样本中发现克隆性IG。在配对样本中，69.2%（36/52）的病例中发现相同的克隆型。在中期分析时，45例可评估患者中32例ctDNA MRD为阴性，13例为阳性，与无进展生存期（PFS）显著相关（MRD阴性组为78.1%，MRD阳性组为30.8%；P<0.0001），中位随访40个月。此外，ctDNA MRD可对27例部分缓解患者的预后进行分层（P = 0.018）。在EOT时，47例患者中37例ctDNA MRD为阴性，10例为阳性（PFS：MRD阴性组为83.8%，MRD阳性组为0%；P<0.0001）。所有完全代谢缓解的MRD阳性患者均复发（P<0.0001）。在多变量分析中，EOT时的MRD独立预测PFS和总生存期。治疗期间及治疗后监测基于IG的ctDNA MRD可预测DLBCL患者的预后。这种非侵入性方法应在风险适应性临床试验中实施，并作为治疗决策工具进行验证。
