Roschewski Mark, Kurtz David M, Westin Jason R, Lynch Ryan C, Gopal Ajay K, Alig Stefan K, Sworder Brian J, Cherng Hua-Jay J, Kuffer Christian, Blair Derek, Brown Krystal, Goldstein Jordan S, Schultz Andre, Close Sandra, Chabon Jacob J, Diehn Maximilian, Wilson Wyndham H, Alizadeh Ash A
Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.
J Clin Oncol. 2025 Aug 13:101200JCO2501534. doi: 10.1200/JCO-25-01534.
Large B-cell lymphomas (LBCL) are curable, but patients with residual disease after therapy invariably experience progression. Ultrasensitive methods to detect circulating tumor DNA (ctDNA) as minimal measurable residual disease (MRD) may improve the determination of remission.
We integrated data from five prospective studies of frontline anthracycline-based chemotherapy in patients with LBCL. Tumor-specific phased variants were identified from pretreatment samples and monitored at landmark timepoints. Serial plasma specimens were blindly analyzed for detectable ctDNA as MRD. MRD status was compared to conventional response criteria for prognosis of progression-free survival (PFS).
We studied ctDNA-MRD in 137 patients by monitoring 409 plasma specimens over time. Detectable ctDNA rates decreased during therapy with 55% and 78% of patients achieving undetectable ctDNA after 2 cycles and at end of therapy, respectively. After a median follow-up of 37 months, the 2-year PFS for patients with detectable vs undetectable ctDNA after 2 cycles was 67% vs 96% (p=0.0025, hazard ratio 6.9) and after therapy was 29% vs 97% (p<0.0001, hazard ratio 28.7), respectively. Ninety-two (94%) patients with undetectable ctDNA at end of therapy remained alive without progression, while 19 (68%) patients with detectable ctDNA progressed or died. MRD status at end of therapy had greater prognostic utility than conventional lymphoma response criteria using PET scans (hazard ratio 3.6 for positive PET, and 28.3 for detectable ctDNA).
Ultrasensitive circulating tumor DNA detection after frontline LBCL therapy is more prognostic than conventional radiographic response criteria. A refined definition of remission with ctDNA-MRD may improve clinical and psychological outcomes for patients with LBCL (Funded by the National Cancer Institute and others; ClinicalTrials.gov numbers, NCT04002947; NCT00398177; NCT02529852; NCT04231877; NCT04134936).
大B细胞淋巴瘤（LBCL）是可治愈的，但治疗后仍有残留病灶的患者最终都会出现病情进展。作为微小残留病（MRD）检测循环肿瘤DNA（ctDNA）的超灵敏方法可能会改善缓解状态的判定。
我们整合了五项关于LBCL患者一线蒽环类化疗的前瞻性研究数据。从预处理样本中鉴定肿瘤特异性阶段性变异，并在关键时间点进行监测。对系列血浆样本进行盲法分析，以检测作为MRD的可检测ctDNA。将MRD状态与无进展生存期（PFS）预后的传统反应标准进行比较。
我们通过长期监测409份血浆样本，对137例患者的ctDNA-MRD进行了研究。治疗期间可检测到的ctDNA率下降，分别有55%和78%的患者在2个周期后及治疗结束时ctDNA检测不到。中位随访37个月后，2个周期后ctDNA可检测与不可检测患者的2年PFS分别为67%和96%（p = 0.0025，风险比6.9），治疗后分别为29%和97%（p < 0.0001，风险比28.7）。治疗结束时ctDNA检测不到的92例（94%）患者存活且无病情进展，而ctDNA可检测的19例（68%）患者病情进展或死亡。治疗结束时的MRD状态比使用PET扫描的传统淋巴瘤反应标准具有更大的预后价值（PET阳性的风险比为3.6，可检测ctDNA的风险比为28.3）。
一线LBCL治疗后超灵敏循环肿瘤DNA检测比传统影像学反应标准更具预后价值。用ctDNA-MRD对缓解进行精准定义可能会改善LBCL患者的临床和心理结局（由美国国立癌症研究所等资助；ClinicalTrials.gov编号，NCT04002947；NCT00398177；NCT02529852；NCT04231877；NCT04134936）。
