Frank Matthew J, Hossain Nasheed M, Bukhari Ali, Dean Erin, Spiegel Jay Y, Claire Gursharan K, Kirsch Ilan, Jacob Allison P, Mullins Chelsea D, Lee Lik Wee, Kong Katherine A, Craig Juliana, Mackall Crystal L, Rapoport Aaron P, Jain Michael D, Dahiya Saurabh, Locke Frederick L, Miklos David B
Division of Blood and Stem Cell Transplantation, Department of Medicine, Stanford University, Stanford, CA.
Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, CA.
J Clin Oncol. 2021 Sep 20;39(27):3034-3043. doi: 10.1200/JCO.21.00377. Epub 2021 Jun 16.
Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes.
Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel-related toxicity.
A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell-associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion ( < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached ( < .0001) and 19 months versus not reached ( = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed ( = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion.
Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials.
尽管大多数复发或难治性大B细胞淋巴瘤患者对axi-cel（阿基仑赛）有反应，但只有少数患者能实现持久缓解。这项前瞻性多中心研究探讨了在标准治疗的axi-cel治疗前后循环肿瘤DNA（ctDNA）对预测患者预后的价值。
从开始淋巴细胞清除化疗时起，直至疾病进展或axi-cel输注后1年，通过下一代测序频繁监测淋巴瘤特异性可变区、多样性区和连接区基因片段（VDJ）克隆型ctDNA序列。我们评估了ctDNA对预测预后和axi-cel相关毒性的价值。
72例入组患者中有69例（96%）成功检测到肿瘤克隆型。治疗前ctDNA浓度较高与axi-cel输注后疾病进展以及发生细胞因子释放综合征和/或免疫效应细胞相关神经毒性综合征有关。33例持久缓解患者中有23例（70%）与31例进展患者中的4例（13%）在axi-cel输注后1周ctDNA检测不到（P<0.0001）。在第28天时，ctDNA可检测到的患者与ctDNA检测不到的患者相比，无进展生存期的中位数分别为3个月和未达到（P<0.0001），总生存期的中位数分别为19个月和未达到（P=0.0080）。在第28天时影像学部分缓解或病情稳定的患者中，同时ctDNA检测不到的10例患者中有1例复发；相比之下，同时ctDNA可检测到的17例患者中有15例复发（P=0.0001）。30例患者中有29例（94%）在影像学复发时或之前检测到ctDNA。所有持久缓解的患者在axi-cel输注后3个月时或之前ctDNA检测不到。
非侵入性ctDNA评估可对接受axi-cel治疗大B细胞淋巴瘤的患者进行风险分层并预测预后。这些结果为设计基于ctDNA的风险适应性嵌合抗原受体T细胞临床试验提供了理论依据。
