Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel Infusion in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial

• Published in: Journal of clinical oncology Vol. 39; no. 27; pp. 3034 - 3043
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer Health 20.09.2021
• Subjects: Adult; Aged; Biological Products - pharmacology; Biological Products - therapeutic use; Circulating Tumor DNA - genetics; Female; Humans; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Middle Aged; Neoplasm Recurrence, Local; ORIGINAL REPORTS; Prospective Studies; Young Adult
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.21.00377

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.