Circulating Tumor DNA Predicts Relapse Following CAR T-cell Treatment

Treatment with the CD19-directed chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel has been demonstrated to produce complete responses in patients with large B-cell lymphoma (LBCL) that resists or recurs following chemotherapy. These responses are sometimes lasting, but relapse is common, and its prediction has been a challenge. After a pilot study involving six patients hinted that levels of LBCL-specific circulating tumor DNA (ctDNA) characterized by lymphoma-specific VDJ clonotypes may have prognostic value in this context, Frank, Hossain, and colleagues conducted a prospective clinical trial to evaluate the utility of ctDNA measurement in 72 patients with LBCL treated with axicabtagene ciloleucel. Among all patients, the overall response rate (84.7%), complete response rate (63.9%), and median progression-free survival (10.3 months) were as expected for this population, as was the safety and toxicity profile. ctDNA levels before lymphodepletion were predictive of response to axicabtagene ciloleucel: Specifically, patients with pre-lymphodepletion lymphoma genomes per mL of plasma (LG/mL) values of between 100 and 1,000 had a median overall survival of 19 months, whereas median overall survival was 7.4 months for patients with 1,000 LG/mL or higher. Importantly, among the 60 patients whose disease responded and for whom samples were available for analysis, 83% (25 of 30) of those who had durable responses after a median follow-up period of one year had no detectable ctDNA on day 28 following CAR T-cell infusion, whereas 73% (22 of 30) of those who had disease progression had detectable ctDNA at the same time point. Additionally, all patients whose disease progressed had at least one ctDNA-positive blood sample prior to relapse. In 94% of patients who experienced disease relapse, ctDNA was detected at or before the time of radiographic relapse detection. Although a longer follow-up period would be required to investigate the use of ctDNA measurement for long-term disease monitoring, these findings indicate that this technique may have use as a noninvasive posttreatment surveillance method in the year following LBCL response to axicabtagene ciloleucel.

Frank MJ, Hossain NM, Bukhari A, Dean E, Spiegel JY, Claire GK, et al. 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. J Clin Oncol 2021 Jun 16 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.