Circulating Tumor DNA Monitoring for Patients With Follicular Lymphoma Undergoing CAR T-Cell Therapy

According to a trial recently published in Frontiers in Immunology, circulating tumor DNA (ctDNA) monitoring using a personalized trackable mutation signature demonstrated efficacy as a non-invasive method in correlating treatment responses and monitoring disease progression among patients with follicular lymphoma (FL) undergoing chimeric antigen receptor (CAR) T-cell therapy. 

Ana Jiménez-Ubieto, MD, Instituto de Investigación Sanitaria Hospital, Madrid, Spain, and coauthors stated, “CAR T therapy has produced a paradigm shift in the treatment of relapsing FL patients. Strategies to optimize disease surveillance after these therapies are increasingly necessary.” 

To further develop the strategies necessary for disease surveillance after CAR T-cell therapy, Jiménez-Ubieto et al aimed to test the effects of using an innovative signature of personable trackable mutations with ctDNA monitoring among patients with FL undergoing this type of therapy. 

There were 11 patients with FL who had received anti-CD19 CAR T-cell therapy and enrolled in this trial, with 1 non-responding patient excluded. Prior to lymphodepletion chemotherapy, genomic profiling was conducted in order to identify the suitable somatic mutations for liquid biopsy minimal residual disease (MRD) monitoring. The dynamics of an average of 4.5 baseline mutations were analyzed in 50 cell-free DNA follow-up samples. Then, positron emission tomography (PET) or computerized tomography (CT) scans were performed on days 90, 180, and 365 and every 6 months until disease progression or death occurred. 

At a median follow-up of 36 months, 100% of patients achieved a complete response (CR), and 2 patients experienced disease progression. The most common mutated genes observed were CREBBP, KMT2D, and EP300. Simultaneous analysis of ctDNA and PET/CT was available for 18 time points. Among PET/CT-positive samples (n = 4), 50% (n = 2) were liquid biopsy MRD negative, both of which belonged to female patients who had a unique mesenteric mass in 2 evaluations, and who had never experienced a relapse. 

Among the 14 PET/CT-negative images, 1000% were mutation-free, and no patients had a negative liquid biopsy MRD analysis by day 7. Additionally, 100% of patients with durable responses had undetectable ctDNA levels at 3 months after CAR T-cell infusion. 2 patients demonstrated differing results between PET/CT and ctDNA level results, but there was no disease progression observed. 100% of patients who experienced disease progression were liquid biopsy MRD-positive prior to progression. 

In conclusion, utilizing ctDNA as a monitoring tool for patients' responses to CAR T-cell therapy for FL yielded efficacious results, and non-invasive liquid biopsy MRD analyses using ctDNA may correlate with treatment responses. 

Dr Jiménez-Ubieto and coauthors stated, “Harmonized definitions of ctDNA molecular response and pinpointing the optimal timing for assessing ctDNA responses are necessary for this setting. If using ctDNA analysis, we suggest restricting follow-up PET/CT in CR [complete response] patients to a clinical suspicion of relapse, to avoid false-positive results.” 

Source: 

Jiménez-Ubieto A, Martín-Muñoz A, Poza M, et al. Personalized monitoring of circulating tumor DNA with a specific signature of trackable mutations after chimeric antigen receptor T-cell therapy in follicular lymphoma patients. Front Immunol. 2023;14:1188818. Published 2023 June 5. doi:10.3389/fimmu.2023.1188818