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ctDNA Monitoring Improves Early Relapse Detection After Treatment with Axicabtagene Ciloleucel in Large B-Cell Lymphoma

The results form a prospective multicentre study provide a rationale for designing ctDNA-based risk-adaptive CAR T-cell clinical studies
22 Jun 2021
Cancer Immunology and Immunotherapy;  Haematologic malignancies;  Translational research

The researchers led by Prof. David Miklos of the Division of Blood and Stem Cell Transplantation, Department of Medicine, Stanford University and Center for Cancer Cell Therapy at Stanford Cancer Institute in Stanford, CA, US reported on 16 June 2021 in the Journal of Clinical Oncology the results from a prospective multicentre study which seeked to determine the utility of circulating tumour DNA (ctDNA) monitoring to risk stratify and assess treatment response for patients with large B-cell lymphoma undergoing chimeric antigen receptor (CAR) T-cell therapy.

They found that ctDNA identifies patients with large B-cell lymphoma at risk for disease relapse after treatment with axicabtagene ciloleucel and at risk of developing higher-grade cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome. Moreover, ctDNA predicts disease progression with added value to standard positron emission tomography (PET) and computed tomography (CT) scans. The study team stated that ctDNA predict progression after CAR-T therapy and should be incorporated as an integral biomarker in future clinical studies of consolidation therapy after CAR-T to prevent relapse.

Axicabtagene ciloleucel is approved for the treatment of chemotherapy-refractory large B-cell lymphoma. Despite an overall response rate of 83% and a complete response (CR) rate of 58%, many patients experience progression resulting in a 2-year progression-free survival (PFS) of approximately 40%.

Serial imaging with PET and CT is the current standard of care to assess response and to detect early asymptomatic relapse after CAR T-cell therapy. However, the clinical utility of PET and CT early after CAR T-cell therapy is limited in approximately 40% of patients who achieve stable disease (SD) or partial response (PR) at 1 month after therapy. Of these patients, approximately 40% will deepen into a CR over time, whereas the remainder progress. 

Clinically validated tools that could identify the patient's trajectory earlier could lead to the development of earlier interventions, which might further improve outcomes, the authors explained in the study background. ctDNA is an emerging biomarker to risk stratify and assess treatment response to chemotherapy for patients with large B-cell lymphoma and other malignancies.

In this study, lymphoma-specific variable, diversity, and joining gene segments clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axicabtagene ciloleucel infusion. The study team assessed the prognostic value of ctDNA to predict outcomes and axicabtagene ciloleucel related toxicity.

A tumour clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axicabtagene ciloleucel infusion and developing CRS and/or immune effector cell–associated neurotoxicity syndrome.

Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated non-detectable ctDNA 1 week after axicabtagene ciloleucel infusion (p < 0.0001).

At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median PFS of 3 months versus not reached (p < 0.0001) and overall survival of 19 months versus not reached (p = 0.0080), respectively.

In patients with a radiographic PR or SD on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed (p = 0.0001).

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 axicabtagene ciloleucel infusion.

The authors concluded that it is the first study to comprehensively evaluate ctDNA dynamics prospectively in patients undergoing CAR therapy. ctDNA-based surveillance of patients with large B-cell lymphoma undergoing axicabtagene ciloleucel may be a useful adjunct to radiographic assessments of disease status. Future studies may leverage this approach to identify patients requiring consolidative therapies following CAR therapy.

The study was supported by the US National Cancer Institute of the National Institutes of Health award and other academic grants.

Reference

Frank MJ, Hossain NM, Bukhari A, 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. JCO; Published online 16 June 2021. DOI: 10.1200/JCO.21.00377

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