ctDNA Testing Outperforms Traditional Imaging in Predicting Patients Outcomes in Large B-Cell Lymphoma

PET/CT scans are the current standard, but they often miss residual disease or provide inconclusive results. Now, a new study has shown that ultrasensitive circulating-tumor DNA (ctDNA)-based minimal residual disease (MRD) detection offers a more accurate and reliable method for remission assessment, outperforming traditional imaging.

Foresight Diagnostics (Boulder, CO, USA) has developed the CLARITY assay, which uses PhasED-Seq, an advanced circulating tumor DNA detection technology capable of finding fewer than one mutant molecule per million. In a pooled analysis integrating data from five prospective clinical studies and 137 patients, this assay was evaluated as a prognostic tool. CLARITY demonstrated improved sensitivity and specificity for identifying minimal residual disease compared to standard imaging techniques.

The study revealed that ctDNA-MRD assessment was prognostic as early as two cycles into chemotherapy. Patients with undetectable MRD at that point had a two-year progression-free survival (PFS) of 96% compared to 67% for MRD-positive patients. At the end of therapy, MRD-negative patients achieved a two-year PFS of 97%, while MRD-positive patients showed only 29%, with far stronger prognostic power than PET/CT.

MRD testing further stratified outcomes within both PET-positive and PET-negative groups, identifying relapse risk even when imaging was clear. Overall, Foresight CLARITY achieved 86% clinical sensitivity for relapse detection and 91% specificity for remission, based on a median follow-up of 37 months. These findings, published in the Journal of Clinical Oncology, underscore the limitations of relying solely on imaging and validate ctDNA as a robust biomarker.

Ongoing trials are now evaluating ctDNA-guided treatment strategies in lymphoma. Studies such as ALPHA3 and SHORTEN-ctDNA are testing whether MRD detection can support therapy de-escalation or identify patients who require additional treatment. Results from this pooled analysis have already been incorporated into National Comprehensive Cancer Network Guidelines, where ctDNA-MRD testing is now recommended to adjudicate PET-positive scans.

“These findings highlight the clinical value of achieving ctDNA-MRD negativity at the end of treatment and underscore the limitations of relying solely on PET/CT for remission assessment,” said Dr. David Kurtz, Chief Medical Officer at Foresight Diagnostics and co-author of the analysis. “With the ultra-high sensitivity of Foresight CLARITY, we can detect disease that imaging misses, offering clinicians a more accurate and actionable tool for post-treatment risk stratification.”

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