Dynamic Profiling of Cell Free Tumour DNA in Aggressive B‐Cell Lymphoma From Diagnosis to Transformation at Relapse

Background Next generation sequencing (NGS) of cell free tumour DNA (ctDNA) provides a snapshot of lymphoma mutations correlating with tumour burden. We evaluated the ability of ctDNA to molecularly profile and track disease burden in patients with aggressive‐B‐cell lymphoma. Methods Patients were prospectively recruited from the ‘standard‐of‐care’ clinic based on high‐risk clinical features. Using error‐corrected, capture‐based NGS of ctDNA, we profiled 17 patients receiving treatment for diffuse large B‐cell lymphoma to determine the utility of molecular profiling and dynamic response assessment through to measurable residual disease (MRD) states. Results Somatic mutations were detected at baseline in 17/17 patients, including 13 with phased variants that could be leveraged for enhanced assay sensitivity. Early molecular response (EMR; ≥ 2 log 10 reduction in ctDNA during cycle 1) was predictive of end‐of‐treatment complete metabolic response (CMR; EMR rate 100% vs. no EMR 12.5%, p = 0.0014) and 24‐month progression free survival (PFS; no progression events for those in EMR vs. no EMR 4.57 months, p = 0.015). Only 1/12 MRD‐negative patients relapsed. Interestingly, all three late relapses demonstrated histological infidelity and potential clonal evolution based on ctDNA results. Conclusion These data further support the potential utility of molecular lymphoma profiling by ctDNA analysis and the predictive value of EMR as reported by independent groups. We also posit that ctDNA alone is insufficient to diagnose late relapses, where shared mutations may associate with differential histopathology.