Case Introduction and ctDNA as Emerging Risk Factor

Dr. Megan Melody from Tampa General Hospital Cancer Institute and Dr. Mark Roschewski from Memorial Sloan Kettering Cancer Center discuss circulating tumor DNA (ctDNA) applications in lymphoma care. They present Maria's case: a 62-year-old woman with stage 3 diffuse large B-cell lymphoma featuring extensive nodal involvement with bulky mediastinal disease and elevated SUV_max values consistent with aggressive lymphoma.

Following tissue diagnosis, a personalized tumor-informed ctDNA assay was designed using whole-exome sequencing to identify unique tumor mutations. Her baseline ctDNA test confirmed tumor DNA detection in circulation. After initiating standard R-CHOP chemotherapy, she achieved ctDNA clearance after 3 cycles, whereas PET-CT showed partial response. At treatment completion, she maintained ctDNA negativity and achieved complete response by imaging. However, 18 months later during routine surveillance, her ctDNA became positive despite remaining clinically asymptomatic with normal imaging.

Dr. Roschewski contextualizes this case within the broader goal of curing aggressive B-cell lymphoma, achieved approximately 75% of the time. He emphasizes limitations of baseline risk assessment tools and introduces ctDNA and PET scans as approaches that provide information after therapy initiation. This case demonstrates discordant results between blood tests (positive direction) and PET scans (partial response), highlighting test limitations and interpretation challenges.

Most patients eliminate cancer cells within the first 2 cycles despite receiving 6-cycle regimens, with approximately two-thirds achieving undetectable ctDNA after several cycles. Persistent detectable ctDNA suggests incomplete cancer elimination or resistance development. Maintaining undetectable ctDNA at treatment completion represents an excellent prognostic sign, though 15% to 20% of patients with complete response by imaging ultimately relapse. Highly sensitive or "ultrasensitive" ctDNA testing combined with imaging negativity reduces this relapse risk to single digits (5% or lower).

The case raises surveillance questions about following patients post-treatment, with many clinicians avoiding routine testing due to false-positive concerns and uncertainty about whether earlier detection improves cure rates. Although intuitive that earlier knowledge benefits patients, proving this advantage in lymphoma remains challenging, leading some physicians to minimize post-treatment monitoring until 18 months or beyond.