Real-World Implementation of Tumor-Informed ctDNA MRD Testing in Frontline Diffuse Large B-Cell Lymphoma: A Single-Center Experience

Circulating tumor DNA (ctDNA) based measurable residual disease (MRD) assessment is recommended by NCCN to clarify equivocal end-of-treatment PET/CT in frontline diffuse large B-cell lymphoma when biopsy is not feasible. Unlike B-ALL, where bone marrow routinely provides an accessible disease-rich specimen, DLBCL requires retrieval of adequate diagnostic lymph node or soft tissue to identify a tumor-specific clonotype before it can be tracked in blood. This multistep workflow creates opportunities for delay that may limit MRD availability at clinical decision points. We evaluated real-world adoption, operational barriers, and turnaround times following implementation of an institutional clonoSEQ® workflow.

We retrospectively identified patients with newly diagnosed DLBCL treated at the University of Nebraska Medical Center (UNMC) from January 2024 through December 2025 following implementation of upfront clonality testing. Patients were classified as MRD-attempted (clonality ordered) or MRD-not-attempted. We compared baseline characteristics and quantified intervals from consultation through tissue-based clonotype identification and subsequent blood-based MRD reporting.

Among 112 eligible patients, MRD was attempted in 67 (60%) and succeeded in 60/67 (90%)(Figure 1); MRD-attempted patients lived closer to the institution (median 11.7 vs 72.5 miles; P<0.001), while other clinical and access factors were similar(Table 1). Once ordered, testing proceeded rapidly: median times from order to tissue receipt, tissue receipt to identification of a trackable tumor-specific DNA sequence, and blood collection to MRD reporting were 6 days (IQR, 3–9; range, 1–59), 11 days (IQR, 9–12; range, 7–15), and 9 days (IQR, 7–11; range, 6–26), respectively. The main delay occurred before testing was initiated: the median consultation-to-order interval was 20 days (IQR, 4–112; range, 0–239), with only 10% ordered at consultation and 36% ordered >90 days later. Among 49 patients with paired end-of-treatment PET/CT and MRD, MRD was available a median of 10 days after PET/CT (IQR, 7–20; range, −13 to 155); 8 (16%) experienced delays >60 days, attributable to late ordering and tissue submission rather than laboratory processing. Of 102 patients undergoing end-of-treatment PET/CT, 29 (28%) had residual metabolic activity. Concurrent MRD was available in 15: all 4 with detectable MRD progressed, whereas none of 11 with undetectable MRD progressed during a median follow-up of 15 months.

Timely MRD may help clarify residual end-of-treatment PET activity. Laboratory turnaround was reasonable, with delays primarily driven by late clonality ordering and tissue submission. Standardizing these steps at diagnosis may improve MRD availability and clinical utility.