Ultrasensitive ctDNA-MRD outperforms PET for defining remission in frontline LBCL

Led by NCI in collaboration with Stanford (developers of PhasED-Seq) and Foresight Diagnostics (CLARITY MRD assay), ultrasensitive ctDNA minimal residual disease (MRD) testing using phased-variant detection (e.g., PhasED-Seq) tracked tumor-specific variants across five prospective first-line anthracycline-based LBCL cohorts (n=137; 409 serial plasma samples; NCT04002947; NCT00398177; NCT02529852; NCT04231877; NCT04134936). Undetectable ctDNA was seen in 55% after 2 cycles and 78% at end of therapy (EOT). Two-year PFS strongly stratified by MRD: after 2 cycles 96% (undetectable) vs 67% (detectable; HR 6.9; p=0.0025), and at EOT 97% vs 29% (HR 28.7; p<0.0001). ctDNA-MRD at EOT had greater prognostic utility than conventional EOT PET (HR 28.3 for detectable ctDNA vs HR 3.6 for PET-positive)—noting contemporary SOC outcomes with pola-R-CHP show ~77% 2-yr PFS overall, so ctDNA-negative patients approach the “cured” plateau while ctDNA-positive patients remain high-risk despite radiographic response.