DIRECT: Prognostic value of PV-supported ctDNA MRD in LBCL

Results from the prospective, multicenter DIRECT study (NCT04226937), investigating the prognostic value of phased variant (PV)-supported circulating tumor DNA (ctDNA) measurable residual disease (MRD) following first-line therapy in patients with large B-cell lymphoma (LBCL), were published in the Journal of Clinical Oncology by Krupka et al. Patients were tested for ctDNA using a lymphoma-customized assay that detected hundreds of PVs per patient (Cohort 1, n = 184). A subgroup of patients (Cohort 2, n = 151) was defined as patients who received full-dose anthracycline-based immunochemotherapy. The primary outcome measure was time to tumor progression (TTP).

Key data: End of treatment (EoT) PV-MRD status was available for 155 patients. The 2-year TTP was 42.2% with detectable PV-MRD vs 95.4% without detectable PV-MRD (hazard ratio [HR], 13.7; p < 0.001), and 2-year progression-free survival (PFS) was 38.0% vs 90.2% (HR, 8.72; p < 0.001). Findings were consistent among patients who received full-dose anthracycline-based immunochemotherapy (Cohort 2); 2-year TTP was 44.8% with detectable PV-MRD vs 95.8% with undetectable PV-MRD (HR, 15.35; p < 0.001), and 2-year PFS was 42.2% vs 91.4% (HR, 9.29; p < 0.001). In an analysis of 111 patients treated with full-dose anthracycline-based immunochemotherapy for whom both EoT positron emission tomography–computed tomography (PET-CT) and EoT PV-MRD status was available, PV-MRD demonstrated superior prognostic discrimination for TTP vs PET-CT (HR, 16.89 vs 6.79). While PV-MRD demonstrated a high negative prognostic value, it was not invariably associated with relapse, particularly in patients with transformed follicular lymphoma.

Key learning: EoT PV-MRD demonstrated robust risk stratification after first-line therapy, supporting its potential clinical utility in refining post-treatment surveillance and informing future response-adapted strategies in LBCL.