Prospective Validation of Circulating Tumor DNA Measurable Residual Disease After First-Line Therapy in Large B-Cell Lymphoma
Steven Wang, Marcel Nijland, Leonie Strobbe, Margriet Oosterveld, Rinske Boersma, Harry R. Koene, Clara Klerk, Eva de Jongh, Ad Koster, Hans Pruijt, Marjolein van der Poel, Erik van Werkhoven, Helma G.J.M. Zanders, Avinash G. Dinmohamed, D. Michiel Pegtel, Stephanie Meek, Sierra M. Love Stowell, Hayley Warinske, Ash A. Alizadeh, David M. Kurtz, Martine E.D. Chamuleau
Abstract
PURPOSE End-of-treatment (EOT) response evaluation by positron emission tomography (PET) remains suboptimal in patients with large B-cell lymphoma (LBCL), because of its limited positive predictive value (PPV). Circulating tumor DNA (ctDNA)—based measurable residual disease (MRD) detection offers a minimally invasive approach and may improve prognostication. We prospectively evaluated EOT MRD using phased variant enrichment and detection sequencing (PhasED-Seq) in patients with first-line LBCL. METHODS Patients were enrolled in the HOVON-902 prospective cohort and received curative-intent first-line treatment. Phased variants (PVs) were identified and tracked using tumor biopsies or pretreatment plasma. The prognostic significance of EOT ctDNA-MRD status in progression-free survival (PFS) and overall survival (OS) was compared with that of the International Prognostic Index (IPI) and EOT PET-computed tomography (CT). RESULTS PV identification was successful in 134 of 136 (99%) using either tissue or plasma. At EOT, 83% of patients were MRD-negative and 17% of patients were MRD-positive. MRD positivity was strongly associated with inferior outcomes: the 3-year PFS was 17% in MRD-positive versus 85% in MRD-negative patients (hazard ratio [HR], 9.8 [95% CI, 5.1 to 19]; P = 9.63 × 10 −12 ), and the OS was 43% versus 92%, respectively (HR, 7.7 [95% CI, 3.4 to 17.4]; P = 1.27 × 10 −6 ). In multivariate analysis, MRD was an independent prognostic factor when controlling for IPI and EOT PET-CT. MRD positivity had a higher PPV for 2-year PFS than positive PET (68% v 56%, P ≤ .001), whereas negative predictive value was similar between negative MRD and PET (89% v 88%, P = .71). MRD positivity was associated with a significantly higher relapse risk within both complete metabolic response (CMR) and non-CMR subgroups. CONCLUSION This study validates ultrasensitive ctDNA-MRD detection using PhasED-Seq in a uniformly treated, prospective real-world LBCL cohort. These findings support further evaluation of MRD integration into clinical response assessment.