End-of-induction circulating tumor DNA outperforms conventional cellular MRD for predicting early progression in follicular lymphoma: an ancillary study of the RELEVANCE randomized trial

Abstract

In this ancillary study of the RELEVANCE phase III trial (NCT01650701), we performed the first direct intra-patient comparison of circulating tumor DNA (ctDNA)-based versus cellular t(BCL2/JH) translocation-based MRD at end of induction (EOI) in 278 patients with advanced FL, for the prediction of progression within 24 months (POD24). Conventional cellular t(BCL2/JH) MRD in peripheral blood (PB) and/or bone marrow (BM) had been previously assessed by digital PCR across MBR, 3’MBR, and mcr breakpoint regions; ctDNA was assessed by targeted NGS of phased variants in cell-free DNA (cfDNA) using a custom 111-gene, 130-kb panel. Trackable phased variants were identified at baseline in 242/278 patients (87%) for cfDNA, versus 145/278 (52%) for PB/BM t(BCL2/JH) (p < 0.001). Among 132 patients informative for both markers, ctDNA-based MRD at EOI predicted PFS more strongly (HR 4.5, 95% CI 2.2–9.1) than t(BCL2/JH)-based MRD (HR 2.9, 95% CI 1.5–5.6), and had a higher positive predictive value for POD24 (50.0% vs 14.3%, p = 0.009) with a numerically higher negative predictive value (94.1% vs 90.1%, p = 0.051). EOI ctDNA positivity was the only MRD marker associated with inferior OS in an exploratory univariate analysis (9 events; HR 5.6, 95% CI 1.3–23.3; log-rank p = 0.008). These data establish ctDNA-based MRD as a more broadly applicable and clinically actionable POD24 predictor than t(BCL2/JH)-based MRD in first-line advanced FL.