Circulating tumor DNA at baseline as a prognostic marker in untreated follicular lymphoma

Follicular lymphoma (FL) is an indolent disease with favorable outcome in patients with symptomatic disease treated with anti-CD20 based immunochemotherapy. However, a subset of patients experiencing progression within 24 months (POD24) have poor prognosis and shown shorter overall survival at 5 years. Identification of patients at high-risk that would benefit for alternative treatment is an unmet medical need, but available clinicogenetic scores show suboptimal performance for predicting early progression. We report a ctDNA analysis in baseline plasma from a large cohort of the global Phase-3 GALLIUM trial, which evaluated the efficacy of obinutuzumab plus chemotherapy versus rituximab plus chemotherapy in patients with untreated FL. We showed that ctDNA measured at baseline is prognostic for the identification of high-risk versus low-risk patients. In this large dataset, mutant molecules per milliliter (MMPM) adds prognostic value beyond known factors to predict POD24 (AUROC 0.69) compared to FLIPI (AUROC 0.57), FLIPI-2 (AUROC 0.59), and SPD (AUROC 0.58) in a univariate analysis, and consistently increased the AUROC of these scores in multivariate models. Using a cross-validated cutoff of 168.57 MMPM high baseline ctDNA was significantly associated with shorter progression free survival (HR = 2.2 [95% CI 1.8-2.6]). This prognostic value was maintained across CHOP or CVP and bendamustine regimens. These results provided a robust assessment of baseline ctDNA as stratification tool in clinical trials for patients treated with standard of care chemoimmunotherapy, and corroborates the growing scientific evidence proposing ctDNA as a novel prognostic biomarker for untreated FL.