Molecular features encoded in the ctDNA reveal heterogeneity and predict outcome in high-risk aggressive B-cell lymphoma

Abstract

Inadequate molecular and clinical stratification of the patients with high-risk diffuse large B-cell lymphoma (DLBCL) is a clinical challenge hampering the establishment of personalized therapeutic options. We studied the translational significance of liquid biopsy in a uniformly treated trial cohort. Pretreatment circulating tumor DNA (ctDNA) revealed hidden clinical and biological heterogeneity, and high ctDNA burden determined increased risk of relapse and death independently of conventional risk factors. Genomic dissection of pretreatment ctDNA revealed translationally relevant phenotypic, molecular, and prognostic information that extended beyond diagnostic tissue biopsies. During therapy, chemorefractory lymphomas exhibited diverging ctDNA kinetics, whereas end-of-therapy negativity for minimal residual disease characterized cured patients and resolved clinical enigmas, including false residual PET positivity. Furthermore, we discovered fragmentation disparities in the cell-free DNA that characterize lymphoma-derived ctDNA and, as a proof-of-concept for their clinical application, utilized machine learning to show that end-of-therapy fragmentation patterns predict outcome. Altogether, we have discovered novel molecular determinants in the liquid biopsy that can non-invasively guide treatment decisions.

Circulating tumor DNA in B-cell lymphoma: technical advances, clinical applications, and perspectives for translational research

“…Several research groups have investigated the relationship between pretreatment ctDNA concentrations and conventional markers of tumor burden and its role as a prognostic biomarker in B-cell lymphoma, as summarized in Table 2 . In DLBCL, baseline ctDNA levels significantly correlate with IPI, TMTV as well as lactate dehydrogenase (LDH) concentrations and Ann Arbor stage [ 12 , 27 , 36 , 39 , 43 , 52 , 57 , 58 ]. Importantly, this correlation can be directly translated into a prognostic effect, as pretreatment ctDNA concentrations have shown to be strongly predictive of clinical outcomes in univariate and multivariate analyses in patients receiving standard immunochemotherapy [ 12 , 27 , 52 , 57 , 58 ].…”

“…In DLBCL, baseline ctDNA levels significantly correlate with IPI, TMTV as well as lactate dehydrogenase (LDH) concentrations and Ann Arbor stage [ 12 , 27 , 36 , 39 , 43 , 52 , 57 , 58 ]. Importantly, this correlation can be directly translated into a prognostic effect, as pretreatment ctDNA concentrations have shown to be strongly predictive of clinical outcomes in univariate and multivariate analyses in patients receiving standard immunochemotherapy [ 12 , 27 , 52 , 57 , 58 ]. Furthermore, Frank et al performed IgHTS on serial plasma samples from 69 patients with relapsed/refractory DLBCL (rrDLBCL) receiving anti-CD19 CAR T-cell therapy and demonstrated that pretreatment ctDNA levels significantly correlate with progression-free survival (PFS) and overall survival (OS) [ 39 ].…”

“…Several other studies explored the prognostic value of ctDNA as a landmark after the end of treatment, a situation in which MRD detection is particularly challenging due to soberingly low amounts of ctDNA in blood plasma. In DLBCL, three studies reported favorable clinical outcomes in patients with undetectable ctDNA after completion of therapy using targeted-capture NGS-based technologies [ 12 , 49 , 52 ]. In MCL, Lakhotia et al showed that ctDNA detection by IgHTS after induction therapy is associated with shorter PFS and OS [ 64 ] (Table 4 ).…”

From Stem Cell Transplantation to CAR-T Therapy in Relapse-Refractory Diffuse Large B-Cell Lymphoma

“…Circulating tumour DNA is not a single assay but can reveal multiple dimensions of a tumour. Dissecting liquid biopsies of aggressive B-cell lymphoma patients revealed novel quantitative, mutational, and fragmentation patterns in ctDNA that can resolve undisclosed heterogeneity and identify patients with incomplete responses and inferior outcomes following uniform therapy (41) . ctDNA is used to detect MRD and/or genotype tumours.…”

Mutation-Attention (MuAt): deep representation learning of somatic mutations for tumour typing and subtyping

“…CUPs are thus often treated with broad spectrum antineoplastic drugs with limited success, instead of site-specific treatments. Liquid biopsies can be used to detect circulating tumor DNA (ctDNA) originating from cancer cells before metastatic spread and to predict disease outcome [8, 9, 10]. Similarly to CUPs, determining the tissue of origin of ctDNA is a key obstacle in enabling clinical action.…”