Molecular features encoded in the ctDNA reveal heterogeneity and predict outcome in high-risk aggressive B-cell lymphoma.
Leo MerirantaAmjad AlkodsiAnnika PasanenMaija LepistöParisa MaparYngvild Nuvin BlakerJudit Meszaros JørgensenMarja-Liisa Karjalainen-LindsbergIdun FiskvikLars Tore G MikalsenMatias AutioMagnus BjörkholmMats JerkemanØystein FlugePeter de Nully BrownSirkku JyrkkiöHarald HolteEsa PitkänenPekka EllonenSirpa LeppaPublished in: Blood (2022)
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 (MRD) 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, used 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 noninvasively guide treatment decisions.
Keyphrases
- circulating tumor
- diffuse large b cell lymphoma
- cell free
- circulating tumor cells
- machine learning
- single cell
- risk factors
- epstein barr virus
- clinical trial
- ultrasound guided
- end stage renal disease
- newly diagnosed
- single molecule
- stem cells
- prognostic factors
- bone marrow
- chronic kidney disease
- gene expression
- positron emission tomography
- copy number
- deep learning
- phase ii
- patient reported
- replacement therapy
- patient reported outcomes
- pet imaging