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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt


  • Fulltext

    Forlagets udgivne version, 2,93 MB, PDF-dokument

  • Leo Meriranta
  • Amjad Alkodsi
  • Annika Pasanen
  • Maija Lepistö
  • Parisa Mapar
  • Yngvild Nuvin Blaker
  • Judit Jørgensen
  • Marja Liisa Karjalainen-Lindsberg
  • Idun Fiskvik
  • Lars Tore G. Mikalsen
  • Matias Autio
  • Magnus Björkholm
  • Mats Jerkeman
  • Øystein Fluge
  • Brown, Peter de Nully
  • Sirkku Jyrkkiö
  • Harald Holte
  • Esa Pitkänen
  • Pekka Ellonen
  • Sirpa Leppä

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.

Udgave nummer12
Sider (fra-til)1863-1877
Antal sider15
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
This article was supported by the Academy of Finland (grant 311171), the Biomedicum Helsinki Foundation, the Digital Precision Cancer Medicine Flagship iCAN, the Finnish Cancer Organizations, the Sigrid Juselius Foundation, the Southern Finland Regional Cancer Center FICAN South, Helsinki University Hospital, The University of Helsinki, the Ida Montin Foundation, the Orion Research Foundation, and the Paolo Foundation.

Publisher Copyright:
© 2022 American Society of Hematology

ID: 346532391