Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphoma

Steven Wang; Parisa Mapar; Norbert Moldovan; Ymke van der Pol; Aram Safrastyan; Erik van Werkhoven; Normastuti Adhini Tantyo; Bart Snieder; André F Do Brito Valente; A Vera de Jonge; Avinash Dinmohamed; Esther E E Drees; Margaretha G M Roemer; Bauke Ylstra; Clara P W Klerk; Leonie Strobbe; Yorick Sandberg; Rinske S Boersma; Harry Koene; Hans Pruijt; Koen de Heer; Rozemarijn van Rijn; Yavuz M Bilgin; Eva de Jongh; Marcel Nijland; Marjolein van der Poel; Ad Koster; Laurens Nieuwenhuizen; Rob Fijnheer; Aart Beeker; Rogier Mous; Vibeke K J Vergote; Joost S P Vermaat; D Michiel Pegtel; Martine E D Chamuleau; Florent Mouliere

doi:10.1016/j.xcrm.2026.103006

Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphoma

Steven Wang
, Parisa Mapar
, Norbert Moldovan
, Ymke van der Pol
, Aram Safrastyan
, Erik van Werkhoven
, Normastuti Adhini Tantyo
, Bart Snieder
, André F Do Brito Valente
, A Vera de Jonge
, Avinash Dinmohamed
, Esther E E Drees
, Margaretha G M Roemer
, Bauke Ylstra
, Clara P W Klerk
, Leonie Strobbe
, Yorick Sandberg
, Rinske S Boersma
, Harry Koene
, Hans Pruijt

Koen de Heer, Rozemarijn van Rijn, Yavuz M Bilgin, Eva de Jongh, Marcel Nijland, Marjolein van der Poel, Ad Koster, Laurens Nieuwenhuizen, Rob Fijnheer, Aart Beeker, Rogier Mous, Vibeke K J Vergote, Joost S P Vermaat, D Michiel Pegtel, Martine E D Chamuleau, Florent Mouliere^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Curative-intent immunochemotherapy fails in ∼30% of patients with large B cell lymphoma (LBCL), yet no validated molecular tool enables early identification of high-risk individuals to guide treatment intensification. Using shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from 190 LBCL patients, we develop and validate the ACT score (aberrations, composition of fragments, and terminal motif analyses), a composite classifier integrating genomic and fragmentomic features from a single post-cycle-1 sample. ACT-positive patients have worse 2-year outcomes versus ACT-negative patients: time-to-progression 29% vs. 83% (hazard ratio [HR]: 4.4, 95% confidence interval [CI]: 1.9-10.0; p = 1.5 × 10-4) and overall survival 47% vs. 93% (HR: 8.7, 95% CI: 3.0-25.4; p = 1.8 × 10-6). The ACT score is independently prognostic of the International Prognostic Index, and their combination identifies the highest risk patients. Unlike mutation-based approaches, this assay requires neither tumor tissue, germline control, nor a baseline plasma sample. Built on open-source tools and sWGS, the ACT score offers a feasible, scalable strategy for early risk stratification in aggressive LBCL.

Original language	English
Article number	103006
Journal	Cell reports. Medicine
Volume	7
Issue number	9
Early online date	24 Aug 2026
DOIs	https://doi.org/10.1016/j.xcrm.2026.103006
Publication status	Published - 15 Sept 2026

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Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphomaFinal published version, 19.3 MBLicence: CC BY

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Wang, S., Mapar, P., Moldovan, N., van der Pol, Y., Safrastyan, A., van Werkhoven, E., Tantyo, N. A., Snieder, B., Do Brito Valente, A. F., de Jonge, A. V., Dinmohamed, A., Drees, E. E. E., Roemer, M. G. M., Ylstra, B., Klerk, C. P. W., Strobbe, L., Sandberg, Y., Boersma, R. S., Koene, H., ... Mouliere, F. (2026). Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphoma. Cell reports. Medicine, 7(9), Article 103006. https://doi.org/10.1016/j.xcrm.2026.103006

@article{a36b30c2b51344638bdda5664dbbc8c9,

title = "Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphoma",

abstract = "Curative-intent immunochemotherapy fails in ∼30\% of patients with large B cell lymphoma (LBCL), yet no validated molecular tool enables early identification of high-risk individuals to guide treatment intensification. Using shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from 190 LBCL patients, we develop and validate the ACT score (aberrations, composition of fragments, and terminal motif analyses), a composite classifier integrating genomic and fragmentomic features from a single post-cycle-1 sample. ACT-positive patients have worse 2-year outcomes versus ACT-negative patients: time-to-progression 29\% vs. 83\% (hazard ratio [HR]: 4.4, 95\% confidence interval [CI]: 1.9-10.0; p = 1.5 {\texttimes} 10-4) and overall survival 47\% vs. 93\% (HR: 8.7, 95\% CI: 3.0-25.4; p = 1.8 {\texttimes} 10-6). The ACT score is independently prognostic of the International Prognostic Index, and their combination identifies the highest risk patients. Unlike mutation-based approaches, this assay requires neither tumor tissue, germline control, nor a baseline plasma sample. Built on open-source tools and sWGS, the ACT score offers a feasible, scalable strategy for early risk stratification in aggressive LBCL.",

author = "Steven Wang and Parisa Mapar and Norbert Moldovan and \{van der Pol\}, Ymke and Aram Safrastyan and \{van Werkhoven\}, Erik and Tantyo, \{Normastuti Adhini\} and Bart Snieder and \{Do Brito Valente\}, \{Andr{\'e} F\} and \{de Jonge\}, \{A Vera\} and Avinash Dinmohamed and Drees, \{Esther E E\} and Roemer, \{Margaretha G M\} and Bauke Ylstra and Klerk, \{Clara P W\} and Leonie Strobbe and Yorick Sandberg and Boersma, \{Rinske S\} and Harry Koene and Hans Pruijt and \{de Heer\}, Koen and \{van Rijn\}, Rozemarijn and Bilgin, \{Yavuz M\} and \{de Jongh\}, Eva and Marcel Nijland and \{van der Poel\}, Marjolein and Ad Koster and Laurens Nieuwenhuizen and Rob Fijnheer and Aart Beeker and Rogier Mous and Vergote, \{Vibeke K J\} and Vermaat, \{Joost S P\} and Pegtel, \{D Michiel\} and Chamuleau, \{Martine E D\} and Florent Mouliere",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/",

year = "2026",

month = sep,

day = "15",

doi = "10.1016/j.xcrm.2026.103006",

language = "English",

volume = "7",

journal = "Cell reports. Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "9",

}

Wang, S, Mapar, P, Moldovan, N, van der Pol, Y, Safrastyan, A, van Werkhoven, E, Tantyo, NA, Snieder, B, Do Brito Valente, AF, de Jonge, AV, Dinmohamed, A, Drees, EEE, Roemer, MGM, Ylstra, B, Klerk, CPW, Strobbe, L, Sandberg, Y, Boersma, RS, Koene, H, Pruijt, H, de Heer, K, van Rijn, R, Bilgin, YM, de Jongh, E, Nijland, M, van der Poel, M, Koster, A, Nieuwenhuizen, L, Fijnheer, R, Beeker, A, Mous, R, Vergote, VKJ, Vermaat, JSP, Pegtel, DM, Chamuleau, MED & Mouliere, F 2026, 'Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphoma', Cell reports. Medicine, vol. 7, no. 9, 103006. https://doi.org/10.1016/j.xcrm.2026.103006

TY - JOUR

T1 - Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphoma

AU - Wang, Steven

AU - Mapar, Parisa

AU - Moldovan, Norbert

AU - van der Pol, Ymke

AU - Safrastyan, Aram

AU - van Werkhoven, Erik

AU - Tantyo, Normastuti Adhini

AU - Snieder, Bart

AU - Do Brito Valente, André F

AU - de Jonge, A Vera

AU - Dinmohamed, Avinash

AU - Drees, Esther E E

AU - Roemer, Margaretha G M

AU - Ylstra, Bauke

AU - Klerk, Clara P W

AU - Strobbe, Leonie

AU - Sandberg, Yorick

AU - Boersma, Rinske S

AU - Koene, Harry

AU - Pruijt, Hans

AU - de Heer, Koen

AU - van Rijn, Rozemarijn

AU - Bilgin, Yavuz M

AU - de Jongh, Eva

AU - Nijland, Marcel

AU - van der Poel, Marjolein

AU - Koster, Ad

AU - Nieuwenhuizen, Laurens

AU - Fijnheer, Rob

AU - Beeker, Aart

AU - Mous, Rogier

AU - Vergote, Vibeke K J

AU - Vermaat, Joost S P

AU - Pegtel, D Michiel

AU - Chamuleau, Martine E D

AU - Mouliere, Florent

PY - 2026/9/15

Y1 - 2026/9/15

N2 - Curative-intent immunochemotherapy fails in ∼30% of patients with large B cell lymphoma (LBCL), yet no validated molecular tool enables early identification of high-risk individuals to guide treatment intensification. Using shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from 190 LBCL patients, we develop and validate the ACT score (aberrations, composition of fragments, and terminal motif analyses), a composite classifier integrating genomic and fragmentomic features from a single post-cycle-1 sample. ACT-positive patients have worse 2-year outcomes versus ACT-negative patients: time-to-progression 29% vs. 83% (hazard ratio [HR]: 4.4, 95% confidence interval [CI]: 1.9-10.0; p = 1.5 × 10-4) and overall survival 47% vs. 93% (HR: 8.7, 95% CI: 3.0-25.4; p = 1.8 × 10-6). The ACT score is independently prognostic of the International Prognostic Index, and their combination identifies the highest risk patients. Unlike mutation-based approaches, this assay requires neither tumor tissue, germline control, nor a baseline plasma sample. Built on open-source tools and sWGS, the ACT score offers a feasible, scalable strategy for early risk stratification in aggressive LBCL.

AB - Curative-intent immunochemotherapy fails in ∼30% of patients with large B cell lymphoma (LBCL), yet no validated molecular tool enables early identification of high-risk individuals to guide treatment intensification. Using shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from 190 LBCL patients, we develop and validate the ACT score (aberrations, composition of fragments, and terminal motif analyses), a composite classifier integrating genomic and fragmentomic features from a single post-cycle-1 sample. ACT-positive patients have worse 2-year outcomes versus ACT-negative patients: time-to-progression 29% vs. 83% (hazard ratio [HR]: 4.4, 95% confidence interval [CI]: 1.9-10.0; p = 1.5 × 10-4) and overall survival 47% vs. 93% (HR: 8.7, 95% CI: 3.0-25.4; p = 1.8 × 10-6). The ACT score is independently prognostic of the International Prognostic Index, and their combination identifies the highest risk patients. Unlike mutation-based approaches, this assay requires neither tumor tissue, germline control, nor a baseline plasma sample. Built on open-source tools and sWGS, the ACT score offers a feasible, scalable strategy for early risk stratification in aggressive LBCL.

U2 - 10.1016/j.xcrm.2026.103006

DO - 10.1016/j.xcrm.2026.103006

M3 - Article

C2 - 42636799

SN - 2666-3791

VL - 7

JO - Cell reports. Medicine

JF - Cell reports. Medicine

IS - 9

M1 - 103006

ER -

Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphoma

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