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Accumulation of high-risk genetic features after chemoimmunotherapy: A longitudinal study in mantle cell lymphoma

Leukemia (2026)Cite this article

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Patients with relapse of mantle cell lymphoma (MCL) have an aggressive disease course and the progression free survival (PFS) decreases with each relapse. The median PFS is approximately 2.5 years after first-line treatment and only 0.7 years after second-line treatment [1]. However, it remains unclear whether the progressively shorter PFS with each relapse is driven by newly acquired high-risk features or mainly by intrinsic tumor resistance present from disease onset. Several previous studies have demonstrated clonal evolution of tumor cells, with greater cytogenetic complexity and higher mutational burden at relapse [2,3,4,5,6]. However, cumulative change in biological risk factors across relapses and their relationship to prior treatments have not been well described for MCL.

We analyzed sequential tumor tissue from 70 MCL patients, including 31 using whole exome sequencing (WES) at two or more time points (Supplementary Figure 1). We found that nine of the patients had three or more consecutive samples available for WES analysis. Patients analyzed with WES did not differ from the rest of the cohort (Supplementary Table 1). DNA was isolated from fresh frozen cells and the samples were analyzed with the GMS560 Solid pipeline as described in Supplementary Material and Methods. Mutations and copy number alterations (CNAs) previously associated with MCL [7] (Supplementary Table 2) were chosen for detailed analysis and referred to as “MCL-associated alterations”. The study was ethically approved by the regional ethical review board in Uppsala and conducted according to the declaration of Helsinki, Dnr 2014/233 and 2019/0013.

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Fig. 1: Accumulation of high-risk features.
Fig. 2: Prognostic impact of new alterations at relapse and correlation with treatment.

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Acknowledgements

The authors would like to acknowledge Clinical Genomics Uppsala, the Science for Life Laboratory, Dept. of Immunology, Genetics and Pathology, Uppsala University, Sweden for performing the sequencing. The material collection was supported by U-CAN, through Uppsala Biobank and the Department of Clinical Pathology, Uppsala University Hospital.

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Authors and Affiliations

  1. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

    Anna Nikkarinen, Jonas Almlöf, Albin Österroos, Claes Ladenvall, Rose-Marie Amini, Peter Hollander, Kristin Ayoola Gustafsson, Panagiotis Baliakas & Ingrid Glimelius

  2. Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    Jonas Almlöf, Claes Ladenvall & Panagiotis Baliakas

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  1. Anna Nikkarinen
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  2. Jonas Almlöf
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Contributions

(CRediT format): Conceptualization: A.N., J.A., C.L., R.-M.A., P.H., P.B., I.G. Methodology: A.N., J.A., C.L., K.A.G., P.H., I.G. Data Curation: A.N., R.-M.A., P.H. K.A.G. I.G. Formal Analysis: A.N., J.A., A.Ö. Investigation: A.N., P.H., K.A.G. Visualization: A.N., A.Ö. I.G. Writing – Original Draft: A.N., J.A., K.A.G., P.B., I.G. Writing – Review & Editing: All authors Supervision: I.G. Funding Acquisition: I.G.

Corresponding author

Correspondence to Ingrid Glimelius.

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Competing interests

A.N. No conflicts of interest J.A. No conflicts of interest A.Ö. No conflicts of interest C.L. No conflicts of interest R-M.A. No conflicts of interest P.H. No conflicts of interest K.A.G. No conflicts of interest P.B. No conflicts of interest I.G. received research support for the department from Takeda and participated in educational sessions arranged by Janssen Cilag, AbbVie and Kite Gilead with all support to the department.

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Nikkarinen, A., Almlöf, J., Österroos, A. et al. Accumulation of high-risk genetic features after chemoimmunotherapy: A longitudinal study in mantle cell lymphoma. Leukemia (2026). https://doi.org/10.1038/s41375-026-02861-1

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