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    Molecular Mechanisms of Disease Progression in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type during Ibrutinib Therapy

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    Author
    Fox, LC; Yannakou, CK; Ryland, G; Lade, S; Dickinson, M; Campbell, BA; Prince, HM
    Date
    2018-06-01
    Source Title
    International Journal of Molecular Sciences
    Publisher
    MDPI
    University of Melbourne Author/s
    Dickinson, Michael; Yannakou, Costas; Lade, Stephen; Campbell, Belinda; Prince, Henry; Ryland, Georgina
    Affiliation
    Medicine and Radiology
    Clinical Pathology
    Sir Peter MacCallum Department of Oncology
    Metadata
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    Document Type
    Journal Article
    Citations
    Fox, L. C., Yannakou, C. K., Ryland, G., Lade, S., Dickinson, M., Campbell, B. A. & Prince, H. M. (2018). Molecular Mechanisms of Disease Progression in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type during Ibrutinib Therapy. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 19 (6), https://doi.org/10.3390/ijms19061758.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255357
    DOI
    10.3390/ijms19061758
    Abstract
    Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an MYD88 p.L265P mutation. Ibrutinib therapy was subsequently commenced, resulting in complete resolution of the skin disease. Despite an ongoing skin response, the patient developed progressive nodal disease at two months. Genomic analysis of the cutaneous tumor sample at baseline was compared to that of the inguinal lymph node upon progression, and revealed the acquisition of multiple genomic changes. These included several aberrations expected to bypass BTK inhibition, including two CARD11-activating mutations, and a deleterious mutation in the nuclear factor kappa B (NF-κB) negative regulator, NFKBIE. In addition, an IgH-IRF8 translocation was detected (which brings the IRF8 transcription factor under control of the immunoglobulin heavy chain locus), representing a third plausible mechanism contributing to ibrutinib resistance. Several copy-number changes occurred in both samples, including an amplification of 18q, which encodes the anti-apoptotic protein BCL2. We describe the first case of novel genomic changes of PCDLBCL-LT that occurred while on ibrutinib, providing important mechanistic insights into both pathogenesis and drug resistance.

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