tofacitinib and Epstein-Barr-Virus-Infections

Iatrogenic lymphoproliferative disorders have been described in patients receiving immunosuppressive/immunomodulatory agents outside the transplantation setting. Novel biological agents such as TNF-α blockers and JAK-inhibitors have also proven to be effective in many disorders including rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis and Crohn disease), psoriasis, and others. A significant dilemma exists in those lymphoproliferative disorders associated with immunosuppressants and rheumatologic conditions, that relies on whether the association of the process is with the medication or the underlying autoimmune condition. In the current case report, we describe an extraordinary case of Epstein-Barr virus-positive anaplastic large cell lymphoma, in association with rheumatoid arthritis and the use of JAK-inhibitors. Comprehensive molecular testing (fluorescence in situ hybridization, OncoScan microarray, pyrosequencing) was done comparing sequential biopsies in this patient from skin and lung, which revealed a driving mutation in the BRAF V600E gene, a crucial finding, given the potential use of targeted therapy in this pathway.

Topics: Aged; Arthritis, Rheumatoid; Epstein-Barr Virus Infections; Humans; Immunocompromised Host; Lymphoma, Large-Cell, Anaplastic; Male; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrimidines; Pyrroles

Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model. We found that all EBV-positive T and NK cell lines and patient samples tested displayed activation of the JAK3/STAT5 pathway. Treatment of these cell lines with tofacitinib reduced the levels of phospho-STAT5, suppressed proliferation, induced G1 cell-cycle arrest and decreased EBV LMP1 and EBNA1 expression. An EBV-negative NK cell line was also sensitive to tofacitinib, whereas an EBV-infected NK cell line was more sensitive to tofacitinib than its parental line. Tofacitinib significantly inhibited the growth of established tumors in NOG mice. These findings suggest that tofacitinib may represent a useful therapeutic agent for patients with EBV-associated T and NK cell lymphoma.

Topics: Animals; Apoptosis; Biomarkers; Cell Line, Tumor; Disease Models, Animal; Epstein-Barr Virus Infections; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Viral; Herpesvirus 4, Human; Humans; Janus Kinase 3; Killer Cells, Natural; Lymphocyte Activation; Lymphoma, T-Cell; Mice; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; STAT5 Transcription Factor; T-Lymphocytes; Tumor Burden; Xenograft Model Antitumor Assays