piperidines and Epstein-Barr-Virus-Infections

BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe, frequently lethal, Epstein-Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI-32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this study, we present BTK and ITK with their signalling pathways and review the development of the corresponding inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Antineoplastic Agents; Autoimmunity; B-Lymphocytes; Epstein-Barr Virus Infections; Gene Expression Regulation, Neoplastic; Genetic Diseases, X-Linked; Humans; Inflammation; Lymphoma; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction; Small Molecule Libraries; T-Lymphocytes

Epstein-Barr virus (EBV) positivity in diffuse large B cell lymphoma (DLBCL) provokes a critical oncogenic mechanism to activate intracellular signaling by LMP1. LMP1 specifically mimics the role of BTK-dependent B cell receptor. Therefore, a trial considering RCHOP therapy along with ibrutinib (I-RCHOP) in combination was conducted among patients with EBV-positive DLBCL. This study was an open-label, single-arm, prospective multicenter phase II clinical trial. Patients received 560 mg of ibrutinib with RCHOP every 3 weeks until 6 cycles were completed or progression or unacceptable toxicity was observed. The primary endpoint was objective response, while secondary endpoints included toxicity, progression-free survival, and overall survival. A matched case-control analysis was completed to compare the efficacy and toxicity of I-RCHOP and RCHOP, respectively, in EBV-positive DLBCL patients. From September 2016 to August 2019, 24 patients proven to have EBV-positive DLBCL in the tissue were enrolled and received I-RCHOP. Their median age was 58 years (range, 28-84 years). The objective overall response was 66.7%, including 16 patients who achieved complete response after 6 cycles. Patients aged younger than 65 years presented a superior OR (87.5%) as compared with those older than 65 years (25.0%; p = 0.01). In a matched case-control study, I-RCHOP therapy provoked a more favorable complete response rate (87.3%) than did RCHOP (68.8%) in those younger than 65 years. Treatment-related mortality was linked most frequently with I-RCHOP therapy (four patients presented with unusual infection without Gr3/4 neutropenia) in the older age group (age ≥ 65 years). In conclusion, in this phase II trial for EBV-positive DLBCL, I-RCHOP was effective but did not show a significant improvement in response and survival in comparison with RCHOP. Also, I-RCHOP promoted serious toxicity and treatment-related death in older patients.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Cyclophosphamide; Doxorubicin; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Piperidines; Prednisone; Prospective Studies; Pyrazoles; Pyrimidines; Rituximab; Vincristine

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).

Topics: Adenine; Central Nervous System; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Piperidines; T-Lymphocytes

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

Topics: Adenine; Antineoplastic Agents; Bone Marrow; Burkitt Lymphoma; Diagnosis, Differential; Disease Progression; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

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