EBV-Positive Diffuse Large B Cell Lymphoma associated with ITK-mutated Primary Immunodeficiency

Patients with primary immunodeficiency are at elevated risk of lymphoproliferative disorders (LPD), especially those mediated by Epstein-Barr virus (EBV). Interleukin-2-inducible T-Cell kinase (ITK) is a member of the TEC family of kinases and plays a key role in T-cell proliferation and differentiation. Here, we present a case of EBV-positive aggressive lymphoma with common-variable immunodeficiency (CVID).

A 31-year-old female with a history of primary immunodeficiency with CVID, Crohn's disease, an extensive history of recurrent sinus and respiratory infections, and a family history of Hodgkin lymphoma (brother), presented with stage IV non-GCB, EBV+, diffuse large B-cell lymphoma (DLBCL). A complete response (CR) was achieved after 6 cycles of R-CHOP chemoimmunotherapy. Therapy was associated with poor tolerance and recurrent hospitalizations due to neutropenic fever. Targeted next-generation sequencing of immune genes identified a homozygous variant in ITK c1134G>T (pGly375Val) causing missense mutation that was attributed as the cause of her underlying immunodeficiency. Immune subset analysis showed low frequency of naïve T cells and high numbers of effector T cells in the peripheral blood. She was placed on long-term immunoglobulin replacement therapy for management of CVID. After remaining in CR for 7 years after R-CHOP, the patient developed new right cervical adenopathy. Biopsy demonstrated CD30+, EBV+, lymphoma with features of both DLBCL and classical Hodgkin lymphoma. Treatment with brentuximab vedotin (BV) monotherapy was initiated and the patient tolerated 6 cycles before discontinuation due to peripheral neuropathy. The patient achieved a CR and remained in clinical remission with negative EBV titer at 2-year follow-up.

Immunodeficiency-associated-LPDs represent a variable spectrum of diseases, and therapy is often challenged by infectious complications, especially with traditional cytotoxic agents. This report demonstrates a previously unpublished ITK variant associated with primary immunodeficiency and EBV-driven lymphoma responsive to single-agent BV in the relapsed setting.