Secondary Immunodeficiency in Marginal Zone Lymphoma and Impact of Bruton Tyrosine Kinase Inhibitor

Secondary immunodeficiencies are clinically challenging and emphasize the need for a multidisciplinary approach. Our case underscores the importance of understanding the potential impact of B cell–targeting therapies, such as Bruton tyrosine kinase (BTK) inhibitors, on immune function, opportunistic infection prophylaxis, and clinical management. A 55-year-old male with a history of systemic lupus erythematosus (SLE) on hydroxychloroquine, antiphospholipid antibody syndrome on warfarin, anal cancer s/p resection, long-standing splenomegaly, and lymphadenopathy with unremarkable core needle biopsy in 2018 was diagnosed with marginal zone lymphoma via excisional lymph node biopsy in 2023. His clinical course was complicated by a hospitalization for septic shock secondary to Streptococcus agalactiae bacteremia and during this admission he was found to have significant immunodeficiency characterized by low T-lymphocyte counts (in cells/μL): CD3+ 141, CD4+ 65, and CD8+ 65, as well as low IgG levels 510 mg/dL (CD19 counts not obtained). Of note, he had persistent lymphopenia (0.06 to 0.49 cells/μL) and intermittent neutropenia (1.26-1.72 cells/μL) since 2009. After starting rituximab for lymphoma, he developed severe neutropenia (0.47 cells/μL), Candida esophagitis (requiring transient PEG tube placement), and a left ethmoid and sphenoid sinus abscess and orbital cellulitis due to Aspergillus fumigatus. Given the severe side effects and disease progression after rituximab, he was transitioned to a selective BTK inhibitor, zanubrutinib. For Pneumocystis jiroveci (PCP), antiviral and antifungal prophylaxis, he receives dapsone, acyclovir, and voriconazole, respectively. He has remained infection free since initiating zanubrutinib despite persistent lymphopenia (in cells/μL: CD3+ 147-183, CD4+ 74-108, CD8+ 48-62, CD19+ 8). His IgG levels improved to 700-800 mg/dL. His most recent PET scan showed stable disease. Notably, genetic testing was nondiagnostic. Our patient’s secondary immunodeficiency is multifactorial from SLE, lymphoma, and rituximab. The impact of selective BTK inhibitors on immune function is not well studied. Ibrutinib, a first-generation BTK inhibitor, improves T cell exhaustion with treatment of B cell lymphomas; similar findings were not observed for zanubrutinib, although studies are limited. Furthermore, recommendations on opportunistic infection prophylaxis often rely on data from HIV patients, yet it is unclear if the immune dysfunction is similar in individuals with non-HIV immunodeficiencies.