D1.420 - Lymphoma in CVID: on the edge between immune dysregulation and malignancy

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and systemic immune dysregulation (e.g.  non-clonal lymphoproliferation, autoimmune cytopenia and GLILD) together with a more than 10-fold higher risk of lymphoma. This study analyzes clinical features and survival in CVID-associated lymphomas, to explore the interplay between immune dysregulation and malignancy, and possibly identify phenotypic predictors of mortality.

In this retrospective multicenter study, we analyzed a cohort of CVID patients from two Italian referral centers, investigating the prevalence of lymphoma and comparing clinical and immunological features with patients without lymphoma. Statistical associations were assessed using Fisher’s exact test and the Mann-Whitney U test, while survival outcomes using Kaplan-Meier estimates and the log-rank test.

We enrolled 404 CVID patients. The prevalence of lymphoma was 4.9% (n=20). Non-Hodgkin lymphoma was the most prevalent, with the most represented histotypes being diffuse large B cell lymphoma (n=5) and Burkitt (n=4). Viral status was assessed only in five patients: 3 were EBV+ and 1 was HHV8+.

On immunophenotypic analysis, patients who developed lymphoma had significantly higher levels of CD8+ (47 vs 33%, p<0.001) and CD3+CD57+ (25.5 vs 15.5%, p=0.006) lymphocytes and lower CD4+ (34 vs 41, p=0.018) and CD19+ cells (7 vs 10.5%, p=0.026) compared to controls. 

There was no significant difference in the prevalence of autoimmune manifestations, GLILD, enteropathy and solid tumors between the 2 groups. The overall mortality rate in the entire cohort was 4.9%, but in the lymphoma group it increased up to 30% (6/20), with death being directly related to lymphoma in four cases. Kaplan-Meier analysis confirmed that lymphoma was associated with a markedly worse prognosis compared to the control group (Log-rank test, p<0.001). Among CVID-related clinical manifestations, only the presence of GLILD (pre-existing in 4 out of 5 patients) was associated with a significantly higher risk of mortality in patients with lymphoma (hazard ratio 6.8; 95% C.I. 1.12-41.64; p=0.03).

Our findings confirm the prevalence and prognostic relevance of lymphoma in CVID, and highlight the role of GLILD in worsening the overall prognosis. The relationship between non-clonal lymphoproliferation in GLILD and lymphoma deserves further investigations, in larger cohorts, in order to assess if GLILD management may affect lymphoma development and outcome.