Baseline CD4 count is associated with early mortality in HIV-associated lymphoma: A retrospective cohort study

Abstract Background: HIV-associated lymphomas remain a leading cause of cancer-related mortality among people living with HIV (PLWH), despite improved outcomes in the antiretroviral therapy (ART) era. While tumor-intrinsic factors such as cell-of-origin (COO) predict survival in immunocompetent patients with diffuse large B-cell lymphoma (DLBCL), their relevance in the context of advanced immunosuppression is uncertain. We evaluated the associations between CD4 count, ART status, insurance coverage, COO, and survival outcomes in a retrospective cohort of PLWH diagnosed with lymphoma. Methods: We retrospectively reviewed 49 PLWH diagnosed with lymphoma between 2014 and 2021 at an urban academic center. Demographic and clinical data included baseline CD4 count, ART status, insurance type, race, lymphoma subtype, and hepatitis B/C coinfection. Cell-of-origin classification was extracted from diagnostic pathology reports, where cases were categorized as activated B-cell-like (ABC) or germinal center B-cell-like (GCB) based on immunohistochemical analysis using the Hans algorithm. The Kaplan–Meier approach was used to estimate overall survival (OS) and progression-free survival (PFS); median survival times and corresponding 95% confidence intervals were reported by clinical subgroup. Univariate regression models were applied to assess associations between plausible predictors and survival outcomes. A multivariable Cox proportional hazards model, stratified by lymphoma subtype and stage, was used to evaluate the effects of baseline CD4 count, age, and insurance status on OS and PFS. The restricted mean survival time (RMST) approach that does not require proportional hazard assumption was employed to compare treatment effects over a 5-year follow-up period. Cumulative incidence of relapse was estimated using a regression model within a competing risks framework. Results: The cohort was predominantly Black (76%) with a median age of 42 (21-71) years. Diffuse large B-cell lymphoma (DLBCL) was the most common subtype (53%); 61% of patients were on antiretroviral therapy (ART) at diagnosis, and 47% had a CD4 count ≤100. Hepatitis B exposure was present in 33% of patients. Median overall survival (OS) and progression-free survival (PFS) were 2.5 and 1.6 years, respectively. Using the RMST approach over a 5-year FUP, we estimated that patients with baseline CD4 > 100 had an average OS that was 1.28 years longer than in patients with CD4 <=100 (95% CI: 0.08-2.28 yrs, p=0.04). The difference in OS was significant in early years (0–5 years: p = 0.02). Median OS was highest among privately insured patients (6.5 years vs. 2.5 years for Medicaid/Medicare and 0.9 years for uninsured), although this was not confirmed by multivariable model (HR = 0.54; 95% CI: 0.18–1.59). ART receipt was not associated with OS or PFS. Among 26 patients with DLBCL and known cell of origin (COO), the activated B-cell (ABC) subtype was not associated with inferior OS or PFS. Overall, 45% of patients achieved complete response, and the 5-year cumulative incidence of relapse exceeded 60%, with no significant differences by CD4 count, ART status, or COO. Cause of death in 30 patients included progressive lymphoma (5/30, 17%), infection (7/30, 23%), and other (18/30, 60%). Conclusion: In this cohort of HIV-associated lymphoma, profound immunosuppression (CD4 ≤100) was the strongest predictor of early mortality. Baseline CD4 count was not associated with overall survival beyond five years post-diagnosis, likely because patients who survive initial treatment for lymphoma and engage in HIV care often experience robust immune reconstitution. Traditional tumor-specific markers, including cell of origin (COO), were not associated with outcomes, suggesting that host immune status and social and structural factors maybe as important as tumor biology in this setting. These findings support the need for prospective studies to clarify the relative impact of immune status and tumor biology on outcomes and to guide structural interventions that improve access to timely, coordinated cancer care for PLWH.