Hbc-positive status for hepatis B virus does not affect CAR-T cell outcomes in lymphoma: Results from the CART-SIE study

Abstract Hepatitis B virus (HBV) reactivation represents a potential complication in immunocompromised patients carrying occult B infection (OBI), including those receiving chimeric antigen receptor T-cell (CAR-T) therapy. However, the clinical impact of HBV carriers remains unclear in this setting. We retrospectively analyzed a real-life cohort of 1124 patients who underwent CAR-T cell therapy for lymphoma to investigate whether HBV positivity without overt infection (anti-HBc positive, HBV-DNA negative) was associated with distinct clinical characteristics or outcomes within the observational CART-SIE Italian study. No patient had active HBV infection, which represents an exclusion criterion for CAR-T cell therapy in Italy. All HBV-positive patients received prophylactic antiviral treatment, predominantly with lamivudine (>90%). Patients were stratified into two groups: HBV-negative (HBV−, n=1010) and HBV-positive (HBV+, n=114). The most common diagnoses were diffuse large B-cell lymphoma (DLBCL, 713 patients; 63.4%), mantle cell lymphoma (MCL, 143; 12.7%), high-grade B-cell lymphoma (HGBCL, 114; 10.1%), primary mediastinal B-cell lymphoma (PMBCL, 98; 8.7%), and follicular lymphoma (FL, 56; 5.0%). The majority of patients were male (715; 63.6%). Axi-cel was the most frequently used CAR-T product (53.5%), followed by tisa-cel (32.8%), brexu-cel (12.6%), and liso-cel (1.2%). The mean number of prior therapy lines was 2.34 (standard deviation: 0.93), with 29.6% of patients having received a prior autologous stem cell transplant. Overall, 77.2% of patients underwent bridging therapy before CAR-T cell infusion. The median follow-up for the entire cohort was 16.5 months (95% CI: 13.2–17.8). Baseline characteristics were largely comparable between the 2 groups: median age was slightly higher among HBV-positive patients (62.2 vs 57.2 years; p<0.001); a significant difference was observed in disease subtype distribution, with a greater prevalence of DLBCL in the HBV-positive cohort (77.2% vs 61.9%; p=0.001). No statistically significant differences were found in response rates at day 30 (complete response [CR] 56.1% vs 57.0%; p=0.913) or day 90 (CR 63.3% vs 60.2%; p=0.791), nor in the relapse rate (42.0% vs 50.9%; p=0.073). Overall survival (OS) was comparable between HBV-positive and HBV-negative patients, with a 36-month OS of 52.6% vs 53.8%, respectively (p=0.239). Similarly, progression-free survival (PFS) did not significantly differ between the groups (36-month PFS 35.8% vs 58.8%; p=0.163). Even within the DLBCL subgroup, regardless of the treatment line, HBV-positivity did not appear to impact overall survival (OS, p=0.808) or progression-free survival (PFS, p=0.890). In the multivariable analysis, HBV positivity was not associated with differences in either overall survival (OS) or progression-free survival (PFS). Specifically, HBV-positive status did not significantly impact OS (HR 1.12, 95% CI 0.80–1.57; p=0.497) or PFS (HR 1.15, 95% CI 0.88–1.51; p=0.304). With regard to CAR-T-related toxicities, no cases of HBV reactivation were observed; the incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) (26.8% vs 28.1%, p=0.824), immune effector cell-associated hematotoxicity (ICAHT) (24.6% vs 18.4%, p=0.165), second malignancies (3.9% vs 6.1%, p=0.219), and infections (11.5% vs 9.6%, p=0.642) was comparable between HBV-negative and HBV-positive patients, respectively. Conversely, cytokine release syndrome (CRS) occurred more frequently in HBV-negative patients (88.4% vs 81.6%, p=0.049), a finding that remained significant after adjustment for age, disease type, and CAR-T product (HR 0.55, 95% CI 0.32–0.95; p=0.033). No significant differences in toxicity grading were observed between the two cohorts for CRS (p=0.217), while HBV-positive patients experienced milder forms of ICANS (p=0.043).These findings suggest that HBV carrier status does not adversely affect response rates or long-term outcomes following CAR-T therapy and should not be considered a contraindication to treatment. The lower incidence of CRS and milder ICANS severity observed in HBV-positive patients may point to potential immunomodulatory effects exerted by OBI status and/or antiviral prophylaxis. Systematic HBV screening and appropriate antiviral prophylaxis remain essential to minimize the rare risk of viral reactivation.