Immune reconstitution and infectious complications following CAR-T cell therapy Free

Background: CAR-T therapies have dramatically improved outcomes of relapsed/refractory B cell lymphoma patients (pts). However, this entails significant toxicities, impacting survival. Infections account for most of the non-relapse mortality, which can reach 5-10% in real world series. Prolonged immune suppression due to B-cell aplasia, T cell abnormalities and cytopenias increase the risk of serious infections. We aimed to analyze the immune recovery after anti-CD19 CAR-T therapy and assess the related incidence and severity of infections in lymphoma pts.

Methods: We performed a single center retrospective analysis of lymphoma pts, who received anti-CD19 CAR-T therapy between November 2019 and March 2025. Demographic and clinical data were collected from pts records. Anti infectious prophylaxis was given as follows: anti-filamentous antifungals during neutropenic periods, acyclovir and anti-Pneumocystis jirovecii (PJP) until CD4+cell count >200 cells/µL. Pts were followed until last contact, death or progression. Infections were categorized by location/pathogen and severity according to CTCAE v5. Immune recovery was assessed through serial lymphocyte subset counts in peripheral blood by flow cytometry and serum immunoglobulin levels. Kaplan-Meier estimates were used to describe time-to-event variables. Univariable analysis, with either chi-square or independent t-test, and multivariable analysis (MVA) were performed to access risk factors for increased infection risk. Two-year progression-free survival (PFS) and overall survival (OS) were also assessed.

Results: We included 67 pts (64% with diffuse large B-cell lymphoma, 13% with mantle cell lymphoma and 9% with follicular lymphoma), with a median age of 59 (26-74) years, 57% males. The median number of prior lines of therapy was 2 (2-5). With a median follow-up of 17 (Q1-Q3: 6-22) months, 2y PFS was 49% (95%CI 36-62%, median PFS of 21 months) and OS was 60% (95%CI 45%-75%, median OS of 31 months). Baseline IgG <600mg/dl was already present in 55% of pts, reaching the lowest levels at 3-4 months after therapy (median 550mg/L Q1-Q3: 470-666) even with immunoglobulin replacement administered in 54% of pts, for a median duration of 5 (Q1-Q3: 3-15) months. Median IgG recovery (>600 mg/dL) occurred at 24 months (95%CI: 7–54) post-therapy. Circulating B cells recovered to detectable levels at a median of 13 months (95%CI 7-19) after treatment. T-cell recovery was slow, with a median time of 12 months (95%CI 11-13) until CD4+ cells reached 200/µL. Infections developed in 79% of pts, 76% of them occurring in the first 6 months post-therapy. There were 4 infection-related deaths (2 due to pneumonia, 1 COVID-19 and 1 HHV6 encephalitis). In the first 6 months, grade ≥3 infections occurred in 34% of pts, respiratory infections being the most common (15% pts), followed by central line-associated bloodstream infections (13% pts). CMV reactivation (without disease but requiring preemptive therapy) was also frequent (37% pts), and BKV reactivation was detected in 12% pts. Of note, campylobacter infections occurred in 7% pts. After 6 months, respiratory infections remained predominant (27% pts), while CMV reactivations declined (8% pts). Notably, 30% of pts still developed infections grade ≥2 beyond 1 year. No HSV-1/2, fungal, or PJP infections were observed.Regarding risk factors for infections, steroid therapy for >10 days (p=0,001), the administration of >1 dose of tocilizumab (p=0,041) and the occurrence of grade ≥2 cytokine release syndrome (CRS) (p=0,036), were associated with increased infectious burden (one grade ≥3 or more than 3 Grade ≥2 infections). In MVA only prolonged steroid therapy was significant (OR 4.35 95%CI 1.29-14.65). Lower IgA levels at 3-4 months post-therapy were also associated with increased infectious burden (p=0,023). Baseline HCT-CI, age, occurrence of any grade CRS or ICANS, IgM levels and CD4+cell counts at 3-4 months were not associated with increased infectious burden. Lower CD4+cell counts at 3–4 months were not associated with increased CMV reactivation.

Conclusion: In this real-world series we confirm that CAR-T cell recipients have prolonged immune dysfunction and infection risk, well beyond the first year after therapy. Prolonged steroid use was associated with increased risk of severe and/or repeated infections. Further immune characterization in larger patient cohorts is needed to further identify risk factors for infections in these patients.