Respiratory syncytial virus (RSV) infection after CAR T-cell therapy

Abstract Background: Respiratory syncytial virus (RSV) is a recognized cause of morbidity and mortality after allogeneic HCT (allo-HCT), but its significance following CAR-T therapy remains poorly defined. Understanding the burden and impact of RSV in this immunocompromised population is essential for informing prevention and treatment strategies. We sought to delineate the clinical course of RSV in CAR-T recipients and identify predictors of progression to lower respiratory tract infection (LRTI), focusing on immune vulnerabilities. Methods: We retrospectively identified laboratory-confirmed RSV infections in patients who underwent commercial CAR-T between 2018 and 2024 in two high-volume international centers. Eligible infections occurred from 5 days before infusion until initiation of subsequent antineoplastic therapy or death, whichever occurred first. RSV infection was characterized as upper or lower respiratory tract (URTI/LRTI) according to EBMT guidelines (Pinana et al., 2024) and graded for severity using both CTCAE v5.0 and BMT-CTN criteria. Immune parameters (absolute lymphocyte count (ALC), absolute neutrophil count (ANC), CD4⁺ T cells, CD19⁺ B cell counts, and immunoglobulin levels (IgG, IgA, IgM)) were computationally extracted within 30 days of infection onset. Data on intravenous immunoglobulin replacement therapy (IGRT) was collected, along with RSV-directed anti-viral therapy, and RSV vaccination status (since September 2023). RSV-attributable mortality was defined as death from respiratory failure within 28 days of RSV-diagnosis in patients with RSV LRTI. Statistical group comparisons were performed using Fisher's exact test for categorical variables or Wilcoxon rank-sum tests for continuous variables. MSK Institutional Review Board granted a HIPAA waiver to conduct the study. Results: During the study period, there were 38 laboratory-confirmed RSV cases among 667 CAR-T recipients. Median age of RSV-infected patients was 61 years (range 23–78), and 58% were male. 63% were treated for lymphoma with CD19 CAR-T and 37%, received BCMA CAR-T for myeloma. Most infections (74%) occurred beyond day +100, with a median onset at 8 months (range 0–71). A majority of infections were URTI (71%), while 29% presented with or progressed to LRTI, of which eight were severe (Grade 3), and a viral co-pathogen was detected in two patients with LRTIs (coronavirus and rhinovirus). RSV-specific treatment (ribavirin ± corticosteroids/IVIG) was administered to 8 patients, all with severe infection, except one who received ribavirin for URTI. This approach aligns with local practice at our center, where treatment is typically reserved for more severe cases. All treated patients survived. Compared with URTI cases, patients with LRTI were older (median 68 vs. 61 years, p = 0.025), had lower ALC (median 0.30 vs. 0.80 ×10⁹/L, p = 0.006), and were more often hospitalized (75% vs. 4%, p < 0.001). CD4⁺ T-cell counts were numerically lower in severe cases (67 vs. 160 ×10⁶/L, p = 0.076). The time interval from CAR-T infusion, product type, CD19⁺ B-cell counts, maximal CRS-grade, prior HCT, number of comorbidities and IGRT use were similar across severity groups. Only two patients (5%) were vaccinated against RSV prior to their infection; both had mild infection. No RSV-attributable deaths occurred; one patient died of bilateral pneumonia 7 weeks after the diagnosis, though no bronchoscopy or autopsy was performed to establish the cause of death. Conclusions: This is the first multicenter study with over 600 CAR-T recipients to systematically evaluate RSV-specific epidemiology following CAR-T therapy. The infection incidence and outcomes were comparable to those reported after HCT, with 6% of recipients diagnosed and almost 30% progressing to LRTI, even beyond day +100. Older age and profound lymphopenia were associated with severe disease. Our findings support extended post-treatment clinical vigilance and underscore the need to study targeted prevention strategies, such as passive and active immunization, in high-risk CAR-T recipients.