In this single-center study, we report a high proportion of infectious complications occurring predominantly within the first 30-days following CAR-T cell infusion, with a modest predominance of bacterial over viral infections. Infections of the respiratory tract were the most common; most ICs were mild-to-moderate in severity, not requiring hospitalization or IV antibiotic therapy. Moreover, our multivariate analysis showed age ≥ 65 years and ≥ 4 prior antitumor treatments as the main risk factors for infection.
Our results are in line with previously reported studies. Hill et al9 analyzed infectious complications in 133 adult patients in a cohort study including ALL (n = 47), CLL (n = 24) and NHL (n = 62) receiving CAR-T in a phase 1/2 study. In this series, 24% of patients experienced any infection, including 5% fungal and 4% of fatal events. Risk factors identified in this series were ≥ 4 prior treatments, a diagnosis of ALL and receiving a higher dose of CAR-T cells (2x 107cells/kg). Strati et al10 analyzed 31 patients with relapsed/refractory DLBCL who underwent CAR-T cell treatment with axicabtagene and were included in the clinical trials ZUMA-1 (NCT02348216) and ZUMA-9 (NCT03153462). Among all 31 patients, 71 infectious events of any grade were reported (42% grade 3–4 infection). Most common infections were viral and 6% of patients developed a fungal infection. Logue et al11 conducted a retrospective, single-center study of 85 patients with relapsed/refractory DLBCL treated with axicabtagene. In the first 30 days, 36.5% patients presented an infection event, with 12.9% of them requiring IV antibiotics or hospitalization. CRS, ICANS, use of tocilizumab or steroids and bridging therapy were risk factors for ICs in this series. After day 30, 44.3% of patients had any infection requiring hospitalization or IV antibiotics. Infection was a contributor to death in 3 cases (3.5%) in this series. Cordeiro et al12 analyzed a cohort of 86 patients with relapsed/refractory ALL, NHL and CLL treated with CAR-T infusion included on a phase 1/2 clinical trial. After day 30th, 61% of patients developed any infection, with 71% respiratory tract involvement. Bacterial was the most frequent (60%), 31% viral and 9% fungal etiology. Moreover, 20% of patients in this series required hospitalization. Lastly, a study by Mikkilineni et al13, focused on infections occurring within the first 30-days of treatment in 162 CAR-T cell patients who received various CAR-T antigen targets (CD19, CD22, D2 and BCMA). The proportion of infectious complications in the first 30-days was 32.7%; greater lines of chemotherapy and a recent infection within 100-days of CAR-T cell infusion were associated with higher risk of infection.
Despite high-degree of immunosuppression and prolonged neutropenia, fungal infections have remained infrequent in patients undergoing CAR-T cell therapy. Depending on the study, the incidence of IFI has ranged between 1–15%, and most of these infections occur as breakthrough to antifungal prophylaxis14. In our series, two patients (3.9%) developed IFIs: one fatal case of disseminated candidemia due to fluconazole-resistant Candida glabrata (breakthrough fluconazole prophylaxis) and one case of invasive pulmonary aspergillosis. Of note, both patients had received immunosuppression augmentation with tocilizumab and high-dose steroids for high-grade CRS. Several reports have described molds other than Aspergillus, complicating CAR-T cell therapy15. Targeted anti-mold prophylaxis has been proposed for individuals with a history of past-fungal infection, severe and prolonged neutropenia (> 3 weeks), previous allogeneic HSCT, and in patients receiving high-dose corticosteroids6. In low-risk patients and/or at treatments centers with low IFIs incidence, a preemptive strategy based on biomarkers and imaging screening could be adopted. As the option for CAR-T cell therapy move upstream in the treatment line for several hematological malignancies, the landscape for IFI complications will continue evolving in the upcoming years. Future studies are needed to elucidate specific risk factors for IFI and define the population who benefit the most of anti-mold prophylaxis.
Our study has several limitations. First, it is restricted to a single-center and included only patients with relapse/refractory CD19 B-cell NHL. As such, the overall results might not be applicable to centers with different antimicrobial prophylaxis practices or centers that offer CAR-T cell for other than CD19 B-cell NHL. Second, our median-time to follow-up was almost 6 months post CAR-T cell infusion. Hence, infections complications that occurred late in the post-CAR-T cell period might have not been entirely captured in our review. Notably, our study did not link laboratory markers for B-cell aplasia, B-cell dysfunction or reconstitution of the T-cell compartment with tangible clinical outcomes for infection. Other factors such as CAR-T-cell-related neutropenia, reactivation of latent viral infections (eg, CMV, HHV-6), and the need for stem-cell reinfusion in refractive cytopenias, might play a role in late-onset infection following CAR-T infusion and should be assessed in prospective studies. Lastly, in our series, serological testing to assess immune response to SARS-CoV-2 vaccination was performed inconsistently and at different time-points following CAR-T cell infusion. For instance, only 21% of patients had anti-spike IgG titers available to assess immunogenicity following two doses of SARS CoV-2 mRNA vaccine. Several studies have described suboptimal vaccination responses in patients with hematological malignancies, including CAR-T cell recipients16− 19. Other markers of vaccine-immune response (eg, T-cell response) and the effect of vaccine boosters over the augmentation of anti-spike IgG titers were not addressed in this study and may play a substantial role in COVID-19 disease prevention following CAR-T cell therapy. Moreover, the ”real-world” impact of prophylactic strategies using anti-SARS-CoV-2 long-lasting monoclonal antibodies (eg, tixagevimab plus cilgavimab [Evusheld®]) remains unknown and deserves further research in this population.
In summary, the reporting of infectious complications from CAR-T cell therapy’s clinical trials has been inconsistent, often lacking details about the nature, timing and course of common infections20. In that context, single-center case series like ours, contribute to understanding the local epidemiology and to guide antimicrobial prophylaxis strategies. Data from patients’ registries are welcome to delineate national and center-specific CAR-T cell associated infection rates and define future research targets. In the upcoming years, several factors will continue reshaping the risk for infection following CAR-T cell therapy. The use of CAR-T cells with novel antigen targets (eg, CAR-T targets NK, anti-BCMA, CD22, disialonganglioside [GD2]) along with the expansion of CAR-T cell indications and its use earlier in the treatment course will inevitably alter the infection risk framework. Research focused on infectious complications CAR-T cells will hopefully provide guidance on adequate standards and extension of antimicrobial prophylaxis in CAR-T cell patients.