Cytomegalovirus Infections Following CAR T-Cell Therapy: A Systematic Review and Meta-Analysis

Introduction:

Chimeric antigen receptor (CAR) T-cell therapy is a rapidly evolving immunotherapy for hematological malignancies. With increasing access to this modality, there is an urgent need for a comprehensive understanding of infectious complications to optimize routine monitoring, prophylaxis and improve clinical outcomes. Cytomegalovirus (CMV) remains a clinically significant pathogen in allogeneic and autologous hematopoietic cell transplant recipients, though the clinical implications of CMV reactivation after CAR T-cell therapy are poorly characterized. . We sought to perform a systematic review and meta-analysis of the published literature to determine the overall incidence of CMV following CAR T-cell therapy.

Methods:

The study was registered on PROSPERO and we searched 5 electronic (MEDLINE, EMBASE, CINAHL, Pubmed, Cochrane) from inception to 2022. Each author independently screened titles, reviewed full texts to identify eligible studies and extracted data from included studies using Covidence, a data extraction tool for conduction of standard systematic reviews. A random effects model was used, and proportions were used as a measure of outcome. We assessed heterogeneity using I^2 statistic. Risk of bias assessments were conducted using the RoB 2.0 for RCTs and ROBINS I tool for non-RCTs.

Results

Our search identified 12,441 studies of which 363 underwent full-text review. 30 studies were eligible for inclusion in the analysis and enrolled a total of 2536 patients. Among these, 18 were observational cohort studies, 10 were nonrandomized clinical trials, and 2 were randomized clinical trials. All studies enrolled patients with hematologic malignancies treated with CAR T-cell therapy. The majority of the studies included patients treated with CD19 targeted CAR T-cell therapy (n=23), compared to BCMA targeted CAR T cell therapy (n=2), multiple targets (n=2) and another investigational CAR T cell product (n=3). The median duration of follow up was ³30 days in 25 studies and <30 days in 5 of the included studies.

The pooled incidence of an infectious event in adult patients after CAR T-cell therapy was 38% (95%CI 0.31, 0.46; p<0.01; I² = 98%]. The pooled incidence of any infectious event was significantly higher in studies where patients were treated with a BCMA-directed CAR T cell agent (64%, 95% CI 0.53;0.74, I² = 65%) compared to CD19-directed CAR T cell product (38%, 95% CI 0.29;0.47, I² = 97%), p <0.01.

Sixteen studies reported viral infectious events with an overall proportion of 36% (0.360, 95% CI 0.267 to 0.453) of the included subjects. Out of the 144 specified viral events, Cytomegalovirus was the most prevalent pathogen with a proportion of 21.53% (0.2153, 95% CI 0.1481-0.2824). Other commonly identified viral pathogens were rhinovirus, respiratory syncytial virus, and influenza with a proportion of 17.36% (0.1736, 95% CI 0.111- 0.2355), 9.72% (0.0972, 95% CI 0.0488-0.1456) and 8.3% (0.0833, 95% CI 0.0382-0.1285) respectively.

Conclusions: Our findings suggest that viral infections are common and seen in about one third of patients after CAR T-cell therapy. Cytomegalovirus was the most commonly identified viral pathogen following CAR T-cell therapy and was responsible for approximately one-fifth of all viral infections reported. Further studies are needed to determine the impact and clinical outcomes of CMV infection following CAR-T cell therapy.