Prevalence and Characteristics of CMV Reactivation after Chimeric Antigen Receptor T cell Therapy: A Referral Center Experience

Chimeric Antigen Receptor T-cell (CAR T) therapy has transformed the treatment landscape of various malignancies. However, immune suppression associated with CAR T therapy has incurred increased risk of infections, including cytomegalovirus reactivation (CMVr). Current guidelines do not mandate routine CMV monitoring post-CAR T therapy, but our clinical observations suggest a different approach may be warranted. Between November 2018 and January 2025, 237 patients received a total of 361 commercial and investigational CAR T-cell products at the University of Iowa Health Care (UIHC). Of these, 225 patients had baseline CMV IgG serology, with 145 testing IgG seropositive. Most patients were male (52.4%) with a median age of 67 years. Indications for CAR T therapy included: relapsed/refractory diffuse large B-cell lymphoma (n=66), multiple myeloma (n=54), mantle cell lymphoma (n=9), B-cell acute lymphoblastic leukemia (n=7), follicular lymphoma (n=5), and other diagnoses (n=4). During the study period, UIHC utilized two different quantitative plasma CMV nucleic acid amplification tests. The DiaSorin CMV assay (Liaison MDX platform; limit of quantification LOQ, 200 IU/mL) was used until October 2024, after which it was replaced by the Roche Cobas CMV assay (Roche 5800 platform; LOQ, 35 IU/mL). Among seropositive patients, 44 (30%) developed CMVr, with cumulative incidence reaching 39% at 6 months and 47% at 12 months post-CAR T infusion. Antiviral treatment was required in 28 patients, most commonly with valganciclovir, ganciclovir, or foscarnet (N=17, 6, 5, respectively). Five patients developed end-organ CMV disease in the retina, liver, esophagus, and colon. All were biopsy-proven except retinitis, which was diagnosed on fundoscopic exam. Most patients treated for CMVr (22/28) cleared the virus within a median of 33 days. Nine patients died from progression of their primary malignancy before CMV clearance. At a median follow-up of 9.2 months, 12- and 60-month overall survival (OS) was 72% and 32%, respectively. Most deaths (78%) were due to disease relapse; none were directly attributed to CMVr. On univariate analysis, age, sex, number of prior lines of therapy, history of autologous stem cell transplant, and CAR T target antigen were not significantly associated with time to CMVr or OS. The pathophysiology of CMVr in CAR T recipients remains incompletely understood. Immune dysregulation, inflammatory cytokines, and T-cell dysfunction—exacerbated by steroids or anti-cytokine agents like tocilizumab or anakinra—may contribute. A study of HSCT patients suggests that CMV-specific T-cell depletion is associated with CMVr, but this has not been validated in the post-CAR T setting. While emerging therapies such as virus-specific CTLs show promise, further research is needed to define optimal CMV monitoring protocols and evaluate prophylactic antiviral strategies.