Late Infectious Complications of Chimeric Antigen Receptor T-Cell Therapy Beyond One Year

Background:

Chimeric antigen receptor (CAR) T-cell therapies have led to substantial improvements in disease response and survival for patients with relapsed/refractory hematologic malignancies. Infections contribute to a significant proportion of non-relapse mortality in this patient population, particularly within the first-year post CAR-T cell therapy. However, later infections (occurring after 1 year) related to persistent defects in host immune function are poorly characterized.

Aims:

We sought to characterize the overall proportion of patients with infections occurring after 12 months following CAR-T cell therapy. We further aimed to characterize and describe outcomes for bacterial, fungal, viral, and parasitic infections in this cohort.

Methods:

We performed a retrospective study of infectious outcomes in adult patients with hematologic malignancies treated with CAR T-cells from 2016 to 2022. Patients were eligible for inclusion and analysis if they were at least 18 years of age at the time of treatment and had at least 12 months of follow-up after infusion. We performed chart review to collect baseline characteristics, disease status, therapy-related details, receipt of antimicrobial prophylaxis, and laboratory measurements. The medical record was then reviewed for documentation of bacterial, fungal, viral, and parasitic infections. We recorded events based on radiographic evidence, microbiologic diagnosis, or clinician concern. We classified fungal infections based on previously published definitions as “proven,” “probable,” or “possible.” The primary outcome was the incidence of infection diagnosed following 12 months after CAR T-cell therapy.

Results:

The study cohort consisted of 42 patients who met inclusion criteria. The median age of the included patients was 66.2 years. The cohort included 26 patients with diffuse large B-cell lymphoma, 11 patients with multiple myeloma, and 5 patients with other B-cell malignancies. Thirteen patients (31.0%) had prior history of autologous stem cell transplant, and the median number of lines of chemotherapy prior to CAR T-cell therapy was 3 (interquartile range 2 - 5). More than half (52.4%) of patients achieved a complete response at 12 months following treatment, though 12 (28.5%) patients were receiving cancer-directed therapy at this time point. Most patients remained on antiviral (90.5%) and Pneumocystis prophylaxis (76.2%). Beginning 12 months after CAR T-cell therapy, a total of 46 bacterial, 28 viral, six fungal, and one parasitic infectious events were documented during a median follow-up time of 73.3 months. The total proportion of patients experiencing an infectious complication was 54.8%. The number and proportion of patients experiencing each infection type was as follows: 18 (42.9%) bacterial, 17 (40.5%) viral, five (11.9%) fungal, and one (2.4%) parasitic. This included one patient with progressive multifocal leukoencephalopathy, two with tissue invasive cytomegalovirus disease, one patient with Listeria meningitis, one proven fungal infection with Scedosporium apiospermum of the maxillary sinus, and Cryptosporidiumdiarrhea. Four patients received a second CAR T-cell treatment during the follow-up period, and collectively these patients contributed 32 infections representing 39.5% of all infectious events.

Conclusions:

Infectious complications continue to occur late after CAR T-cell therapy, and patients remain susceptible to opportunistic infections beyond 12 months after treatment. Patients receiving a second CAR had a greater proportion of infections than patients who had received a single infusion. Further prospective investigation is warranted to characterize the incidence, risk factors, and prevention strategies for late infections after CAR T-cell therapy.

Liegel:Seagen: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Beth Israel Deaconess Medical Center: Current Employment. Arnason:BMS: Other: Speaker fees; Regeneron Pharmaceuticals, Inc.: Other: Speaker fees. Alonso:Academy for Continued Healthcare Learning: Honoraria; American Society of Health System Pharmacists and Clinical care options: Honoraria; Cidara Therapeutics: Consultancy; AiCuris: Consultancy; Merck: Consultancy, Research Funding; DSM-Firmenich: Consultancy; Pfizer: Consultancy.