Infectious Complications Following CD19 Chimeric Antigen Receptor T-cell Therapy for Children, Adolescents, and Young Adults

Abstract

Background Infectious complications of chimeric antigen receptor (CAR) T-cell immunotherapy in children and young adults have not been well described. Methods Medical records of patients ≤26 years old receiving CD19 CAR T-cell infusion (CTI) at a single institution between 2014 and 2017 were reviewed. The number of infections per 100 days-at-risk (infection density) in the 90 days preceding and 0–28 and 29–90 days after CTI was calculated. Poisson regression and Cox analyses were utilized to identify risk factors for infections. Results Eighty-three patients received CTI during the study period. Most patients (98%) had refractory or relapsed acute lymphoblastic leukemia (ALL). Infections occurred in 54% of patients in the 90 days before CTI (infection density, 1.23) and in 40% of patients in the first 28 days following CTI (infection density, 2.89). Infection density decreased to 0.55 in the 29–90 days post-CTI. Most infections were bacteremias (39%) or respiratory viral infections (43%). Pre-CTI risk factors associated with infection included prior hematopoietic cell transplantation (HCT), immunoglobulin G (IgG) level <400 mg/dL, and lymphodepletion other than cyclophosphamide plus fludarabine; post-CTI risk factors included higher-severity CRS and IgG <400 mg/dL. Conclusions Infection rates in children and young adults receiving CD19 CAR T-cell therapy increase in the first month and then decline. Understanding types and timing of infections and contributing risk factors may help inform prophylactic and monitoring strategies. Specific attention should be given to patients with prior HCT, severe hypogammaglobulinemia, and severe CRS.

Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma

“…The incidence of overall infection in our study was comparable to these landmark trials. Moreover, the patterns of infection in our cohort were similar to the findings from previous reports 5 , 7 , 10 . Bacterial and viral infections were commonly observed, with bacteria being the most common pathogen, especially during the first 30 days 5 , 7 , 10 .…”

“…Moreover, the patterns of infection in our cohort were similar to the findings from previous reports 5 , 7 , 10 . Bacterial and viral infections were commonly observed, with bacteria being the most common pathogen, especially during the first 30 days 5 , 7 , 10 . Recently, Cordeiro and colleagues reported the incidence of adverse events beyond day 90 from CAR T cell infusion 16 and described a relatively low incidence of late infections (2.08 per patient-year), with most being of mild to moderate severity.…”

“…Besides immune-mediated toxicities, B cell aplasia, and resultant hypogammaglobulinemia are common consequences of CD19 CAR T cell therapy, which put patients at risk for infectious complications 3,4 . Although there have been some initial reports on the infectious complications of CAR T cell therapy, most studies included patients treated in clinical trials or with multiple underlying B cell malignancies [5][6][7][8][9][10] . Currently, there are limited real-world data on infectious risks in patients treated with CD19 CAR T cell therapy for DLBCL.…”

Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies

“…29 In another retrospective study in pediatric patients treated with CD19 CAR T cells, 37 infections were reported in 33 of 83 (40%) patients. 36 Among the pivotal trials, 41 of 108 (38%) patients in ZUMA-1, 38 of 111 (34%) patients in JULIET, 32 of 75 (43%) patients in the ELIANA trial, and 14 of 33 (42%) patients treated with bb2121 developed an infection. [1][2][3]8,30 The prolonged immunosuppression seen in our study, along with the reported high rates of infections, underscores the need to consider antimicrobial prophylaxis, although no standard guidelines are available at this time.…”

Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper

“…In some cases, anakinra (IL-1R inhibitor) has been used for the treatment of CRS and neurotoxicity [21]; this drug could also potentially increase the risk of infection [22,23], but clinical experience in these patients is scarce. Finally, CAR T therapy causes a variable-length B-cell aplasia (while circulating CAR T persists, which varies from a few days to several years) [24,25] and a progressive secondary hypogammaglobulinemia, exposing them to lifethreatening infections, especially in pediatric patients with ALL [26].…”