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.

Keywords: ALL; CAR T-cell; immunotherapy; infection; pediatric.

Figure 1.

Cumulative incidence curves of time to first infections in the first 28 days after CAR T-cell therapy. A–D, Cumulative incidences among all patients (n = 83) of any (A), bacterial (B), viral (C), and fungal (D) infections within 28 days after CTI. Dotted lines represent 95% confidence intervals. Death and loss to follow-up were treated as competing risks. Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome.

Figure 2.

Infection density before and after CAR T-cell therapy. Infection density was calculated as the total number of infection events per patient-days-at-risk multiplied by 100. Only data obtained during person-days-at risk contributed to these estimates. Infection densities are shown for any infection and by pathogen category for the time periods 90 days before CTI and 0–28 and 29–90 days after CTI. Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome.

Figure 3.

Infection events in the first 28 days after CAR T-cell therapy stratified by CRS and the presence of neutropenia. A, Proportion of patients with infection by grade: 0 (no CRS): 30% (95% CI, 7%–65%); 1: 46% (95% CI, 28%–66%); 2: 32% (95% CI, 18%–50%); ≥3: 62% (95% CI, 24%–91%). Of note, the infection episode may have occurred before, during, or after CRS during this time period. B, The number of patients with each infection type stratified by the presence or absence of neutropenia (ANC < 500 cells/µL) at the time of infection. Abbreviations: CAR, chimeric antigen receptor; CI, confidence interval; CRS, cytokine release syndrome.