Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy

Abstract

Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T)-cell immunotherapy is a novel treatment for refractory or relapsed B-cell malignancies. Infectious complications of this approach have not been systematically studied. We evaluated infections occurring between days 0 to 90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study. We used Poisson and Cox regression to evaluate pre- and posttreatment risk factors for infection, respectively. The cohort included patients with acute lymphoblastic leukemia (ALL; n = 47), chronic lymphocytic leukemia (n = 24), and non-Hodgkin lymphoma (n = 62). There were 43 infections in 30 of 133 patients (23%) within 28 days after CAR-T-cell infusion with an infection density of 1.19 infections for every 100 days at risk. There was a lower infection density of 0.67 between days 29 and 90 (P = .02). The first infection occurred a median of 6 days after CAR-T-cell infusion. Six patients (5%) developed invasive fungal infections and 5 patients (4%) had life-threatening or fatal infections. Patients with ALL, ≥4 prior antitumor regimens, and receipt of the highest CAR-T-cell dose (2 × 10⁷ cells per kg) had a higher infection density within 28 days in an adjusted model of baseline characteristics. Cytokine release syndrome (CRS) severity was the only factor after CAR-T-cell infusion associated with infection in a multivariable analysis. The incidence of infections was comparable to observations from clinical trials of salvage chemoimmunotherapies in similar patients. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

Figure 1.

Cumulative-incidence curves of time-to-first infection for any infection and for specific infection categories. (A-D) Cumulative incidences among all patients (n = 133) of any (A), bacterial (B), viral (C), and fungal (D) infections within the first 28 days after CAR–T-cell infusion. Dotted lines represent 95% CIs.

Figure 2.

Infection density and severity after CAR–T-cell infusion. (A-B) Infection densities are shown for infections occurring during the first 28 days (A) and day 29 to day 90 (B) after CAR–T-cell infusion. *Bacteremia and respiratory virus categories are subsets of the bacterial and viral categories, respectively. (C-D) Number of patients with a maximum grade of mild/moderate, severe, or life-threatening/fatal infection severity during the first 28 days (C) and between days 29 and 90 (D). (E-F) Severity of all infection events during the first 28 days (E) and days 29 to 90 (F) after CAR–T-cell infusion.

Figure 3.

Cumulative-incidence curves of time-to-first infection stratified by baseline characteristics. (A-C) Cumulative incidences of any infection within 28 days after CAR–T-cell infusion stratified by underlying disease (A), number of prior antitumor treatment regimens (B), and CAR–T-cell dose of 2 × 10⁵ cells per kg (dose level 1), 2 × 10⁶ cells per kg (dose level 2), or 2 × 10⁷ cells per kg (dose level 3) (C). P values are derived from adjusted Poisson regression (Table 3). Dotted lines represent the 95% CIs. DL, dose level; Ptx, prior therapy.