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

Joshua A. Hill, Daniel Li, Kevin A. Hay, Margaret L. Green, Sindhu Cherian, Xueyan Chen, Stanley R. Riddell, David G. Maloney, Michael Boeckh and Cameron J. Turtle

Key points

  • The incidence of infections after CD19 CAR-T cell immunotherapy was similar to the incidence after other salvage chemoimmunotherapies.

  • Infections were more frequent in patients who had ALL, more prior anti-tumor treatment, a higher CAR-T cell dose, or greater CRS severity.

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. However, infectious complications of this approach have not been systematically studied. We evaluated infection events occurring between days 0-28 and 29-90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study (https://clinicaltrials.gov/ct2/show/NCT01865617). We used multivariable Poisson and Cox regression to evaluate pre- and post-treatment risk factors for infection, respectively. The cohort included patients with acute lymphoblastic leukemia (ALL, n=47), chronic lymphocytic leukemia (CLL, n=24), and non-Hodgkin lymphoma (NHL, 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 29-90 (p=0.02). 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 anti-tumor regimens, and receipt of the highest CAR-T cell dose (2x107 cells/kg) had a higher infection density within 28 days in an adjusted model of baseline characteristics. Cytokine release syndrome 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. Modification of the treatment regimen to reduce severe CRS resulted in fewer and less severe infections.

  • Submitted July 13, 2017.
  • Accepted October 8, 2017.