Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated With Chimeric Antigen Receptor T Cells

Abstract

Background: Chimeric antigen receptor (CAR)-modified T cells that target the CD19 antigen present a novel promising therapy for the treatment of relapsed B-cell acute lymphoblastic leukemia (B-ALL). Although cytokine release syndrome (CRS) and neurotoxicity have emerged as predominant noninfectious complications of CD19 CAR T-cell therapy, infections associated with this treatment modality have not been well documented.

Methods: We analyzed infectious complications that followed CD19 CAR T-cell therapy in 53 adult patients with relapsed B-ALL enrolled in a phase I clinical trial at Memorial Sloan Kettering Cancer Center (NCT01044069).

Results: Overall, 22 patients (42%) experienced 26 infections (17 bacterial, 4 fungal, and 5 viral) within the first 30 days of CAR T-cell infusion. In 10 of 32 (31%) patients in whom complete remission was achieved, 15 infections developed between days 31 and 180; the majority of these late infections were due to respiratory viruses. In general, bacterial, fungal, and viral infections were detected at a median of 18, 23, and 48 days, respectively, after CAR T-cell infusion. CRS grade 3 or higher was independently associated with increased risk of subsequent infection (adjusted hazard ratio [HR], 2.67; P = .05) and in particular with bloodstream infection (adjusted HR, 19.97; P < .001). Three of 53 patients (6%) died of an infection-related cause.

Conclusions: Infections in adult patients with relapsed B-ALL are common after CD19 CAR T-cell therapy. Understanding the infectious complications that are temporally coincident with CD19 CAR T-cell therapy is critical for developing effective prophylactic and other supportive care measures to improve clinical outcomes.

Clinical trials registration: NCT01044069.

Figure 1.

Overview of infections and clinical events in patients treated with chimeric antigen receptor (CAR) T cells. Timeline depicts the periods of neutropenia, cytokine release syndrome, and bacterial, fungal, and viral infections for 53 study patients after CAR T-cell infusion (CTI) until allogeneic transplantation, death, or last follow-up date through day 180. Abbreviations: allo-HSCT, allogeneic hematopoietic stem cell transplantation; BSI, bloodstream infection; CDI, Clostridium difficile infection; CRE, carbapenem-resistant Enterobacteriaceae; CTI, CAR T-cell infusion; E. coli, Escherichia coli; ESBL, extended-spectrum β-lactamase; G. sputi, Gordonia sputi; HSV, herpes simplex virus; IPA, invasive pulmonary aspergillosis; K. pneumoniae, Klebsiella pneumoniae; MDR, multidrug-resistant; P. aeruginosa, Pseudomonas aeruginosa; PIV, parainfluenza virus; PNA, pneumonia; S. maltophilia, Stenotrophomonas maltophilia; URTI, upper respiratory tract infection; UTI, urinary tract infection; VRE, vancomycin-resistant Enterococcus.

Figure 2.

Cumulative incidence of infection after chimeric antigen receptor T-cell infusion (CTI) and cytokine release syndrome (CRS). A, Cumulative incidence of any infection in patients by CRS grade. B, Cumulative incidence of bloodstream infection by CRS grade. Note that all the analysis time was CRS grade 3–4.