Infectious Complications Following CD19 CAR T Cell Immunotherapy for Children and Young Adults with Refractory ALL

Abstract

Background The use of chimeric antigen receptor (CAR) T cell immunotherapy for refractory malignancy and other diagnoses is increasing rapidly. This approach has resulted in high response rates in children with refractory acute lymphoblastic leukemia (ALL). However many patients presenting for this therapy are at high risk for infections due to prior chemotherapy regimens and history of multiple relapses. Adding to the risk of infection is pre-infusion immunosuppressive lymphodepletion chemotherapy and post-therapy cytokine release syndrome (CRS) which often requires treatment with tocilizumab and steroids. In addition, CD19 CAR T cells may deplete normal CD19+ B cells, potentially resulting in low immunoglobulin G levels, further increasing the risk of infection. The infectious complications of this therapeutic approach have not been well studied in children. Methods We reviewed medical records of patients receiving CD 19+ CAR T cells for refractory ALL and non-Hodgkin's lymphoma through protocol PLAT 02 at Seattle Children's Hospital between 2014 and 2017. Pre-therapy infections, antimicrobial prophylaxis and development and treatment of CRS and neurotoxicity were noted. We assessed the timing, type and severity (1=no treatment, 2=oral treatment required, 3=intravenous therapy required, 4=life threatening, 5=fatal) of each incident infection. Primary outcomes were the incidence and type of infection in the 28 days post T- cell infusion. Mortality was a secondary outcome. Results 83 patients received CAR T-cell therapy during the study period. The median age was 12 years (range 1-25). All but three had ALL as an underlying diagnosis and 55% had preceding hematopoietic cell transplantation. More than half of participants (61%) had a new infection or were actively being treated for an infection in the 90 days prior to T cell infusion. 90% of patients developed CRS. 25 patients (30%) developed 32 episodes of infection in the first 28 days post CAR T cell infusion (Figure 1a). Bacterial infections were most common (n=20, 18%) consisting of 16 episodes of bacteremia (N = 6 gram negative bacteria and N = 10 gram positive bacteria), 2 clostridium difficile infections and 2 bacterial site infections (Figure 1b). 95% of bacterial infections were deemed grade 3 severity or higher. Ten participants (12%) had viral infections, of which 90% were caused by respiratory viruses (Figure 1c). One patient developed an incident invasive mold infection. Three patients died in the four weeks following therapy; none of these deaths were clearly infection related. Conclusions Infection occurs frequently in patients receiving CD19 targeted CAR T cell therapy for refractory ALL and NHL. Understanding the type and timing of infections and contributing risk factors could help inform prophylactic and monitoring strategies to improve outcomes in this patient population.