Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

Abstract

CD19-specific chimeric antigen receptor (CAR) T cell therapy has changed the treatment paradigm for pediatric, adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, data on the associated infectious disease challenges in this patient population are scarce. Knowledge of infections presenting during treatment, and associated risk factors, is critical for pediatric cellular therapy and infectious disease specialists as we seek to formulate effective anti-infective prophylaxis, infection monitoring schemas, and empiric therapy regimens. In this work we describe our institutional experience in a cohort of 38 pediatric and AYA patients with CD19-positive malignancy treated with lymphodepleting chemotherapy (fludarabine/cyclophosphamide) followed by a single infusion of CD19-CAR T cells (total infusions, n=39), including tisagenlecleucel (n=19; CD19/4-1BB) or on an institutional clinical trial (n=20; CD19/4-1BB; NCT03573700). We demonstrate that infections were common in the 90 days post CAR T cells, with 19 (50%) patients experiencing a total of 35 infections. Most of these (73.7%) occurred early post infusion (day 0 to 28; infection density of 2.36 per 100 patient days-at-risk) compared to late post infusion (day 29 to 90; infection density 0.98 per 100 patient days-at-risk), respectively. Bacterial infections were more frequent early after CAR T cell therapy, with a predominance of bacterial blood stream infections. Viral infections occurred throughout the post infusion period and included primarily systemic reactivations and gastrointestinal pathogens. Fungal infections were rare. Pre-infusion disease burden, intensity of bridging chemotherapy, lymphopenia post lymphodepleting chemotherapy/CAR T cell infusion and development of CAR-associated hemophagocytic lymphohistiocytosis (carHLH) were all significantly associated with either infection density or time to first infection post CAR T cell infusion. A subset of patients (n=6) had subsequent CAR T cell reinfusion and did not appear to have increased risk of infectious complications. Our experience highlights the risk of infections after CD19-CAR T cell therapy, and the need for continued investigation of infectious outcomes as we seek to improve surveillance, prophylaxis and treatment algorithms.

Infectious complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy

“…For example, among B cell lymphoid neoplasms treated with CD19 CAR T-cells, there was evidence showing that patients with B-ALL tended to carry a higher risk of infection post-CAR T-cell therapy than CLL and B-NHL [13]. In addition, history of previous infection prior to CAR T-cell therapy has been shown in many studies to be strongly associated with increased risk of infection after CAR T-cells [17,18,44]. Age may also impact the patterns and incidence of infections [29].…”

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas

“…Grade ≥ 3 neutropenia is observed in <40% of patients and the cumulative incidence of neutrophil recovery at 28 days was 75%. HGG was pronounced in roughly half of the cohorts, while irAEs, pre-therapy lymphopenia, and duration of low IgG were significantly associated with infection density [ 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 ]. According to the FDA Adverse Event Reporting System for tisagenlecleucel in the post-marketing period for the pediatric population, infection was the second most frequent cause of death (11.3%) after disease progression [ 172 ].…”

Olecranon bursitis caused by Scedosporium apiospermum in a patient treated with CAR-T cells

“…Fungal infections reported following CAR-T cell treatment include infections with Candida, Aspergillus, Fusarium, Pneumocystis jirovecii and Mucorales [ [9] , [10] , [11] , [12] , [13] ], but so far the consensus in the literature is that (invasive) fungal infections after CAR-T cell treatment are uncommon, at least compared to bacterial and viral infections [ [13] , [14] , [15] ].…”