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.

Highlights

  • CD19-targeted chimeric antigen receptor (CAR) T cell therapy has provided impressive initial response rates for pediatric and adolescent and young adult (AYA) patients with relapsed/ refractory B-cell acute lymphoblastic leukemia (B-ALL) [1–5]

  • Patients with relapsed and/or refractory CD19-positive malignancy received lymphodepleting chemotherapy followed by infusion of CD19-CAR T cells, for a total of initial infusions

  • Three patients had viral infections, including 2 patients with systemic reactivations and 1 with viral respiratory pathogens. No patients in this cohort had a fungal infection (Supplemental Table 4). In this single institution retrospective analysis, we report on the infectious complications of 38 pediatric and AYA patients with relapsed/refractory CD19-positive malignancy, who received lymphodepleting chemotherapy followed by CD19-CAR T cell infusion

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Summary

Introduction

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has provided impressive initial response rates for pediatric and adolescent and young adult (AYA) patients with relapsed/ refractory B-cell acute lymphoblastic leukemia (B-ALL) [1–5]. Prior to receiving CD19-CAR T cell therapy, patients have several potential risks factors for infection, including recent intensive therapy, active malignancy, presence of a central venous catheter, and prolonged cytopenias. These are compounded by i) receipt of lymphodepleting chemotherapy prior to CAR T cell infusion, ii) CAR T cell associated inflammation and immune mediated side effects, iii) exposure to immunomodulatory agents to treat CAR T cellrelated toxicities (including high-dose corticosteroids and anticytokine therapies), and/or iv) anticipated on-target off-tumor effects, such as B cell aplasia (BCA) [7–11]. Immune reconstitution and recovery of bone marrow function have been identified as important factors in mitigating infections after CAR T cell therapy, though limited information is available in the pediatric setting [8, 15, 16]

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