Burden and Impact of Toxicities on Outcomes for Aggressive B Cell Non-Hodgkin Lymphoma Patients after CD19-Directed Chimeric Antigen Receptor T Cell: Real-World Experience

Abstract

<h3>Introduction</h3> Despite the remarkable activity of chimeric antigen receptor T (CAR T) cells in relapsed/refractory aggressive B cell non-Hodgkin Lymphoma (B-NHL), they possess unique and significant adverse effect profiles, notably cytokine release syndromes (CRS) and neurological toxicity (ICANS). Although there have been data demonstrating impacts of CRS and ICANS on short term outcomes after CAR T cells, the burden and impact of organ-based toxicities on long-term outcomes is largely unknown. Here, we describe toxicity patterns stratified by organ involvement and their association with overall survival (OS) in aggressive B-NHL patients treated with CD19 CAR T cells. <h3>Methods</h3> We conducted a retrospective analysis of 60 aggressive B-NHL patients who received CD19 targeted CAR T cell products (tisagenleucel or axicabtagene ciloleucel) at our center between January 2018-June 2019. We collected all CTCAE v5.0 grade ≥2 toxicities from the date of CAR T cell infusion (except hematologic toxicities which were recorded after day +30) and classified into 17 organ-based toxicity categories. Relapse, progression, and death were competing events for toxicities. Risk factors, cumulative incidence, and survival impacts of toxicities were reported. <h3>Results</h3> Figure 1 summarizes baseline characteristics of 60 patients in this study cohort. With a median follow up of 121 days (range 21-365), 59 of 60 patients (98%) developed at least one CTCAE grade ≥2 toxicity. There were 435 individual toxicity events stratified among 14 different organ systems. Among all patients, the most common grade ≥ 2 organ-based toxicities were: infectious, metabolic, cardiovascular, hematologic, neurological, pulmonary, gastrointestinal, and hepatic. The corresponding 1-year cumulative incidence of grade ≥2 toxicities were 86.7%, 70%, 53.3%, 52.8%, 41.7%, 33.6% 31.6%, and 18.3% respectively (Figure 2A), whereas the corresponding 1-year cumulative incidence of grade ≥3 toxicities were 81.7%, 28.4%, 16.7%, 36.3%, 18.3%, 12.2%, 8.7%, and 5% respectively (Figure 2B). Incidence of toxicities were similar between CAR T cell products except infectious complication which was higher in axicabtagene (p=0.011). Most toxicities (74%) developed within the first 30 days after CAR T cell infusion. At the time of analysis, 16 patients had died. Causes of death included disease progression (n=15) and infection (n=1). The 1-year non-relapse mortality, disease free survival and overall survival were 2%, 44.1% and 66.9% respectively (Figure 3). CAR T cell related organ-based toxicities were not associated with increased risk of death. <h3>Conclusions</h3> There is a high incidence and burden of toxicities in aggressive B-NHL patients treated with CD19 CAR T cell therapy. However, most CAR T cell organ-based toxicities are manageable and not associated with an increased risk of death.