Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells

Abstract

CD19-targeted chimeric antigen receptor-modified T cell (CAR-T cell) therapy has shown excellent antitumor activity in patients with relapsed/refractory B cell malignancies, with very encouraging response rates and outcomes. However, the late effects following this therapy remain unknown. Here we report late adverse events-defined as starting or persisting beyond 90 days after CAR-T cell infusion-in patients who survived at least 1 year after therapy. The median duration of follow-up was 28.1 months (range, 12.5 to 62.6 months). At last follow-up, 73% of patients were still alive and 24% were in ongoing complete remission (CR). The most common late adverse event was hypogammaglobulinemia (IgG <400 mg/dL or i.v immunoglobulinm (IVIG) replacement, observed in 67% of the patients with available data. Infection density was .55 infection/100 days at risk (2.08 per patient-year). The majority (80%) of the infections were treated in the outpatient setting, and 5% necessitated admission to the intensive care unit (ICU). Subsequent malignancies occurred in 15% of patients, including 5% with myelodysplastic syndrome (MDS). Among patients with ongoing CR and with no MDS, 16% experienced prolonged cytopenia requiring transfusions or growth factor support. Graft-versus-host disease occurred in 3 of 15 patients (20%) who had undergone previous allogeneic hematopoietic cell transplantation. Most of the late events observed in this cohort were not severe, and many could be related to previous or subsequent therapies, suggesting a safe long-term profile of CD19-targeted CAR-T cell immunotherapy.

Keywords: CD19-targeted CAR-T cells; Cytopenia; Hypogammaglobulinemia; Late events; Subsequent malignancies.

Figure 1. Late infections.

A. Late infections managed outpatient (N=122) and inpatient (N=31), including infections requiring intensive care (N=7, all LRI). URI – upper respiratory infection, LRI – lower respiratory infection, Other – other infections (N=37): bacteremia (N=1), febrile neutropenia (N=1), conjunctivitis (N=2), oral infections (including HSV and candida) (N=4), genitourinary tract infections (N=4), gastrointestinal infections (N=5), osteomyelitis (N=1), skin including cellulitis, HPV, HSV, zoster, tinea (N=19). B. Infections with microbiologic evidence: 37 infections.

Figure 2.. Late events in patients with ongoing CR.

MM = multiple myeloma, hypogamma = hypogammaglobulinemia (IgG <400 and/or IVIG replacement), MDS = myelodysplastic syndrome, cGVHD = chronic graft-versus-host disease, aGVHD = acute graft-versus-host disease. Hypogammaglobulinemia data were not available for patients 38 and 80.