Toxicities and Response Rates of Secondary CNS Lymphoma After Adoptive Immunotherapy With CD19-Directed Chimeric Antigen Receptor T Cells

Abstract

Background and objectives: Secondary CNS involvement in systemic B-cell lymphoma (SCNSL) is difficult to treat and displays dismal clinical outcomes. Chimeric antigen receptor (CAR) T cells emerged as a powerful treatment for systemic lymphoma. We aimed to evaluate whether CAR T cells also represent a safe and effective therapy for SCNSL.

Methods: We retrospectively searched our institutional database for patients with SCNSL treated with CD19-directed CAR T cells.

Results: We identified 10 cases, including 7 patients with intraparenchymal lesions and 3 patients with leptomeningeal disease. CNS staging at 1 month after CAR T-cell transfusion showed disease response (stable disease, partial response, and complete response) in 7 patients (70%), including 2 cases of long-lasting complete response (20%). One patient developed pseudoprogression, which resolved under steroids. Response of CNS disease was associated with systemic 1-month response. With a median follow-up of 6 months, median overall and systemic progression-free survival was 7 and 3 months, respectively. Neurotoxic symptoms occurred in 6 patients, with 3 patients developing severe neurotoxicity (American Society for Transplantation and Cellular Therapy grade ≥3).

Discussion: CAR T cells induce considerable antitumor effects in SCNSL, and CNS response reflects systemic response. Neurotoxicity appears similar to previous reports on patients with lymphoma without CNS involvement. CAR T cells may therefore represent an effective and safe therapy for SCNSL.

Figure. Toxicities and Outcome After CAR T-Cell Therapy for Secondary CNS Lymphoma

(A) Kinetics of immune effector cell-associated neurotoxicity syndrome (ICANS) through 30 days after transfusion of CD19-directed CAR T cells (n = 10). Each row represents one patient, each column a single day after CAR T-cell transfusion, and the highest ICANS grade (graded according to American Society for Transplantation and Cellular Therapy recommendations) on each day is color coded. Note that the patient number matches the individual patient number provided in the tables. Median time to fever ≥38°C for patients with grade 0–2 ICANS (yellow dotted line) and grade 3–4 ICANS (red dotted line) is indicated. *Patient #10 with ICANS grade 4 deceased because of a pulmonary infection. (B and C) Axial MRI of the brain with contrast-enhanced T1-weighted sequences from patients with lymphoma involvement of the left optic nerve (B) and of the right temporal lobe (C; arrows). In the patient with optic nerve affection (B), note the pseudoprogression characterized by nerve swelling (arrowheads) particularly on FLAIR-weighted imaging (left image in the middle panel) preceding complete response. In the patient with temporal lobe affection (C), note the substantial edema before CAR T-cell transfusion on FLAIR-weighted imaging (right image on each panel). (D) Kaplan-Meier estimates of overall survival, CNS progression-free survival, and systemic progression-free survival for our entire cohort (n = 10). Numbers in brackets indicate median survival times. In the subgroup of patients with systemic response (n = 3; dashed line), favorable systemic response was reflected by the CNS response.