Patterns, risk factors and management of CD19-directed chimeric antigen receptor T-cell therapy failure in CNS lymphoma.

BACKGROUND: CD19-directed chimeric antigen receptor T-cell therapy (CD19-CAR) has yielded encouraging efficacy in CNS lymphomas (CNSL), but most patients ultimately experience progressive disease (PD). Risk factors, progression patterns as well as optimal salvage therapies remain unclear. METHODS: Clinical and radiological characteristics of CD19-CAR failure were therefore retrospectively defined in CNSL treated at Massachusetts General Hospital from 2018 to 2024. PD patterns were defined as local or distant. CNS-progression-free survival from CD19-CAR infusion (CNS-PFS1) and first subsequent progression (CNS-PFS2) were analyzed. RESULTS: CD19-CAR achieved a 60% overall response rate (45% complete (CR), 15% partial response) in 60 recurrent CNSL. Median CNS-PFS1 was 4 months with radiographic PD in 36 patients (local 23.3%; local and distant 16.7%; distant 20%). PD patterns were associated with prior CD19-CAR response: Distant relapse typically occurred after CR whereas local PD followed CD19-CAR refractory disease. Peripherally contrast enhancing CNSL (pCE) at CD19-CAR infusion correlated with refractory disease. Leptomeningeal involvement (LMD) was associated with recurrence after CR. On multivariable Cox regression, pCE (Hazard ratio [HR]: 2.75; 95%-Confidence interval [CI]: 1.08-6.68, p = 0.03) and LMD (HR: 2.72; CI: 1.20-6.25, p = 0.02) were independently associated with shorter CNS-PFS1. At progression, peripheral CD19+-B-cell aplasia suggested CD19-CAR persistence in 93% of patients. Median CNS-PFS2 after CD19-CAR failure was one month. Salvage immune checkpoint inhibition, and lenalidomide with rituximab/tafasitamab yielded prolonged responses. CONCLUSIONS: This study identifies novel radiological risk factors for CD19-CAR failure in CNSL, namely pCE and LMD. Outcome in this setting is unfavorable and encouraging salvage treatments warrant prospective evaluation.