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

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.

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.

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.

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.