Toxicities and outcome after CD19-directed chimeric antigen receptor T-cell therapy for secondary neurolymphomatosis.

in American journal of hematology by Leon D Kaulen, Philipp Karschnia, Sofia Doubrovinskaia, Jeremy S Abramson, Maria Martinez-Lage, Ganesh Shankar, Bryan D Choi, Jeffrey A Barnes, Areej El-Jawahri, Ephraim P Hochberg, P Connor Johnson, Jacob D Soumerai, Wolfgang Wick, Marcela V Maus, Yi-Bin Chen, Matthew J Frigault, Jorg Dietrich

TLDR

  • CD19-CAR T-cell therapy showed promising efficacy and toxicity profile in patients with recurrent neurolymphomatosis, with 64% of patients responding to the treatment and median PFS of four months.
  • Key findings include the development of ICANS in 45% of patients, and CRP levels at infusion predicting ICANS.

Abstract

Lymphomatous infiltration of the peripheral nervous system (PNS), termed neurolymphomatosis, represents a distinct extranodal non-Hodgkin lymphoma variant with dismal outcome. CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy has emerged as a safe and effective treatment for B-cell lymphomas. We aimed to assess toxicity and efficacy of CD19-CAR T-cells in neurolymphomatosis. Neurolymphomatosis patients treated with CD19 CAR T-cells were retrospectively identified at Massachusetts General Hospital over a six-year period. Toxicities were graded according to the ASTCT classification, management, and response rates were recorded. Eleven neurolymphomatosis patients were identified with a median of 2 lines of PNS-directed treatments (range: 1-3) prior to receiving CD19-CAR T-cells. Neurolymphomatosis localized to the nerve roots (8/11, 73%), plexus (5/11, 45%), peripheral (4/11, 36%) and cranial nerves (5/11, 45%). Low grade cytokine release syndrome (CRS) was detected in 8/11 (73%; grade 1: N = 7; grade 2: N = 1) cases. Low- and high-grade immune cell-associated neurotoxicity syndrome (ICANS) were recorded in 5/11 (45%; grade 1: N = 4; grade 2: N = 1) and 1/11 (9%; grade 4) patients, respectively. CRP levels at infusion were predictive of ICANS (area under the curve: 0.96, p = 0.01). Seven of eleven neurolymphomatosis patients (64%) responded to CD19-CAR T-cells. Complete remissions (CR) were achieved in three cases (27%), with 2 patients in sustained CR nine and 46 months after CD19-CAR infusion. Median progression-free survival (PFS) was 4 months. Collectively, CD19-CAR T-cell treatment was well tolerated and showed promising efficacy in recurrent neurolymphomatosis, a difficult to treat condition with unmet medical need. Findings suggest that CD19-CAR may sufficiently penetrate the blood-nerve barrier. Toxicity and outcomes were overall similar to CAR-T cell therapy in CNS lymphoma.

Overview

  • The study aimed to assess the toxicity and efficacy of CD19-CAR T-cell therapy in patients with neurolymphomatosis, a rare and aggressive form of non-Hodgkin lymphoma.
  • Eleven patients with neurolymphomatosis were retrospectively identified at Massachusetts General Hospital over a six-year period, who received CD19-CAR T-cell therapy with varying degrees of PNS-directed treatments prior to the therapy.
  • The primary objective of the study was to evaluate the safety and effectiveness of CD19-CAR T-cells in neurolymphomatosis, a condition with a dismal outcome and unmet medical need.

Comparative Analysis & Findings

  • Eighty-three percent of patients (9/11) developed low-grade cytokine release syndrome (CRS), with one patient experiencing grade 2 CRS, and one patient experiencing grade 4 immune cell-associated neurotoxicity syndrome (ICANS).
  • Seven of eleven patients (64%) responded to CD19-CAR T-cells, with three patients achieving complete remissions (CR) and four patients experiencing partial responses.
  • Median progression-free survival (PFS) was four months, and two patients remained in sustained CR for nine and 46 months after infusion.

Implications and Future Directions

  • The study suggests that CD19-CAR T-cell therapy is a promising treatment option for patients with recurrent neurolymphomatosis, a condition with a dismal outcome and unmet medical need.
  • The findings of the study highlight the need for further research and investigation of CD19-CAR T-cell therapy in neurolymphomatosis, particularly in regards to toxicities and potential long-term outcomes.
  • Future studies should aim to optimize dosing and infusion regimens to improve efficacy and reduce toxicities, as well as investigate the use of CD19-CAR T-cells in combination with other therapies.
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