Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: A phase I/II clinical trial

The CD19 chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel, demonstrated efficacy and acceptable levels of safety in patients with primary CNS lymphoma (PCNSL). Due to concerns regarding potential immune cell associated neurotoxicity syndrome (ICANS), this highly refractory patient population has previously been excluded from studies of this nature. Below, we summarize the findings of Frigault, et al., as published in Blood.¹

Study design

In total, 12 patients with a median age of 63 years who had relapsed or refractory PCNSL were enrolled in this study. To be eligible, each patient had to be aged ≥18 years with disease progression or relapse following systemic high-dose methotrexate-based therapy. Patients aged >60 years were eligible if they were intolerant to first line therapy due to Grade ≥3 kidney or liver injury. All patients were required to have a confirmed diagnosis of PCNSL with no evidence of systemic disease.

Patients underwent leukapheresis before receiving a dose of 0.6–6.0 × 10⁸ tisagenlecleucel CAR T-cells in line with current FDA approval for the treatment of systemic large B-cell lymphoma. Bridging therapy was allowed if followed by a 2-week washout from lymphodepleting agents before cell collection.

Post treatment MRI and CSF assessments were carried out monthly for 6 months, and quarterly up to 24 months. Radiographic responses were assessed independently by the Tumour Imaging Metrics Core in collaboration with the neuro-oncology department at Massachusetts General Hospital.

Key findings

• Tisagenlecleucel demonstrated safety and efficacy in patients with PCNSL.
• CAR T-cells were noted to effectively expand in peripheral blood and traffic to the CNS in the absence of systemic disease.
• Tisagenlecleucel expansion in peripheral blood was observed using flow cytometry in 11/12 patients (91.6%). In addition, CAR T-cell trafficking into the cerebrospinal fluid was observed in all of these patients.
• Grade 1 cytokine release syndrome was observed in 7/12 patients (58.3%) and Grade 1/Grade 2 ICANS was observed in 5/12 (41.6%), 1/12 patients (8.3%) experienced Grade 3 ICANS. No patients required tocilizumab for the management of cytokine release syndrome symptoms.
• All patients were able to discontinue corticosteroids within 28 days of tisagenlecleucel infusion.
• Responses were observed in 7/12 (58.3%) patients. These consisted of six complete responses and one partial response as per the International PCNSL Collaborative Group (IPCG).
• At data cut-off, 7/12 (58.3%) patients were alive and 3/12 patients had not experienced disease progression.

Conclusion

The results of this phase I/II clinical trial point to the viability of tisagenlecleucel as a treatment option for relapsed or refractory patients with PCNSL. The high response rate and acceptable safety profile are encouraging signs. The data in this trial are preliminary and the authors note that additional studies may be required; however, they suggest that broadening access to tisagenlecleucel for patients with PCNSL may improve clinical outcomes in this highly refractory patient population.