In patients with primary or secondary central nervous system (CNS) large B-cell lymphoma (LBCL), chimeric antigen receptor (CAR) T-cell agents axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi), induced responses without increased risk of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS).1
According to a systematic review and analysis of published data presented at the Transplantation & Cellular Therapy 2022 meetings, among 113 patients who met the review’s inclusion criteria in 17 prior studies, 56.6% of patients with LBCL involving the CNS achieved a complete response (CR), and 8.9% of patients had a partial response (PR). Additionally, disease progression occurred in 39.8% of patients and 3.3% of patients had stable disease. Notably, disease progression occurred later in 21.9% and 60% of patients who underwent CR or PR, respectively.
“We recommend including these patients [with CNS-involved LBCL]in the future CAR T[-cell] clinical trials to improve outcomes for these patients,” study authors Muhammad Husnain, MD, and Noureen Asghar, MD, of the University of Arizona Cancer Center, wrote in the poster presentation.
Axi-cel, tisagenlecleucel, and liso-cel are all FDA-approved for the treatment of patients with LBCL. However, patients with primary and secondary CNS lymphoma have been excluded from clinical trials using these agents due to the risk of toxicities such as CRS and ICANS.2
This systematic review aimed to investigate the safety and efficacy of these CAR T-cell therapies in patients with primary/secondary CNS LBCL.
The bibliographic databases MEDLINE, EMBASE, The Cochrane Library, Scopus and Web of Science were searched to identify all records associated with CAR T therapy published before 2021. This included all retrospective and prospective studies reporting efficacy and the safety of CAR T-cell therapy in adult patients with lymphoma involving the CNS. Data on eligible patients from qualified studies were taken, including baseline characteristics, efficacy and safety.
The systematic review assessed patient responses as CR, PR, active disease, and stable disease. Notably, progression-free survival (PFS) data were not available for most studies, although they were calculated by combining all event-free and alive patients in the study and then approximated to month on month. closer (1, 3, 6 and 12 months).
Among the patients evaluated, 47.6% were men. In addition, 28.3% of patients had primary CNS lymphoma and 71.8% of patients had secondary CNS lymphoma. Most patients received lymphodepleting chemotherapy, fludarabine, and cyclophosphamide prior to CAR T-cell therapy infusion. Notably, 2 patients received a conditioning regimen of BEAM (carmustine, etoposide, cytarabine and melphalan) plus TBC (thiotepa, busulfan and cyclophosphamide) and MATRIX salvage chemotherapy (methotrexate and cytarabine plus thiotepa and rituximab [Rituxan]).
All patients received doses of CAR-T therapy ranging from 0.6 x 108 T cells to 6 x 108 T cells.
Additional data showed that the estimated response rates at 1 month were 45.1% for CR, 17.1% for PR, 17.1% for active disease and 12.2% for stable disease.
Notably, 14 studies reported disease status for patients at baseline, and 62.8% of patients had active disease at the time of CAR T-cell therapy. Of these patients, 53.5% achieved CR, 14.1% had PR and 36.6% had progressive disease.
The PFS rates at 1 month, 3 months, 6 months and 12 months were 72.1%, 57%, 44.2% and 37.5%, respectively.
Regarding safety, data from 108 patients in 16 studies were assessed for CRS, and 70.1% of patients developed CRS grade 1 or 2, and 6.5% experienced CRS grade 3 or 4. In addition, 109 patients from 16 studies were assessed for ICANS, where data showed that 31.8% of patients had grade 1 or 2 ICANS, and 21.1% had ICANS grade 3 or higher. Notably, no deaths have been reported due to CRS or ICANS.
Data for each CAR T-cell therapy showed that 84.6% of all patients who received axi-cel experienced CRS of any grade, including grade 1 or 2 in 76.9% and grade 3 or 4 in 10.6%. Additionally, 69% of patients treated with tisagenlecleucel experienced any grade of CRS, including grade 1 or 2 in 62.1% and grade 3 or 4 in 6.9%. CRS of any grade occurred in 28.6% of all patients who received liso-cel, and all of these cases were grade 1 or 2.
With respect to ICANS, 70.4% of all patients treated with axi-cel experienced some degree of toxicity, including 37% who had ICANS grade 1 or 2 and 34.8% who had grade 3 or 4. ICANS of any grade occurred in 41.4% of all patients who received tisagenlecleucel, including grade 1 or 2 in 34.5%, and grade 3 or 4 in 6.9%. In patients who received liso-cel, 33.3% of patients experienced ICANS of any grade, and all cases were considered grade 3 or 4.
1. Husnain M, Asghar N. Chimeric antigen receptor T-cell therapy is effective in primary/secondary large CNS B-cell lymphoma: a systematic review and meta-analysis. Presented at: 2022 Transplantation & Cellular Therapy Meetings; Salt Lake City, Utah; April 23-26, 2022. LBA9 Summary.
2. Frigault MJ, Dietrich J, Gallagher KME, et al. Tisagenlecleucel demonstrates its safety, efficacy and CNS trafficking in primary CNS lymphoma. Blood. 2021;138(supplement 1):258. doi:10.1182/sang-2021-148444