CAR T Cells Shown Effective Without Increased Risk of CRS or ICANS in CNS-Involved LBCL

Muhammad Husnain, MD

In patients with primary or secondary central nervous system (CNS) large B-cell lymphoma (LBCL), the 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 2022 Transplantation & Cellular Therapy Meetings, among 113 patients who met the review’s inclusion criteria from 17 prior studies, 56.6% of patients with CNS-involved LBCL 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 experienced a CR or PR, respectively.

“We recommend including these patients [with CNS-involved LBCL] in future CAR T[-cell] clinical trials to improve the outcomes of 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 utilizing these agents because of 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-cell therapy published prior to 2021. This included all retrospective and prospective studies reporting the efficacy and safety of CAR T-cell therapy in adult patients with CNS-involved lymphoma. Data on eligible patients from qualified studies were taken, including baseline characteristics, efficacy, and safety.

The systematic review evaluated patient responses as CR, PR, progressive disease, and stable disease. Notably, data on progression-free survival (PFS) was not available for most studies, although it was calculated by combining all patients who were event free and alive in the study, then approximated to the nearest month (1, 3, 6, and 12 months).

Among the patients evaluated, 47.6% were male. Additionally, 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 salvage MATRIX chemotherapy (methotrexate and cytarabine plus thiotepa and rituximab [Rituxan]).

All patients were infused with doses of CAR T-cell therapy ranging from 0.6 x 108 T cells to 6 x 108 T cells.

Additional data showed the estimated 1-month response rates were 45.1% for CR, 17.1% for PR, 17.1% for progressive disease, and 12.2% for stable disease.

Notably, 14 studies reported the status of disease for patients at baseline, and 62.8% of patients had active disease at the time of CAR T-cell therapy. Of those patients, 53.5% achieved a CR, 14.1% had a PR, and 36.6% had progressive disease.

The 1-month, 3-month, 6-month, and 12-month PFS rates were 72.1%, 57%, 44.2%, and 37.5%, respectively.

Regarding safety, data from 108 patients across 16 studies were evaluated for CRS, and 70.1% of patients developed grade 1 or 2 CRS, and 6.5% experienced grade 3 or 4 CRS. Additionally, 109 patients from 16 studies were evaluated for ICANS, where data showed 31.8% of patients experienced grade 1 or 2 ICANS, and 21.1% had grade 3 or higher ICANS. Notably, no deaths were 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 any-grade CRS, including grade 1 or 2 in 76.9%, and grade 3 or 4 in 10.6%. Furthermore, 69% of patients treated with tisagenlecleucel experienced any-grade 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 those instances were grade 1 or 2.

Regarding ICANS, 70.4% of all patients treated with axi-cel experienced any grade of the toxicity, including 37% who had grade 1 or 2 ICANS, 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 any grade of ICANS, and all instances were considered grade 3 or 4.

_References

_{1. Husnain M, Asghar N. Chimeric antigen receptor T cell therapy is effective in primary/secondary CNS large B cell lymphoma: a systematic review and meta-analysis. Presented at: 2022 Transplantation & Cellular Therapy Meetings; Salt Lake City, UT; April 23-26, 2022. Abstract LBA9.}

_{2. Frigault MJ, Dietrich J, Gallagher KME, et al. Tisagenlecleucel demonstrates safety, efficacy and CNS trafficking in primary CNS lymphoma. Blood. 2021;138(suppl 1):258. doi:10.1182/blood-2021-148444}