Balancing Toxicity, Tolerability, Efficacy Is Essential for CAR T-Cell Therapies in Indolent B-Cell Lymphoma

As various chimeric antigen receptor (CAR) T-cell therapies show promise for the treatment of follicular lymphoma and marginal zone lymphoma (MZL), clinicians must weigh toxicity and tolerability almost as strongly as efficacy because patients can live years with these diseases, according to a presentation at the Society of Hematologic Oncology (SOHO) 2021 Annual Meeting.

Presenter Caron A. Jacobson, MD, MMSc, of the Dana-Farber Cancer Institute, reviewed results from the ZUMA-5 and ELARA clinical trials, both of which have found encouraging data with CAR T-cell therapies. ZUMA-5 is a phase 2 clinical trial in relapsed or refractory indolent B-cell Non-Hodgkin lymphoma (NHL) studying the use of axicabtagene ciloleucel, whereas the ELARA trial is investigating tisagenlecleucel in relapsed or refractory follicular lymphoma.

Jacobson said the ZUMA-5 trial enrolled 124 patients with follicular lymphoma and 22 with MZL, all of whom are considered high-risk. Significantly, 55% of participants experienced progression of disease within 24 months of their first anti-CD20 monoclonal antibody-containing therapy (POD24) and most patients were in the third-line treatment setting.

After receiving treatment with axicabtagene ciloleucel, researchers found a 92% overall response rate (ORR) and a 78% complete response rate (CRR). The median time to first response was 1 month. Furthermore, among 25 patients with follicular lymphoma who originally had a partial response, 52% subsequently converted to a complete response after a median of 2.2 months.

The median duration of response, progression-free survival (PFS), and overall survival (OS) rates have not yet been reached for patients with follicular lymphoma, and 78% of patients with follicular lymphoma are maintaining their response. Jacobson noted that the duration of response data for patients with MZL are immature.

Among patients with POD24 status, Jacobson said researchers saw a lower CRR and shorter duration of response and PFS rates, but this was most notably in the MZL cohort, which had a 58% complete response rate and 11.1-month duration of response rate.

The safety profile for axicabtagene ciloleucel is favorable, Jacobson said, with only 9% of patients experiencing grade 3 or higher cytokine release syndrome (CRS). The most common CRS symptoms of any grade were pyrexia (96%) and hypotension (41%) and the most common neurologic evens of any grade were tremor (52%) and confused state (40%).

Patients in the ZUMA-5 trial were allowed to be retreated if their response lasted at least 3 months and 13 patients were retreated. Among those patients, researchers found a 100% response rate and a 58% 12-month estimated PFS, as well as a similar safety profile and peak cytokine profile as the first infusion.

Jacobson next turned to a discussion about the ELARA trial, which is investigating the use of tisagenlecleucel in relapsed or refractory follicular lymphoma. The phase 2, single-arm, multicenter, open-label trial enrolled 94 participants. According to the presentation, the CRR was 66% with an ORR of 86% and a median follow-up of 11 months. A high proportion of patients were maintaining response at the data cutoff point and the median PFS and OS were not reached.

Jacobson also noted improvements in the toxicity profile compared with studies of diffuse large B-cell lymphoma, with 47 patients experiencing CRS, 9 of whom were grade 3 or higher. The median time to onset for CRS was 4 days.

Based on these findings and other ongoing research, Jacobson said CD19 CAR T cells have shown activity across B-cell NHL histologies and can lead to a high rate of durable remissions in indolent B-cell lymphoma. Toxicity for these patients appears to be the same or better than in aggressive B-cell NHL. Longer follow-up is needed to determine whether the responses seen in the ZUMA-5 and ELARA trials represent cures for these historically incurable diseases.

REFERENCES

Jacobson, C. Car T-Cell Therapy in Indolent Lymphoma. Presented at: Society of Hematologic Oncology 2021 Annual Meeting. September 10, 2021. Accessed September 10, 2021.