Exploring CAR T-Cell Therapies in the Indolent Lymphoma Setting

Caron A. Jacobson MD, MMSC

CD19 chimeric antigen receptor (CAR) T-cells demonstrate activity across B-cell histologies and can lead to a higher rate of durable remissions in patients with indolent B-cell non Hodgkin lymphoma. Furthermore, early data from first-in-human studies of these CAR T-cells at single institutions appear promising, with toxicity profiles that appear to be the same, or better, than in aggressive B-cell non Hodgkin lymphoma. Longer follow-up is needed to determine if these responses represent cures in these historically difficult-to-treat malignancies.¹

Caron A. Jacobson MD, MMSC, medical director, Immune Effector Cell Therapy Program and senior physician at Dana-Farber Cancer Institute in Boston, Massachusetts, discussed results from the ZUMA-5 trial (NCT03105336), provided a comparison between ZUMA-5 and the SCHOLAR-5 trials,² and interim results from the ELARA study (NCT03568461) in a presentation at the Society of Hematologic Oncology 2021 Annual Meeting on September 10, 2021.

ZUMA-5 evaluated axicabtagene ciloleucel (axi-cel; Yescarta) in 124 patients with follicular lymphoma (FL) and 22 patients with marginal zone lymphoma (MZL) who had undergone 3 lines of prior therapy. The primary end point was overall response rate (ORR), and key secondary end points were complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs).

“These were a group of patients at high-risk, with the majority [46.5%] having FLIPI scores greater than 3,” Jacobson, an assistant professor of medicine at Harvard Medical School, said. In addition, many patients (54.1%) were classified as POD24, ie, having progression of disease within 24 months of receiving their first anti-CD20 monoclonal antibody–containing therapy.

In ZUMA-5, ORR was 92% with a CR rate of 76%. For patients with FL, after 12 months of follow up, the ORR was 94% (n = 84) with a CR of 80%. For patients with MZL, the ORR was 85% (n = 20) with a CR rate of 60% (n = 12). “It is notable that 52% of patients who had had an initial partial response at first tumor restaging, went on to have a CR after a median of 2.2 months of follow-up,” Jacobson said in her presentation.

In patients with FL, median DFS, PFS, and OS have not been reached; among patients who had responded at a median follow-up of 18 months, 78% were maintaining their response. Jacobson said the MZL survival curves were quite immature because patients only needed one month of follow-up to be included in the efficacy analysis. “We are awaiting longer-term follow-up for this cohort,” Jacobson noted.

When outcomes by POD24 were reviewed, patients with FL and MZL with POD24 had a lower CR rate and a shorter DOR and PFS than those without POD24. “This was most notable in the MZL cohort, where only 58% of patients had a CR in the POD24 group compared with 75% and the median DOR was 11.1 months. Median PFS was 9.2 months for patients with POD24 compared with not reached for both end points for patients with MZL without POD24,” Jacobson explained.

The safety profile appeared more favorable than that observed with axi-cel in patients with diffuse large B-cell lymphoma (DLBCL) with only 7% of patients having grade 3 or greater cytokine release syndrome (CRS) and 19% of patients with grade 3 or greater neurologic events. Also, the median time to onset of CRS was later in FL and MZL at 4 days, compared with DLBCL at 2 days, according to findings from the ZUMA-1 study (NCT02348216).

Comparative Trials

Results from the SCHOLAR-5 study were presented at the 2021 European Hematology Association Meeting (EHA2021).² This was a retrospective meta-analysis comparing clinical outcomes from the updated 18-month ZUMA-5 study to a matched sample from the SCHOLAR-5 study. Data from the pivotal DELTA trial (NCT01282424) evaluating idelalisib (Zydelig) was included in the SCHOLAR-5 cohort. Eighty-five patients in the SCHOLAR-5 study and 86 patients in ZUMA-5 were evaluable after propensity score weighing was applied to the cohorts.

In third-line or higher, the ORR was 49.9% in SCHOLAR-5 compared with 94.2% for an OR of 16.2 (95% CI, 5.6-46.9). The median PFS and OS were not reached in ZUMA-5 and in SCHOLAR-5 were 12.7 months and 59.8 months, respectively. “The analysis revealed a statistically significant improvement in both overall response rate from 49.9% to 94.2%, and a complete response rate from 29.9% to 79.2%,” Jacobson said (TABLE). “This translates to an improvement in PFS, time-to-next treatment, and a statistically significant improvement in overall survival that was seen even within the first 3 years of follow-up.”

ELARA

Another study that evaluates CD19-directed CAR T cell therapy in follicular therapy is the ELARA study.3 The study evaluated tisagenlecleucel (Kymriah) in relapsed FL in patients who are in the third line setting and beyond. Investigators reported a complete response rate of 66%, with an ORR of 86% and a median follow-up of 11 months. Jacobson noted that a high proportion of patients maintained their response and that the PFS and OS curves were like those presented in ZUMA-5.

Regarding safety, Jacobson said the toxicity profile for tisagenlecleucel in FL was improved over the toxicity for the agent in patients with DLBCL and was better than the safety profile of axicabtagene ciloleucel. Investigators reported that 48.5% of patients had any grade CRS and no patients had grade 3 or higher CRS. In terms of immune cell–associated neurologic syndrome (ICANS), 9.3% of patients had any grade ICANS and 1% of patients had grade 3 or higher ICANS.³

According to Jacobson, other ongoing studies include ZUMA-5, explores axi-cel in patients with marginal zone lymphoma, the ongoing ELARA study, and the TRANSCEND study (NCT02631044), which evaluates lisocabtagene maraleucel (Breyanzi) in follicular lymphoma. Further, phase 1/2 studies that explore new agents include both allogeneic and natural killer CAR T-cells, as well as dual antigen targeting CARs that involve patients with indolent lymphomas.

“We are hopeful that these emerging therapies will change the course of these cancers and provide curative therapy for our patients,” concluded Jacobson.

_REFERENCES:

_{1. Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-hodgkin lymphoma (iNHL). Presented at: 62nd American Society of Hematology Annual Meeting and Exposition, December 5-8, 2020. Abstract 700. Accessed September 8, 2021. https://ash.confex.com/ash/2020/webprogram/Paper136834.html}

_{2. Ghione P, Patel A, Bobillo S, et al. A comparison of clinical outcomes from ZUMA-5 (axicabtagene ciloleucel) and the international scholar-5 external control cohort in relapsed/refractory follicular lymphoma (R/R FL). Presented at: European Hematology Association 2021 Virtual Congress. Abstract LB1904. Accessed September 8, 2021. https://bit.ly/3n8LfgG}

_{3. Schuster SJ, Dickinson MJ, Dreyling MH, et al. Efficacy and safety of tisagenlecleucel (Tisa-cel) in adult patients (Pts) with relapsed/refractory follicular lymphoma (r/r FL): Primary analysis of the phase 2 Elara trial. J Clin Oncol. 2021;39 (suppl 15): abstr 7508. doi: 10.1200/JCO.2021.39.15_suppl.7508}