The journey ahead for CAR T-cell therapy in r/r follicular lymphoma

Preliminary results from 3 independent phase 2 trials are promising for CAR T-cell therapies in patients with relapsed or refractory (r/r) follicular lymphoma.

Follicular lymphoma has a generally good prognosis, but approximately 20% of patients experience disease relapse within 2 years of initial first-line chemo-immunotherapy and survival rates are as poor as 50% in these patients [1]. With each line of therapy, survival rates significantly decline [2]. CAR T-cell therapy is being developed as an option for early treatment failures as well as multiple relapses, as discussed by Dr Bastian von Tresckow (University Hospital Essen, Germany) [1].

Long-term data from a single-centre, phase 2a study (NCT02650999) with CAR T-cell therapy with pembrolinzumab (targeting cell surface receptor PD-1) in patients with r/r follicular lymphoma showed a 71% complete response with tisagenlecleucel, a probability of remaining in response for 5 years of 60% (95% CI 25–83) with a median response duration not reached at a median follow-up of over 5 years (60.7 months). However, the study only included 14 patients and no definitive conclusions can be drawn from these results [3].

Dr von Tresckow also discussed previously presented data from the phase 2 ZUMA-5 study (NCT03105336), which investigated axicabtagene ciloleucel (2 x 10⁶ cells/kg; targeting CD19, CD28, and CD3zeta) in patients with r/r follicular lymphoma with a median of 3 prior lines of therapy. Preliminary outcomes after a median follow-up of 17.5 months are encouraging, with an overall response rate of 94%, 80% complete response, and 77.5% 12-month progression-free survival rate (PFS). Cytokine release syndrome occurred in 84 of 124 patients, in only patients 6 being grade ≥3 [4].

The phase 2 ELARA trial (NCT03568461) of tisagenlecleucel-T (0.6–6 x 10⁸ cells; targeting CD19) in r/r follicular lymphoma with a median of 4 prior lines of therapy also demonstrated promising outcomes with favourable safety profiles. A primary analysis after a median follow-up of 10.9 months showed an overall response rate of 86% with 66% complete response. Six-month PFS was 76% (95% CI 65–84). Median duration of response, PFS, and OS were not reached. Of 97 treated patients, 48.5% developed cytokine release syndrome, all grade ≤2 [5].

In summary, in FL patients, first-line therapies typically induce remission and delay disease progression by several years but are not curative; almost all patients eventually develop progressive disease. Several CAR T-cell therapies are currently under investigation in phase 2 trials, and preliminary results suggest that CAR T-cell therapy could be effective even in extensively pre-treated patients.

1. 
   
   1. Von Tresckow B. CAR-T Cell Therapy: Journey Ahead in r/r Follicular Lymphoma (FL) and Second-Line r/r DLBCL. 1SS11-SL4-1, EHA 2021 Virtual Congress, 9–17 June.
   2. Casulo C, et al. J Clin Oncol 2015:33(23):2516–22.
   3. Chong EA, et al. N Engl J Med. 2021:384(7):673–4.
   4. Jacobson C, et al. Abstract 700, ASH 2020, 5–8 December.
   5. Schuster SJ, et al. Oral 7508, ASCO 2021, 4–8 June.

 

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Posted on 5 August 202119 November 2021