Felipe Peña* comments on the publication entitled “Building the Future Management of Follicular Lymphoma with T-Cell-Redirecting Strategies” published in Blood.
* Felipe Peña, Clinical Hematology Department, Institut Català d'Oncologia-L'Hospitalet, Barcelona, Spain
Building the Future Management of Follicular Lymphoma with T-Cell Redirecting Strategies
Gloria Iacoboni, Franck Morschhauser
Blood blood.2024025699.
https://doi.org/10.1182/blood.2024025699
Follicular lymphoma (FL) is now the second most common subtype of non-Hodgkin's lymphoma and is considered an indolent disease that is not curable with conventional chemotherapy. To date, treatment strategies have focused on immunochemotherapy and immunomodulatory regimens. Recently, new options have emerged, particularly for third-line or later refractory patients, including chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (BsAbs) as T-cell redirection strategies.
In this article, G. Iacobonni and F. Morschhauser review the limitations of conventional chemoimmunotherapy in the treatment of FL and highlight the potential of recently approved T-cell redirection therapies, such as CAR T-cells and BsAbs, to improve patient outcomes.
In R/R FL beyond three prior lines of treatment, three CAR T constructs have been FDA-approved based on the results of 3 prospective clinical trials (ZUMA 5, ELARA, TRANSCEND) that show promising results with an overall response rates (ORR) as high as 97% [complete remission rate (CRR) 94%] and excellent safety profiles with very low incidences of >grade3 CRS and ICANS. Responses appear durable in all 3 arms, but current estimates of progression free survival (PFS) show no clear plateau. ZUMA 5 is the one with the longest follow-up to date with 57 months and a 4-year PFS of 57%. On the other hand, Lisocel, with the shortest follow-up, reported a median 1-year PFS of 81%, which was not achieved. In terms of real-world data, results are similar despite a shorter follow-up. Also, there are now 4 bispecific antibodies available for these refractory patients: mosunetuzumab, epcoritamab, glofitamab and odronextamab. With very similar ORRs around 80% and CRRs close to 60% and very similar safety profiles in terms of CRS and ICANS, they are also offering interesting treatment strategies in this patient population.
In earlier lines of treatment, CAR-T cells preliminary results from TRANSCEND trial, show a CRR of 96% vs 3L+ in patients with high-risk FL. Additional trials and data are necessary to confirm these findings in order to approve cellular therapies in the second line setting. BsAbs are also under investigation in prospective clinical trials such as CELESTIMO, EPCORE FL-1, OLYMPIA-5 in the 2L setting; results are expected by 2025.
The first-line setting has also seen the potential advent of BsAbs; the MorningSun (mosunetuzumab) study showed an 83% CRR with tolerable CRS rates. Other studies have reported similar results. The future results of the ongoing phase 3 trials in 1L (MorningLyte, EPCORE FL-2, OLYMPIA-1 and 2) would eventually represent a significant change in the FL treatment algorithm.
Although BsAbs have the potential to replace anti-CD20 MoAb in earlier lines of therapy, open questions include the duration of treatment, the value of maintenance and the risk of CD20-negative relapse, and whether they should be used before or after CAR-T cell therapies.
This manuscript highlights how quickly the therapeutic algorithm for FL is changing and what we can expect to see as options for first-line and refractory patients in the next few years.