Lisocabtagene maraleucel: transcending tolerability in CAR-T for mantle cell lymphoma

Mantle cell lymphoma (MCL) straddles the space of both indolent and aggressive lymphomas. While in some patients, it can present in a less-threatening manner that can be initially observed (1), in others it can be rapidly progressive, and patients can quickly cycle through treatments. There are fewer Food and Drug Administration (FDA)-available choices for relapsed and refractory MCL than for other B-cell non-Hodgkin lymphomas (NHL), so clinicians need to be more thoughtful with sequencing. When this reality is combined with the fact that mantle cell lymphoma is a disease of older patients at risk for significant toxicity from the most aggressive therapies, clinicians must be even more considerate in therapy recommendations. We provide commentary on the recently published TRANSCEND NHL 001 trial (2) which presents patients with mantle cell lymphoma with an impactful treatment choice.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of several types of refractory/relapsed (R/R) B-cell NHLs, and mantle cell lymphoma is no exception. Brexucabtagene autolecucel (brexu-cel), a CD19-directed CAR with a CD28 costimulatory molecule, was approved for R/R mantle cell lymphoma in 2020 on the basis of the ZUMA-2 clinical trial (3). In the 68 treated patients, there was an overall response rate of 91% and a complete response (CR) rate of 68%. With a median follow-up of 36 months, the median progression free survival was 26 months and median overall survival was 47 months (4). A real-world analysis from the US CAR-T consortium (5) and an intention-to-treat real-world analysis from the UK (6) showed similar efficacy to the trial population. It should be noted that these studies revealed non-relapse mortality rates at 1-year (mostly due to infections) of 9% and 15%, respectively. This suggests that CAR-T can be an effective treatment for R/R MCL, with potential for long-term responders, however, it must be balanced against the real potential for treatment-related mortality.

Mantle cell lymphoma is largely a disease of older adults, and the toxicity profile of brexu-cel can be challenging considering the comorbidities and frailty of these patients. While low grade cytokine release syndrome (CRS) and the potential for immune effector cell associated neurotoxicity syndrome (ICANS) are relatively common with CAR-T cell therapy, the potential for severe toxicity with brexu-cel in MCL was notable with a 15% rate of grade 3 or higher CRS. Additionally, both grade 3 or higher ICANS and infections were experienced by nearly 1/3 of patients, even in the pre-coronavirus disease (COVID) era. In the real-world analyses in which additional time and experience could have resulted in improved management of these toxicities, the rate of high-grade events was very similar to the trial (4,5,7). The risk for severe toxicity may limit the ability to treat frail older patients or those with significant comorbidities.

Lisocabtagene maraleucel (liso-cel), a CD19 directed CAR with a 4-1BB costimulatory domain, was approved by the FDA on May 31, 2024 for mantle cell lymphoma on the basis of the TRANSCEND NHL 001 trial (2). Liso-cel has current approvals for diffuse large B-cell lymphoma and follicular lymphoma, and while indirect comparisons of clinical trials are fraught with bias due to patient selection and confounding variables, it has demonstrated lower rates of severe CRS and ICANS when compared with other CAR-T cell products (8,9). One potential explanation for this is the difference in costimulatory molecules. Rather consistently across trials, CAR constructs with CD28 costimulatory molecules have been associated with higher rates of ICANS than 4-1BB constructs, but without head-to-head comparisons, it is not possible to determine if this is the sole reason for this noted difference (10).

The TRANSCEND NHL 001 mantle cell cohort included 88 patients who received liso-cel; the total enrollment was 104 patients, with the balance of patients not accounted for due to death (9 patients) loss of eligibility (3 patients) and receiving non-conforming product (4 patients). The trial population included an expected 23% with TP53 mutation and was heavily pre-treated, with 30% of patients receiving ≥5 lines of therapy. Sixty-nine percent of patients had refractory disease, including 53% who were refractory to a BTK inhibitor. Notably, this trial also allowed patients with CNS disease (8%), who are often excluded from clinical trials. The cells were manufactured and ready to ship after a median of 24.5 days.

The efficacy findings were consistent with that of brexu-cel, with an overall response rate of 83.1% and a CR rate of 72.3%, with consistent results across high-risk subgroups including TP53 mutation and CNS disease. The median duration of response was 15.7 months with median follow-up of 22.8 months. Results of long-term follow up will be important to describe the durability of responses. The safety data were consistent with liso-cel trials for other B-cell lymphomas in terms of tolerability, with 1% and 10% of patients experiencing high-grade (≥ grade 3) CRS and ICANS, respectively. Similarly, there was a 15% rate of high-grade infections. Table 1 provides a side-by-side presentation of relevant clinical characteristics of liso-cel and brexu-cel in MCL patients, although it should be noted that these are data from two separate clinical trials and is not intended to be a direct comparison.

So what does this mean for patients with relapsed or refractory MCL and the clinicians who treat them? Liso-cel represents a viable third-line treatment option, especially in older patients who may not have tolerated the significant toxicity associated with brexu-cel. It should be noted that liso-cel, consistent with other liso-cel B-cell NHLs trials, averages a longer manufacturing time than brexu-cel and more patients received bridging therapy than in ZUMA-2 (66% vs. 37%). In ZUMA-2, allowable bridging treatments included BTK inhibitors or steroids. In the real-world analyses of brexu-cel discussed above, patients in the US received a variety of agents for bridging including BTK inhibitors, venetoclax, lenalidomide or combinations of these agents, or traditional chemotherapy (7). In the UK, patients were most likely to receive bendamustine as bridging treatment (6). The current presentation of the TRANSCEND trial does not include details of bridging therapy received beyond systemic treatment (71%), radiation therapy (5%), or both (24%). In patients with very aggressive disease, the difference in manufacturing time can be significant and may sway clinicians to select brexu-cel in younger, fit patients who are otherwise more likely to tolerate toxicity.

Secondary CNS involvement in MCL is rare, but as systemic disease control options improve, it is likely to increase over time (11). This is an unmet need, and liso-cel represents a now clinical-trial tested method for addressing this disease compartment with overall similar efficacy to patients with systemic only disease.

The therapeutic landscape for relapsed mantle cell lymphoma now firmly includes CAR-T for most patients, and many will likely receive this treatment in the second line as practice changes to include BTK inhibitors in the frontline setting (12,13). Future research is needed investigating optimal timing of CAR-T cell treatment as well as strategies to efficiently bridge patients to CAR-T, especially in those who are BTK inhibitor refractory. In addition, management of CAR-T toxicity is an ongoing area of research, such as the recently presented interim results of an ongoing phase II trial of prophylactic anakinra in the management of ICANS, which includes patients receiving brexu-cel (14). Despite the promising results of TRANSCEND NHL 001 and ZUMA-2, most patients will relapse and will need subsequent therapy. Thus, the results of studies with CD3/CD20 bispecific antibodies, such as glofitamab (15), are eagerly awaited. In the interim, patients now have another CAR-T option to choose from in the form of liso-cel.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-103/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-103/coif). D.S.W. reports consulting fees and honoraria from Integrity, Elsevier and Gather-ed and research grant support from the Lymphoma Research Foundation. P.M.R. reports research funding to institution from Seattle Genetics and Genentech; consulting fees from Kite Pharma and Caribou Biosciences; and was a speaker for Kite Pharma. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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