How Liso-Cel Is Shifting the Treatment Paradigm of Marginal Zone Lymphoma

Marginal zone lymphoma (MZL) presents a unique clinical challenge due to its inherent heterogeneity, encompassing a spectrum of subtypes from localized extranodal disease to systemic splenic involvement. While many patients experience a prolonged, indolent disease course managed through localized interventions like radiation and antimicrobial therapy, a significant subset faces a more aggressive clinical trajectory.

Despite high initial response rates to frontline chemo-immunotherapy and anti-CD20 monoclonal antibodies, MZL remains a noncurable malignancy characterized by a pattern of inevitable relapse. For the approximately 20% of patients who exhibit early relapse or refractory disease, the prognosis is notably poor, with life expectancy historically limited to 3 to 5 years. This high-risk cohort represents the primary unmet need in the field, necessitating a shift toward novel therapeutic mechanisms.

In an interview with Targeted Oncology, Maria L. Palomba, MD, hematologist-oncologist and lymphoma specialist at Memorial Sloan Kettering Cancer Center, explored the shifting treatment paradigm for MZL, with a specific focus on the emergence of immune-based therapies. Key insights include an analysis of the TRANSCEND FL (NCT04245839)¹ study—the largest chimeric antigen therapy (CAR) T-cell trial to date for MZL—which evaluated the efficacy and safety of lisocabtagene maraleucel (liso-cel; Breyanzi), which received FDA approval in December 2025 in a heavily pretreated population, including patients with splenic MZL.

Targeted Oncology: What is the treatment paradigm for MZL, and what are the unmet needs in this patient group?

M. Lia Palomba, MD: [MZL] is not a single histologic and clinical disease. There are different treatment paradigm[s] depending on what type of MZL the patient has. For instance, there are antimicrobial therapies that might be used for [MZL] of the stomach, or [for] hepatitis C-associated [MZL], and radiation therapy is typically utilized for localized disease, such as extranodal MZL of the stomach, the lacrimal glands, and the parotids.

Patients with low-burden disease, normal blood counts and no symptoms, those [patients] can be observed, and sometimes the observation period can last years. However, there are patients with more aggressive disease[, who] may present with multiple or bulky lymph node involvement [or] severe symptomatic cytopenias, [and] those patients will require therapy. Often, the initial regimen is chemo-immunotherapy, and sometimes anti-CD20 monoclonal antibody monotherapy, and they usually respond. So, it is expected that patients, after their initial therapy, will respond for sometimes years, but eventually the majority will relapse.

Could you discuss the study that led to the approval of liso-cel in this disease state?

The study is called TRANSCEND FL and it included patients with relapsed/ refractory indolent lymphomas, including follicular and [MZL]. The [MZL] cohort included patients who were refractory to or had relapsed after at least 2 prior lines of therapy, and they had to have measurable disease and to meet criteria for treatment. The patient received standard lymphodepleting chemotherapy with Cyclophosphamide and Fludarabine, followed by infusion of 100 million CAR T cells, containing an equal dose of CD4+ and CD8+ T cells.

An important point is that all MZL subtypes were included in this study, including splenic [MZL], which was excluded in other CAR T cell studies. And on top of that, this is the largest CAR T cell study for [MZL]. There were 77 patients that were enrolled in the MZL cohort, 67 [patients] received liso-cel and 66 [patients] were evaluable for efficacy. These patients were heavily pretreated. They had received between 2 and 12 lines of therapy, and the median was 3. The median follow-up of the study was about 2 years, and there was a very impressive overall response rate of 95% with 62% complete responses. Responses were durable, with duration of response of 89% at 2 years. All histologic types of MZL responded. Toxicity was low overall, and many patients received their liso-cel infusion in the outpatient setting.

What patients would you consider to be good candidates for liso-cel?

Any patient who is refractory to or has relapsed after 2 lines of therapy, particularly those patients [who] relapse within 2 years of their initial therapy, which have a shorter survival compared with patient with late relapses, should be considered for CAR T cells therapy as their next line. Given the low toxicity of liso-cel in this setting, the majority of patients will be eligible for this therapy.

What are the notable safety and tolerability concerns with liso-cel, and how are they being managed?

Liso-cel has been shown to have [a] better toxicity profile compared [with] other commercially available CAR T cells, and for this reason, the investigators were allowed to administer it as outpatient. Even for those patients who develop symptoms of toxicity, who will end up being admitted at some point after the infusion, the length of those admission typically is shorter that if they had been admitted at day 0.

Regarding the specific toxicities of liso-cel in the MZL cohort, cytokine release syndrome [CRS] developed in 76% of patients, but only 3 out of the 67 patients that were eligible for evaluation of toxicity experienced grade 3 CRS, and no [patients] experienced grade 4 or 5. Neurological events were seen in 33% of patients, but again, only 3 patients had grade 3 neurological events, and there were no [grade] 4 or 5 neurological events.

How accessible is liso-cel for these patients?

In the [US], in general, access to CAR T cells is expanding, and many more centers are becoming very familiar with managing their toxicities, which was the blocking step in the past. But I think that it is still a good idea, particularly for difficult cases, to consult an expert in a highly specialized center. That is particularly important for patients that might not be considered CAR T cell-eligible by a community oncologist, but upon our expert evaluation, they might actually be considered eligible after optimization of their function status prior to receiving the cells.

REFERENCE

1.A study to evaluate the efficacy and safety of JCAR017 in adult subjects with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL) (TRANSCEND FL). ClinicalTrials.gov. Updated November 5, 2025. Accessed January 12, 2026. https://clinicaltrials.gov/study/NCT04245839