CAR-T Cell Therapy in Follicular Lymphoma and CLL: Identifying the High-Risk Patients Who Need It Most

CAR-T Cell Therapy in Follicular Lymphoma and CLL: Identifying the High-Risk Patients Who Need It Most

CAR-T cell therapy is reshaping the treatment landscape for follicular lymphoma and chronic lymphocytic leukemia (CLL), especially for patients with high-risk disease features such as POD24 and elevated FLIPI-2 scores. In this expert commentary, Dr. Bradley W. Christensen reviews the latest evidence on approved CAR-T therapies, compares them with emerging bispecific antibodies, and explains how clinicians can identify patients most likely to benefit from cellular therapy.

Introduction: Follicular Lymphoma – A Heterogenous Disease

Follicular lymphoma is among the most clinically and biologically heterogeneous malignancies in oncology, with outcomes ranging from patients who achieve a functional cure after frontline therapy to those who experience early progression, histologic transformation, and lymphoma-related mortality. Precisely because of the disease’s heterogenous biology and variable clinical trajectories, selecting appropriate patients for CAR-T therapy represents an enormous clinical challenge.

Two groups consistently emerge from the data as high-risk populations deserving particular consideration: patients with a FLIPI-2 score of 3 to 5, who have approximately 50% overall survival at five years; and POD24 patients, those who progress within 24 months of frontline chemoimmunotherapy. POD24 is not merely a marker of early relapse; it may reflect underlying biologic transformation. Studies have shown that up to 75% of patients who progress after bendamustine-rituximab (BR) within 24 months have occult or overt transformation to a more aggressive histology.

The Pivotal CAR-T Trials in Follicular Lymphoma

Three commercial CAR-T products have led to approved indications in follicular lymphoma: axi-cel (ZUMA-5), tisa-cel (ELARA), and liso-cel (Transcend FL). Each study enrolled a predominantly high-risk population, with over 50% of patients meeting POD24 criteria across all three trials.

ZUMA-5 was a phase 2 multicenter study of axi-cel in follicular and marginal zone lymphoma patients who had received at least two prior lines of therapy including an anti-CD20 agent. The overall response rate was 94%, with approximately 80% complete responses. At 60-plus months of follow-up — the most mature follow-up available among the three studies — the median PFS was 57 months in the follicular cohort. However, the toxicity immediately after infusion and in extended follow up was alarming: high-grade CRS occurred in approximately 6% of patients (including one death), grade 3 or higher ICANS in approximately 20%, a 7% infection-related mortality at five years, 13% grade 3 or 4 infection rate, and a 4% rate of secondary malignancy mortality. Some of this toxicity burden reflects longer follow-up compared to the other products, but it is nonetheless clinically meaningful.

ELARA evaluated tisa-cel in a pure follicular lymphoma cohort, including patients who were post-autologous transplant. This was an even higher-risk population than ZUMA-5: nearly two-thirds were POD24, 60% had FLIPI of 3 or higher. The overall response rate was 86% with a complete response rate of approximately 68%, and at 28 months of follow-up, approximately three-quarters of patients achieving complete response remained in CR. The safety profile was substantially more favorable than ZUMA-5 — very few high-grade CRS events and dramatically lower ICANS rates. However, the shorter follow-up makes efficacy comparison to ZUMA-5 inherently limited.

Transcend FL studied liso-cel in two cohorts: a standard cohort (third-line and beyond) and a high-risk cohort enriched for POD24. The complete response rates were 94 to 96% across both cohorts, with approximately 70% of patients in ongoing CR at three years in the more mature cohort. The safety profile here was the most reassuring of the three — no high-grade CRS events published, very low rates of grade 3 or higher ICANS.

In a cross-trial comparison, acknowledging all the caveats that comparison entails, a clear pattern emerges: liso-cel and tisa-cel offer a more manageable toxicity profile compared to axi-cel, with comparable efficacy across different timepoints. Given that follicular lymphoma patients often have meaningful alternative options and reasonable baseline life expectancy, the toxicity differential matters considerably in clinical decision-making.

CAR-T Versus Bispecific Antibodies in Follicular Lymphoma: How to Choose

The indolent lymphoma treatment landscape has been transformed not only by CAR-T but also by the emergence of bispecific antibodies — mosunetuzumab, epcoritamab, and others — which are now FDA-approved or pending approval for third-line and beyond follicular lymphoma.

How do I choose between them? Several factors inform that decision.

Efficacy over time. The bispecifics currently show approximately 24 months of median PFS with complete response rates 15 to 20% lower than the CAR-T trials. CAR-T has the most mature follow-up data supporting durability, with a median 57 months of PFS in ZUMA-5 for axi-cel and a 70% CR rate at three years for liso-cel in TRANSCEND. For those patients who can tolerate CAR-T therapy and its toxicity, the benefit in PFS is likely to be measured in years.

Toxicity. Rates of CRS and neurotoxicity with bispecifics are significantly lower than CAR-T across trials to date. In addition, while most patients require hospitalization for CAR-T therapy of up to 2 weeks, most patients who receive bispecific antibodies do not need to be hospitalized at any point in their therapy. For elderly or frail patients, or those unwilling to be hospitalized, bispecifics are preferred over CAR-T.

Time at center. Given the need for step-up dosing and repeated dosing schedule, the “time toxicity” of bispecifics can be substantial. The first year of epcoritamab injections requires a minimum of 30 visits to a cancer center, which can significantly impact patient adherence and quality of life. CAR-T therapy, while a single infusion, may require hospitalization for up to 2 weeks and frequent follow up visits thereafter to monitor for post-therapy complications.

Bendamustine exposure. Patients who received bendamustine within the prior 12 months have significantly inferior CAR-T outcomes due to its direct T-cell toxicity. In those patients, bispecifics — which are less affected by prior T-cell-depleting therapy — are a better choice.

Patient profile in practice. For POD24 patients, especially those outside 12 months from last bendamustine, I favor CAR-T; specifically liso-cel, given the three-year follow-up showing 70% ongoing CR and more favorable safety profile. For patients with very late relapses after BR who have had a decade of remission, the risk-benefit calculation shifts toward single-agent bispecific antibodies in the third line. The emerging Epcore-FL2 study is evaluating Rituximab plus Revlimid plus epcoritamab in the frontline setting in randomized fashion, which could reshape second-line decision-making significantly once mature follow-up is available.

CAR-T in CLL and SLL: A Different Calculus

CAR-T in CLL presents a fundamentally different clinical picture than in follicular lymphoma. The pivotal TRANSCEND CLL 004 study enrolled 137 patients with liso-cel, at least two prior lines of therapy including a BTK inhibitor, with approximately 60% having been exposed to both BTK and BCL-2 inhibitors. The MRD-negative rate at day 30 was approximately 60% in peripheral blood. Unfortunately, patients who did not achieve MRD-negativity had very poor outcomes with a median PFS of only 2 months. Patients who achieved an MRD-negative stage at day 30 had a median PFS of approximately 26 months.

What does this mean clinically? The patients who benefit most from liso-cel in CLL are those who achieve MRD negativity — and they achieve meaningfully durable responses. But approximately 40% of patients do not achieve that threshold, and for them, the therapy offers minimal benefit. This likely reflects the inherent T-cell defect well-described in CLL patients: years of disease-driven immunosuppression result in T cells that may be dysfunctional and exhausted, limiting the quality of the CAR-T product that can be manufactured.

For CLL patients who are double-refractory to BTK and BCL-2 inhibitors without known resistance mutations, pirtobrutinib (a non-covalent BTK inhibitor) is an approved option, with median PFS of approximately 11 months in that population based on the BRUIN 321 study. In younger, fit patients or those with BTK resistance mutations that portend a suboptimal response to pirtobrutinib, CAR-T remains a compelling option with the awareness that MRD status at day 30 will be highly informative for prognosis. Allogeneic CAR-T products — which address the T-cell fitness concern by using healthy donor cells — are under active investigation for and may ultimately represent the more appropriate cellular therapy approach for this disease.

When to Refer: Guidance for Community Oncologists

• Identify high-risk follicular lymphoma patients early. FLIPI-2 of 3 to 5 and POD24 status define the populations who benefit most from CAR-T rather than conventional therapies; these patients should be identified and referred promptly.
• Prefer liso-cel or tisa-cel over axi-cel in follicular lymphoma based on comparable or near-comparable efficacy with a dramatically more favorable safety profile — a critical consideration in a disease where patients may otherwise live many years.
• Bendamustine exposure within 12 months is a contraindication to autologous CAR-T. In those patients, bispecific antibodies are a better choice and should be used as the primary salvage strategy.
• Combination and sequencing strategies are maturing rapidly. The evolving bispecific-plus-immunomodulatory combinations, incorporation of novel agents such as CELMoDs, and allogeneic CAR-T products will reshape the standard of care over the next several years.

Patient Perspective: What This Means for You

If you have follicular lymphoma or CLL that has relapsed or is no longer responding to standard treatment, you now have more options than ever, including CAR-T cell therapy and a new class of drugs called bispecific antibodies. The best choice depends on your specific situation: how long ago you last had treatment, what that treatment was, your age and overall health, and how your cancer has behaved over time. Patients who progress quickly after initial therapy — a pattern called POD24 — may benefit particularly from CAR-T cell therapy. Ask your oncologist whether you are in a high-risk group that should be referred to a specialized center for evaluation. The earlier that conversation happens, the more options are likely to be available.

Key Takeaways

• POD24 patients and those with FLIPI-2 of 3 to 5 represent the high-risk follicular lymphoma populations most likely to benefit from early cellular therapy rather than continued conventional treatment.
• Liso-cel (Transcend FL) offers the most favorable safety profile among the three approved CAR-T products for follicular lymphoma, with approximately 70% of patients remaining in complete response at three years and substantially lower high-grade toxicity than axi-cel (ZUMA-5).
• Bispecific antibodies are a legitimate alternative with approximately 24 months median PFS, particularly for patients with recent bendamustine exposure (within 12 months) that would impair T-cell product quality, or for those with comorbid conditions/age that would preclude more intensive cellular therapies.
• CAR-T in CLL is effective but highly MRD-dependent: MRD negativity at day 30 separates a group with approximately 26 months median PFS from those who derive minimal durable benefit, reflecting the intrinsic T-cell defect of this disease.
• Allogeneic CAR-T products are under active investigation as an alternative to autologous CAR-T for CLL, addressing the T-cell fitness challenge by using healthy donor cells rather than the patient's own potentially dysfunctional T cells.

References and Resources

1. Jacobson CA, et al. (ZUMA-5). Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma. Nature Medicine, 2022.
2. Fowler NH, et al. (ELARA). Tisagenlecleucel in adult relapsed or refractory follicular lymphoma. Nature Medicine, 2022.
3. Morschhauser F, et al. (Transcend FL). Lisocabtagene maraleucel in follicular lymphoma and marginal zone lymphoma. The Lancet Oncology, 2023.
4. Wierda WG, et al. (TRANSCEND CLL 004). Lisocabtagene maraleucel in CLL/SLL. Journal of Clinical Oncology, 2024.
5. National Comprehensive Cancer Network (NCCN). B-Cell Lymphomas Guidelines. Available at: nccn.org

About the Author

Dr. Bradley W. Christensen, MD, is a hematologist and medical oncologist at Texas Oncology — Baylor Charles A. Sammons Cancer Center in Dallas, Texas. His main clinical interests include the management of indolent and aggressive lymphomas and the use of bispecific antibody and CAR-T cell therapies. His research interests include the toxicity of targeted lymphoma therapies, the cost of lymphoma cancer care, and the incorporation of novel agents in the management of lymphomas.