On December 4, 2025, the U.S. Food and Drug Administration approved lisocabtagene maraleucel (Breyanzi, Juno Therapeutics, Inc., a Bristol Myers Squibb company), a CD19-directed CAR T-cell therapy, for adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least two prior lines of systemic therapy.
Eligible patients include those with R/R MZL after two or more prior systemic regimens or after relapse following hematopoietic stem cell transplant (HSCT).
TRANSCEND FL-MZL Cohort (NCT04245839)
Efficacy was evaluated in the TRANSCEND FL-MZL cohort (NCT04245839).
- Study design: Open-label, multicenter, single-arm trial
- Population: Adult patients with relapsed or refractory MZL who had
- Received ≥2 prior lines of systemic therapy, or
- Relapsed after HSCT
- ECOG performance status 0–1
Lymphodepleting chemotherapy:
- Fludarabine 30 mg/m²/day
- Cyclophosphamide 300 mg/m²/day
- Administered concurrently for 3 consecutive days
CAR T-cell infusion:
- Single dose of lisocabtagene maraleucel
- Given 2–7 days after completion of lymphodepleting chemotherapy
Analysis populations:
- Intention-to-treat (ITT) population: 77 leukapheresed patients
- Efficacy-evaluable treated cohort: 66 patients
- Measurable disease by CT at baseline
- Received conforming product within the intended dose range
- Had ≥9 months of follow-up from date of first response
Efficacy results: high response rates and durable remissions
The main efficacy endpoints, assessed per Lugano criteria by an independent review committee, were:
- Overall response rate (ORR: CR + PR)
- Duration of response (DOR)
In the ITT population (n=77):
- ORR: 84.4% (95% CI: 74.4, 91.7)
- CR rate (CRR): 55.8% (95% CI: 44.1, 67.2)
- Median DOR: not reached (NR)
- 95% CI: 25.59 months, NR
These results indicate substantial anti-tumor activity in a heavily pretreated R/R MZL population, with a high rate of complete remissions and a duration of response that has not yet been fully characterized.
Safety profile and key warnings
The prescribing information for Breyanzi includes boxed warnings and precautions typical of CAR T-cell therapies, including:
- Cytokine release syndrome (CRS)
- Neurologic toxicities
- Hypersensitivity reactions
- Serious infections
- Prolonged cytopenias
- Hypogammaglobulinemia
- Secondary malignancies
- Immune effector cell–associated hemophagocytic lymphohistiocytosis-like syndrome
In clinical practice, careful monitoring and early management of CRS and neurotoxicity, as well as long-term surveillance for cytopenias, infections, and hypogammaglobulinemia, are essential.
Recommended dose
The recommended dose of lisocabtagene maraleucel for adults with R/R MZL is:
- 90 to 110 × 106 CAR-positive viable T cells
- With a 1:1 ratio of CD4-positive and CD8-positive components
The product is administered as a single intravenous infusion following lymphodepleting chemotherapy.
Regulatory considerations: priority review and orphan designation
- This review utilized the Assessment Aid, a voluntary submission from the applicant intended to facilitate the FDA’s assessment.
- The application was granted priority review.
- Lisocabtagene maraleucel received orphan drug designation for MZL.
FDA’s expedited programs for serious conditions are described in the guidance “Expedited Programs for Serious Conditions – Drugs and Biologics,” and additional considerations for regenerative medicine advanced therapies are outlined in “Expedited Programs for Regenerative Medicine Therapies for Serious Conditions.”
Editorial perspective (Morningglorysciences)
Marginal zone lymphoma is generally an indolent B-cell lymphoma, but patients who have progressed through multiple prior therapies face increasingly limited options. The approval of Breyanzi for R/R MZL after ≥2 prior systemic regimens introduces a potent, one-time treatment option with:
- ORR >80% and CRR ~56% in a heavily pretreated population
- A median DOR that has not yet been reached
At the same time, the well-recognized challenges of CAR T-cell therapy remain:
- Acute toxicities (CRS, neurotoxicity) requiring experienced centers and close monitoring
- Prolonged cytopenias, infection risk, and hypogammaglobulinemia
- Logistics and cost that may restrict access in many healthcare systems
Going forward, key questions include:
- How to sequence CAR T-cell therapy relative to BTK inhibitors, bispecific antibodies, and other emerging agents in MZL
- Which patient subgroups derive the greatest long-term benefit
- How to optimize supportive care and survivorship management after CAR T
Overall, this approval further expands the role of CD19 CAR T-cell therapy into indolent lymphoma subtypes and underscores the trend toward highly personalized, cell-based strategies even in diseases historically considered “low grade.”
*This article is based on the AACR “FDA Approval Alert” and FDA source documents, summarized and edited by Morningglorysciences.
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