Which CAR‑T (chimeric antigen receptor T‑cell) therapy is FDA‑approved as second‑line treatment for adult diffuse large B‑cell lymphoma (DLBCL)?

Second-Line CAR-T Cell Therapy for DLBCL

Lisocabtagene maraleucel (BREYANZI), axicabtagene ciloleucel, and tisagenlecleucel are all FDA-approved CAR-T therapies for second-line treatment of adult DLBCL, specifically for patients with refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line therapy. 1, 2

FDA-Approved Products for Second-Line DLBCL

The following anti-CD19 CAR-T products have regulatory approval for second-line use:

• Axicabtagene ciloleucel received FDA approval in April 2022 for adults with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line therapy, based on the ZUMA-7 trial demonstrating superior event-free survival (median 8.3 months vs. 2.0 months) compared to standard chemotherapy followed by autologous stem cell transplantation. 2

• Lisocabtagene maraleucel (BREYANZI) is FDA-approved for DLBCL patients with refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line therapy, as well as for those not eligible for hematopoietic stem cell transplantation due to comorbidities or age. 1

• Tisagenlecleucel is also approved for second-line DLBCL treatment in similar patient populations, though the specific FDA approval details are referenced in the context of randomized phase 3 trials. 3

Clinical Rationale for Second-Line CAR-T

The shift to second-line CAR-T represents a paradigm change based on compelling outcome data:

• CAR-T therapy provides superior outcomes compared to the traditional autologous stem cell transplantation pathway in patients with early-relapsed disease, according to the European Society for Medical Oncology. 4

• Patients who relapse within 12 months after rituximab-containing first-line therapy achieve only approximately 23% three-year progression-free survival with conventional ASCT, demonstrating the limited efficacy of transplant in this high-risk population. 4

• The ZUMA-7 trial enrolled 359 patients with primary refractory LBCL (74%) or early relapse who were transplant candidates, with 94% of the experimental arm receiving CAR-T product versus only 35% of the control arm receiving on-protocol HSCT, highlighting the superior deliverability of CAR-T. 2

Patient Selection Criteria

Do not proceed directly to autologous stem cell transplantation without first evaluating CAR-T cell therapy in patients with early-relapsed or refractory DLBCL. 4

Eligibility Requirements

• Candidates must have creatinine clearance ≥60 mL/min to meet renal function requirements for CAR-T therapy. 4

• Candidates must demonstrate cardiac ejection fraction ≥45% to satisfy organ-function criteria. 4

• Salvage chemotherapy followed by ASCT should be reserved exclusively for patients who do not meet CAR-T eligibility criteria or who are unsuitable for cellular therapy. 4

Absolute Contraindication

• CAR-T cell therapy is not indicated for primary CNS lymphoma; the FDA label for lisocabtagene maraleucel explicitly states this limitation. 1

Expected Toxicity Profile

Clinicians must anticipate and prepare for CAR-T-specific toxicities:

• Cytokine release syndrome (CRS) occurs in 92% of axicabtagene ciloleucel recipients (Grade ≥3 in 7%), typically manifesting from hours to 10-15 days post-infusion with fever, hypotension, tachycardia, and hypoxia. 2, 5

• Neurologic toxicity occurs in 74% of axicabtagene ciloleucel recipients (Grade ≥3 in 25%), typically 1-2 weeks post-infusion, with manifestations including encephalopathy, delirium, aphasia, seizures, and potentially fatal cerebral edema. 2, 5

• Prolonged cytopenias occur in 33% of patients, and fatal adverse reactions occurred in 1.8% of axicabtagene ciloleucel recipients in the pivotal trial. 2

• Management of Grade 2 or higher CRS requires tocilizumab 8 mg/kg IV (maximum 800 mg/dose), with repeat dosing every 8 hours if no improvement, and addition of dexamethasone 10 mg IV for persistent refractory hypotension. 5

Historical Context

• The 2019 NCCN guidelines limited CAR-T cell therapy to patients who had received two or more prior chemo-immunotherapy regimens, effectively restricting its use to third-line or later treatment. 5, 4

• Current evidence positions CAR-T cell therapy as at least equivalent, and likely superior, to ASCT for early-relapsed or refractory DLBCL, supporting its preferential use in the second-line setting. 4