When large B-cell lymphoma does not respond to the first treatment or comes back within a year, the old approach was salvage chemotherapy followed by a stem-cell transplant, which worked in only a small group of patients. This study showed that CAR-T therapy (engineering the patient's own immune cells) at this stage controls the disease much better, and with longer follow-up it also helped patients live longer. Important side effects include fever and low blood pressure (CRS) and sometimes confusion or nervous system problems, which are usually temporary but need a well-equipped centre.
Key results
8.3 vs 2.0 months
Median event-free survival
HR 0.40 (95% CI 0.31 to 0.51); P<0.001; median follow-up 24.9 months
41% vs 16%
24-month event-free survival
83% / 65% vs 50% / 32%
Overall response / complete response
54.6% vs 46.0%
4-year overall survival (final OS analysis)
HR 0.73 (95% CI 0.54 to 0.98); P = 0.03; Westin et al., NEJM 2023
Large B-cell lymphoma refractory to first-line therapy or relapsed within 12 months of first-line therapy; or after 2 or more lines of therapyCycle length: One-timeOn the page “Blood cancers (leukaemia, lymphoma and myeloma)” · Treatment regimens and dosing in lymphomas
Large B-cell lymphoma refractory to first-line therapy or relapsed within 12 months of first-line therapy; or after 2 or more lines of therapy
Second-line CAR T-cell therapy: axicabtagene ciloleucel (ZUMA-7) or lisocabtagene maraleucel (TRANSFORM)
Large B-cell lymphoma refractory to first-line treatment or relapsing within 12 months of it (candidates for intensive therapy)Cycle length: Single doseOn the page “Lymphoma” · Treatment regimens and dosing: relapsed or refractory DLBCL, eligible for transplantation or CAR T-cell therapy
Large B-cell lymphoma refractory to first-line treatment or relapsing within 12 months of it (candidates for intensive therapy)
Once, 2 to 7 days after completion of lymphodepletion
Cycle length
Single dose
Duration
One-time infusion
Doses from the FDA labels for YESCARTA and BREYANZI. Before infusion, acetaminophen and an H1 antihistamine; tocilizumab and emergency equipment must be available; the patient should stay near the treatment centre for at least 2 weeks after axi-cel infusion. In ZUMA-7, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21% of patients. In renal impairment, adjust the fludarabine and cyclophosphamide doses according to the labels of these drugs.
On the fifth, fourth and third days before the CAR-T infusion
Fludarabine
30 mg/m² daily
IV
On the fifth, fourth and third days before the CAR-T infusion
Cycle length
Once
Duration
3 days (day 0: cell infusion)
Doses and days as per the FDA label for axicabtagene ciloleucel (Yescarta) and the ZUMA-7 trial. Before starting lymphodepletion, make sure the patient's CAR-T product is available.
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Treatment arms and regimens
1Axicabtagene ciloleucel (axi-cel)
Conditioning chemotherapy with cyclophosphamide 500 mg/m² per day and fludarabine 30 mg/m² per day IV for 3 days, followed by a single IV infusion of axicabtagene ciloleucel at a target dose of 2 × 106 anti-CD19 CAR T cells per kg on day 0.
2Standard care
Two or three 21-day cycles of investigator-selected salvage chemoimmunotherapy (R-ICE, R-ESHAP, R-GDP or R-DHAP at protocol-defined doses), and in responders high-dose chemotherapy with autologous stem-cell transplantation.
Source of the regimen details: ClinicalTrials.gov NCT03391466 (target dose 2 × 10⁶ CAR-T cells/kg and conditioning regimen); OS results from Westin JR et al., NEJM 2023 (doi:10.1056/NEJMoa2301665)
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Adults with large B-cell lymphoma that was refractory to first-line chemoimmunotherapy or relapsed within 12 months after it (early relapse), who were candidates for autologous transplantation.
Endpoints
Primary endpoint: event-free survival by blinded central review.
Key secondary endpoints: response and overall survival; safety.
Safety and side effects
Grade 3 or higher adverse events in 91% of axi-cel recipients and 83% of the standard-care group. In the axi-cel group: grade 3 or higher cytokine release syndrome (CRS) 6% and grade 3 or higher neurological events 21%. No deaths were due to CRS or neurological events.
Clinical significance and place in guidelines
Based on this study, the FDA approved axi-cel (Yescarta) in April 2022 for large B-cell lymphoma refractory to first-line therapy or relapsed within 12 months, and the EMA also approved it. The final overall survival analysis (Westin et al., NEJM 2023), with a median follow-up of 47.2 months, showed superior overall survival (4-year overall survival 54.6% versus 46.0%; HR 0.73; P = 0.03). CAR-T is now the guideline standard second-line treatment for early relapse or primary refractory disease.
Limitations
The study was open-label. Only transplant-eligible patients were enrolled. In the standard-care group many patients did not respond to salvage chemotherapy and did not reach transplantation; many of them later received CAR-T. CAR-T requires specialised infrastructure, manufacturing time and high cost.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.
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