# Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma

Source: https://onco.cc/key-papers/paper-belinda-tisagenlecleucel-second-line-nejm-2022/  
OnCo record `paper-belinda-tisagenlecleucel-second-line-nejm-2022` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The one second-line CAR-T trial that failed. Its result is best explained by how long the cells took to make and what patients received while they waited.

## Summary

An international phase 3 trial in patients whose aggressive B-cell lymphoma was refractory to, or progressed within 12 months of, first-line therapy. 322 patients were randomised to tisagenlecleucel with optional bridging therapy or to salvage chemotherapy and autologous haematopoietic stem-cell transplantation, with crossover allowed if a defined event occurred at or after the week 12 assessment.

Median event-free survival was 3.0 months in both groups (hazard ratio 1.07, 95 per cent confidence interval 0.82 to 1.40, p = 0.61), and response occurred in 46.3 per cent against 42.5 per cent. 95.7 per cent of the tisagenlecleucel group received the product and 32.5 per cent of the standard-care group received an autologous transplant. The median time from leukapheresis to infusion was 52 days, and 25.9 per cent of the tisagenlecleucel group had lymphoma progression by week 6 against 13.8 per cent of the standard-care group. Baseline imbalances favoured the standard-care group: 24.1 against 16.9 per cent had high-grade lymphoma and 65.4 against 57.5 per cent an International Prognostic Index of 2 or more. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events.

## Fields

- Kind: Key paper
- Last checked: 2026-10-01
- Also known as: BELINDA; Bishop 2022
- Tags: lymphoma-evidence
- Journal: New England Journal of Medicine
- Year: 2022
- DOI: 10.1056/NEJMoa2116596
- Authors: Bishop MR, Dickinson M, Purtill D, et al.
- Findings: Median event-free survival was 3.0 months in both groups (hazard ratio 1.07, 95 per cent confidence interval 0.82 to 1.40, p = 0.61).; Response occurred in 46.3 per cent of the tisagenlecleucel group and 42.5 per cent of the standard-care group.; The median time from leukapheresis to tisagenlecleucel infusion was 52 days.; 25.9 per cent of the tisagenlecleucel group had lymphoma progression at week 6 against 13.8 per cent of the standard-care group.; At baseline the tisagenlecleucel group had more high-grade lymphoma (24.1 against 16.9 per cent) and more patients with an International Prognostic Index of 2 or higher (65.4 against 57.5 per cent).; 32.5 per cent of patients in the standard-care group received an autologous transplant.
- What it means: The reason second-line CAR-T is offered with axicabtagene ciloleucel or lisocabtagene maraleucel rather than tisagenlecleucel. The trial is also the strongest evidence in the field that the interval between apheresis and infusion, and what is given during it, is part of the treatment rather than logistics around it.
- Caveats: The baseline imbalance in high-grade histology and prognostic index favoured the standard-care group and was not adjusted for in the primary analysis.; Extensive bridging chemotherapy was permitted and widely used, which blurs the comparison with the salvage arm.; A 52-day median manufacturing interval is longer than in ZUMA-7 and TRANSFORM, which is the explanation most often offered for the difference in result, but it is a cross-trial comparison and not a tested hypothesis.; The event-free survival definition, which counted stable or progressive disease at or after week 12, differed from those used in the other two trials.

## Sources

- New England Journal of Medicine 2022: https://doi.org/10.1056/NEJMoa2116596
- PubMed: https://pubmed.ncbi.nlm.nih.gov/34904798/
- Europe PMC: https://europepmc.org/article/MED/34904798

## Connected records

- roadmaps: [Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting](https://onco.cc/roadmaps/lymphoma-roadmap/)
- cancers: [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/)
- fronts: [Cell Therapy](https://onco.cc/fronts/cell-therapy/)
- technologies: [CAR-T cell therapy](https://onco.cc/technologies/car-t/)
- targets: [CD19](https://onco.cc/targets/cd19/)
- drugs: [Tisagenlecleucel](https://onco.cc/drugs/tisagenlecleucel/)
- companies: [Novartis](https://onco.cc/companies/novartis/)
- terms: [Autologous stem cell transplant (ASCT)](https://onco.cc/terms/autologous-transplant/), [Bridging therapy](https://onco.cc/terms/bridging-therapy/), [International Prognostic Index (IPI)](https://onco.cc/terms/ipi-score/), [The CAR-T pathway in lymphoma: referral, apheresis, bridging and the waiting](https://onco.cc/terms/lymphoma-tx-car-t-pathway/)
- trials: [BELINDA](https://onco.cc/trials/belinda/), [JULIET](https://onco.cc/trials/juliet/), [TRANSFORM](https://onco.cc/trials/transform/), [ZUMA-7](https://onco.cc/trials/zuma-7/)
- people: [Jason R. Westin](https://onco.cc/people/jason-westin/), [Michael Dickinson](https://onco.cc/people/michael-dickinson/)
- bottlenecks: [Failures are hidden](https://onco.cc/bottlenecks/b-negative-results/), [Manufacturing cost and time for living and radioactive medicines](https://onco.cc/bottlenecks/b-manufacturing-cell-therapy/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- ideas: [Report the time from apheresis to infusion as a trial endpoint, not a logistics footnote](https://onco.cc/ideas/lymphoma-ev-manufacturing-time-as-a-trial-endpoint/)
- key papers: [JULIET: tisagenlecleucel for adults with relapsed or refractory diffuse large B-cell lymphoma](https://onco.cc/key-papers/paper-juliet-tisagenlecleucel-dlbcl-nejm-2019/), [TRANSFORM: liso-cel CAR-T versus salvage chemotherapy and transplant in early-relapsing large B-cell lymphoma](https://onco.cc/key-papers/paper-transform-liso-cel-lancet-2022/), [ZUMA-7: axi-cel CAR-T instead of salvage chemotherapy and transplant for large B-cell lymphoma that relapses early](https://onco.cc/key-papers/paper-zuma-7-axi-cel-second-line-nejm-2022/)

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