Second-line CAR T cells for lymphomas

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Anti-CD19 chimeric antigen receptor (CAR) T cells have shown huge therapeutical potential in the treatment of aggressive B-cell lymphomas beyond second-line of therapy. 1 Neelapu SS Locke FL Bartlett NL et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017; 377: 2531-2544 Crossref PubMed Scopus (2573) Google Scholar , 2 Schuster SJ Bishop MR Tam CS et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019; 380: 45-56 Crossref PubMed Scopus (1599) Google Scholar , 3 Abramson JS Palomba ML Gordon LI et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020; 396: 839-852 Summary Full Text Full Text PDF PubMed Scopus (569) Google Scholar But the use of such therapies as a second-line of therapy is a current matter of debate. At the 2021 American Society of Hematology meeting, results of the three randomised clinical trials addressing this question were presented. The ZUMA7, 4 Locke FL Miklos DB Jacobson CA et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022; 386: 640-654 Crossref PubMed Scopus (120) Google Scholar BELINDA, 5 Bishop MR Dickinson M Purtill D et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med. 2022; 386: 629-639 Crossref PubMed Scopus (66) Google Scholar and the TRANSFORM 6 Kamdar M Solomon SR Arnason JE et al. Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, versus standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pts) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL): results from the randomized phase 3 Transform study. Blood. 2021; 138 (abstr).: 91 PubMed Google Scholar trials included only patients with aggressive B-cell lymphomas with primary refractory disease or with relapse within 12 months of completion of first-line therapy. The pivotal ZUMA7 trial 4 Locke FL Miklos DB Jacobson CA et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022; 386: 640-654 Crossref PubMed Scopus (120) Google Scholar was the first to show a superiority of axicabtagene ciloleucel versus salvage chemotherapy plus autologous haematopoietic cell transplant. Event-free survival, the primary endpoint of all these trials, was significantly superior in the CAR T-cell therapy cohort (8·3 months [95% CI 4·5–15·8] vs 2·0 months [1·6–2·8]) in the ZUMA7 trial. Also, complete response rate was higher in this cohort (65% vs 32%). It is important to remember that grade 3 or worse cytokine release syndrome was 6% and neurotoxicity was 21%. The BELINDA study 5 Bishop MR Dickinson M Purtill D et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med. 2022; 386: 629-639 Crossref PubMed Scopus (66) Google Scholar did not show superiority of tisagenlecleucel versus standard-of-care treatment. Several hypotheses have been discussed over the past months to explain such differences. A different definition of event-free survival, the use of bridging chemotherapy (allowed in the BELINDA trial but not in the ZUMA7 trial), differences in vein-to-vein time, and differences in the product itself were, among others, factors that could explain the different results of the two studies. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trialThese results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL. Full-Text PDF