Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: The autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel has not improved event-free survival (EFS) over standard second-line treatment for the BELINDA trial participants with aggressive, treatment-refractory or progressing B-cell lymphoma.
Michael Bishop, from the University of Chicago in Illinois, USA, presented the study findings at the 63rd American Society of Hematology Annual Meeting & Exposition in Atlanta, Georgia, USA, to coincide with publication in The New England Journal of Medicine.
The phase III trial included 322 patients whose lymphoma had not responded to first-line treatment with an anti-CD20 antibody and anthracycline-containing chemotherapy, or who had relapsed within 12 months of completing this regimen.
The participants all had an ECOG performance status of 0–1 and were eligible for autologous haematopoietic stem-cell transplantation (HSCT) at time of randomisation. They were given either tisagenlecleucel therapy, with or without an investigator’s choice of optional bridging platinum-containing chemotherapy, or standard therapy consisting of one or more salvage regimens of an investigator’s choice of platinum-containing chemotherapy followed by autologous HSCT.
The investigators note that at baseline the 162 patients in the tisagenlecleucel arm were more likely than the 160 patients in the control arm to have high-grade lymphoma (24.1 vs 16.9%) and to have an International Prognostic Index score of at least 2 on the 5-point measure, where higher scores indicate a poorer prognosis (65.4 vs 57.5%).
Overall, 83.3% of patients in the tisagenlecleucel arm received bridging therapy and 95.7% received CAR T-cell infusion at median of 52 days after leukapheresis. The median time interval from leukapheresis to infusion for patients who received no, one or two bridging therapy regimens was a median 44, 47 and 58 days, respectively.
Just 32.5% of the control arm completed chemotherapy and HSCT, a median of 3 months after randomisation, say Michael Bishop and co-authors.
The primary endpoint of EFS – defined as time to stable or progressive disease at or after the week 12 assessment – was a median 3.0 months in both treatment arms. Treatment response at or after week 12 occurred in a comparable 46.3% of the tisagenlecleucel arm and 42.5% of the standard therapy group. Overall survival (OS) is yet to mature but showed a stratified, adjusted hazard ratio of 0.99 at data cutoff, the researchers say.
Michael Bishop and colleagues note that both EFS and OS were shorter among patients with high-grade lymphoma than those with primary mediastinal B-cell lymphoma or diffuse large B-cell lymphoma, regardless of treatment arm.
The team also observes that six of the patients who responded to tisagenlecleucel infusion had showed stable disease or progression before or soon after infusion; exploratory post-hoc analysis indicated that patients with stable or progressive disease before infusion were 2.3 times more likely to experience stable or progressing disease after infusion than patients who had achieved a complete or partial response before infusion, with some suggestion of a CAR T-cell dose–response relationship in this subgroup.
“In patients with stable or progressive disease before infusion, for whom a lower CAR T-cell dose was manufactured because of technical and patient-related challenges, an attempt to reduce tumor burden before infusion may be beneficial”, write Michael Bishop et al.
“The tisagenlecleucel dose–exposure relationship is influenced by factors such as T-cell function at the time of leukapheresis, tisagenlecleucel product phenotype, disease burden, and previous therapies”, they comment.
The investigators conclude that their findings indicate the “importance of disease control with more effective bridging therapy before CAR T-cell infusion”, adding that “a shorter time to infusion may be needed for this population of patients with disease refractory to chemotherapy.”
The authors of an accompanying editorial surmise that “the factors that drive the ‘curative’ potential of CAR T-cell therapy may be fundamentally different than the factors that drive outcomes with [autologous stem-cell transplantation], which are predominantly related to chemotherapy sensitivity.”
Mark Roschewski, from the National Institutes of Health in Bethesda, Maryland, USA, and co-authors add: “Although chemotherapy sensitivity appears to have less influence on the efficacy of CAR T-cell therapy, the presence of bulky or rapidly progressing disease may well be a major barrier to successful outcomes with CAR T cells.”
Bishop MR, Dickinson M, Purtill D, et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med; Advance online publication 14 December 2021. Doi: 10.1056/NEJMoa2116596
Roschewski M, Longo DL, Wilson WH. CAR T-cell therapy for large B-cell lymphoma–Who, when and how? N Engl J Med; Advance online publication 14 December 2021. Doi: 10.1056/NEJMe2118899
Bishop MR, Dickinson M, Purtill D, et al. Tisagenlecleucel Vs Standard of Care As Second-Line Therapy of Primary Refractory or Relapsed Aggressive B-Cell Non-Hodgkin Lymphoma: Analysis of the Phase III Belinda Study. Abstract LBA-6. 63rd American Society of Hematology Annual Meeting & Exposition; Atlanta, Georgia, USA: 11–14 December 2021.
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