CAR T-Cells for the Treatment of Refractory or Relapsed Large B-Cell Lymphoma: A Single-Center Retrospective Canadian Study

Highlights

• Our cohort showed a clear loss of efficacy at 3 months, which was only impacted by the presence of a bulky disease.

• Grade 3 and 4 CRS and ICANS were lower than previously reported.

• Severe hematotoxicity was associated with axi-cel, advanced and refractory disease and with cytokine release syndrome.

Abstract

Background: Chimeric antigen receptor (CAR) T-cells are an important new third-line treatment option for large B-cell lymphoma (LBCL). The objective response rates in pivotal early phase clinical trials with CAR T-cells were very promising. The objective of this study was to describe the efficacy results obtained with CAR T-cells infusions in our institution and to compare the toxicities of our cohort with those of pivotal trials and studies conducted in a real-life setting.

Patients and Methods: Efficacy and safety data were retrospectively collected from 25 patients with LBCL treated with CAR T-cells therapy at CHU de Québec-Université Laval. A literature search was then performed to identify other efficacy or safety data from a real-life setting. Results: At 3 months post infusion, the objective response rate (ORR) in our population with tisagenlecleucel and axicabtagene-ciloleucel were 20% and 47%, respectively. Bulky disease was the only negative predictor of poor response at 3 months (0% vs. 53%, P = .03). Bulky disease was associated with a median PFS of 2 months compared to 5 months for non-bulky disease (P = .0009). Grade ≥ 3 hematological toxicities were greater in patients treated with axi-cel (60% vs. 20%, P = .048), without bone marrow involvement (55% vs. 0%, P =.046), without stage IV disease (72% vs. 21%, P =.02), with refractory disease (67% vs. 10%, P =.01) or having been affected by cytokine release syndrome (58% vs. 0%, P =.02).

Conclusion: The poor response rate at 3 months after infusion in our cohort was influenced mainly by bulky disease. Further studies are needed to better characterize the loss of efficacy of CAR T-cells because the majority of patients will relapse over time.

Introduction

The prevalence of non-Hodgkin's lymphoma is increasing in Canada; the incidence rate per 100,000 increased from 20.8 to 25.7 cases between 2017 and 2021. It is the seventh most diagnosed cancer in North America and the eighth leading cause of cancer-related death.¹

Large B-cell lymphoma (LBCL) is an aggressive non-Hodgkin's lymphoma. The standard frontline treatment consists of an anthracycline based chemotherapy with an anti-CD20 antibody. However, 10% to 15% will have primary refractory disease and 20% to 25% will relapse.² In second line, salvage chemotherapy followed by autologous transplantation will only cure 25% of those patients.³ CAR T-cell treatment has been authorized in the province of Quebec as a third line option since September 2019 for tisagenlecleucel (tisa-cel) and December 2020 for axicabtagene-ciloleucel (axi-cel). The decisions were guided by the results of the ZUMA-1 and JULIET studies.4, 5, 6, 7 These products are autologous T-cells modified by the addition of a chimeric antigen receptor (CAR) directed against the CD19 antigen.

Two pivotal clinical studies investigated the use of CAR T-cell therapy for r/r LBCL in third line: the ZUMA-1 and the JULIET trials. The ZUMA-1 trial included 101 patients with r/r LBCL and showed a best objective response rate (ORR) of 82% with a complete response (CR) rate of 58% with axi-cel.⁶ The JULIET trial included 111 patients with r/r LBCL and reported a best ORR of 53% with a CR rate of 40% with tisa-cel.⁷ In comparison, the SCHOLAR-1 retrospective study explored the responses to third line immunochemotherapy in r/r LBCL and observed a CR rate of only 7% with overall poor long-term responses.⁸ Thus, CAR T-cell therapy is as a promising alternative for patients with r/r LBCL after 2 lines of treatment. More recently, it was also accepted in second line treatment for patient eligible for autologous transplants in the United States.

Despite these impressive results, cellular-based immunotherapies have considerable toxicities, require significant hospital resources, and the manufacturing process can be long, expensive, and complex which leads to the implementation of early and rigorous evaluation. The aim of this study was to describe the efficacy results obtained by CAR T-cell infusions in our Canadian institution and to compare the toxicity of our cohort with those of pivotal clinical trials and other studies conducted in a real-life setting.