Fewer than 50% of patients with relapsed or refractory large B-cell lymphomas achieve a response to subsequent treatment after a standard second-line salvage regimen, and few are cured.1, 2, 3, 4 Outcomes are worse in patients with chemotherapy-refractory disease, with 7% achieving a complete response to conventional treatment and overall survival of 6 months.5 Older age (>65 years), CNS involvement,6, 7 and comorbidities8 further portend adverse outcomes.
CD19-directed chimeric antigen receptor (CAR) T-cell treatments have shown high response rates and durable remission in patients with relapsed or refractory diffuse large B-cell lymphoma, diffuse large B-cell lymphoma transformed from follicular lymphoma, primary mediastinal B-cell lymphoma, and high-grade B-cell lymphoma.9, 10, 11, 12 However, data for other subtypes of large B-cell lymphomas and high-risk populations, such as older patients (aged ≥65 years) and those with comorbidities or CNS involvement, remain scarce. Furthermore, severe CAR T-cell-related toxicities, including cytokine release syndrome and neurological events, continue to represent a challenge in the clinical management of these patients.13, 14
Research in context
Evidence before this study
We searched PubMed on April 9, 2020, with the terms “CD19” AND “chimeric antigen receptor T-cell therapy” AND “lymphoma”. We restricted our search to clinical trials but did not restrict by date or language. Search results were subsequently restricted to reports of interventional clinical trials. Patients with large B-cell lymphomas whose disease has progressed after two or more lines of systemic treatment are unlikely to benefit from other existing treatments. However, since 2017, the treatment landscape for third-line or later large B-cell lymphomas has changed, with approval of two CD19-directed chimeric antigen receptor (CAR) T-cell products, axicabtagene ciloleucel (in 2017) and tisagenlecleucel (in 2018). Both these CAR T-cell treatments have shown high response rates and durable remission in patients with relapsed or refractory large B-cell lymphomas. However, severe CAR T-cell-related toxicities, including cytokine release syndrome and neurological events, have challenged clinical management of these patients. Additionally, eligibility criteria for the ZUMA-1 and JULIET trials, which led to regulatory approval of axicabtagene ciloleucel and tisagenlecleucel by the US Food and Drug Administration, respectively, resulted in limited treatment experience in some patient subgroups.
Added value of this study
Lisocabtagene maraleucel (liso-cel) is a novel CD19-directed CAR T-cell with a 4-1BB co-stimulatory domain administered as sequential infusions of equal target doses of CD8+ and CD4+ CAR+ T cells. The TRANSCEND NHL 001 study of liso-cel enrolled a broad range of patients with relapsed or refractory large B-cell lymphomas, compared with study populations of the previous ZUMA-1 and JULIET trials, including B-cell lymphomas with diverse histological features and patients with low creatinine clearance or poor cardiac function, and high-risk features such as CNS involvement. Additionally, patients could receive bridging therapy during the liso-cel manufacturing process.
Implications of all the available evidence
TRANSCEND NHL 001 data build on those from previous studies of CAR T-cell treatment in large B-cell lymphomas. Clinically meaningful activity was noted with liso-cel across various patient subgroups, with low rates of grade 3 or worse cytokine release syndrome and neurological events. These data support use of CAR T-cell treatment in patients with multiple subtypes of large B-cell lymphoma, who have high-risk features, including older patients (aged ≥65 years) and those who have moderate comorbidities.
Lisocabtagene maraleucel (liso-cel) is an investigational, autologous, CD19-directed CAR T-cell product with a 4-1BB co-stimulatory domain,15 which is administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses.16 Each of the CD8+ and CD4+ CAR T-cell target doses is required to meet quality specifications. In animal models, a 1:1 ratio of CD8+:CD4+ CAR T cells showed improved expansion and activity over treatment with either T-cell component alone.17 During liso-cel manufacturing, CD8+ and CD4+ T cells are selected from leukapheresis material and then independently activated, transduced, and expanded.18 The manufacturing process results in a clonally diverse, less differentiated pure T-cell product with predominant memory T-cell composition and CD19+ cells below the level of quantitation.18
In the seamless design TRANSCEND NHL 001 study (TRANSCEND), we aimed to assess the safety and activity of liso-cel in a broad population of patients with relapsed or refractory large B-cell lymphomas, including lymphomas with diverse histological features and patients with aggressive disease and high-risk features. Preliminary data from the dose-finding portion of the study showed a promising risk:benefit ratio after liso-cel infusion.19 Therefore, additional expansion cohorts were enrolled via seamless design. Here, we report results from the entire cohort with large B-cell lymphoma in TRANSCEND.