Elsevier

The Lancet

Volume 396, Issue 10254, 19–25 September 2020, Pages 839-852
The Lancet

Articles
Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study

https://doi.org/10.1016/S0140-6736(20)31366-0Get rights and content

Summary

Background

Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas.

Methods

We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044.

Findings

Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1–8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0–19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8–78·0) patients and a complete response by 136 (53%, 46·8–59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells.

Interpretation

Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies.

Funding

Juno Therapeutics, a Bristol-Myers Squibb Company.

Introduction

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.

Section snippets

Study design and patients

TRANSCEND is a multicentre, multicohort, seamless design study at 14 cancer centres in the USA (appendix p 1). Eligible patients (aged ≥18 years) had PET-positive relapsed or refractory diffuse large B-cell lymphoma (de novo or transformed from any indolent lymphoma), high-grade B-cell lymphoma with rearrangements in MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), primary mediastinal B-cell lymphoma, or follicular lymphoma grade 3B.20 Patients must have received two or

Results

Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells. Median follow-up for overall survival for all patients who had leukapheresis was 18·8 months (95% CI 15·0–19·3). Data cutoff for this analysis was on Aug 12, 2019. Follow-up is ongoing.

Of 344 patients with large B-cell lymphoma who underwent leukapheresis, 294 received CAR T cells a median of 3 days (IQR 3–4) after lymphodepleting chemotherapy. Product could not be manufactured for two

Discussion

TRANSCEND is the largest clinical study reported to date of CD19-directed CAR T-cell treatment for patients with relapsed or refractory large B-cell lymphomas. Of 344 patients who underwent leukapheresis, 50 (15%) did not receive CAR T cells, primarily because of death from progression (n=33), which shows the aggressiveness of this disease in a high-risk patient population. Of the remaining 294 patients, 25 received non-conforming CAR+ T cells. Among 256 patients in the efficacy-evaluable set

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