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Lisocabtagene Maraleucel in Relapsed or Refractory Large B-cell Lymphomas

Findings of the TRANSCEND study
07 Sep 2020
Cancer Immunology and Immunotherapy;  Haematologic malignancies

Results of the TRANSCEND study show that lisocabtagene maraleucel, an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product causes low incidence of all grade and severe cytokine release syndrome and neurological events and can lead to rapid and durable remission among patients with high-risk aggressive relapsed or refractory large B-cell lymphomas. Clinically meaningful activity was noted across populations with unmet medical need, including uncommon histological subtypes and patients with characteristics of poor prognosis. The study findings are published by Dr Jeremy S. Abramson of the Massachusetts General Hospital in Boston, MA, US and colleagues on 1 September 2020 in The Lancet.

Lisocabtagene maraleucel is an investigational, autologous, CD19-directed CAR T-cell product with a 4-1BB co-stimulatory domain, which is administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T-cells) at equal target doses.

In the seamless design TRANSCEND NHL 001 study (TRANSCEND), the study team aimed to assess the safety and activity of lisocabtagene maraleucel 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 lisocabtagene maraleucel infusion.  Therefore, additional expansion cohorts were enrolled via seamless design. In the article published in The Lancet, the authors reported the results from the entire cohort with large B-cell lymphoma included in the TRANSCEND study.

Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2BCL6, 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 lisocabtagene maraleucel 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 of the study were adverse events, dose-limiting toxicities, and the objective response rate assessed per Lugano criteria. The 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 lisocabtagene maraleucel.

In total, 344 patients underwent leukapheresis for manufacture of lisocabtagene maraleucel, of whom 269 patients received at least one dose. Patients had received a median of three previous lines of systemic treatment with 260 patients (97%) having had at least two lines. There were 112 patients (42%) who were aged 65 years or older, 181 patients (67%) had chemotherapy-refractory disease, and 7 patients (3%) had secondary CNS involvement.

Median follow-up for overall survival for all 344 patients who had leukapheresis was 18.8 months (95% confidence interval [CI] 15.0–19.3).

Overall safety and activity of lisocabtagene maraleucel 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 patients (73%) and a complete response by 136 patients (53%).

The most common grade 3 or worse adverse events were neutropenia in 161 patients (60%), anaemia in 101 patients (37%) and thrombocytopenia in 72 patients (27%). Cytokine release syndrome and neurological events occurred in 113 patients (42%) and 80 patients (30%), respectively. Grade 3 or worse cytokine release syndrome and neurological events occurred in 6 patients (2%) and 27 patients (10%), respectively. Nine patients (6%) had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T-cells.

The authors wrote that since 2017, the treatment landscape in third-line or later therapy for large B-cell lymphomas has changed with approval of two CD19-directed CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel. Both 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.

The TRANSCEND study 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 lisocabtagene maraleucel manufacturing process.

The 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. The study data build on those from previous studies of CAR T-cell treatment in large B-cell lymphomas. Clinically meaningful activity was noted across various patient subgroups, with low rates of grade 3 or worse cytokine release syndrome and neurological events. These data support the use of CAR T-cell treatment in patients with multiple subtypes of large B-cell lymphoma, who have high-risk features, including older patients and those who have moderate comorbidities.

Lisocabtagene maraleucel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies.

The study was funded by Juno Therapeutics, a Bristol-Myers Squibb company.

Reference

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. The Lancet; Published online 1 September 2020. DOI: https://doi.org/10.1016/S0140-6736(20)31366-0 

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