Journal Article

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

Albertson, Tina M, Kim, Yeonhee, Siddiqi, Tanya, Sehgal, Alison, Ogasawara, Ken, Newhall, Kathryn, Solomon, Scott R, Gordon, Leo I, Maloney, David G, Lunning, Matthew A, Mallaney, Mary, Wang, Michael, Abramson, Jeremy S, Andreadis, Charalambos, Palomba, M Lia, Ghosh, Nilanjan, Kostic, Ana, Arnason, Jon, Mehta, Amitkumar, Garcia, Jacob, Li, Daniel, Purev, Enkhtsetseg

2020

Overview

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. 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. 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. 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. Juno Therapeutics, a Bristol-Myers Squibb Company.

• Publisher: Elsevier Ltd,Elsevier B.V,Elsevier Limited
• Subject: Aged / Aged, 80 and over / Alveoli / Anemia / Anemia - epidemiology / Antigens / Antigens, CD19 - administration & dosage / Antigens, CD19 - adverse effects / Antigens, CD19 - therapeutic use / B-cell lymphoma / Bcl-6 protein / Care and treatment / CD19 antigen / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - transplantation / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - transplantation / Chemotherapy / Chimeric antigen receptors / Clinical trials / Constraining / Creatinine / Cytokine Release Syndrome - epidemiology / Cytokines / Dosage / FDA approval / Female / Health services / Humans / Immunotherapy, Adoptive - adverse effects / Immunotherapy, Adoptive - methods / Infusions, Intravenous / Leukapheresis / Leukapheresis - methods / Lymphocytes / Lymphocytes B / Lymphocytes T / Lymphoma / Lymphoma, Large B-Cell, Diffuse - classification / Lymphoma, Large B-Cell, Diffuse - immunology / Lymphoma, Large B-Cell, Diffuse - pathology / Lymphoma, Large B-Cell, Diffuse - therapy / Lymphomas / Male / Manufacturing / Myc protein / Nervous System Diseases - epidemiology / Neutropenia / Neutropenia - epidemiology / Patients / Pharmaceutical industry / Positron emission tomography / Product safety / Professional hockey / Recurrence / Regulatory approval / Safety / Subgroups / Survival Analysis / Thrombocytopenia / Thrombocytopenia - epidemiology / Toxicity / Treatment Outcome