TY - JOUR
T1 - Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001)
T2 - a multicentre seamless design study
AU - Abramson, Jeremy S.
AU - Palomba, M. Lia
AU - Gordon, Leo I.
AU - Lunning, Matthew A.
AU - Wang, Michael
AU - Arnason, Jon
AU - Mehta, Amitkumar
AU - Purev, Enkhtsetseg
AU - Maloney, David G.
AU - Andreadis, Charalambos
AU - Sehgal, Alison
AU - Solomon, Scott R.
AU - Ghosh, Nilanjan
AU - Albertson, Tina M.
AU - Garcia, Jacob
AU - Kostic, Ana
AU - Mallaney, Mary
AU - Ogasawara, Ken
AU - Newhall, Kathryn
AU - Kim, Yeonhee
AU - Li, Daniel
AU - Siddiqi, Tanya
N1 - Funding Information:
JSA is an advisor or consultant for AbbVie, Allogene, Amgen, AstraZeneca, Bayer, BeiGene, Celgene, C4 Therapeutics, EMD Serono, Genentech, Gilead Sciences, Incyte, Janssen, Juno Therapeutics, a Bristol-Myers Squibb Company, Karyopharm, Kite Pharma, Morphosys, Merck, Novartis, Seattle Genetics, and Verastem, outside of the submitted work; and has received speaker honoraria from Celgene, outside of the submitted work. MLP has held consulting or advisory roles for Kite Pharma, Novartis, Merck, and Pharmacyclics, outside of the submitted work; a family member has received honoraria from Amgen, Evelo, Flagship Pioneering, Jazz Pharmaceuticals, Merck, Novartis, Seres Therapeutics, and Therakos; and a family member holds stock in Seres Therapeutics and patents or other intellectual property for Juno Therapeutics, a Bristol-Myers Squibb Company, and Seres Therapeutics. LIG is a consultant or advisor for Bayer, Gilead Sciences, Juno Therapeutics, a Bristol-Myers Squibb Company, and Kite Pharma outside of the submitted work; and has patents or intellectual property with Zylem (no royalties). MAL has received funding as a consultant or advisor from AbbVie, Acotech, ADC Therapeutics, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Gilead Sciences, Janssen, Pharmacyclics, Kite Pharma, Karyopharm, Legend, Novartis, Portola, Seattle Genetics, Spectrum, TG Therapeutics, and Verastem outside of the submitted work; and personal fees from DAVA, OncLive, and Vanium outside of the submitted work. MW reports grants from MD Anderson, during the conduct of the study; stock ownership and participation in advisory boards for MoreHealth, outside of the submitted work; research funding from Beigene, BioInvent, Eli Lilly, Juno Therapeutics, a Bristol-Myers Squibb Company, Kite Pharma, Loxo Oncology, Novartis, Pharmacyclics, VelosBio, and Verastem, outside of the submitted work; is an advisor or consultant for AstraZeneca, Acerta Pharma, Celgene, Guidepoint Global, Janssen, Kite Pharma, Loxo Oncology, Pharmacyclics, and Pulse Biosciences, outside of the submitted work; reports honoraria or travel support from AstraZeneca, Acerta Pharma, Celgene, Janssen, OMI, Pharmacyclics, and Targeted Oncology, outside of the submitted work; and provided expert testimony for AstraZeneca and Acerta Pharma, outside of the submitted work. JA reports grants from Juno Therapeutics, a Bristol-Myers Squibb Company, during the conduct of the study; and is a consultant or advisor for Juno Therapeutics, a Bristol-Myers Squibb Company, and Regeneron. AM reports grants from Juno Therapeutics, a Bristol-Myers Squibb Company, during the conduct of the study; grants from Incyte, Fortyseven, Takeda, Affimed, Merck, Genentech, Astex, Bristol-Myers Squibb, TG Therapeutics, Miragen, Rhizen, and ADC Therapeutics, outside of the submitted work; grants and personal fees from Celgene, Gilead, Seattle Genetics, Kite Pharma, and Pharmacyclics, outside of the submitted work; and personal fees from AstraZeneca, Incyte, Morphosys, and TG Therapeutics, outside of the submitted work. EP was affiliated with the University of Colorado during the conduct of the study but is currently an employee of Genentech. DGM has received grants to his institution and honoraria from Juno Therapeutics, a Bristol-Myers Squibb Company, and Celgene, during the conduct of the study; grants to his institution from Kite Pharma, outside of the submitted work; has participated in advisory board meetings and honoraria for Amgen, Bioline RX, Genentech, Gilead Sciences, Kite Pharma, MorphoSys, Novartis, and Pharmacyclics, outside of the submitted work; has a patent pending with Juno Therapeutics, a Bristol-Myers Squibb Company; and is a member of the A2 Biotherapeutics Scientific Advisory Board and has stock options. CA reports research funding from Amgen, Celgene, Juno Therapeutics, a Bristol-Myers Squibb Company, Merck, and Novartis, outside of the submitted work; has acted as an advisor to Astellas Pharma, Jazz Pharmaceuticals, Kite Pharma, Gilead, and Seattle Genetics, outside of the submitted work; and reports a family member with employment and stock in Genentech, outside of the submitted work. AS reports funding for clinical trials from Celgene and Juno Therapeutics, a Bristol-Myers Squibb Company, during the conduct of the study; and research funding from Celgene, Juno Therapeutics, a Bristol-Myers Squibb Company, Kite Pharma, Gilead, and Merck, outside of the submitted work. NG received research funding from Celgene, Fortyseven, Genentech, Pharmacyclics, and TG Therapeutics, outside of the submitted work; has participated in speaker bureaus for AbbVie, AstraZeneca, Celgene, Gilead Sciences, Janssen, Pharmacyclics, and Seattle Genetics, outside of the submitted work; and has provided consulting for Bristol-Myers Squibb, Celgene, Genmab, Gilead Sciences, Incyte, Janssen, Karyopharm, Pharmacyclics, Seattle Genetics, and TG Therapeutics, outside of the submitted work. TMA, JG, AK, MM, YK, and DL are employees of Juno Therapeutics, a Bristol-Myers Squibb Company, and hold stock in Bristol-Myers Squibb. KO and KN are employees of and hold stock in Bristol-Myers Squibb. TS is an advisor for AstraZeneca, BeiGene, Celgene, Juno Therapeutics, a Bristol-Myers Squibb Company, and Kite Pharma, outside of the submitted work; and has participated in speaker bureaus for AstraZeneca, Janssen, Pharmacyclics, and Seattle Genetics, outside of the submitted work. SRS declares no competing interests.
Funding Information:
This study was funded by Juno Therapeutics, a Bristol-Myers Squibb Company. Medical writing support was provided by Beate Quednau (Juno Therapeutics, a Bristol-Myers Squibb Company). Additional editorial and graphics assistance were provided by Nancy Price (The Lockwood Group, Stamford, CT, USA) and funded by Juno Therapeutics, a Bristol-Myers Squibb Company.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/9/19
Y1 - 2020/9/19
N2 - 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.
AB - 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.
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U2 - 10.1016/S0140-6736(20)31366-0
DO - 10.1016/S0140-6736(20)31366-0
M3 - Article
C2 - 32888407
AN - SCOPUS:85090978508
SN - 0140-6736
VL - 396
SP - 839
EP - 852
JO - The Lancet
JF - The Lancet
IS - 10254
ER -