PMID- 35717989
OWN - NLM
STAT- MEDLINE
DCOM- 20220621
LR  - 20220717
IS  - 1474-547X (Electronic)
IS  - 0140-6736 (Linking)
VI  - 399
IP  - 10343
DP  - 2022 Jun 18
TI  - Lisocabtagene maraleucel versus standard of care with salvage chemotherapy 
      followed by autologous stem cell transplantation as second-line treatment in 
      patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results 
      from an interim analysis of an open-label, randomised, phase 3 trial.
PG  - 2294-2308
LID - S0140-6736(22)00662-6 [pii]
LID - 10.1016/S0140-6736(22)00662-6 [doi]
AB  - BACKGROUND: Patients with large B-cell lymphoma (LBCL) primary refractory to or 
      relapsed within 12 months of first-line therapy are at high risk for poor 
      outcomes with current standard of care, platinum-based salvage immunochemotherapy 
      and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene 
      maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor 
      (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety 
      in third-line or later LBCL. In this Article, we report a prespecified interim 
      analysis of liso-cel versus standard of care as second-line treatment for primary 
      refractory or early relapsed (within 12 months after response to initial therapy) 
      LBCL. METHODS: TRANSFORM is a global, phase 3 study, conducted in 47 sites in the 
      USA, Europe, and Japan, comparing liso-cel with standard of care as second-line 
      therapy in patients with primary refractory or early (</=12 months) relapsed LBCL. 
      Adults aged 18-75 years, Eastern Cooperative Oncology Group performance status 
      score of 1 or less, adequate organ function, PET-positive disease per Lugano 2014 
      criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use 
      of interactive response technology, to liso-cel (100 x 10(6) CAR(+) T cells 
      intravenously) or standard of care. Standard of care consisted of three cycles of 
      salvage immunochemotherapy delivered intravenously-R-DHAP (rituximab 375 mg/m(2) 
      on day 1, dexamethasone 40 mg on days 1-4, two infusions of cytarabine 2000 
      mg/m(2) on day 2, and cisplatin 100 mg/m(2) on day 1), R-ICE (rituximab 375 
      mg/m(2) on day 1, ifosfamide 5000 mg/m(2) on day 2, etoposide 100 mg/m(2) on days 
      1-3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), 
      or R-GDP (rituximab 375 mg/m(2) on day 1, dexamethasone 40 mg on days 1-4, 
      gemcitabine 1000 mg/m(2) on days 1 and 8, and cisplatin 75 mg/m(2) on day 
      1)-followed by high-dose chemotherapy and autologous HSCT in responders. Primary 
      endpoint was event-free survival, with response assessments by an independent 
      review committee per Lugano 2014 criteria. Efficacy was assessed per 
      intention-to-treat (ie, all randomly assigned patients) and safety in patients 
      who received any treatment. This trial is registered with ClinicalTrials.gov, 
      NCT03575351, and is ongoing. FINDINGS: Between Oct 23, 2018, and Dec 8, 2020, 232 
      patients were screened and 184 were assigned to the liso-cel (n=92) or standard 
      of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 
      2021, the median follow-up was 6.2 months (IQR 4.4-11.5). Median event-free 
      survival was significantly improved in the liso-cel group (10.1 months [95% CI 
      6.1-not reached]) compared with the standard-of-care group (2.3 months [2.2-4.3]; 
      stratified hazard ratio 0.35; 95% CI 0.23-0.53; stratified Cox proportional 
      hazards model one-sided p<0.0001). The most common grade 3 or worse adverse 
      events were neutropenia (74 [80%] of 92 patients in the liso-cel group vs 46 
      [51%] of 91 patients in the standard-of-care group), anaemia (45 [49%] vs 45 
      [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 
      [43%] vs three [3%]). Grade 3 cytokine release syndrome and neurological events, 
      which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) 
      of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). 
      Serious treatment-emergent adverse events were reported in 44 (48%) patients in 
      the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel 
      safety concerns were identified in the second-line setting. There were no 
      treatment-related deaths in the liso-cel group and one treatment-related death 
      due to sepsis in the standard-of-care group. INTERPRETATION: These results 
      support liso-cel as a new second-line treatment recommendation in patients with 
      early relapsed or refractory LBCL. FUNDING: Celgene, a Bristol-Myers Squibb 
      Company.
CI  - Copyright (c) 2022 Elsevier Ltd. All rights reserved.
FAU - Kamdar, Manali
AU  - Kamdar M
AD  - Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, 
      University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: 
      manali.kamdar@cuanschutz.edu.
FAU - Solomon, Scott R
AU  - Solomon SR
AD  - Transplant and Cellular Immunotherapy Program, Northside Hospital Cancer 
      Institute, Atlanta, GA, USA.
FAU - Arnason, Jon
AU  - Arnason J
AD  - Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, 
      MA, USA.
FAU - Johnston, Patrick B
AU  - Johnston PB
AD  - Division of Hematology, Mayo Clinic, Rochester, MN, USA.
FAU - Glass, Bertram
AU  - Glass B
AD  - Department of Hematology and Cell Therapy, Helios Klinikum Berlin-Buch, Berlin, 
      Germany.
FAU - Bachanova, Veronika
AU  - Bachanova V
AD  - Division of Hematology, Oncology and Transplantation, University of Minnesota, 
      Minneapolis, MN, USA.
FAU - Ibrahimi, Sami
AU  - Ibrahimi S
AD  - Transplant and Cellular Therapy Clinic, University of Oklahoma Stephenson Cancer 
      Center, Oklahoma City, OK, USA.
FAU - Mielke, Stephan
AU  - Mielke S
AD  - Departments of Laboratory Medicine and Medicine at Huddinge, Center of Allogeneic 
      Stem Cell Transplantation and Cellular Therapy (CAST), Karolinska Institutet and 
      University Hospital, Karolinska Comprehensive Cancer Center, Stockholm, Sweden.
FAU - Mutsaers, Pim
AU  - Mutsaers P
AD  - Department of Hematology, Erasmus University Medical Center, Rotterdam, 
      Netherlands, on behalf of HOVON/LLPC.
FAU - Hernandez-Ilizaliturri, Francisco
AU  - Hernandez-Ilizaliturri F
AD  - Department of Hematologic Oncology, Roswell Park Comprehensive Cancer Center, 
      Buffalo, NY, USA.
FAU - Izutsu, Koji
AU  - Izutsu K
AD  - Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
FAU - Morschhauser, Franck
AU  - Morschhauser F
AD  - Departement d'Hematologie, Universite de Lille, Centre Hospitalier Universitaire 
      de Lille, Groupe de Recherche sur les formes Injectables et les Technologies 
      Associees, Lille, France.
FAU - Lunning, Matthew
AU  - Lunning M
AD  - Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, NE, 
      USA.
FAU - Maloney, David G
AU  - Maloney DG
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 
      USA.
FAU - Crotta, Alessandro
AU  - Crotta A
AD  - Celgene, a Bristol-Myers Squibb Company, Boudry, Switzerland.
FAU - Montheard, Sandrine
AU  - Montheard S
AD  - Celgene, a Bristol-Myers Squibb Company, Boudry, Switzerland.
FAU - Previtali, Alessandro
AU  - Previtali A
AD  - Celgene, a Bristol-Myers Squibb Company, Boudry, Switzerland.
FAU - Stepan, Lara
AU  - Stepan L
AD  - Bristol Myers Squibb, Lawrence Township, NJ, USA.
FAU - Ogasawara, Ken
AU  - Ogasawara K
AD  - Bristol Myers Squibb, Lawrence Township, NJ, USA.
FAU - Mack, Timothy
AU  - Mack T
AD  - Bristol Myers Squibb, Lawrence Township, NJ, USA.
FAU - Abramson, Jeremy S
AU  - Abramson JS
AD  - Lymphoma Program, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
CN  - TRANSFORM Investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT03575351
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - England
TA  - Lancet
JT  - Lancet (London, England)
JID - 2985213R
RN  - 4F4X42SYQ6 (Rituximab)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
CIN - Lancet. 2022 Jun 18;399(10343):2247-2249. PMID: 35717975
EIN - Lancet. 2022 Jul 16;400(10347):160. PMID: 35843242
MH  - Adult
MH  - Antineoplastic Combined Chemotherapy Protocols
MH  - Cisplatin
MH  - Dexamethasone
MH  - *Hematopoietic Stem Cell Transplantation
MH  - Humans
MH  - *Lymphoma, Large B-Cell, Diffuse/drug therapy
MH  - Rituximab/therapeutic use
MH  - Standard of Care
MH  - *Thrombocytopenia/drug therapy
MH  - Transplantation, Autologous
COIS- Declaration of interests MK is a consultant for ADC Therapeutics, Celgene, a 
      Bristol Myers Squibb (BMS) company, Adaptive Biotechnologies, AbbVie, 
      AstraZeneca, and BeiGene, outside of the submitted work; reports speakers bureau 
      fees for Seagen outside of the submitted work; and reports research funding from 
      TG Therapeutics, Genentech, and Novartis, outside of the submitted work. JA 
      reports honoraria from Juno Therapeutics and BMS, outside of the submitted work. 
      BG is a consultant for BMS, Roche, Kite, and Novartis, outside of the submitted 
      work; reports research funding from Roche and Riemser, outside of the submitted 
      work; reports speakers bureau from Roche outside of the submitted work; and is a 
      current employee of Helios Klinik Berlin-Buch. VB reports membership on Board of 
      Directors or advisory committees for Karyopharm, FATE, and Gamida Cell, outside 
      of the submitted work; and research funding from Incyte, FATE, and Gamida Cell, 
      outside of the submitted work. SI reports divested equity in the past 24 months 
      from Karyopharm Therapeutics outside of the submitted work. SM reports speakers 
      bureaus for Novartis, DNA Prime, and Celgene-BMS, outside of the submitted work; 
      travel support and expert panel from Gilead Kite, outside of the submitted work; 
      and is on the data safety monitoring board for Miltenyi Biotec and Immunicum, 
      outside of the submitted work. PM is a consultant for BMS and received research 
      funding from AstraZeneca, outside of the submitted work. FH-I reports advisory 
      boards from Amgen, Kite, Pharmacyclics, BMS, Celgene, Incyte, Abbvie, Gilead, and 
      Epizyme, outside of the submitted work. KI reports honoraria from Daiichi Sankyo, 
      Eisai, Fuji Film Toyama Chemical, Genmab, Janssen, Kyowa Kirin, Novartis, Ono 
      Pharmaceutical, Symbio, Takeda, Chugai, Celgene, AstraZeneca, Allergan Japan, and 
      AbbVie outside of the submitted work; and research funding from Daiichi Sankyo, 
      Eisai, Genmab, Incyte, Huya Biosciences, Janssen, Kyowa Kirin, Merck Sharpe & 
      Dohme, Novartis, Ono Pharmaceutical, Pfizer, Solasia, Takeda, Yakult, Chugai, 
      Celgene, BeiGene, Bayer, and AstraZeneca, outside of the submitted work. FM is a 
      member on Board of Directors or advisory committees for AstraZeneca, Novartis, 
      Celgene, Incyte, Epizyme, BMS, F Hoffmann-La Roche, AbbVie, Gilead, and Genmab, 
      outside of the submitted work; is a consultant for Genentech, Novartis, Epizyme, 
      BMS, Servier, F Hoffmann-La Roche, AbbVie, and Gilead, outside of the submitted 
      work; and reports honoraria from Janssen, F Hoffmann-La Roche, and Chugai; and 
      reports speakers bureau from F Hoffmann-La Roche outside of the submitted work. 
      ML is a consultant for Karyopharm Therapeutics, AstraZeneca, Legend, Verastem, 
      Janssen, Myeloid Therapeutics, Daiichi Sankyo, Novartis, Spectrum, Celgene, a BMS 
      company, AbbVie, Acrotech, Beigene, ADC Therapeutics, TG Therapeutics, MorphoSys, 
      Kite, a Gilead company, and Kyowa Kirin, outside of the submitted work. DGM 
      reports honoraria from Amgen, Celgene, A2 Biotherapeutics, BMS, Umoja, Janssen, 
      Legend Biotech, Genentech, Novartis, MorphoSys, Navan Technologies, Kite Pharma, 
      and Juno Therapeutics, outside of the submitted work; rights to royalties from 
      Fred Hutchinson Cancer Research Center for patents licensed to Juno 
      Therapeutics/BMS from Celgene, BMS, and Juno Therapeutics, outside of the 
      submitted work; research funding paid to his institution from Celgene, Juno 
      Therapeutics, and Kite Pharma, outside of the submitted work; stock options from 
      A2 Biotherapeutics and Navan Technologies, outside the submitted work; and 
      research funding from Celgene and Juno Therapeutics, outside of the submitted 
      work. AC, AP, and SM are current employees of Celgene, a BMS company; and current 
      equity holders in BMS. KO and LS are current employees of BMS; and current equity 
      holders in BMS. TM was an employee of BMS at the time this research was 
      conducted; and is a current equity holder in BMS. JSA is a consultant for Kymera, 
      Genentech, Incyte Corporation, BeiGene, AstraZeneca, MorphoSys, Bluebird Bio, 
      Genmab, EMD Serono, BMS, C4 Therapeutics, Karyopharm Therapeutics, AbbVie, 
      Allogene Therapeutics, Kite Pharma, and Novartis, outside of the submitted work; 
      and received research funding from BMS and Seagen, outside of the submitted work. 
      SRS and PBJ declare no competing interests.
EDAT- 2022/06/20 06:00
MHDA- 2022/06/22 06:00
CRDT- 2022/06/19 19:03
PHST- 2022/02/24 00:00 [received]
PHST- 2022/03/29 00:00 [revised]
PHST- 2022/04/06 00:00 [accepted]
PHST- 2022/06/20 06:00 [pubmed]
PHST- 2022/06/22 06:00 [medline]
PHST- 2022/06/19 19:03 [entrez]
AID - S0140-6736(22)00662-6 [pii]
AID - 10.1016/S0140-6736(22)00662-6 [doi]
PST - ppublish
SO  - Lancet. 2022 Jun 18;399(10343):2294-2308. doi: 10.1016/S0140-6736(22)00662-6.