PMID- 30782611
OWN - NLM
STAT- MEDLINE
DCOM- 20191227
LR  - 20211130
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 133
IP  - 17
DP  - 2019 Apr 25
TI  - The response to lymphodepletion impacts PFS in patients with aggressive 
      non-Hodgkin lymphoma treated with CD19 CAR T cells.
PG  - 1876-1887
LID - 10.1182/blood-2018-11-887067 [doi]
AB  - Factors associated with durable remission after CD19 chimeric antigen receptor 
      (CAR)-modified T-cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma 
      (NHL) have not been identified. We report multivariable analyses of factors 
      affecting response and progression-free survival (PFS) in patients with 
      aggressive NHL treated with cyclophosphamide and fludarabine lymphodepletion 
      followed by 2 x 10(6) CD19-directed CAR T cells/kg. The best overall response 
      rate was 51%, with 40% of patients achieving complete remission. The median PFS 
      of patients with aggressive NHL who achieved complete remission was 20.0 months 
      (median follow-up, 26.9 months). Multivariable analysis of clinical and treatment 
      characteristics, serum biomarkers, and CAR T-cell manufacturing and 
      pharmacokinetic data showed that a lower pre-lymphodepletion serum lactate 
      dehydrogenase (LDH) level and a favorable cytokine profile, defined as serum day 
      0 monocyte chemoattractant protein-1 (MCP-1) and peak interleukin-7 (IL-7) 
      concentrations above the median, were associated with better PFS. MCP-1 and IL-7 
      concentrations increased after lymphodepletion, and higher intensity of 
      cyclophosphamide and fludarabine lymphodepletion was associated with higher 
      probability of a favorable cytokine profile. PFS was superior in patients who 
      received high-intensity lymphodepletion and achieved a favorable cytokine profile 
      compared with those who received the same intensity of lymphodepletion without 
      achieving a favorable cytokine profile. Even in high-risk patients with 
      pre-lymphodepletion serum LDH levels above normal, a favorable cytokine profile 
      after lymphodepletion was associated with a low risk of a PFS event. Strategies 
      to augment the cytokine response to lymphodepletion could be tested in future 
      studies of CD19 CAR T-cell immunotherapy for aggressive B-cell NHL. This trial 
      was registered at www.clinicaltrials.gov as #NCT01865617.
CI  - (c) 2019 by The American Society of Hematology.
FAU - Hirayama, Alexandre V
AU  - Hirayama AV
AUID- ORCID: 0000-0001-7980-3882
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Gauthier, Jordan
AU  - Gauthier J
AUID- ORCID: 0000-0002-5769-8409
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Hay, Kevin A
AU  - Hay KA
AUID- ORCID: 0000-0002-9398-2677
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
FAU - Voutsinas, Jenna M
AU  - Voutsinas JM
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Wu, Qian
AU  - Wu Q
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Gooley, Ted
AU  - Gooley T
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Li, Daniel
AU  - Li D
AD  - Juno Therapeutics, Seattle, WA; and.
FAU - Cherian, Sindhu
AU  - Cherian S
AD  - Department of Laboratory Medicine and.
FAU - Chen, Xueyan
AU  - Chen X
AD  - Department of Laboratory Medicine and.
FAU - Pender, Barbara S
AU  - Pender BS
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Hawkins, Reed M
AU  - Hawkins RM
AUID- ORCID: 0000-0001-8611-2588
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Vakil, Aesha
AU  - Vakil A
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Steinmetz, Rachel N
AU  - Steinmetz RN
AUID- ORCID: 0000-0001-8847-112X
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
FAU - Acharya, Utkarsh H
AU  - Acharya UH
AUID- ORCID: 0000-0002-5920-2796
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Cassaday, Ryan D
AU  - Cassaday RD
AUID- ORCID: 0000-0002-3424-2425
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Chapuis, Aude G
AU  - Chapuis AG
AUID- ORCID: 0000-0002-9574-5448
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Dhawale, Tejaswini M
AU  - Dhawale TM
AUID- ORCID: 0000-0003-0163-2061
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Hendrie, Paul C
AU  - Hendrie PC
AUID- ORCID: 0000-0003-1902-5972
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Kiem, Hans-Peter
AU  - Kiem HP
AUID- ORCID: 0000-0001-5949-4947
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Lynch, Ryan C
AU  - Lynch RC
AUID- ORCID: 0000-0001-6703-0894
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Ramos, Jorge
AU  - Ramos J
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Shadman, Mazyar
AU  - Shadman M
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Till, Brian G
AU  - Till BG
AUID- ORCID: 0000-0002-4718-8288
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Riddell, Stanley R
AU  - Riddell SR
AUID- ORCID: 0000-0002-4688-9920
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Maloney, David G
AU  - Maloney DG
AUID- ORCID: 0000-0002-8477-6919
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
FAU - Turtle, Cameron J
AU  - Turtle CJ
AUID- ORCID: 0000-0002-4722-4461
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
AD  - Department of Medicine, University of Washington, Seattle, WA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01865617
GR  - P30 CA015704/CA/NCI NIH HHS/United States
GR  - P30 DK056465/DK/NIDDK NIH HHS/United States
GR  - R01 CA136551/CA/NCI NIH HHS/United States
GR  - S10 OD020069/OD/NIH HHS/United States
GR  - U54 DK106829/DK/NIDDK NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190219
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antigens, CD19)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - FA2DM6879K (Vidarabine)
RN  - P2K93U8740 (fludarabine)
SB  - IM
CIN - Blood. 2019 Apr 25;133(17):1799-1800. PMID: 31023743
MH  - Antigens, CD19/*immunology
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Cell- and Tissue-Based Therapy/*methods
MH  - Combined Modality Therapy
MH  - Cyclophosphamide/administration & dosage
MH  - Female
MH  - Follow-Up Studies
MH  - Humans
MH  - Immunotherapy/*methods
MH  - Lymphocyte Depletion/*methods
MH  - Lymphoma, Non-Hodgkin/immunology/*mortality/pathology/therapy
MH  - Male
MH  - Middle Aged
MH  - Prognosis
MH  - Receptors, Antigen, T-Cell/*immunology
MH  - Survival Rate
MH  - Vidarabine/administration & dosage/analogs & derivatives
PMC - PMC6484391
COIS- Conflict-of-interest disclosure: K.A.H. has served on advisory boards for 
      Celgene. D.L. is an employee of and has equity ownership in Juno Therapeutics, a 
      Celgene company. U.H.A. received research funding from Juno Therapeutics, a 
      Celgene company. R.D.C. received research funding from Amgen, Incyte, Kite, a 
      Gilead Company, Merck, Pfizer, and Seattle Genetics; and has served on advisory 
      boards for Amgen, Jazz Pharmaceuticals, and Pfizer. H.-P.K. received research 
      funding from Calimmune and Rocket Pharma; and has served on advisory boards for 
      CSL, Homology, and Rocket Pharma. R.C.L. received research funding from Incyte, 
      Juno Therapeutics, a Celgene company, Rhyzen Pharmaceuticals, Takeda, and TG 
      Therapeutics. J.R. is an employee of and has equity ownership in Seattle 
      Genetics. M.S. received research funding from Acerta Pharma, Beigene, Celgene, 
      Genentech, Gilead Sciences, Mustang Bio, Pharmacyclics, and TG Therapeutics; and 
      has served on advisory boards for AbbVie, AstraZeneca, Genentech, Qilu Puget 
      Sound Biotherapeutics, and Verastem. B.G.T. received research funding from and 
      has patents licensed to Mustang Bio. S.R.R. received research funding from and 
      has patents licensed to Juno Therapeutics, a Celgene company; has equity 
      ownership in Celgene; and has served on advisory boards for Adaptive 
      Biotechnologies, Cell Medica, Juno Therapeutics, a Celgene company, and Nohla 
      Therapeutics. D.G.M. received research funding from GlaxoSmithKline and Juno 
      Therapeutics, a Celgene company. C.J.T. received research funding from Juno 
      Therapeutics, a Celgene company, and Nektar Therapeutics; has patents licensed to 
      Juno Therapeutics, a Celgene company; has served on advisory boards and has 
      equity ownership in Caribou Biosciences, Eureka Therapeutics, and Precision 
      Biosciences; and has served on advisory boards for Aptevo, Juno Therapeutics, a 
      Celgene company, Kite, a Gilead Company, Nektar Therapeutics, and Novartis. The 
      remaining authors declare no competing financial interests.
EDAT- 2019/02/21 06:00
MHDA- 2019/12/28 06:00
PMCR- 2020/04/25
CRDT- 2019/02/21 06:00
PHST- 2018/11/28 00:00 [received]
PHST- 2019/02/12 00:00 [accepted]
PHST- 2019/02/21 06:00 [pubmed]
PHST- 2019/12/28 06:00 [medline]
PHST- 2019/02/21 06:00 [entrez]
PHST- 2020/04/25 00:00 [pmc-release]
AID - S0006-4971(20)42607-2 [pii]
AID - 2019/887067 [pii]
AID - 10.1182/blood-2018-11-887067 [doi]
PST - ppublish
SO  - Blood. 2019 Apr 25;133(17):1876-1887. doi: 10.1182/blood-2018-11-887067. Epub 
      2019 Feb 19.