PMID- 38113468
OWN - NLM
STAT- MEDLINE
DCOM- 20240129
LR  - 20240208
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 8
IP  - 3
DP  - 2024 Feb 13
TI  - Bendamustine lymphodepletion before axicabtagene ciloleucel is safe and 
      associates with reduced inflammatory cytokines.
PG  - 653-666
LID - 10.1182/bloodadvances.2023011492 [doi]
AB  - Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell 
      (CART) immunotherapies. In this study, we compared the safety and efficacy of 
      bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before 
      CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for 
      patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We 
      analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively 
      treated with axi-cel at the University of Pennsylvania. We also analyzed serum 
      samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy 
      and Benda demonstrated similar efficacy, with complete remission rates of 51.4% 
      and 50.0% (P = .981), respectively, and similar progression-free and overall 
      survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients 
      receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade 
      neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% 
      of patients (P = .031). In addition, Flu/Cy was associated with a higher 
      incidence of grade >/=3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 
      27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results 
      were confirmed both in patients with LBCL and those with FL. Mechanistically, 
      patients with Flu/Cy had a greater increase in inflammatory cytokines associated 
      with neurotoxicity and reduced levels of metabolites critical for redox balance 
      and biosynthesis. This study suggests that Benda LD may be a safe alternative to 
      Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and 
      reduced toxicities. Benda is associated with reduced levels of inflammatory 
      cytokines and increased anabolic metabolites.
CI  - (c) 2024 by The American Society of Hematology. Licensed under Creative Commons 
      Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), 
      permitting only noncommercial, nonderivative use with attribution. All other 
      rights reserved.
FAU - Ghilardi, Guido
AU  - Ghilardi G
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Paruzzo, Luca
AU  - Paruzzo L
AUID- ORCID: 0000-0002-6505-0194
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
AD  - Department of Oncology, University of Turin, Turin, Italy.
FAU - Svoboda, Jakub
AU  - Svoboda J
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Chong, Eise A
AU  - Chong EA
AUID- ORCID: 0000-0001-8895-1625
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Shestov, Alexander A
AU  - Shestov AA
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, PA.
FAU - Chen, Linhui
AU  - Chen L
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Cohen, Ivan J
AU  - Cohen IJ
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Gabrielli, Giulia
AU  - Gabrielli G
AUID- ORCID: 0000-0002-1162-8712
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
AD  - Department of Molecular Biotechnology and Health Sciences, University of Turin, 
      Turin, Italy.
FAU - Nasta, Sunita D
AU  - Nasta SD
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Porazzi, Patrizia
AU  - Porazzi P
AUID- ORCID: 0000-0002-1372-7482
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Landsburg, Daniel J
AU  - Landsburg DJ
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Gerson, James N
AU  - Gerson JN
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Carter, Jordan
AU  - Carter J
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Barta, Stefan K
AU  - Barta SK
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Yelton, Rebecca
AU  - Yelton R
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Pajarillo, Raymone
AU  - Pajarillo R
AUID- ORCID: 0000-0003-3299-0929
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Patel, Vrutti
AU  - Patel V
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - White, Griffin
AU  - White G
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Ballard, Hatcher J
AU  - Ballard HJ
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Weber, Elizabeth
AU  - Weber E
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Napier, Ellen
AU  - Napier E
AUID- ORCID: 0000-0003-4019-6266
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Chong, Emeline R
AU  - Chong ER
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Fraietta, Joseph A
AU  - Fraietta JA
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
FAU - Garfall, Alfred L
AU  - Garfall AL
AUID- ORCID: 0000-0003-2791-5748
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Porter, David L
AU  - Porter DL
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Milone, Michael C
AU  - Milone MC
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, PA.
FAU - O'Connor, Roderick
AU  - O'Connor R
AUID- ORCID: 0000-0001-5645-4544
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, PA.
FAU - Schuster, Stephen J
AU  - Schuster SJ
AUID- ORCID: 0000-0002-3376-8978
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
FAU - Ruella, Marco
AU  - Ruella M
AUID- ORCID: 0000-0003-4301-5811
AD  - Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, 
      Philadelphia, PA.
AD  - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, 
      PA.
AD  - Division of Hematology-Oncology, Hospital of the University of Pennsylvania, 
      Philadelphia, PA.
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, PA.
LA  - eng
GR  - R01 CA278837/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - U2I8T43Y7R (axicabtagene ciloleucel)
RN  - 981Y8SX18M (Bendamustine Hydrochloride)
RN  - 0 (Cytokines)
RN  - 0 (CD28 Antigens)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - 0 (Biological Products)
SB  - IM
MH  - Humans
MH  - Bendamustine Hydrochloride/adverse effects
MH  - *Cytokines
MH  - CD28 Antigens
MH  - Immunotherapy, Adoptive/adverse effects/methods
MH  - *Lymphoma, Follicular
MH  - Cyclophosphamide
MH  - *Biological Products
PMC - PMC10839610
COIS- Conflict-of-interest dislcoure: G. Ghilardi served as a scientific consultant for 
      viTToria Biotherapeutics. M.R. holds patents related to CD19 CARTs; served as a 
      consultant for NanoString, Bristol Myers Squibb, GlaxoSmithKline, Scaylite, 
      Bayer, and AbClon; receives research funding from AbClon, NanoString, Oxford 
      NanoImaging, viTToria Biotherapeutics, Curiox Biosystems, and Beckman Coulter; 
      and is the scientific founder of viTToria Biotherapeutics. J.S. received research 
      funding from Incyte, Merck, and TG Therapeutics; reports consultancy for, and 
      having received research funding from, Bristol Myers Squibb, Seagen Inc, 
      Pharmacyclics, and AstraZeneca; reports consultancy for ADC Therapeutics, 
      Adaptive, Atara, Genmab, and Imbrium. E.A.C. served as a consultant for Novartis, 
      BeiGene, Kite Pharma, Tessa, and Juno/Bristol Myers Squibb. S.K.B. served as a 
      consultant to Acrotech, Kyowa Kirin, Daiichi Sankyo, and Seagen. S.D.N. received 
      research funding from Pharmacyclics, Roche, Rafael, and FortySeven/Gilead. D.J.L. 
      received research funding from Curis, Takeda, and Triphase; and served on the 
      board of directors, advisory committees, or data and safety monitoring board for 
      Incyte, ADC Therapeutics, Karyopharm, and MorphoSys. S.J.S. served as a 
      consultant to AstraZeneca, BeiGene, Celgene, Genentech, Genmab, Fate 
      Therapeutics, Roche, Incyte, Juno Therapeutics, Legend Biotech, Loxo Oncology, 
      MorphoSys, Mustang Biotech, Nordic Nanovector, Novartis, and Regeneron; received 
      research funding from AbbVie, Adaptive Biotechnologies, Celgene, DTRM Biopharma, 
      Genentech, Roche, Juno Therapeutics, Merck, Novartis, Incyte, Pharmacyclics, and 
      TG Therapeutics; received honoraria from Celgene and Novartis; and holds patents 
      related to CD19 CARTs and autologous costimulated T cells. D.L.P. reports 
      membership on an entity's board of directors or advisory committees for the 
      National Marrow Donor Program; reports membership on an entity's board of 
      directors or advisory committees for Kite/Gilead, Janssen, Incyte, DeCART 
      Therapeutics, American Society of Hematology, and Novartis; reports patents with, 
      and royalties from, Novartis and Tmunity; is a current equity holder in publicly 
      traded company (Genentech), and ended employment in the past 24 months at 
      Genentech; received honoraria from the American Society for Transplantation and 
      Cellular Therapy and Wiley and Sons Publishing; and received research funding 
      from Novartis. A.G. received research support (via institution) from Janssen, 
      Novartis, Tmunity, and CRISPR Therapeutics; reports consultancies for, and 
      honoraria from, Janssen, Novartis, Bristol Myers Squibb, GlaxoSmithKline, and 
      Legend Bio; and reports data and safety monitoring board membership for Janssen, 
      AbbVie, and Regeneron. The remaining authors declare no competing financial 
      interests.
EDAT- 2023/12/19 19:54
MHDA- 2024/01/29 06:43
PMCR- 2023/12/21
CRDT- 2023/12/19 16:32
PHST- 2023/11/27 00:00 [accepted]
PHST- 2023/08/21 00:00 [received]
PHST- 2024/01/29 06:43 [medline]
PHST- 2023/12/19 19:54 [pubmed]
PHST- 2023/12/19 16:32 [entrez]
PHST- 2023/12/21 00:00 [pmc-release]
AID - 506669 [pii]
AID - 10.1182/bloodadvances.2023011492 [doi]
PST - ppublish
SO  - Blood Adv. 2024 Feb 13;8(3):653-666. doi: 10.1182/bloodadvances.2023011492.