The advent of T-cell redirecting strategies, including chimeric antigen receptor T cells and bispecific antibodies, has significantly improved the prognosis of patients with relapsed/refractory large B-cell lymphoma. Current, ongoing clinical trials are exploring their role in earlier treatment lines, rapidly reshaping the treatment landscape of this disease entity. The field has shifted from the concept of transplant-eligible to chimeric antigen receptor T-cell eligible, albeit current trials still consider the former to define the target patient population. Here, we discuss 2 clinical cases to deliberately illustrate this dynamic era of T-cell redirecting strategies, highlighting the main learning points but also presenting the opportunities and open questions to be addressed in the future.

1.
Mounier
N
,
El Gnaoui
T
,
Tilly
H
, et al
.
Rituximab plus gemcitabine and oxaliplatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A phase II Lymphoma Study Association trial
.
Haematologica
.
2013
;
98
(
11
):
1726
-
1731
.
2.
Sehn
LH
,
Hertzberg
M
,
Opat
S
, et al
.
Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data
.
Blood Adv
.
2022
;
6
(
2
):
533
-
543
.
3.
Duell
J
,
Abrisqueta
P
,
Andre
M
, et al
.
Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety findings in the phase II L-MIND study
.
Haematologica
.
2024
;
109
(
2
):
553
-
566
.
4.
Neelapu
SS
,
Jacobson
CA
,
Ghobadi
A
, et al
.
Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma
.
Blood
.
2023
;
141
(
19
):
2307
-
2315
.
5.
Schuster
SJ
,
Tam
CS
,
Borchmann
P
, et al
.
Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study
.
Lancet Oncol
.
2021
;
22
(
10
):
1403
-
1415
.
6.
Abramson
JS
,
Palomba
ML
,
Gordon
LI
, et al
.
Two-year follow-up of lisocabtagene maraleucel in relapsed or refractory large B-cell lymphoma in TRANSCEND NHL 001
.
Blood
.
2024
;
143
(
5
):
404
-
416
.
7.
Westin
JR
,
Oluwole
OO
,
Kersten
MJ
, et al
.
Survival with axicabtagene ciloleucel in large B-cell lymphoma
.
N Engl J Med
.
2023
;
389
(
2
):
148
-
157
.
8.
Abramson
JS
,
Solomon
SR
,
Arnason
J
, et al
.
Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study
.
Blood
.
2023
;
141
(
14
):
1675
-
1684
.
9.
Houot
R
,
Bachy
E
,
Cartron
G
, et al
.
Axicabtagene ciloleucel as second-line therapy in large B cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial
.
Nat Med
.
2023
;
29
(
10
):
2593
-
2601
.
10.
Sehgal
A
,
Hoda
D
,
Riedell
PA
, et al
.
Lisocabtagene maraleucel as second- line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study
.
Lancet Oncol
.
2022
;
23
(
8
):
1066
-
1077
.
11.
Bobillo
MSO
,
Kambhampati
S
,
Lee
D
, et al
.
Real-world (RW) outcomes of lisocabtagene maraleucel (liso-cel) as second-line (2L) therapy in patients (pts) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL): first results from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry
.
Blood
.
2024
;
144
(suppl
1
):
470
.
12.
Bachy
E
,
Le Gouill
S
,
Di Blasi
R
, et al
.
A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma
.
Nat Med
.
2022
;
28
(
10
):
2145
-
2154
.
13.
Dickinson
MJ
,
Carlo-Stella
C
,
Morschhauser
F
, et al
.
Glofitamab for relapsed or refractory diffuse large B-cell lymphoma
.
N Engl J Med
.
2022
;
387
(
24
):
2220
-
2231
.
14.
Thieblemont
C
,
Karimi
YH
,
Ghesquieres
H
, et al
.
Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial
.
Leukemia
.
2024
;
38
(
12
):
2653
-
2662
.
15.
Bannerji
R
,
Arnason
JE
,
Advani
RH
, et al
.
Odronextamab, a human CD20  ×  CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial
.
Lancet Haematol
.
2022
;
9
(
5
):
e327
-
e339
.
16.
Brody
JD
,
Jørgensen
J
,
Belada
D
, et al
.
Epcoritamab plus GemOx in transplant- ineligible relapsed/refractory DLBCL: results from the EPCORE NHL-2 trial
.
Blood
.
2025
;
145
(
15
):
1621
-
1631
.
17.
Maloney
DG
,
Kuruvilla
J
,
Liu
FF
, et al
.
Matching-adjusted indirect treatment comparison of liso-cel versus axi-cel in relapsed or refractory large B cell lymphoma
.
J Hematol Oncol
.
2021
;
14
(
1
):
140
.
18.
Crochet
G
,
Iacoboni
G
,
Couturier
A
, et al
.
Efficacy of CAR T-cell therapy is not impaired by previous bispecific antibody treatment in large B-cell lymphoma
.
Blood
.
2024
;
144
(
3
):
334
-
338
.
19.
Qualls
DA
,
Lambert
N
,
Caimi
PF
, et al
.
Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study
.
Blood
.
2023
;
142
(
26
):
2327
-
2331
.
20.
Iacoboni
G
,
Navarro
V
,
Martín-López
A
, et al
.
Recent bendamustine treatment before apheresis has a negative impact on outcomes in patients with large B-cell lymphoma receiving chimeric antigen receptor T-cell therapy
.
J Clin Oncol
.
2024
;
42
(
2
):
205
-
217
.
21.
Tilly
H
,
Morschhauser
F
,
Sehn
LH
, et al
.
Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma
.
N Engl J Med
.
2022
;
386
(
4
):
351
-
363
.
22.
Iacoboni
G
,
Navarro
V
,
Sesques
P
, et al
.
Development and validation of the post-CAR prognostic index for large B-cell lymphoma patients after CAR-T progression in third or later line treatment
.
J Hematol Oncol
.
2024
;
17
(
1
):
102
.
23.
Shumilov
E
,
Scholz
JK
,
Seib
M
, et al
.
Outcomes of bispecific antibody therapy after CAR T-cell failure in relapsed/refractory large B-cell lymphoma
.
Blood Adv
.
2025
;
9
(
15
):
3955
-
3966
.
24.
Brooks
TR
,
Zabor
EC
,
Bedelu
Y
, et al
.
Real-world outcomes of patients with aggressive B-cell lymphoma treated with epcoritamab or glofitamab [published online 15 July 2025]
.
Blood
.
25.
Stock
S
,
Bücklein
VL
,
Blumenberg
V
, et al
.
Prognostic significance of immune reconstitution following CD19 CAR T-cell therapy for relapsed/refractory B-cell lymphoma
.
Hemasphere
.
2025
;
9
(
1
):
e70062
.
26.
Topp
MS
,
Matasar
M
,
Allan
JN
, et al
.
Odronextamab monotherapy in R/R DLBCL after progression with CAR T-cell therapy: primary analysis of the ELM-1 study
.
Blood
.
2025
;
145
(
14
):
1498
-
1509
.
27.
Cartron
G
,
Houot
R
,
Al Tabaa
Y
, et al
.
Glofitamab in refractory or relapsed diffuse large B cell lymphoma after failing CAR-T cell therapy: a phase 2 LYSA study
.
Nat Cancer
.
2025
;
6
(
7
):
1173
-
1183
.
28.
Hutchings
M
,
Sureda Balari
A
,
Bosch
F
, et al
.
Glofitamab in combination with polatuzumab vedotin maintains durable responses and a manageable safety profile in patients with heavily pre-treated relapsed/refractory (R/R) large B-cell lymphoma (LBCL) including high-grade B-cell lymphoma (HGBCL): extended follow-up of a phase Ib/II study
.
Blood
.
2024
;
144
(suppl
1
):
988
.
29.
Caimi
PF
,
Ai
W
,
Alderuccio
JP
, et al
.
Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open- label, single-arm, phase 2 trial
.
Lancet Oncol
.
2021
;
22
(
6
):
790
-
800
.
30.
Spiegel
JY
,
Dahiya
S
,
Jain
MD
, et al
.
Outcomes of patients with large B-cell lymphoma progressing after axicabtagene ciloleucel therapy
.
Blood
.
2021
;
137
(
13
):
1832
-
1835
.
31.
Zelikson
V
,
Gurumurthi
A
,
Sawalha
Y
, et al
.
Loncastuximab in high-risk and heavily pretreated relapsed/refractory diffuse large B-cell lymphoma: a real-world analysis from 21 US centers
.
Haematologica
.
2025
;
110
(
3
):
706
-
714
.
32.
Camus
V
,
Houot
R
,
Brisou
G
, et al
.
Outcome of patients with large B-cell lymphoma treated with tafasitamab plus lenalidomide either before or after CAR T-cell therapy
.
Blood Adv
.
2024
;
8
(
20
):
5371
-
5381
.
33.
Bartlett
NL
,
Hahn
U
,
Kim
WS
, et al
.
Brentuximab vedotin combination for relapsed diffuse large B-cell lymphoma
.
J Clin Oncol
.
2025
;
43
(
9
):
1061
-
1072
.
34.
Major
A
,
Yu
J
,
Shukla
N
, et al
.
Efficacy of checkpoint inhibition after CAR-T failure in aggressive B-cell lymphomas: outcomes from 15 U.S. institutions
.
Blood Adv
.
2023
;
7
(
16
):
4528
-
4538
.
35.
Gauthier
J
,
Bezerra
ED
,
Hirayama
AV
, et al
.
Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies
.
Blood
.
2021
;
137
(
3
):
323
-
335
.
36.
Chavez
JC
,
Dickinson
M
,
Munoz
J
, et al
.
Three-year follow-up analysis of first-line axicabtagene ciloleucel in high-risk large B-cell lymphoma (ZUMA-12)
.
Blood
.
2025
;
145
(
20
):
2303
-
2311
.
37.
Dickinson
MJ
,
Barba
P
,
Jäger
U
, et al
.
A Novel autologous CAR-T therapy, YTB323, with preserved T-cell stemness shows enhanced CAR T-cell efficacy in preclinical and early clinical development
.
Cancer Discov
.
2023
;
13
(
9
):
1982
-
1997
.
38.
Nabrinsky
E
,
Macklis
J
,
Bitran
J
.
A review of the abscopal effect in the era of immunotherapy
.
Cureus
.
2022
;
14
(
9
):
e29620
.
39.
Grigg
S
,
Minson
A
,
Prins
E
,
Dickinson
MJ
.
Relapse after glofitamab has a poor prognosis and rates of CD20 loss are high
.
Br J Haematol
.
2024
;
205
(
1
):
122
-
126
.
40.
Locke
FL
,
Filosto
S
,
Chou
J
, et al
.
Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma
.
Nat Med
.
2024
;
30
(
2
):
507
-
518
.
41.
Thieblemont
C
,
Phillips
T
,
Ghesquieres
H
, et al
.
Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: dose expansion in a phase I/II Trial
.
J Clin Oncol
.
2023
;
41
(
12
):
2238
-
2247
.
42.
Di Blasi
R
,
Le Gouill
S
,
Bachy
E
, et al
.
Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis
.
Blood
.
2022
;
140
(
24
):
2584
-
2593
.
43.
Zurko
J
,
Nizamuddin
I
,
Epperla
N
, et al
.
Peri-CAR-T practice patterns and survival predictors for all CAR-T patients and post-CAR-T failure in aggressive B-NHL
.
Blood Adv
.
2023
;
7
(
12
):
2657
-
2669
.
44.
Iacoboni
G
,
Iraola-Truchuelo J, O’Reilly M, et al
. Treatment outcomes in patients with large B-cell lymphoma after progression to chimeric antigen receptor T-cell therapy.
Hemasphere
.
2024
;
8
(
5
):
e62
.
You do not currently have access to this content.