Abstract

Follicular lymphoma (FL) usually requires multiple lines of therapy, and disease control remains largely insufficient with conventional chemoimmunotherapy. Several T-cell–redirecting strategies recently approved in the relapsed/refractory setting have the potential to improve outcomes and change the treatment algorithm in FL. This review focuses on the role of chimeric antigen receptor T cells and bispecific antibodies in FL, paying special attention to sequencing approaches and future directions.

1.
Alaggio
R
,
Amador
C
,
Anagnostopoulos
I
, et al
.
The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms
.
Leukemia
.
2022
;
36
(
7
):
1720
-
1748
.
2.
Kanas
G
,
Ge
W
,
Quek
RGW
,
Keeven
K
,
Nersesyan
K
,
Arnason
Jon E
.
Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe: population-level projections for 2020-2025
.
Leuk Lymphoma
.
2022
;
63
(
1
):
54
-
63
.
3.
Casulo
C
,
Byrtek
M
,
Dawson
KL
, et al
.
Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study
.
J Clin Oncol
.
2015
;
33
(
23
):
2516
-
2522
.
4.
Link
BK
,
Day
BM
,
Zhou
X
, et al
.
Second-line and subsequent therapy and outcomes for follicular lymphoma in the United States: data from the observational National LymphoCare Study
.
Br J Haematol
.
2019
;
184
(
4
):
660
-
663
.
5.
Batlevi
CL
,
Sha
F
,
Alperovich
A
, et al
.
Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups
.
Blood Cancer J
.
2020
;
10
(
7
):
74
.
6.
Solal-Céligny
P
,
Lepage
E
,
Brousse
N
, et al
.
Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial
.
J Clin Oncol
.
1998
;
16
(
7
):
2332
-
2338
.
7.
Dave
SS
,
Wright
G
,
Tan
B
, et al
.
Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells
.
N Engl J Med
.
2004
;
351
(
21
):
2159
-
2169
.
8.
de Jong
D
,
Koster
A
,
Hagenbeek
A
, et al
.
Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols
.
Haematologica
.
2009
;
94
(
1
):
70
-
77
.
9.
Leonard
JP
,
Trneny
M
,
Izutsu
K
, et al
.
AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma
.
J Clin Oncol
.
2019
;
37
(
14
):
1188
-
1199
.
10.
Morschhauser
F
,
Le Gouill
S
,
Feugier
P
, et al
.
Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study
.
Lancet Haematol
.
2019
;
6
(
8
):
e429
-
e437
.
11.
Lansigan
F
,
Andorsky
DJ
,
Coleman
M
, et al
.
P1156: magnify phase 3B study of lenalidomide + rituximab (R2) followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma: complete induction phase analysis
.
Hemasphere
.
2022
;
6
:
1043
-
1044
.
12.
Morschhauser
F
,
Fowler
NH
,
Feugier
P
, et al
.
Rituximab plus lenalidomide in advanced untreated follicular lymphoma
.
N Engl J Med
.
2018
;
379
(
10
):
934
-
947
.
13.
Morschhauser
F
,
Nastoupil
L
,
Feugier
P
, et al
.
Six-year results from RELEVANCE: lenalidomide plus rituximab
.
J Clin Oncol
.
2022
;
40
(
28
):
3239
-
3245
.
14.
Morschhauser
F
,
Tilly
H
,
Chaidos
A
, et al
.
Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial
.
Lancet Oncol
.
2020
;
21
(
11
):
1433
-
1442
.
15.
Zinzani
PL
,
Mayer
J
,
Flowers
CR
, et al
.
ROSEWOOD: a phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma
.
J Clin Oncol
.
2023
;
41
(
33
):
5107
-
5117
.
16.
Lee
DW
,
Santomasso
BD
,
Locke
FL
, et al
.
ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells
.
Biol Blood Marrow Transplant
.
2019
;
25
(
4
):
625
-
638
.
17.
Santomasso
BD
,
Nastoupil
LJ
,
Adkins
S
, et al
.
Management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy: ASCO guideline
.
J Clin Oncol
.
2021
;
39
(
35
):
3978
-
3992
.
18.
Hayden
PJ
,
Roddie
C
,
Bader
P
, et al
.
Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA)
.
Ann Oncol
.
2022
;
33
(
3
):
259
-
275
.
19.
Cordeiro
A
,
Bezerra
ED
,
Hirayama
AV
, et al
.
Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells
.
Biol Blood Marrow Transplant
.
2020
;
26
(
1
):
26
-
33
.
20.
Rejeski
K
,
Subklewe
M
,
Aljurf
M
, et al
.
Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations
.
Blood
.
2023
;
142
(
10
):
865
-
877
.
21.
Rejeski
K
,
Wang
Y
,
Hansen
DK
, et al
.
Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality
.
Blood Adv
.
2024
;
8
(
8
):
1857
-
1868
.
22.
Cordas Dos Santos
DM
,
Tix
T
,
Shouval
R
, et al
.
A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy
.
Nat Med
.
2024
;
30
(
9
):
2667
-
2678
.
23.
Hamilton
MP
,
Sugio
T
,
Noordenbos
T
, et al
.
Risk of second tumors and T-cell lymphoma after CAR T-cell therapy
.
N Engl J Med
.
2024
;
390
(
22
):
2047
-
2060
.
24.
Tix
T
,
Alhomoud
M
,
Shouval
R
, et al
.
Second primary malignancies after CAR T-cell therapy: a systematic review and meta-analysis of 5,517 lymphoma and myeloma patients
.
Clin Cancer Res
.
2024
;
30
(
20
):
4690
-
4700
.
25.
Jacobson
CA
,
Chavez
JC
,
Sehgal
AR
, et al
.
Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial
.
Lancet Oncol
.
2022
;
23
(
1
):
91
-
103
.
26.
Neelapu
SS
,
Chavez
JC
,
Sehgal
A
, et al
.
Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5)
.
Blood
.
2024
;
143
(
6
):
496
-
506
.
27.
Neelapu
SS
,
Chavez
JC
,
Sehgal
AR
, et al
.
Axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: 4-year follow-up from the phase 2 ZUMA-5 trial [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
4868
.
28.
Fowler
NH
,
Dickinson
M
,
Dreyling
M
, et al
.
Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial
.
Nat Med
.
2022
;
28
(
2
):
325
-
332
.
29.
Dreyling
M
,
Fowler
NH
,
Dickinson
M
, et al
.
Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update
.
Blood
.
2024
;
143
(
17
):
1713
-
1725
.
30.
Morschhauser
F
,
Dahiya
S
,
Palomba
ML
, et al
.
Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study
.
Nat Med
.
2024
;
30
(
8
):
2199
-
2207
.
31.
Meignan
M
,
Cottereau
AS
,
Versari
A
, et al
.
Baseline metabolic tumor volume predicts outcome in high-tumor-burden follicular lymphoma: a pooled analysis of three multicenter studies
.
J Clin Oncol
.
2016
;
34
(
30
):
3618
-
3626
.
32.
Schuster
SJ
,
Bishop
MR
,
Tam
CS
, et al
.
Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma
.
N Engl J Med
.
2019
;
380
(
1
):
45
-
56
.
33.
Vercellino
L
,
Di Blasi
R
,
Kanoun
S
, et al
.
Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma
.
Blood Adv
.
2020
;
4
(
22
):
5607
-
5615
.
34.
Iacoboni
G
,
Simó
M
,
Villacampa
G
, et al
.
Prognostic impact of total metabolic tumor volume in large B-cell lymphoma patients receiving CAR T-cell therapy
.
Ann Hematol
.
2021
;
100
(
9
):
2303
-
2310
.
35.
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
.
36.
Flinn
IW
,
Jacobson
CA
,
Nastoupil
LJ
, et al
.
ZUMA-22: A phase 3, randomized controlled study of axicabtagene ciloleucel (axi-cel) versus standard-of-care therapy in patients with relapsed or refractory (R/R) follicular lymphoma (FL) [abstract]
.
J Clin Oncol
.
2023
;
41
(
suppl 16
):
TPS7579
.
37.
Randomized
A
.
Open-label, multi-center phase III trial comparing tisagenlecleucel to standard of care in adult participants with relapsed or refractory follicular lymphoma (FL) ClinicalTrials.gov identifier: NCT05888493
. Updated 23 October 2023. Accessed 18 September 2024. https://clinicaltrials.gov/study/NCT05888493.
38.
Jacobson
C
,
Hemmer
MT
,
Hu
Z
, et al
.
Real-world early outcomes of axicabtagene ciloleucel for relapsed or refractory (R/R) follicular lymphoma (FL)
.
Hematol Oncol
.
2023
;
41
(
S2
):
375
-
376
.
39.
Ysebaert
L
,
Houot
R
,
Casasnovas
O
, et al
.
Real-word experience of CAR T-cells in patients with relapsed/refractory follicular lymphoma: a Descart registry analysis from the Lysa [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
296
.
40.
Pasquini
MC
,
Hu
ZH
,
Curran
K
, et al
.
Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma
.
Blood Adv
.
2020
;
4
(
21
):
5414
-
5424
.
41.
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
.
42.
Kwon
M
,
Iacoboni
G
,
Reguera
JL
, et al
.
Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma
.
Haematologica
.
2023
;
108
(
1
):
110
-
121
.
43.
Jacobson
CA
,
Locke
FL
,
Ma
L
, et al
.
Real-world evidence of axicabtagene ciloleucel for the treatment of large B cell lymphoma in the United States
.
Transplant Cell Ther
.
2022
;
28
(
9
):
581.e1
-
581.e8
.
44.
Bethge
WA
,
Martus
P
,
Schmitt
M
, et al
.
GLA/DRST real-world outcome analysis of CAR T-cell therapies for large B-cell lymphoma in Germany
.
Blood
.
2022
;
140
(
4
):
349
-
358
.
45.
Blanco
B
,
Domínguez-Alonso
C
,
Alvarez-Vallina
L
.
Bispecific immunomodulatory antibodies for cancer immunotherapy
.
Clin Cancer Res
.
2021
;
27
(
20
):
5457
-
5464
.
46.
Budde
LE
,
Sehn
LH
,
Matasar
M
, et al
.
Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study
.
Lancet Oncol
.
2022
;
23
(
8
):
1055
-
1065
.
47.
Schuster
SJ
,
Sehn
LH
,
Bartlett
NL
, et al
.
Mosunetuzumab monotherapy continues to demonstrate durable responses in patients with relapsed and/or refractory follicular lymphoma after ≥2 prior therapies: 3-year follow-up from a pivotal phase II study [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
603
.
48.
Budde
LE
,
Assouline
S
,
Sehn
LH
, et al
.
Durable responses with mosunetuzumab in relapsed/refractory indolent and aggressive B-cell non-Hodgkin lymphomas: extended follow-up of a phase I/II study
.
J Clin Oncol
.
2024
;
42
(
19
):
2250
-
2256
.
49.
Linton
KM
,
Vitolo
U
,
Jurczak
W
, et al
.
Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study
.
Lancet Haematol
.
2024
;
11
(
8
):
e593
-
e605
.
50.
Kim
TM
,
Taszner
M
,
Novelli
S
, et al
.
Safety and efficacy of odronextamab in patients with relapsed or refractory follicular lymphoma
.
Ann Oncol
.
2024
;
35
(
11
):
1039
-
1047
.
51.
Morschhauser
F
,
Carlo-Stella
C
,
Dickinson
M
, et al
.
Glofitamab as monotherapy and in combination with obinutuzumab induces high complete response rates in patients (pts) with multiple relapsed or refractory (R/R) follicular lymphoma (FL) [abstract]
.
Blood
.
2021
;
138
(
suppl 1
):
128
.
52.
Phase III randomized, open-label, multicenter study evaluating efficacy and safety of mosunetuzumab in combination with lenalidomide in comparison to rituximab in combination with lenalidomide with a non-randomized single arm US extension of mosunetuzumab in combination with lenalidomide in patients with follicular lymphoma after at least one line of systemic therapy. ClinicalTrials.gov identifier: NCT04712097
. Updated 26 October 2021. Accessed 18 September 2024. https://clinicaltrials.gov/study/NCT04712097.
53.
Flinn
IW
,
Budde
LE
,
Tun
AM
, et al
.
Subcutaneous mosunetuzumab is active and has a manageable safety profile in patients with previously untreated, low-tumor burden follicular lymphoma: initial results from the phase II Morningsun study [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
3029
.
54.
Falchi
L
,
Okwali
M
,
Ghione
P
, et al
.
Subcutaneous (SC) mosunetuzumab (mosun) as first-line therapy for patients (pts) with high tumor-burden follicular lymphoma (FL): first results of a multicenter phase 2 study [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
604
.
55.
Lynch
RC
,
Poh
C
,
Shadman
M
, et al
.
Early complete responses with mosunetuzumab monotherapy in treatment-naïve follicular and marginal zone lymphomas with only low-grade cytokine release syndrome [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
4397
.
56.
Reynolds
G
,
Maclean
M
,
Cliff
ERS
, et al
.
Infections in lymphoma patients treated with bispecific antibodies: a systematic review and meta-analysis
.
Blood Adv
.
2024
;
8
(
13
):
3555
-
3559
.
57.
Wang
M
,
Munoz
J
,
Goy
A
, et al
.
Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study
.
J Clin Oncol
.
2022
;
41
(
3
):
555
-
567
.
58.
Wang
Y
,
Jain
P
,
Locke
FL
, et al
.
Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: results From the US Lymphoma CAR T Consortium
.
J Clin Oncol
.
2023
;
41
(
14
):
2594
-
2606
.
59.
Rejeski
K
,
Perez
A
,
Iacoboni
G
, et al
.
The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL
.
J Immunother Cancer
.
2022
;
10
(
5
):
e004475
.
60.
Lemoine
J
,
Bachy
E
,
Cartron
G
, et al
.
Nonrelapse mortality after CAR T-cell therapy for large B-cell lymphoma: a LYSA study from the DESCAR-T registry
.
Blood Adv
.
2023
;
7
(
21
):
6589
-
6598
.
61.
Ghilardi
G
,
Fraietta
JA
,
Gerson
JN
, et al
.
T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy
.
Nat Med
.
2024
;
30
(
4
):
984
-
989
.
62.
Storgard
R
,
Rejeski
K
,
Perales
MA
,
Goldman
A
,
Shouval
R
.
T-cell malignant neoplasms after chimeric antigen receptor T-cell therapy
.
JAMA Oncol
.
2024
;
10
(
6
):
826
-
828
.
63.
Levine
BL
,
Pasquini
MC
,
Connolly
JE
, et al
.
Unanswered questions following reports of secondary malignancies after CAR-T cell therapy
.
Nat Med
.
2024
;
30
(
2
):
338
-
341
.
64.
Harrison
SJ
,
Nguyen
T
,
Rahman
M
, et al
.
CAR+ T-cell lymphoma post ciltacabtagene autoleucel therapy for relapsed refractory multiple myeloma [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
6939
.
65.
Bosch
F
,
Kuruvilla
J
,
Vassilakopoulos
TP
, et al
.
Indirect treatment comparisons of mosunetuzumab with third- and later-line treatments for relapsed/refractory follicular lymphoma
.
Clin Lymphoma Myeloma Leuk
.
2024
;
24
(
2
):
105
-
121
.
66.
Nastoupil
L J
,
Bonner
A
,
Wang
P
, et al
.
Matching-adjusted indirect comparison (MAIC) of efficacy and safety of lisocabtagene maraleucel (liso-cel) and mosunetuzumab for the treatment (Tx) of third line or later (3L+) relapsed or refractory (R/R) follicular lymphoma (FL) [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
2338
.
67.
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
.
68.
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
.
69.
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
.
2022
;
41
(
12
):
2238
-
2247
.
70.
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
.
71.
Schuster
SJ
,
Huw
LY
,
Bolen
CR
, et al
.
Loss of CD20 expression as a mechanism of resistance to mosunetuzumab in relapsed/refractory B-cell lymphomas
.
Blood
.
2024
;
143
(
9
):
822
-
832
.
72.
Maurer
MJ
,
Prochazka
VK
,
Flowers
CR
, et al
.
FLIPI24: an improved international prognostic model developed on early events in follicular lymphoma [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
2292
-
2295
.
73.
Casulo
C
,
Larson
MC
,
Flowers
CR
, et al
.
The FLIPI24 prognostic model identifies poor outcomes in non-immunochemotherapy treated patients with follicular lymphoma [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
1657
.
74.
Morschhauser
F GG
,
Dickinson
M
, et al
. Englumafusp alfa (CD19/4-1BBL) combined with glofitamab is safe and shows high efficacy in patients with R/R aggressive B-NHL: final results of the dose-escalation part of phase 1 trial BP41072.
Madrid, Spain
:
Paper presented at: European Hematology Association Congress
;
13-16 June 2024
.
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