Abstract

The introduction of BTK inhibitors and BCL2 antagonists to the treatment of chronic lymphocytic leukemia (CLL) has revolutionized therapy and improved patient outcomes. These agents have replaced chemoimmunotherapy as standard of care. Despite this progress, a new group of patients is currently emerging, which has become refractory or intolerant to both classes of agents, creating an unmet medical need. Here, we propose that the targeted modulation of the tumor microenvironment provides new therapeutic options for this group of double-refractory patients. Furthermore, we outline a sequential strategy for tumor microenvironment-directed combination therapies in CLL that can be tested in clinical protocols.

1.
Eichhorst
B
,
Niemann
CU
,
Kater
AP
, et al
.
First-line venetoclax combinations in chronic lymphocytic leukemia
.
N Engl J Med
.
2023
;
388
(
19
):
1739
-
1754
.
2.
Burger
JA
,
Tedeschi
A
,
Barr
PM
, et al
.
Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia
.
N Engl J Med
.
2015
;
373
(
25
):
2425
-
2437
.
3.
Al-Sawaf
O
,
Zhang
C
,
Tandon
M
, et al
.
Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial
.
Lancet Oncol
.
2020
;
21
(
9
):
1188
-
1200
.
4.
Al-Sawaf
O
,
Zhang
C
,
Lu
T
, et al
.
Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study
.
J Clin Oncol
.
2021
;
39
(
36
):
4049
-
4060
.
5.
Munir
T
,
Cairns
DA
,
Bloor
A
, et al
.
Chronic lymphocytic leukemia therapy guided by measurable residual disease
.
N Engl J Med
.
2024
;
390
(
4
):
326
-
337
.
6.
Hallek
M
,
Al-Sawaf
O
.
Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures
.
Am J Hematol
.
2021
;
96
(
12
):
1679
-
1705
.
7.
Furstenau
M
,
De Silva
N
,
Eichhorst
B
,
Hallek
M
.
Minimal residual disease assessment in CLL: ready for use in clinical routine?
.
Hemasphere
.
2019
;
3
(
5
):
e287
.
8.
Al-Sawaf
O
,
Zhang
C
,
Jin
HY
, et al
.
Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia
.
Nat Commun
.
2023
;
14
(
1
):
2147
.
9.
Seymour
JF
,
Kipps
TJ
,
Eichhorst
BF
, et al
.
Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab
.
Blood
.
2022
;
140
(
8
):
839
-
850
.
10.
Thompson
MC
,
Harrup
RA
,
Coombs
CC
, et al
.
Venetoclax retreatment of patients with chronic lymphocytic leukemia after a previous venetoclax-based regimen
.
Blood Adv
.
2022
;
6
(
15
):
4553
-
4557
.
11.
Aronson
JH
,
Skånland
SS
,
Roeker
LE
,
Thompson
MC
,
Mato
AR
.
Approach to a patient with “double refractory” chronic lymphocytic leukemia: “double, double toil and trouble” (Shakespeare)
.
Am J Hematol
.
2022
;
97
(
suppl 2
):
S19
-
S25
.
12.
Kater
AP
,
Owen
C
,
Moreno
C
, et al
.
Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities
.
NEJM Evid
.
2022
;
1
(
7
):
EVIDoa2200006
.
13.
Tam
CS
,
Allan
JN
,
Siddiqi
T
, et al
.
Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort
.
Blood
.
2022
;
139
(
22
):
3278
-
3289
.
14.
Huber
H
,
Tausch
E
,
Schneider
C
, et al
.
Final analysis of the CLL2-GIVe trial: obinutuzumab, ibrutinib, and venetoclax for untreated CLL with del(17p)/TP53mut
.
Blood
.
2023
;
142
(
11
):
961
-
972
.
15.
Lew
TE
,
Lin
VS
,
Cliff
ER
, et al
.
Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition
.
Blood Adv
.
2021
;
5
(
20
):
4054
-
4058
.
16.
Hampel
PJ
,
Rabe
KG
,
Call
TG
, et al
.
Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia
.
Br J Haematol
.
2022
;
199
(
2
):
239
-
244
.
17.
Samples
L
,
Ujjani
CS
,
Khajaviyan
S
, et al
.
Clinical outcomes in patients treated with both covalent Btkis and venetoclax and the significance of “double-refractory” status in patients with CLL/SLL
.
Blood
.
2023
;
142
(
suppl1
):
4650
.
18.
Hyak
JM
,
Huang
Y
,
Rogers
KA
, et al
.
Combined BCL2 and BTK inhibition in CLL demonstrates efficacy after monotherapy with both classes
.
Blood Adv
.
2022
;
6
(
17
):
5124
-
5127
.
19.
Byrd
JC
,
Hillmen
P
,
Ghia
P
, et al
.
Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial
.
J Clin Oncol
.
2021
;
39
(
31
):
3441
-
3452
.
20.
Awan
FT
,
Schuh
A
,
Brown
JR
, et al
.
Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib
.
Blood Adv
.
2019
;
3
(
9
):
1553
-
1562
.
21.
DiPippo
AJ
,
McGhie
A
,
Lee
J
, et al
.
Tolerability of acalabrutinib after prior ibrutinib treatment in patients with CLL: experience of a Tertiary Cancer Care Center
.
Blood
.
2022
;
140
(
suppl 1
):
4153
-
4155
.
22.
Brown
JR
,
Eichhorst
B
,
Hillmen
P
, et al
.
Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia
.
N Engl J Med
.
2023
;
388
(
4
):
319
-
332
.
23.
Hallek
M
,
Fischer
K
,
Fingerle-Rowson
G
, et al
.
Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial
.
Lancet
.
2010
;
376
(
9747
):
1164
-
1174
.
24.
Fischer
K
,
Cramer
P
,
Busch
R
, et al
.
Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group
.
J Clin Oncol
.
2012
;
30
(
26
):
3209
-
3216
.
25.
Mato
AR
,
Roeker
LE
,
Jacobs
R
, et al
.
Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy
.
Clin Cancer Res
.
2020
;
26
(
14
):
3589
-
3596
.
26.
Furman
RR
,
Sharman
JP
,
Coutre
SE
, et al
.
Idelalisib and rituximab in relapsed chronic lymphocytic leukemia
.
N Engl J Med
.
2014
;
370
(
11
):
997
-
1007
.
27.
Flinn
IW
,
Hillmen
P
,
Montillo
M
, et al
.
The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL
.
Blood
.
2018
;
132
(
23
):
2446
-
2455
.
28.
Hanlon
A
,
Brander
DM
.
Managing toxicities of phosphatidylinositol-3-kinase (PI3K) inhibitors
.
Hematology
.
2020
;
2020
(
1
):
346
-
356
.
29.
Woyach
JA
,
Ruppert
AS
,
Guinn
D
, et al
.
BTK(C481S)-mediated resistance to ibrutinib in chronic lymphocytic leukemia
.
J Clin Oncol
.
2017
;
35
(
13
):
1437
-
1443
.
30.
Woyach
JA
,
Furman
RR
,
Liu
T-M
, et al
.
Resistance mechanisms for the bruton's tyrosine kinase inhibitor ibrutinib
.
N Engl J Med
.
2014
;
370
(
24
):
2286
-
2294
.
31.
Mato
AR
,
Woyach
JA
,
Brown
JR
, et al
.
Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia
.
N Engl J Med
.
2023
;
389
(
1
):
33
-
44
.
32.
Wang
E
,
Mi
X
,
Thompson
MC
, et al
.
Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors
.
N Engl J Med
.
2022
;
386
(
8
):
735
-
743
.
33.
Dobrovolsky
D
,
Wang
ES
,
Morrow
S
, et al
.
Bruton tyrosine kinase degradation as a therapeutic strategy for cancer
.
Blood
.
2019
;
133
(
9
):
952
-
961
.
34.
Mato
AR
,
Wierda
WG
,
Ai
WZ
, et al
.
NX-2127-001, a first-in-human trial of NX-2127, a Bruton's tyrosine kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies
.
Blood
.
2022
;
140
(
suppl 1
):
2329
-
2332
.
35.
Thijssen
R
,
Tian
L
,
Anderson
MA
, et al
.
Single-cell multiomics reveal the scale of multilayered adaptations enabling CLL relapse during venetoclax therapy
.
Blood
.
2022
;
140
(
20
):
2127
-
2141
.
36.
Thomalla
D
,
Beckmann
L
,
Grimm
C
, et al
.
Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies
.
Blood
.
2022
;
140
(
20
):
2113
-
2126
.
37.
Jayappa
KD
,
Gordon
VL
,
Morris
CG
, et al
.
Extrinsic interactions in the microenvironment in vivo activate an antiapoptotic multidrug-resistant phenotype in CLL
.
Blood Adv
.
2021
;
5
(
17
):
3497
-
3510
.
38.
Jayappa
KD
,
Portell
CA
,
Gordon
VL
, et al
.
Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL
.
Blood Adv
.
2017
;
1
(
14
):
933
-
946
.
39.
Park
E
,
Chen
J
,
Moore
A
, et al
.
Stromal cell protein kinase C-beta inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance
.
Sci Transl Med
.
2020
;
12
(
526
):
eaax9340
.
40.
Hormi
M
,
Birsen
R
,
Belhadj
M
, et al
.
Pairing MCL-1 inhibition with venetoclax improves therapeutic efficiency of BH3-mimetics in AML
.
Eur J Haematol
.
2020
;
105
(
5
):
588
-
596
.
41.
Roberts
AW
,
Wei
AH
,
Huang
DCS
.
BCL2 and MCL1 inhibitors for hematologic malignancies
.
Blood
.
2021
;
138
(
13
):
1120
-
1136
.
42.
de Vos
S
,
Leonard
JP
,
Friedberg
JW
, et al
.
Safety and efficacy of navitoclax, a BCL-2 and BCL-X(L) inhibitor, in patients with relapsed or refractory lymphoid malignancies: results from a phase 2a study
.
Leuk Lymphoma
.
2021
;
62
(
4
):
810
-
818
.
43.
Kipps
TJ
.
ROR1: an orphan becomes apparent
.
Blood
.
2022
;
140
(
14
):
1583
-
1591
.
44.
Ghia
EM
,
Rassenti
LZ
,
Choi
MY
, et al
.
High expression level of ROR1 and ROR1-signaling associates with venetoclax resistance in chronic lymphocytic leukemia
.
Leukemia
.
2022
;
36
(
6
):
1609
-
1618
.
45.
Cui
B
,
Ghia
EM
,
Chen
L
, et al
.
High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia
.
Blood
.
2016
;
128
(
25
):
2931
-
2940
.
46.
Lee
HJ
,
Choi
MY
,
Siddiqi
T
, et al
.
Phase 1/2 study of zilovertamab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL)
.
J Clin Oncol
.
2022
;
40
(
16 suppl
):
7520
.
47.
Townsend
W
,
Leong
S
,
Shah
M
, et al
.
Time limited exposure to a ROR1 targeting bispecific T cell engager (NVG-111) leads to durable responses in subjects with relapsed refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL)
.
Blood
.
2023
;
142
(
suppl 1
):
329
.
48.
Vom Stein
AF
,
Hallek
M
,
Nguyen
PH
.
Role of the tumor microenvironment in CLL pathogenesis
.
Semin Hematol
.
2024
;
61
(
3
):
142
-
154
.
49.
Vlachonikola
E
,
Stamatopoulos
K
,
Chatzidimitriou
A
.
T cells in chronic lymphocytic leukemia: a two-edged sword
.
Front Immunol
.
2020
;
11
:
612244
.
50.
Purroy
N
,
Tong
YE
,
Lemvigh
CK
, et al
.
Single-cell analysis reveals immune dysfunction from the earliest stages of CLL that can be reversed by ibrutinib
.
Blood
.
2022
;
139
(
14
):
2252
-
2256
.
51.
Riches
JC
,
Davies
JK
,
McClanahan
F
, et al
.
T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production
.
Blood
.
2013
;
121
(
9
):
1612
-
1621
.
52.
Qorraj
M
,
Bruns
H
,
Böttcher
M
, et al
.
The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia
.
Leukemia
.
2017
;
31
(
2
):
470
-
478
.
53.
Carlino
MS
,
Larkin
J
,
Long
GV
.
Immune checkpoint inhibitors in melanoma
.
Lancet
.
2021
;
398
(
10304
):
1002
-
1014
.
54.
Reck
M
,
Rodríguez-Abreu
D
,
Robinson
AG
, et al
.
Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer
.
N Engl J Med
.
2016
;
375
(
19
):
1823
-
1833
.
55.
McClanahan
F
,
Hanna
B
,
Miller
S
, et al
.
PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia
.
Blood
.
2015
;
126
(
2
):
203
-
211
.
56.
Ding
W
,
LaPlant
BR
,
Call
TG
, et al
.
Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL
.
Blood
.
2017
;
129
(
26
):
3419
-
3427
.
57.
Goedhart
NB
,
Simon-Molas
H
,
Montironi
C
, et al
.
Multifactorial basis of T cell dysfunction in CLL: disrupted mitochondrial metabolism induces T cell senescence
.
Blood
.
2023
;
142
(
suppl 1
):
4629
.
58.
Martens
AWJ
,
Kavazovic
I
,
Krapic
M
, et al
.
Chronic lymphocytic leukemia presence impairs antigen-specific CD8(+) T-cell responses through epigenetic reprogramming towards short-lived effectors
.
Leukemia
.
2023
;
37
(
3
):
606
-
616
.
59.
van Bruggen
JAC
,
Martens
AWJ
,
Fraietta
JA
, et al
.
Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy
.
Blood
.
2019
;
134
(
1
):
44
-
58
.
60.
Fraietta
JA
,
Lacey
SF
,
Orlando
EJ
, et al
.
Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia
.
Nat Med
.
2018
;
24
(
5
):
563
-
571
.
61.
Montironi
C
,
Jacobs
CF
,
Cretenet
G
, et al
.
T-cell dysfunction by pseudohypoxia and autocrine purinergic signaling in chronic lymphocytic leukemia
.
Blood Adv
.
2023
;
7
(
21
):
6540
-
6552
.
62.
Hanna
BS
,
Yazdanparast
H
,
Demerdash
Y
, et al
.
Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice
.
Haematologica
.
2021
;
106
(
4
):
968
-
977
.
63.
Younes
A
,
Brody
J
,
Carpio
C
, et al
.
Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study
.
Lancet Haematol
.
2019
;
6
(
2
):
e67
-
e78
.
64.
Jain
N
,
Senapati
J
,
Thakral
B
, et al
.
A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL
.
Blood Adv
.
2023
;
7
(
10
):
1958
-
1966
.
65.
Al-Sawaf
O
,
Ligtvoet
R
,
Robrecht
S
, et al
.
Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial
.
Nat Med
.
2024
;
30
(
1
):
240
-
248
.
66.
Li
J
,
Xu
J
,
Li
Z
.
Obatoclax, the pan-Bcl-2 inhibitor sensitizes hepatocellular carcinoma cells to promote the anti-tumor efficacy in combination with immune checkpoint blockade
.
Transl Oncol
.
2021
;
14
(
8
):
101116
.
67.
Kohlhapp
FJ
,
Haribhai
D
,
Mathew
R
, et al
.
Venetoclax increases intratumoral effector T cells and antitumor efficacy in combination with immune checkpoint blockade
.
Cancer Discov
.
2021
;
11
(
1
):
68
-
79
.
68.
Jain
N
,
Ferrajoli
A
,
Yilmaz
M
, et al
.
Venetoclax, obinutuzumab and atezolizumab (PD-L1 checkpoint inhibitor) for first-line treatment for patients with chronic lymphocytic leukemia (CLL)
.
Blood
.
2021
;
138
(
suppl 1
):
2626
.
69.
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
.
70.
Hutchings
M
,
Mous
R
,
Clausen
MR
, et al
.
Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study
.
Lancet
.
2021
;
398
(
10306
):
1157
-
1169
.
71.
Robinson
HR
,
Qi
J
,
Cook
EM
, et al
.
A CD19/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era
.
Blood
.
2018
;
132
(
5
):
521
-
532
.
72.
Kater
AP
,
Ye
JC
,
Sandoval-Sus
J
, et al
.
Subcutaneous epcoritamab in patients with Richter's syndrome: early results from phase 1b/2 trial (EPCORE CLL-1)
.
Blood
.
2022
;
140
(
suppl 1
):
850
-
851
.
73.
Kater
A
,
Eradat
H
,
Niemann
C
, et al
. Epcoritamab in patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 1b/2 EPCORE CLL-1 Trial Expansion Cohort - Abstract 1546171. Paper presented at: 2023 International Workshop on CLL.
6-9 October 2023
. Boston, MA.
74.
Mhibik
M
,
Gaglione
EM
,
Eik
D
, et al
.
Cytotoxicity of the CD3xCD20 bispecific antibody epcoritamab in CLL is increased by concurrent BTK or BCL-2 targeting
.
Blood Adv
.
2023
;
7
(
15
):
4089
-
4101
.
75.
Melenhorst
JJ
,
Chen
GM
,
Wang
M
, et al
.
Decade-long leukaemia remissions with persistence of CD4(+) CAR T cells
.
Nature
.
2022
;
602
(
7897
):
503
-
509
.
76.
Todorovic
Z
,
Todorovic
D
,
Markovic
V
, et al
.
CAR T cell therapy for chronic lymphocytic leukemia: successes and shortcomings
.
Curr Oncol
.
2022
;
29
(
5
):
3647
-
3657
.
77.
Funk
CR
,
Wang
S
,
Chen
KZ
, et al
.
PI3Kdelta/gamma inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity
.
Blood
.
2022
;
139
(
4
):
523
-
537
.
78.
Gauthier
J
,
Hirayama
AV
,
Purushe
J
, et al
.
Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure
.
Blood
.
2020
;
135
(
19
):
1650
-
1660
.
79.
Gill
S
,
Vides
V
,
Frey
NV
, et al
.
Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia
.
Blood Adv
.
2022
;
6
(
21
):
5774
-
5785
.
80.
Liu
M
,
Deng
H
,
Mu
J
, et al
.
Ibrutinib improves the efficacy of anti-CD19-CAR T-cell therapy in patients with refractory non-Hodgkin lymphoma
.
Cancer Sci
.
2021
;
112
(
7
):
2642
-
2651
.
81.
Fraietta
JA
,
Beckwith
KA
,
Patel
PR
, et al
.
Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia
.
Blood
.
2016
;
127
(
9
):
1117
-
1127
.
82.
Zhou
J
,
Tang
Z
,
Gao
S
,
Li
C
,
Feng
Y
,
Zhou
X
.
Tumor-associated macrophages: recent insights and therapies
.
Front Oncol
.
2020
;
10
:
188
.
83.
Fiorcari
S
,
Maffei
R
,
Atene
CG
,
Potenza
L
,
Luppi
M
,
Marasca
R
.
Nurse-like cells and chronic lymphocytic leukemia B cells: a mutualistic crosstalk inside tissue microenvironments
.
Cells
.
2021
;
10
(
2
):
217
.
84.
Burger
JA
,
Tsukada
N
,
Burger
M
,
Zvaifler
NJ
,
Dell'Aquila
M
,
Kipps
TJ
.
Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell–derived factor-1
.
Blood
.
2000
;
96
(
8
):
2655
-
2663
.
85.
Tsukada
N
,
Burger
JA
,
Zvaifler
NJ
,
Kipps
TJ
.
Distinctive features of “nurselike” cells that differentiate in the context of chronic lymphocytic leukemia
.
Blood
.
2002
;
99
(
3
):
1030
-
1037
.
86.
Nishio
M
,
Endo
T
,
Tsukada
N
, et al
.
Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1α
.
Blood
.
2005
;
106
(
3
):
1012
-
1020
.
87.
Boissard
F
,
Laurent
C
,
Ramsay
AG
, et al
.
Nurse-like cells impact on disease progression in chronic lymphocytic leukemia
.
Blood Cancer J
.
2016
;
6
(
1
):
e381
.
88.
Jia
L
,
Clear
A
,
Liu
F-T
, et al
.
Extracellular HMGB1 promotes differentiation of nurse-like cells in chronic lymphocytic leukemia
.
Blood
.
2014
;
123
(
11
):
1709
-
1719
.
89.
Hanna
BS
,
McClanahan
F
,
Yazdanparast
H
, et al
.
Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo
.
Leukemia
.
2016
;
30
(
3
):
570
-
579
.
90.
Galletti
G
,
Scielzo
C
,
Barbaglio
F
, et al
.
Targeting macrophages sensitizes chronic lymphocytic leukemia to apoptosis and inhibits disease progression
.
Cell Rep
.
2016
;
14
(
7
):
1748
-
1760
.
91.
Ravichandran
KS
.
Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums
.
J Exp Med
.
2010
;
207
(
9
):
1807
-
1817
.
92.
Montalvao
F
,
Garcia
Z
,
Celli
S
, et al
.
The mechanism of anti-CD20-mediated B cell depletion revealed by intravital imaging
.
J Clin Invest
.
2013
;
123
(
12
):
5098
-
5103
.
93.
Gul
N
,
Babes
L
,
Siegmund
K
, et al
.
Macrophages eliminate circulating tumor cells after monoclonal antibody therapy
.
J Clin Invest
.
2014
;
124
(
2
):
812
-
823
.
94.
Chao
MP
,
Alizadeh
AA
,
Tang
C
, et al
.
Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma
.
Cell
.
2010
;
142
(
5
):
699
-
713
.
95.
Willingham
SB
,
Volkmer
JP
,
Gentles
AJ
, et al
.
The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors
.
Proc Natl Acad Sci U S A
.
2012
;
109
(
17
):
6662
-
6667
.
96.
Ansell
SM
,
Maris
MB
,
Lesokhin
AM
, et al
.
Phase I study of the CD47 blocker TTI-621 in patients with relapsed or refractory hematologic malignancies
.
Clin Cancer Res
.
2021
;
27
(
8
):
2190
-
2199
.
97.
Daver
NG
,
Vyas
P
,
Kambhampati
S
, et al
.
Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in frontline TP53m AML patients: phase 1b results
.
J Clin Oncol
.
2022
;
40
(
16 suppl
):
7020
.
98.
Chauchet
X
,
Cons
L
,
Chatel
L
, et al
.
CD47xCD19 bispecific antibody triggers recruitment and activation of innate immune effector cells in a B-cell lymphoma xenograft model
.
Exp Hematol Oncol
.
2022
;
11
(
1
):
26
.
99.
Valentin
R
,
Peluso
MO
,
Lehmberg
TZ
, et al
.
The fully human anti-CD47 antibody SRF231 has dual-mechanism antitumor activity against chronic lymphocytic leukemia (CLL) cells and increases the activity of both rituximab and venetoclax
.
Blood
.
2018
;
132
(
suppl 1
):
4393
.
100.
Zeller
T
,
Lutz
S
,
Munnich
IA
, et al
.
Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages
.
Front Immunol
.
2022
;
13
:
929339
.
101.
Hartley
GP
,
Chow
L
,
Ammons
DT
,
Wheat
WH
,
Dow
SW
.
Programmed cell death ligand 1 (PD-L1) signaling regulates macrophage proliferation and activation
.
Cancer Immunol Res
.
2018
;
6
(
10
):
1260
-
1273
.
102.
Wang
J
,
Sun
Y
,
Chu
Q
, et al
.
Phase I study of IBI322 (anti-CD47/PD-L1 bispecific antibody) monotherapy therapy in patients with advanced solid tumors in China
. Abstract CT513.
Cancer Res
.
2022
;
82
(
12 suppl
).
103.
Wang
Y
,
Ni
H
,
Zhou
S
, et al
.
Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity
.
Cancer Immunol Immunother
.
2021
;
70
(
2
):
365
-
376
.
104.
Sportoletti
P
,
De Falco
F
,
Del Papa
B
, et al
.
NK cells in chronic lymphocytic leukemia and their therapeutic implications
.
Int J Mol Sci
.
2021
;
22
(
13
):
6665
.
105.
Parry
HM
,
Stevens
T
,
Oldreive
C
, et al
.
NK cell function is markedly impaired in patients with chronic lymphocytic leukaemia but is preserved in patients with small lymphocytic lymphoma
.
Oncotarget
.
2016
;
7
(
42
):
68513
-
68526
.
106.
Lotz
M
,
Ranheim
E
,
Kipps
TJ
.
Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells
.
J Exp Med
.
1994
;
179
(
3
):
999
-
1004
.
107.
Wagner
B
,
da Silva Nardi
F
,
Schramm
S
, et al
.
HLA-E allelic genotype correlates with HLA-E plasma levels and predicts early progression in chronic lymphocytic leukemia
.
Cancer
.
2017
;
123
(
5
):
814
-
823
.
108.
Maki
G
,
Hayes
GM
,
Naji
A
, et al
.
NK resistance of tumor cells from multiple myeloma and chronic lymphocytic leukemia patients: implication of HLA-G
.
Leukemia
.
2008
;
22
(
5
):
998
-
1006
.
109.
McWilliams
EM
,
Mele
JM
,
Cheney
C
, et al
.
Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia
.
Oncoimmunology
.
2016
;
5
(
10
):
e1226720
.
110.
Hofland
T
,
Endstra
S
,
Gomes
CKP
, et al
.
Natural killer cell hypo-responsiveness in chronic lymphocytic leukemia can be circumvented in vitro by adequate activating signaling
.
Hemasphere
.
2019
;
3
(
6
):
e308
.
111.
Deuse
T
,
Hu
X
,
Agbor-Enoh
S
, et al
.
The SIRPα–CD47 immune checkpoint in NK cells
.
J Exp Med
.
2021
;
218
(
3
):
e20200839
.
112.
Xie
G
,
Dong
H
,
Liang
Y
,
Ham
JD
,
Rizwan
R
,
Chen
J
.
CAR-NK cells: a promising cellular immunotherapy for cancer
.
EBioMedicine
.
2020
;
59
:
102975
.
113.
Liu
E
,
Marin
D
,
Banerjee
P
, et al
.
Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors
.
N Engl J Med
.
2020
;
382
(
6
):
545
-
553
.
114.
Bachanova
V
,
Ghobadi
A
,
Patel
K
, et al
.
Safety and efficacy of FT596, a first-in-class, multi-antigen targeted, off-the-shelf, iPSC-derived CD19 CAR NK cell therapy in relapsed/refractory B-cell lymphoma
.
Blood
.
2021
;
138
(
suppl 1
):
823
.
115.
Pinto
S
,
Pahl
J
,
Schottelius
A
,
Carter
PJ
,
Koch
J
.
Reimagining antibody-dependent cellular cytotoxicity in cancer: the potential of natural killer cell engagers
.
Trends Immunol
.
2022
;
43
(
11
):
932
-
946
.
116.
Gleason
MK
,
Verneris
MR
,
Todhunter
DA
, et al
.
Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production
.
Mol Cancer Ther
.
2012
;
11
(
12
):
2674
-
2684
.
117.
Dubois
N
,
Crompot
E
,
Meuleman
N
,
Bron
D
,
Lagneaux
L
,
Stamatopoulos
B
.
Importance of crosstalk between chronic lymphocytic leukemia cells and the stromal microenvironment: direct contact, soluble factors, and extracellular vesicles
.
Front Oncol
.
2020
;
10
:
1422
.
118.
Heinig
K
,
Gatjen
M
,
Grau
M
, et al
.
Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B-cell activation and proliferation
.
Cancer Discov
.
2014
;
4
(
12
):
1448
-
1465
.
119.
Lutzny
G
,
Kocher
T
,
Schmidt-Supprian
M
, et al
.
Protein kinase c-beta-dependent activation of NF-kappaB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo
.
Cancer Cell
.
2013
;
23
(
1
):
77
-
92
.
120.
Paggetti
J
,
Haderk
F
,
Seiffert
M
, et al
.
Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts
.
Blood
.
2015
;
126
(
9
):
1106
-
1117
.
121.
Böttcher
M
,
Bruns
H
,
Völkl
S
, et al
.
Control of PD-L1 expression in CLL-cells by stromal triggering of the Notch-c-Myc-EZH2 oncogenic signaling axis
.
J Immunother Cancer
.
2021
;
9
(
4
):
e001889
.
122.
vom Stein
AF
,
Rebollido-Rios
R
,
Lukas
A
, et al
.
LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1
.
Nat Commun
.
2023
;
14
(
1
):
1330
.
123.
Sakemura
R
,
Hefazi
M
,
Siegler
EL
, et al
.
Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma
.
Blood
.
2022
;
139
(
26
):
3708
-
3721
.
124.
Tauriello
DVF
,
Palomo-Ponce
S
,
Stork
D
, et al
.
TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
.
Nature
.
2018
;
554
(
7693
):
538
-
543
.
125.
Metropulos
AE
,
Munshi
HG
,
Principe
DR
.
The difficulty in translating the preclinical success of combined TGFbeta and immune checkpoint inhibition to clinical trial
.
EBioMedicine
.
2022
;
86
:
104380
.
126.
Ten Hacken
E
,
Burger
JA
.
Microenvironment interactions and B-cell receptor signaling in chronic lymphocytic leukemia: implications for disease pathogenesis and treatment
.
Biochim Biophys Acta
.
2016
;
1863
(
3
):
401
-
413
.
127.
Parvin
S
,
Aryal
A
,
Yin
S
, et al
.
Targeting conditioned media dependencies and FLT-3 in chronic lymphocytic leukemia
.
Blood Adv
.
2023
;
7
(
19
):
5877
-
5889
.
128.
McWilliams
EM
,
Lucas
CR
,
Chen
T
, et al
.
Anti-BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib
.
Blood Adv
.
2019
;
3
(
3
):
447
-
460
.
129.
Andritsos
LA
,
Byrd
JC
,
Cheverton
P
, et al
.
A multicenter phase 1 study of plerixafor and rituximab in patients with chronic lymphocytic leukemia
.
Leuk Lymphoma
.
2019
;
60
(
14
):
3461
-
3469
.
130.
Tandler
C
,
Schmidt
M
,
Heitmann
JS
, et al
.
Neutralization of B-cell activating factor (BAFF) by belimumab reinforces small molecule inhibitor treatment in chronic lymphocytic leukemia
.
Cancers (Basel)
.
2020
;
12
(
10
):
2725
.
131.
Svanberg
R
,
Janum
S
,
Patten
PEM
,
Ramsay
AG
,
Niemann
CU
.
Targeting the tumor microenvironment in chronic lymphocytic leukemia
.
Haematologica
.
2021
;
106
(
9
):
2312
-
2324
.
132.
Nguyen
P-H
,
Niesen
E
,
Hallek
M
.
New roles for B cell receptor associated kinases: when the B cell is not the target
.
Leukemia
.
2019
;
33
(
3
):
576
-
587
.
133.
Dubovsky
JA
,
Beckwith
KA
,
Natarajan
G
, et al
.
Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes
.
Blood
.
2013
;
122
(
15
):
2539
-
2549
.
134.
Palma
M
,
Mulder
TA
,
Osterborg
A
.
BTK inhibitors in chronic lymphocytic leukemia: biological activity and immune effects
.
Front Immunol
.
2021
;
12
:
686768
.
135.
Mhibik
M
,
Wiestner
A
,
Sun
C
.
Harnessing the effects of BTKi on T cells for effective immunotherapy against CLL
.
Int J Mol Sci
.
2019
;
21
(
1
):
68
.
136.
Zou
Y-X
,
Zhu
H-Y
,
Li
X-T
, et al
.
The impacts of zanubrutinib on immune cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma
.
Hematol Oncol
.
2019
;
37
(
4
):
392
-
400
.
137.
de Weerdt
I
,
Hofland
T
,
Lameris
R
, et al
.
Improving CLL Vgamma9Vdelta2-T-cell fitness for cellular therapy by ex vivo activation and ibrutinib
.
Blood
.
2018
;
132
(
21
):
2260
-
2272
.
138.
Mhibik
M
,
Gaglione
EM
,
Eik
D
, et al
.
BTK inhibitors, irrespective of ITK inhibition, increase efficacy of a CD19/CD3-bispecific antibody in CLL
.
Blood
.
2021
;
138
(
19
):
1843
-
1854
.
139.
Kaneda
MM
,
Messer
KS
,
Ralainirina
N
, et al
.
PI3Kγ is a molecular switch that controls immune suppression
.
Nature
.
2016
;
539
(
7629
):
437
-
442
.
140.
De Henau
O
,
Rausch
M
,
Winkler
D
, et al
.
Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells
.
Nature
.
2016
;
539
(
7629
):
443
-
447
.
141.
Isoyama
S
,
Mori
S
,
Sugiyama
D
, et al
.
Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal
.
J Immunother Cancer
.
2021
;
9
(
8
):
e002279
.
142.
Contri
A
,
Brunati
AM
,
Trentin
L
, et al
.
Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis
.
J Clin Invest
.
2005
;
115
(
2
):
369
-
378
.
143.
Kater
AP
,
Spiering
M
,
Liu
RD
, et al
.
Dasatinib in combination with fludarabine in patients with refractory chronic lymphocytic leukemia: a multicenter phase 2 study
.
Leuk Res
.
2014
;
38
(
1
):
34
-
41
.
144.
Amrein
PC
,
Attar
EC
,
Takvorian
T
, et al
.
Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia
.
Clin Cancer Res
.
2011
;
17
(
9
):
2977
-
2986
.
145.
Kadia
T
,
Delioukina
ML
,
Kantarjian
HM
, et al
.
A pilot phase II study of the Lyn kinase inhibitor bafetinib in patients with relapsed or refractory B cell chronic lymphocytic leukemia
.
Blood
.
2011
;
118
(
21
):
2858
.
146.
Nguyen
PH
,
Fedorchenko
O
,
Rosen
N
, et al
.
LYN kinase in the tumor microenvironment is essential for the progression of chronic lymphocytic leukemia
.
Cancer Cell
.
2016
;
30
(
4
):
610
-
622
.
147.
Thijssen
R
,
Slinger
E
,
Weller
K
, et al
.
Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors
.
Haematologica
.
2015
;
100
(
8
):
e302
-
e306
.
148.
Hallaert
DY
,
Jaspers
A
,
van Noesel
CJ
,
van Oers
MH
,
Kater
AP
,
Eldering
E
.
c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches
.
Blood
.
2008
;
112
(
13
):
5141
-
5149
.
149.
Schade
AE
,
Schieven
GL
,
Townsend
R
, et al
.
Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation
.
Blood
.
2008
;
111
(
3
):
1366
-
1377
.
150.
Mestermann
K
,
Giavridis
T
,
Weber
J
, et al
.
The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells
.
Sci Transl Med
.
2019
;
11
(
499
):
eaau5907
.
151.
Weber
EW
,
Lynn
RC
,
Sotillo
E
,
Lattin
J
,
Xu
P
,
Mackall
CL
.
Pharmacologic control of CAR-T cell function using dasatinib
.
Blood Adv
.
2019
;
3
(
5
):
711
-
717
.
152.
Baur
K
,
Heim
D
,
Beerlage
A
, et al
.
Dasatinib for treatment of CAR T-cell therapy-related complications
.
J Immunother Cancer
.
2022
;
10
(
12
):
e005956
.
153.
Leclercq
G
,
Haegel
H
,
Schneider
A
, et al
.
Src/lck inhibitor dasatinib reversibly switches off cytokine release and T cell cytotoxicity following stimulation with T cell bispecific antibodies
.
J Immunother Cancer
.
2021
;
9
(
7
):
e002582
.
154.
Redin
E
,
Garmendia
I
,
Lozano
T
, et al
.
SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation
.
J Immunother Cancer
.
2021
;
9
(
3
):
e001496
.
155.
Philipp
N
,
Kazerani
M
,
Nicholls
A
, et al
.
T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals
.
Blood
.
2022
;
140
(
10
):
1104
-
1118
.
156.
Weber
EW
,
Parker
KR
,
Sotillo
E
, et al
.
Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling
.
Science
.
2021
;
372
(
6537
):
eaba1786
.
157.
Harrington
P
,
Dillon
R
,
Radia
D
, et al
.
Differential inhibition of T cell receptor and STAT5 signalling pathways determines the immunomodulatory effects of dasatinib in chronic phase chronic myeloid leukemia
.
Haematologica
.
2023
;
108
(
6
):
1555
-
1566
.
158.
Hassold
N
,
Seystahl
K
,
Kempf
K
, et al
.
Enhancement of natural killer cell effector functions against selected lymphoma and leukemia cell lines by dasatinib
.
Int J Cancer
.
2012
;
131
(
6
):
E916
-
E927
.
159.
Uchiyama
T
,
Sato
N
,
Narita
M
, et al
.
Direct effect of dasatinib on proliferation and cytotoxicity of natural killer cells in in vitro study
.
Hematol Oncol
.
2013
;
31
(
3
):
156
-
163
.
160.
Rodriguez-Agustin
A
,
Casanova
V
,
Grau-Exposito
J
,
Sanchez-Palomino
S
,
Alcami
J
,
Climent
N
.
Immunomodulatory activity of the tyrosine kinase inhibitor dasatinib to elicit NK cytotoxicity against cancer, HIV infection and aging
.
Pharmaceutics
.
2023
;
15
(
3
):
917
.
161.
Kutsch
N
,
Pallasch
C
,
Tausch
E
, et al
.
Efficacy and safety of the combination of tirabrutinib and entospletinib with or without obinutuzumab in relapsed chronic lymphocytic leukemia
.
Hemasphere
.
2022
;
6
(
4
):
e692
.
162.
Awan
FT
,
Thirman
MJ
,
Patel-Donnelly
D
, et al
.
Entospletinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia previously treated with B-cell receptor inhibitors: results of a phase 2 study
.
Leuk Lymphoma
.
2019
;
60
(
8
):
1972
-
1977
.
163.
Liu
T-M
,
Woyach
JA
,
Zhong
Y
, et al
.
Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation
.
Blood
.
2015
;
126
(
1
):
61
-
68
.
164.
Paiva
C
,
Rowland
TA
,
Sreekantham
B
, et al
.
SYK inhibition thwarts the BAFF - B-cell receptor crosstalk and thereby antagonizes Mcl-1 in chronic lymphocytic leukemia
.
Haematologica
.
2017
;
102
(
11
):
1890
-
1900
.
165.
Colado
A
,
Almejun
MB
,
Podaza
E
, et al
.
The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage-mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients
.
Cancer Immunol Immunother
.
2017
;
66
(
4
):
461
-
473
.
166.
Elias
EE
,
Sarapura Martinez
VJ
,
Amondarain
M
, et al
.
Venetoclax-resistant CLL cells show a highly activated and proliferative phenotype
.
Cancer Immunol Immunother
.
2022
;
71
(
4
):
979
-
987
.
167.
Chanan-Khan
A
,
Miller
KC
,
Musial
L
, et al
.
Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study
.
J Clin Oncol
.
2006
;
24
(
34
):
5343
-
5349
.
168.
Badoux
XC
,
Keating
MJ
,
Wen
S
, et al
.
Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia
.
J Clin Oncol
.
2013
;
31
(
5
):
584
-
591
.
169.
Chavez
JC
,
Piris-Villaespesa
M
,
Dalia
S
, et al
.
Results of a phase II study of lenalidomide and rituximab for refractory/relapsed chronic lymphocytic leukemia
.
Leuk Res
.
2016
;
47
:
78
-
83
.
170.
Chanan-Khan
A
,
Porter
CW
.
Immunomodulating drugs for chronic lymphocytic leukaemia
.
Lancet Oncol
.
2006
;
7
(
6
):
480
-
488
.
171.
Fink
EC
,
Ebert
BL
.
The novel mechanism of lenalidomide activity
.
Blood
.
2015
;
126
(
21
):
2366
-
2369
.
172.
Fiorcari
S
,
Martinelli
S
,
Bulgarelli
J
, et al
.
Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia
.
Haematologica
.
2015
;
100
(
2
):
253
-
262
.
173.
Maffei
R
,
Fiorcari
S
,
Martinelli
S
, et al
.
Lenalidomide promotes a pro-inflammatory switch of nurse-like cells derived from chronic lymphocytic leukemia
.
Blood
.
2014
;
124
(
21
):
3286
.
174.
Schulz
A
,
Dürr
C
,
Zenz
T
, et al
.
Lenalidomide reduces survival of chronic lymphocytic leukemia cells in primary cocultures by altering the myeloid microenvironment
.
Blood
.
2013
;
121
(
13
):
2503
-
2511
.
175.
Ioannou
N
,
Jain
K
,
Ramsay
AG
.
Immunomodulatory drugs for the treatment of B cell malignancies
.
Int J Mol Sci
.
2021
;
22
(
16
):
8572
.
176.
Roider
T
,
Brinkmann
BJ
,
Kim
V
, et al
.
An autologous culture model of nodal B-cell lymphoma identifies ex vivo determinants of response to bispecific antibodies
.
Blood Adv
.
2021
;
5
(
23
):
5060
-
5071
.
177.
Andritsos
LA
,
Johnson
AJ
,
Lozanski
G
, et al
.
Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia
.
J Clin Oncol
.
2008
;
26
(
15
):
2519
-
2525
.
178.
Saleem
K
,
Franz
J
,
Klem
ML
, et al
.
Second primary malignancies in patients with haematological cancers treated with lenalidomide: a systematic review and meta-analysis
.
Lancet Haematol
.
2022
;
9
(
12
):
e906
-
e918
.
179.
Li
B
,
Rampal
RK
,
Xiao
Z
.
Targeted therapies for myeloproliferative neoplasms
.
Biomark Res
.
2019
;
7
:
15
.
180.
Zeiser
R
,
von Bubnoff
N
,
Butler
J
, et al
.
Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease
.
N Engl J Med
.
2020
;
382
(
19
):
1800
-
1810
.
181.
Jain
P
,
Keating
M
,
Renner
S
, et al
.
Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial
.
Lancet Haematol
.
2017
;
4
(
2
):
e67
-
e74
.
182.
Blunt
MD
,
Koehrer
S
,
Dobson
RC
, et al
.
The dual Syk/JAK inhibitor cerdulatinib antagonizes B-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia
.
Clin Cancer Res
.
2017
;
23
(
9
):
2313
-
2324
.
183.
Spaner
DE
,
Luo
Y
,
Wang
G
,
Gallagher
J
,
Tsui
H
,
Shi
Y
.
Janus kinases restrain chronic lymphocytic leukemia cells in patients on ibrutinib: results of a phase II trial
.
Cancer Med
.
2021
;
10
(
24
):
8789
-
8798
.
184.
Ibrahim
S
,
Keating
M
,
Do
KA
, et al
.
CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia
.
Blood
.
2001
;
98
(
1
):
181
-
186
.
185.
Malavasi
F
,
Deaglio
S
,
Damle
R
,
Cutrona
G
,
Ferrarini
M
,
Chiorazzi
N
.
CD38 and chronic lymphocytic leukemia: a decade later
.
Blood
.
2011
;
118
(
13
):
3470
-
3478
.
186.
Manna
A
,
Aulakh
S
,
Jani
P
, et al
.
Targeting CD38 enhances the antileukemic activity of ibrutinib in chronic lymphocytic leukemia
.
Clin Cancer Res
.
2019
;
25
(
13
):
3974
-
3985
.
187.
Aurran-Schleinitz
T
,
Tomowiak
C
,
Roos-Weil
D
, et al
.
Combined treatment with ibrutinib and anti-CD38 monoclonal antibody daratumumab in relapsed/refractory chronic lymphocytic leukemia with TP53 aberrations: results of the Filo Phase II Study IDA53
.
Blood
.
2022
;
140
(
suppl 1
):
7030
-
7031
.
188.
Matas-Cespedes
A
,
Vidal-Crespo
A
,
Rodriguez
V
, et al
.
The human CD38 monoclonal antibody daratumumab shows antitumor activity and hampers leukemia-microenvironment interactions in chronic lymphocytic leukemia
.
Clin Cancer Res
.
2017
;
23
(
6
):
1493
-
1505
.
189.
Krejcik
J
,
Casneuf
T
,
Nijhof
IS
, et al
.
Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma
.
Blood
.
2016
;
128
(
3
):
384
-
394
.
190.
Scholler
N
,
Perbost
R
,
Locke
FL
, et al
.
Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma
.
Nat Med
.
2022
;
28
(
9
):
1872
-
1882
.
191.
Friedrich
MJ
,
Neri
P
,
Kehl
N
, et al
.
The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients
.
Cancer Cell
.
2023
;
41
(
4
):
711
-
725.e6
.
192.
Apollonio
B
,
Spada
F
,
Petrov
N
, et al
.
Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma
.
J Clin Invest
.
2023
;
133
(
13
):
e166070
.
193.
Jain
MD
,
Zhao
H
,
Wang
X
, et al
.
Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma
.
Blood
.
2021
;
137
(
19
):
2621
-
2633
.
194.
van Bruggen
JAC
,
van der Windt
GJW
,
Hoogendoorn
M
,
Dubois
J
,
Kater
AP
,
Peters
FS
.
Depletion of CLL cells by venetoclax treatment reverses oxidative stress and impaired glycolysis in CD4 T cells
.
Blood Adv
.
2022
;
6
(
14
):
4185
-
4195
.
195.
Meermeier
EW
,
Welsh
SJ
,
Sharik
ME
, et al
.
Tumor burden limits bispecific antibody efficacy through T-cell exhaustion averted by concurrent cytotoxic therapy
.
Blood Cancer Discov
.
2021
;
2
(
4
):
354
-
369
.
196.
Kater
AP
,
Levin
MD
,
Dubois
J
, et al
.
Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION): primary analysis of an open-label, randomised, phase 2 trial
.
Lancet Oncol
.
2022
;
23
(
6
):
818
-
828
.
197.
Gruber
M
,
Bozic
I
,
Leshchiner
I
, et al
.
Growth dynamics in naturally progressing chronic lymphocytic leukaemia
.
Nature
.
2019
;
570
(
7762
):
474
-
479
.
198.
Munir
T
,
Moreno
C
,
Owen
C
, et al
.
Impact of minimal residual disease on progression-free survival outcomes after fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in the GLOW study
.
J Clin Oncol
.
2023
;
41
(
21
):
3689
-
3699
.
199.
Yeh
P
,
Hunter
T
,
Sinha
D
, et al
.
Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia
.
Nat Commun
.
2017
;
8
:
14756
.
200.
Furstenau
M
,
Weiss
J
,
Giza
A
, et al
.
Circulating tumor DNA-based MRD assessment in patients with CLL treated with obinutuzumab, acalabrutinib, and venetoclax
.
Clin Cancer Res
.
2022
;
28
(
19
):
4203
-
4211
.
201.
Palma
M
,
Gentilcore
G
,
Heimersson
K
, et al
.
T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers
.
Haematologica
.
2017
;
102
(
3
):
562
-
572
.
202.
Vardi
A
,
Vlachonikola
E
,
Papazoglou
D
, et al
.
T-cell dynamics in chronic lymphocytic leukemia under different treatment modalities
.
Clin Cancer Res
.
2020
;
26
(
18
):
4958
-
4969
.
203.
Viel
S
,
Charrier
E
,
Marcais
A
, et al
.
Monitoring NK cell activity in patients with hematological malignancies
.
Oncoimmunology
.
2013
;
2
(
9
):
e26011
.
204.
Gauthier
M
,
Durrieu
F
,
Martin
E
, et al
.
Prognostic role of CD4 T-cell depletion after frontline fludarabine, cyclophosphamide and rituximab in chronic lymphocytic leukaemia
.
BMC Cancer
.
2019
;
19
(
1
):
809
.
205.
Elston
L
,
Fegan
C
,
Hills
R
, et al
.
Increased frequency of CD4+PD-1+HLA-DR+ T cells is associated with disease progression in CLL
.
Br J Haematol
.
2020
;
188
(
6
):
872
-
880
.
206.
Yin
Q
,
Sivina
M
,
Robins
H
, et al
.
Ibrutinib therapy increases T cell repertoire diversity in patients with chronic lymphocytic leukemia
.
J Immunol
.
2017
;
198
(
4
):
1740
-
1747
.
207.
Kim
JM
,
Yi
E
,
Cho
H
, et al
.
Assessment of NK cell activity based on NK cell-specific receptor synergy in peripheral blood mononuclear cells and whole blood
.
Int J Mol Sci
.
2020
;
21
(
21
):
8112
.
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