Abstract

Deuterated (“heavy”) water labeling in patients with chronic lymphocytic leukemia (CLL) demonstrates that IGHV unmutated and ZAP-70+ patients have higher blood and tissue CLL death rates on ibrutinib therapy, resulting in lower measurable residual disease levels with long-term ibrutinib treatment. This trial was registered at www.clinicaltrials.gov as #NCT01752426.

1.
Burger
JA
,
Li
KW
,
Keating
MJ
, et al
.
Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib
.
JCI Insight
.
2017
;
2
(
2
):
e89904
.
2.
Burger
JA
.
Treatment of chronic lymphocytic leukemia
.
N Engl J Med
.
2020
;
383
(
5
):
460
-
473
.
3.
Burger
JA
,
Barr
PM
,
Robak
T
, et al
.
Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study
.
Leukemia
.
2020
;
34
(
3
):
787
-
798
.
4.
Hamblin
TJ
,
Davis
Z
,
Gardiner
A
,
Oscier
DG
,
Stevenson
FK
.
Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia
.
Blood
.
1999
;
94
(
6
):
1848
-
1854
.
5.
Damle
RN
,
Wasil
T
,
Fais
F
, et al
.
Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia
.
Blood
.
1999
;
94
(
6
):
1840
-
1847
.
6.
Packham
G
,
Krysov
S
,
Allen
A
, et al
.
The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy
.
Haematologica
.
2014
;
99
(
7
):
1138
-
1148
.
7.
D'Avola
A
,
Drennan
S
,
Tracy
I
, et al
.
Surface IgM expression and function are associated with clinical behavior, genetic abnormalities, and DNA methylation in CLL
.
Blood
.
2016
;
128
(
6
):
816
-
826
.
8.
Burger
JA
,
Wiestner
A
.
Targeting B cell receptor signalling in cancer: preclinical and clinical advances
.
Nat Rev Cancer
.
2018
;
18
(
3
):
148
-
167
.
9.
Ten Hacken
E
,
Sivina
M
,
Kim
E
, et al
.
Functional differences between IgM and IgD signaling in chronic lymphocytic leukemia
.
J Immunol
.
2016
;
197
(
6
):
2522
-
2531
.
10.
Rassenti
LZ
,
Huynh
L
,
Toy
TL
, et al
.
ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia
.
N Engl J Med
.
2004
;
351
(
9
):
893
-
901
.
11.
Chen
J
,
Sathiaseelan
V
,
Reddy Chilamakuri
CS
, et al
.
ZAP-70 augments tonic B-cell receptor and CCR7 signaling in IGHV-unmutated chronic lymphocytic leukemia
.
Blood Adv
.
2024
;
8
(
5
):
1167
-
1178
.
12.
Chen
L
,
Huynh
L
,
Apgar
J
, et al
.
ZAP-70 enhances IgM signaling independent of its kinase activity in chronic lymphocytic leukemia
.
Blood
.
2008
;
111
(
5
):
2685
-
2692
.
13.
Rawstron
AC
,
Villamor
N
,
Ritgen
M
, et al
.
International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia
.
Leukemia
.
2007
;
21
(
5
):
956
-
964
.
14.
Admirand
JH
,
Rassidakis
GZ
,
Abruzzo
LV
,
Valbuena
JR
,
Jones
D
,
Medeiros
LJ
.
Immunohistochemical detection of ZAP-70 in 341 cases of non-Hodgkin and Hodgkin lymphoma
.
Mod Pathol
.
2004
;
17
(
8
):
954
-
961
.
15.
Messmer
BT
,
Messmer
D
,
Allen
SL
, et al
.
In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells
.
J Clin Invest
.
2005
;
115
(
3
):
755
-
764
.
16.
Wodarz
D
,
Garg
N
,
Komarova
NL
, et al
.
Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib
.
Blood
.
2014
;
123
(
26
):
4132
-
4135
.
17.
Murphy
EJ
,
Neuberg
DS
,
Rassenti
LZ
, et al
.
Leukemia-cell proliferation and disease progression in patients with early stage chronic lymphocytic leukemia
.
Leukemia
.
2017
;
31
(
6
):
1348
-
1354
.
18.
Woyach
JA
,
Smucker
K
,
Smith
LL
, et al
.
Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy
.
Blood
.
2014
;
123
(
12
):
1810
-
1817
.
19.
Sharman
JP
,
Egyed
M
,
Jurczak
W
, et al
.
Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of Elevate-TN [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
636
.
20.
Thompson
PA
,
Tam
CS
,
O'Brien
SM
, et al
.
Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia
.
Blood
.
2016
;
127
(
3
):
303
-
309
.
21.
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
.
22.
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
.
23.
Niemann
CU
,
Munir
T
,
Moreno
C
, et al
.
Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial
.
Lancet Oncol
.
2023
;
24
(
12
):
1423
-
1433
.
24.
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
.
You do not currently have access to this content.
Sign in via your Institution