Abstract

The management of chronic lymphocytic leukemia (CLL) has undergone dramatic changes over the previous 2 decades with the introduction of multiple new therapies and new combinations. Management of the newly diagnosed asymptomatic patient has not significantly changed outside of the development of a number of prognostic factors and the CLL International Prognostic Index, which is helpful in discussions regarding prognosis and likelihood of requiring treatment. When therapy is required, initial treatment of most patients now includes either the Bruton tyrosine kinase inhibitor ibrutinib or the B-cell lymphoma 2 inhibitor venetoclax in combination with obinutuzumab. Current frontline trials are focused on the optimal sequencing or combination of targeted therapies. In this review, we will discuss the management of previously untreated CLL with an emphasis on the clinical trials that have formed the standard of care, as well as those newer studies that are likely to form the next generation of therapy.

References

References
1.
Rai
KR
.
A critical analysis of staging in CLL
. In:
Gale
RP
,
Rai
KR
, eds.
Chronic Lymphocytic Leukemia: Recent Progress and Future Directions
.
Vol. 59
.
New York, NY
:
Liss
;
1987
:
253
-
264
.
2.
Binet
JL
,
Leporrier
M
,
Dighiero
G
, et al
.
A clinical staging system for chronic lymphocytic leukemia: prognostic significance
.
Cancer
.
1977
;
40
(
2
):
855
-
864
.
3.
Döhner
H
,
Stilgenbauer
S
,
Benner
A
, et al
.
Genomic aberrations and survival in chronic lymphocytic leukemia
.
N Engl J Med
.
2000
;
343
(
26
):
1910
-
1916
.
4.
Landau
DA
,
Tausch
E
,
Taylor-Weiner
AN
, et al
.
Mutations driving CLL and their evolution in progression and relapse
.
Nature
.
2015
;
526
(
7574
):
525
-
530
.
5.
Rossi
D
,
Khiabanian
H
,
Spina
V
, et al
.
Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia
.
Blood
.
2014
;
123
(
14
):
2139
-
2147
.
6.
Yu
L
,
Kim
HT
,
Kasar
S
, et al
.
Survival of del17p CLL depends on genomic complexity and somatic mutation
.
Clin Cancer Res
.
2017
;
23
(
3
):
735
-
745
.
7.
Rigolin
GM
,
Cavallari
M
,
Quaglia
FM
, et al
.
In CLL, comorbidities and the complex karyotype are associated with an inferior outcome independently of CLL-IPI
.
Blood
.
2017
;
129
(
26
):
3495
-
3498
.
8.
Baliakas
P
,
Iskas
M
,
Gardiner
A
, et al
.
Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data
.
Am J Hematol
.
2014
;
89
(
3
):
249
-
255
.
9.
Huang
SJ
,
Bergin
K
,
Smith
AC
, et al
.
Clonal evolution as detected by interphase fluorescence in situ hybridization is associated with worse overall survival in a population-based analysis of patients with chronic lymphocytic leukemia in British Columbia, Canada
.
Cancer Genet
.
2017
;
210
:
1
-
8
.
10.
Shanafelt
TD
,
Witzig
TE
,
Fink
SR
, et al
.
Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia
.
J Clin Oncol
.
2006
;
24
(
28
):
4634
-
4641
.
11.
Stilgenbauer
S
,
Sander
S
,
Bullinger
L
, et al
.
Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival
.
Haematologica
.
2007
;
92
(
9
):
1242
-
1245
.
12.
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
.
13.
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
.
14.
Wierda
WG
,
O’Brien
S
,
Wang
X
, et al
.
Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia
.
Blood
.
2007
;
109
(
11
):
4679
-
4685
.
15.
Abrisqueta
P
,
Pereira
A
,
Rozman
C
, et al
.
Improving survival in patients with chronic lymphocytic leukemia (1980-2008): the Hospital Clinic of Barcelona experience
.
Blood
.
2009
;
114
(
10
):
2044
-
2050
.
16.
Molica
S
,
Shanafelt
TD
,
Giannarelli
D
, et al
.
The chronic lymphocytic leukemia international prognostic index predicts time to first treatment in early CLL: independent validation in a prospective cohort of early stage patients
.
Am J Hematol
.
2016
;
91
(
11
):
1090
-
1095
.
17.
Hallek
M
,
Cheson
BD
,
Catovsky
D
, et al
.
iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL
.
Blood
.
2018
;
131
(
25
):
2745
-
2760
.
18.
Dighiero
G
,
Maloum
K
,
Desablens
B
, et al;
French Cooperative Group on Chronic Lymphocytic Leukemia
.
Chlorambucil in indolent chronic lymphocytic leukemia
.
N Engl J Med
.
1998
;
338
(
21
):
1506
-
1514
.
19.
Schweighofer
CD
,
Cymbalista
F
,
Müller
C
, et al
.
Early versus deferred treatment with combined fludarabine, cyclophosphamide and rituximab (FCR) improves event-free survival in patients with high-risk Binet stage A chronic lymphocytic leukemia–first results of a randomized German-French Cooperative phase III trial [abstract]
.
Blood
.
2013
;
122
(
21
):
524
.
20.
Goede
V
,
Fischer
K
,
Busch
R
, et al
.
Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions
.
N Engl J Med
.
2014
;
370
(
12
):
1101
-
1110
.
21.
Eichhorst
B
,
Fink
AM
,
Bahlo
J
, et al;
German CLL Study Group (GCLLSG)
.
First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial
.
Lancet Oncol
.
2016
;
17
(
7
):
928
-
942
.
22.
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
.
23.
Michallet
AS
,
Aktan
M
,
Hiddemann
W
, et al
.
Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study
.
Haematologica
.
2018
;
103
(
4
):
698
-
706
.
24.
Byrd
JC
,
Furman
RR
,
Coutre
SE
, et al
.
Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia
.
N Engl J Med
.
2013
;
369
(
1
):
32
-
42
.
25.
O’Brien
S
,
Furman
RR
,
Coutre
S
, et al
.
Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience
.
Blood
.
2018
;
131
(
17
):
1910
-
1919
.
26.
Burger
JA
,
Tedeschi
A
,
Barr
PM
, et al;
RESONATE-2 Investigators
.
Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia
.
N Engl J Med
.
2015
;
373
(
25
):
2425
-
2437
.
27.
Barr
PM
,
Robak
T
,
Owen
C
, et al
.
Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2
.
Haematologica
.
2018
;
103
(
9
):
1502
-
1510
.
28.
Woyach
JA
,
Ruppert
AS
,
Heerema
NA
, et al
.
Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL
.
N Engl J Med
.
2018
;
379
(
26
):
2517
-
2528
.
29.
Guha
A
,
Derbala
MH
,
Zhao
Q
, et al
.
Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies
.
J Am Coll Cardiol
.
2018
;
72
(
6
):
697
-
698
.
30.
Moreno
C
,
Greil
R
,
Demirkan
F
, et al
.
Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial
.
Lancet Oncol
.
2019
;
20
(
1
):
43
-
56
.
31.
Hallek
M
,
Fischer
K
,
Fingerle-Rowson
G
, et al;
German Chronic Lymphocytic Leukaemia Study Group
.
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
.
32.
Fischer
K
,
Bahlo
J
,
Fink
AM
, et al
.
Long term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial
.
Blood
.
2016
;
127
(
2
):
208
-
215
.
33.
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
.
34.
Shanafelt
TD
,
Wang
XV
,
Kay
NE
, et al
.
Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia
.
N Engl J Med
.
2019
;
381
(
5
):
432
-
443
.
35.
Fischer
K
,
Al-Sawaf
O
,
Bahlo
J
, et al
.
Venetoclax and obinutuzumab in patients with CLL and coexisting conditions
.
N Engl J Med
.
2019
;
380
(
23
):
2225
-
2236
.
36.
Mato
AR
,
Nabhan
C
,
Thompson
MC
, et al
.
Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis
.
Haematologica
.
2018
;
103
(
5
):
874
-
879
.
37.
Hillmen
P
,
Rawstron
A
,
Brock
K
, et al
.
Ibrutinib plus venetoclax in relapsed/refractory CLL: results of the Bloodwise TAP clarity study [abstract]
.
Blood
.
2018
;
132
(
suppl 1
):
182
.
38.
Jain
N
,
Keating
M
,
Thompson
P
, et al
.
Ibrutinib and venetoclax for first-line treatment of CLL
.
N Engl J Med
.
2019
;
380
(
22
):
2095
-
2103
.
39.
Rogers
K
,
Huang
Y
,
Stark
A
, et al
.
Initial results of the phase 2 treatment naive cohort in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax in chronic lymphocytic leukemia [abstract]
.
Blood
.
2017
;
130
(
suppl 1
):
431
.
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