• Fixed-duration combination treatment including venetoclax or ibrutinib plus obinutuzumab can induce deep remissions in high-risk CLL.

  • Responses are also durable after MRD-guided discontinuation of treatment.

Fifty-one of 189 evaluable patients from 3 prospective phase 2 trials evaluating a sequential targeted treatment had high-risk chronic lymphocytic leukemia (CLL) with a 17p deletion, TP53 mutation, or both. Twenty-seven patients started treatment with bendamustine debulking before induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13, and venetoclax/obinutuzumab (AG) in 17. The primary end point was overall response rate after 8 months of induction treatment, which was 81%, 100%, and 94% for IO, IG, and AG, respectively. Minimal residual disease (MRD) was undetectable (uMRD) in peripheral blood (<10−4 by flow cytometry) in 0%, 23%, and 82% of patients, respectively. Median progression-free survival (PFS) was 45 months. Seventeen patients discontinued maintenance treatment due to uMRD: 9 progressed, 2 died without progression (median PFS, 28 months after discontinuation of treatment), and 6 remained in remission after a median observation time of 46 months (range, 6-47 months) after treatment discontinuation. Thus, MRD-guided fixed-duration therapies combining obinutuzumab with venetoclax or ibrutinib can induce deep and durable remissions in CLL patients with high-risk genetic lesions, which can persist after treatment discontinuation (due to a predefined fixed-duration or MRD-guided early termination). The median PFS was 45 months. These trials were registered at www.clinicaltrials.gov as #NCT02345863, #NCT02401503, and #NCT02689141.

1.
Hallek
M
,
Shanafelt
TD
,
Eichhorst
B
.
Chronic lymphocytic leukaemia
.
Lancet.
2018
;
391
(
10129
):
1524
-
1537
.
2.
Fürstenau
M
,
Hallek
M
,
Eichhorst
B
.
Sequential and combination treatments with novel agents in chronic lymphocytic leukemia
.
Haematologica.
2019
;
104
(
11
):
2144
-
2154
.
3.
Byrd
JC
,
Brown
JR
,
O’Brien
S
, et al;
RESONATE Investigators
.
Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia
.
N Engl J Med.
2014
;
371
(
3
):
213
-
223
.
4.
Munir
T
,
Brown
JR
,
O’Brien
S
, et al
.
Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma
.
Am J Hematol.
2019
;
94
(
12
):
1353
-
1363
.
5.
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
.
6.
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
.
7.
Woyach
JA
,
Ruppert
AS
,
Heerema
NA
, et al
.
Ibrutinib regimens vs chemoimmunotherapy in older patients with untreated CLL
.
N Engl J Med.
2018
;
379
(
26
):
2517
-
2528
.
8.
Moreno
C
,
Greil
R
,
Demirkan
F
, et al
.
Ibrutinib plus obinutuzumab vs 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
.
9.
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
.
10.
Woyach
JA
,
Furman
RR
,
Liu
TM
, et al
.
Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib
.
N Engl J Med.
2014
;
370
(
24
):
2286
-
2294
.
11.
Jain
P
,
Keating
M
,
Wierda
W
, et al
.
Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib
.
Blood.
2015
;
125
(
13
):
2062
-
2067
.
12.
Maddocks
KJ
,
Ruppert
AS
,
Lozanski
G
, et al
.
Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia
.
JAMA Oncol.
2015
;
1
(
1
):
80
-
87
.
13.
Lampson
BL
,
Brown
JR
.
Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?
Expert Rev Hematol.
2018
;
11
(
3
):
185
-
194
.
14.
Ahn
IE
,
Tian
X
,
Wiestner
A
.
Ibrutinib for chronic lymphocytic leukemia with TP53 alterations
.
N Engl J Med.
2020
;
383
(
5
):
498
-
500
.
15.
Roberts
AW
,
Davids
MS
,
Pagel
JM
, et al
.
Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia
.
N Engl J Med.
2016
;
374
(
4
):
311
-
322
.
16.
Stilgenbauer
S
,
Eichhorst
B
,
Schetelig
J
, et al
.
Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study
.
Lancet Oncol.
2016
;
17
(
6
):
768
-
778
.
17.
Stilgenbauer
S
,
Eichhorst
B
,
Schetelig
J
, et al
.
Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial [published correction appears in J Clin Oncol. 2019;37(25):2299]
.
J Clin Oncol.
2018
;
36
(
19
):
1973
-
1980
.
18.
Seymour
JF
,
Kipps
TJ
,
Eichhorst
B
, et al
.
Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia
.
N Engl J Med.
2018
;
378
(
12
):
1107
-
1120
.
19.
Kater
AP
,
Seymour
JF
,
Hillmen
P
, et al
.
Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study
.
J Clin Oncol.
2019
;
37
(
4
):
269
-
277
.
20.
Al-Sawaf
O
,
Zhang
C
,
Tandon
M
, et al
.
Venetoclax plus obinutuzumab vs 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
.
21.
Hallek
M
.
Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies [published correction appears in Blood. 2014;123(26):4153]
.
Blood.
2013
;
122
(
23
):
3723
-
3734
.
22.
Cramer
P
,
von Tresckow
J
,
Bahlo
J
, et al
.
CLL2-BXX Phase II trials: sequential, targeted treatment for eradication of minimal residual disease in chronic lymphocytic leukemia
.
Future Oncol.
2018
;
14
(
6
):
499
-
513
.
23.
Cramer
P
,
von Tresckow
J
,
Bahlo
J
, et al
.
Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary end point analysis of a multicentre, open-label, phase 2 trial
.
Lancet Oncol.
2018
;
19
(
9
):
1215
-
1228
.
24.
von Tresckow
J
,
Cramer
P
,
Bahlo
J
, et al
.
CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia
.
Leukemia.
2019
;
33
(
5
):
1161
-
1172
.
25.
Cramer
P
,
von Tresckow
JV
,
Robrecht
S
, et al
.
Bendamustine, followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia (CLL2-BIO): primary end point analysis of a multicentre, open-label phase-II trial
.
Haematologica.
2021
;
106
(
2
):
543
-
554
.
26.
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
.
27.
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
.
28.
Böttcher
S
,
Ritgen
M
,
Kneba
M
.
Flow cytometric MRD detection in selected mature B-cell malignancies
.
Methods Mol Biol.
2013
;
971
:
149
-
174
.
29.
Böttcher
S
,
Ritgen
M
,
Fischer
K
, et al
.
Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial
.
J Clin Oncol.
2012
;
30
(
9
):
980
-
988
.
30.
Ahn
IE
,
Farooqui
MZH
,
Tian
X
, et al
.
Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study
.
Blood.
2018
;
131
(
21
):
2357
-
2366
.
31.
Tausch
E
,
Schneider
C
,
Robrecht
S
, et al
.
Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax
.
Blood.
2020
;
135
(
26
):
2402
-
2412
.
32.
Burger
JA
,
Sivina
M
,
Jain
N
, et al
.
Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia
.
Blood.
2019
;
133
(
10
):
1011
-
1019
.
33.
Al-Sawaf
O
,
Zhang
C
,
Robrecht
S
, et al
.
Clonal dynamics after venetoclax-obinutuzumab therapy: novel insights from the randomized, phase 3 CLL14 trial [abstract]
.
Blood.
2020
;
136
(
suppl 1
):
22
-
23
.
34.
Sharman
JP
,
Egyed
M
,
Jurczak
W
, et al
.
Acalabrutinib with or without obinutuzumab vs chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial
.
Lancet.
2020
;
395
(
10232
):
1278
-
1291
.
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.
Malcikova
J
,
Smardova
J
,
Rocnova
L
, et al
.
Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage
.
Blood.
2009
;
114
(
26
):
5307
-
5314
.
37.
Zenz
T
,
Benner
A
,
Dohner
H
,
Stilgenbauer
S
.
Chronic lymphocytic leukemia and treatment resistance in cancer: the role of the p53 pathway
.
Cell Cycle.
2008
;
7
(
24
):
3810
-
3814
.
38.
Cramer
P
,
Von Tresckow
J
,
Robrecht
S
, et al
.
Value of bendamustine debulking ahead of combined targeted treatment: meta-analysis of three phase II studies evaluating different combinations of a targeted agent with a CD20-antibody in patients with treatment-naive and relapsed/refractory CLL [abstract]
. In:
iwCLL 2019
; 20 September-24 September 2019; Edinburgh, United Kingdom. Poster 1946.
39.
Barr
PM
,
Brown
JR
,
Hillmen
P
, et al
.
Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL
.
Blood.
2017
;
129
(
19
):
2612
-
2615
.
40.
Jain
P
,
Thompson
PA
,
Keating
M
, et al
.
Long-term outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib
.
Cancer.
2017
;
123
(
12
):
2268
-
2273
.
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