Key Points

  • Ibrutinib, obinutuzumab, and venetoclax combination is well tolerated and can be safely given in relapsed or untreated patients with MCL.

  • The triple combination provides durable complete molecular responses for treatment-naive or relapsed patients with high-risk genetics.

Abstract

Ibrutinib, obinutuzumab, and venetoclax demonstrate synergy in preclinical models of mantle cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multicenter prospective phase 1/2 trial, aimed to determine the maximum tolerated dose of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide quantitative polymerase chain reaction. Between 14 October 2015 and 29 May 2018, 48 patients were enrolled. No dose-limiting toxicity was reported, and venetoclax at 400 mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events. The complete response rate assessed by positron emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10/14 patients) and 100% of untreated MRD-evaluable patients (n = 12) at the end of 3 cycles. The median follow-up for relapsed patients was 17 months (range, 10-35 months). The 2-year progression-free survival (PFS) was 69.5% (95% confidence interval [CI], 52.9%-91.4%) and 68.6% (95% CI, 49.5%-95.1%) for overall survival. The median follow-up was 14 months (range, 5-19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5%-100%). The combination of obinutuzumab, ibrutinib, and venetoclax is well tolerated and provides high response rates, including at the molecular level, in relapsed and untreated MCL patients. This trial was registered at www.clinicaltrials.gov as #NCT02558816.

REFERENCES

REFERENCES
1.
Jares
P
,
Colomer
D
,
Campo
E
.
Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics
.
Nat Rev Cancer
.
2007
;
7
(
10
):
750
-
762
.
2.
Dreyling
M
,
Campo
E
,
Hermine
O
, et al
.
Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
.
Ann Oncol
.
2017
;
28
:
iv62
-
iv71
.
3.
Kluin-Nelemans
HC
,
Hoster
E
,
Hermine
O
, et al
.
Treatment of older patients with mantle-cell lymphoma
.
N Engl J Med
.
2012
;
367
(
6
):
520
-
531
.
4.
Le Gouill
S
,
Thieblemont
C
,
Oberic
L
, et al;
LYSA Group
.
Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma
.
N Engl J Med
.
2017
;
377
(
13
):
1250
-
1260
.
5.
Wang
ML
,
Rule
S
,
Martin
P
, et al
.
Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma
.
N Engl J Med
.
2013
;
369
(
6
):
507
-
516
.
6.
Chiron
D
,
Di Liberto
M
,
Martin
P
, et al
.
Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma
.
Cancer Discov
.
2014
;
4
(
9
):
1022
-
1035
.
7.
Rahal
R
,
Frick
M
,
Romero
R
, et al
.
Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma
.
Nat Med
.
2014
;
20
(
1
):
87
-
92
.
8.
Zhao
X
,
Lwin
T
,
Silva
A
, et al
.
Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma
.
Nat Commun
.
2017
;
8
:
14920
.
9.
Zhang
L
,
Yao
Y
,
Zhang
S
, et al
.
Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma
.
Sci Transl Med
.
2019
;
11
(
491
):
eaau1167
.
10.
Davids
MS
,
Roberts
AW
,
Seymour
JF
, et al
.
Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma
.
J Clin Oncol
.
2017
;
35
(
8
):
826
-
833
.
11.
Chiron
D
,
Dousset
C
,
Brosseau
C
, et al
.
Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma
.
Oncotarget
.
2015
;
6
(
11
):
8750
-
8759
.
12.
Tessoulin
B
,
Papin
A
,
Gomez-Bougie
P
, et al
.
BCL2-family dysregulation in B-cell malignancies: from gene expression regulation to a targeted therapy biomarker
.
Front Oncol
.
2019
;
8
:
645
.
13.
Zhao
X
,
Ren
Y
,
Lawlor
M
, et al
.
BCL2 amplicon loss and transcriptional remodeling drives ABT-199 resistance in B cell lymphoma models
.
Cancer Cell
.
2019
;
35
(
5
):
752
-
766.e9
.
14.
Tam
CS
,
Anderson
MA
,
Pott
C
, et al
.
Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma
.
N Engl J Med
.
2018
;
378
(
13
):
1211
-
1223
.
15.
Chiron
D
,
Bellanger
C
,
Papin
A
, et al
.
Rational targeted therapies to overcome microenvironment-dependent expansion of mantle cell lymphoma
.
Blood
.
2016
;
128
(
24
):
2808
-
2818
.
16.
Hoster
E
,
Dreyling
M
,
Klapper
W
, et al;
German Low Grade Lymphoma Study Group (GLSG)
;
European Mantle Cell Lymphoma Network
.
A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma
.
Blood
.
2008
;
111
(
2
):
558
-
565
.
17.
van der Velden
VHJ
,
Cazzaniga
G
,
Schrauder
A
, et al;
European Study Group on MRD detection in ALL (ESG-MRD-ALL)
.
Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data
.
Leukemia
.
2007
;
21
(
4
):
604
-
611
.
18.
Gressin
R
,
Daguindau
N
,
Tempescul
A
, et al;
Lymphoma Study Association
.
A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma
.
Haematologica
.
2019
;
104
(
1
):
138
-
146
.
19.
Ghia
P
,
Stamatopoulos
K
,
Belessi
C
, et al;
European Research Initiative on CLL
.
ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia
.
Leukemia
.
2007
;
21
(
1
):
1
-
3
.
20.
O’Quigley
J
,
Pepe
M
,
Fisher
L
.
Continual reassessment method: a practical design for phase 1 clinical trials in cancer
.
Biometrics
.
1990
;
46
(
1
):
33
-
48
.
21.
Garrett-Mayer
E
.
The continual reassessment method for dose-finding studies: a tutorial
.
Clin Trials
.
2006
;
3
(
1
):
57
-
71
.
22.
Sweeting
M
,
Mander
A
,
Sabin
T
.
bcrm: Bayesian continual reassessment method designs for phase I dose-finding trials
.
J Stat Softw
.
2013
;
54
:
1
-
26
.
23.
Wang
M
,
Munoz
J
,
Goy
A
, et al
.
KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma
.
N Engl J Med
.
2020
;
382
(
14
):
1331
-
1342
.
24.
Delfau-Larue
M-H
,
Klapper
W
,
Berger
F
, et al;
European Mantle Cell Lymphoma Network
.
High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma
.
Blood
.
2015
;
126
(
5
):
604
-
611
.
25.
Agarwal
R
,
Chan
Y-C
,
Tam
CS
, et al
.
Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma
.
Nat Med
.
2019
;
25
(
1
):
119
-
129
.
You do not currently have access to this content.

Sign in via your Institution

Sign In