Venetoclax: A new wave in hematooncology

Jana Mihalyova; Tomas Jelinek; Katerina Growkova; Matous Hrdinka; Michal Simicek; Roman Hajek

doi:10.1016/j.exphem.2018.02.002

Venetoclax: A new wave in hematooncology

Jana Mihalyova
Jana Mihalyova
Affiliations
Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
Search for articles by this author
Tomas Jelinek
Tomas Jelinek
Correspondence
Offprint requests to:Department of Haematooncology, University Hospital Ostrava, 17. listopadu 1790, 708 52, Ostrava, Czech Republic;
Contact
Affiliations
Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
Faculty of Science, University of Ostrava, Ostrava, Czech Republic
Search for articles by this author
Katerina Growkova
Katerina Growkova
Affiliations
Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
Faculty of Science, University of Ostrava, Ostrava, Czech Republic
Search for articles by this author
Matous Hrdinka
Matous Hrdinka
Affiliations
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
Faculty of Science, University of Ostrava, Ostrava, Czech Republic
Search for articles by this author
Michal Simicek
Michal Simicek
Affiliations
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
Faculty of Science, University of Ostrava, Ostrava, Czech Republic
Search for articles by this author
Roman Hajek
Roman Hajek
Affiliations
Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
Search for articles by this author

Open ArchivePublished:February 22, 2018DOI:https://doi.org/10.1016/j.exphem.2018.02.002

Highlights

•
Cancer cells survive via overexpressed anti-apoptotic BCL2 proteins.
•
Venetoclax is highly selective BCL2 inhibitor with an acceptable toxicity profile.
•
Venetoclax overcomes resistance to ibrutinib and idelalisib in chronic lymphocytic leukemia.
•
Venetoclax is effective in a subset of multiple myeloma patients with translocation t(11;14).
•
Venetoclax has synergic activity with low-dose cytarabine, 5-azacytidine (5-Aza) in acute myeloid leukemia.

Inhibitors of antiapoptotic proteins of the BCL2 family can successfully restart the deregulated process of apoptosis in malignant cells. Whereas nonselective agents have been limited by their affinity to different BCL2 members, thus inducing excessive toxicity, the highly selective BCL2 inhibitor venetoclax (ABT-199, Venclexta™) has an acceptable safety profile. To date, it has been approved in monotherapy for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion. Extension of indications can be expected in monotherapy and in combination regimens. Sensitivity to venetoclax is not common in lymphomas, but promising outcomes have been achieved in the mantle cell lymphoma group. Venetoclax is also active in multiple myeloma patients, especially in those with translocation t(11;14), even if high-risk features such as del17p are also present. Surprisingly, positive results are being obtained in elderly acute myeloid leukemia patients, in whom inhibition of BCL2 is able to substantially increase the efficacy of low-dose cytarabine or hypomethylating agents. Here, we provide a summary of available results from clinical trials and describe a specific mechanism of action that stands behind the efficacy of venetoclax in hematological malignancies.

Eukaryotic cells can die in many ways, including physiological and mostly beneficial modes of death (e.g., apoptosis, necroptosis, and pyroptosis), as well as nonphysiological and harmful necrotic cell destruction [

1

Fink S.L.
Cookson B.T.

Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells.

]. The classical form of cell death, apoptosis, is a gene-directed process of cell suicide characterized by specific biochemical and morphological changes including activation of proteolytic enzymes, caspases, cell shrinkage, membrane blebbing, chromatin condensation, and nuclear fragmentation. In this process, the cellular content is not released, so apoptosis is noninflammatory and the remaining apoptotic bodies are removed by phagocytes [

2

Kerr J.F.
Wyllie A.H.
Currie A.R.

Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.

]. Apoptosis plays vital roles in embryogenesis, tissue homeostasis, defense against pathogens, and elimination of neoplastic cells. However, deregulated apoptotic processes might promote the development of autoimmune, neurodegenerative, and oncologic diseases as well as resistance of cancer cells to chemotherapy [

3

Cory S.
Adams J.M.

The Bcl2 family: regulators of the cellular life-or-death switch.

,

4

Hanahan D.
Weinberg R.A.

The hallmarks of cancer.

].

Apoptosis is triggered by two independent signaling pathways, intrinsic or extrinsic. Although both pathways in the last steps rely on the same executioner caspases (caspase-3, caspase-6, and caspase-7), each pathway is activated differently [

5

Huang D.C.S.
Hahne M.
Schroeter M.
et al.

Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-xL.

,

6

Strasser A.
Harris A.W.
Huang D.C.
Krammer P.H.
Cory S.

Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis.

]. The extrinsic pathway is set off by membrane death receptors belonging to the tumor necrosis factor (TNF) receptor superfamily, which recognize their cognate extracellular ligands (e.g., FasR/FasL or CD95/CD95L, TNFR1/TNFα, DR3/TL1A, DR4/TRAIL-RI, and DR5/TRAIL-RII) [

7

Guicciardi M.E.
Gores G.J.

Life and death by death receptors.

]. Conversely, the intrinsic (mitochondrial) pathway is activated by excessive cellular stress and other pro-apoptotic events (e.g., heat, radiation, nutrient deprivation, viral infection, hypoxia, increased intracellular calcium concentration, and DNA mutations) and is orchestrated by proteins of the BCL2 family [

3

Cory S.
Adams J.M.

The Bcl2 family: regulators of the cellular life-or-death switch.

]. Each BCL2 family member harbors one or more BCL2 homology (BH) domains (BH1-4), that mediate protein–protein interactions. The BCL2 family is divided into two major functional groups. The first group includes the pro-apoptotic (pro-death) proteins BAD, BIK, NOXA, BMF, PUMA, BIM, BID, and HRK (BH3-only proteins) that activate the apoptotic effectors BAX and BAK. The second group contains the anti-apoptotic (prosurvival) proteins BCL2, BCL-XL, BCL-W, A1, and MCL-1 that bind and sequester members of the first group to prevent apoptosis. Mechanistically, when the cell receives the right signals to undergo apoptosis, the BH3-only proteins oligomerize with the effectors BAX and BAK and cause permeabilization of mitochondrial outer membrane. As a result, cytochrome c is released from mitochondria and activates caspase-dependent cell death [

8

Chen L.
Willis S.N.
Wei A.
et al.

Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.

,

9

Chittenden T.

BH3 domains: intracellular death-ligands critical for initiating apoptosis.

,

10

Czabotar P.E.
Lessene G.
Strasser A.
Adams J.M.

Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.

,

11

Huang D.C.
Strasser A.

BH3-Only proteins-essential initiators of apoptotic cell death.

,

12

Willis S.N.
Chen L.
Dewson G.
et al.

Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins.

,

13

Willis S.N.
Fletcher J.I.
Kaufmann T.
et al.

Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.

].

Clearly, enhanced function of anti-apoptotic proteins would make cells more resistant to apoptosis induction. Indeed, deregulation of BCL2 and other anti-apoptotic proteins has been demonstrated to be an important resistance mechanism in solid tumors [

14

Gazzaniga P.
Gradilone A.
Vercillo R.
et al.

bcl-2/bax mRNA expression ratio as prognostic factor in low-grade urinary bladder cancer.

,

15

Jiang S.-X.
Sato Y.
Kuwao S.
Kameya T.

Expression of bcl-2 oncogene protein is prevalent in small cell lung carcinomas.

,

16

Joensuu H.
Pylkkänen L.
Toikkanen S.

Bcl-2 protein expression and long-term survival in breast cancer.

] and hematologic malignancies [

17

Calin G.A.
Dumitru C.D.
Shimizu M.
et al.

Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.

,

18

Monni O.
Joensuu H.
Franssila K.
Knuutila S.

DNA copy number changes in diffuse large B-cell lymphoma–comparative genomic hybridization study.

,

19

Pekarsky Y.
Croce C.M.

Role of miR-15/16 in CLL.

,

20

Tsujimoto Y.
Finger L.R.
Yunis J.
Nowell P.C.
Croce C.M.

Cloning of the chromosome breakpoint of neoplastic B cells with the t (14;18) chromosome translocation.

]. For instance, the main player, BCL2, is often overexpressed due to 18q21 translocations; for example, t(14;18)(q32;q21), which juxtaposes the BCL2 gene under the constitutive activation of the immunoglobulin heavy-chain gene promoter [

20

Tsujimoto Y.
Finger L.R.
Yunis J.
Nowell P.C.
Croce C.M.

Cloning of the chromosome breakpoint of neoplastic B cells with the t (14;18) chromosome translocation.

] or due to various chromosome amplifications and deletions [

17

Calin G.A.
Dumitru C.D.
Shimizu M.
et al.

Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.

,

21

Döhner H.
Stilgenbauer S.
Benner A.
et al.

Genomic aberrations and survival in chronic lymphocytic leukemia.

,

22

Edelmann J.
Holzmann K.
Miller F.
et al.

High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations.

]. Alternatively, the cells can acquire an anti-apoptotic advantage indirectly via mechanisms involving tumor suppressor protein p53. As a transcription factor, p53 is able to induce transcription of BAX [

23

Toshiyuki M.
Reed J.C.

Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.

] and some BH3-only proteins (PUMA, NOXA, BID) [

24

Nakano K.
Vousden K.H.

PUMA, a novel proapoptotic gene, is induced by p53.

,

25

Yu J.
Wang Z.
Kinzler K.W.
Vogelstein B.
Zhang L.

PUMA mediates the apoptotic response to p53 in colorectal cancer cells.

] directly or even act as a BH3-only protein itself [

26

Petros A.M.
Gunasekera A.
Xu N.
Olejniczak E.T.
Fesik S.W.

Defining the p53 DNA-binding domain/Bcl-x (L)-binding interface using NMR.

,

27

Zilfou J.T.
Lowe S.W.

Tumor suppressive functions of p53.

]. Therefore, mutations of the TP53 gene interfering with these p53 functions can inactivate mitochondrial apoptotic pathway. Similarly, the proto-oncogene c-MYC regulates apoptosis by inducing expression of pro-apoptotic genes (BAX, BAK, BIM, PUMA and NOXA) [

28

Dansen T.B.
Whitfield J.
Rostker F.
Brown-Swigart L.
Evan G.I.

Specific requirement for Bax, not Bak, in Myc-induced apoptosis and tumor suppression in vivo.

,

29

Egle A.
Harris A.W.
Bouillet P.
Cory S.

Bim is a suppressor of Myc-induced mouse B cell leukemia.

,

30

Nikiforov M.A.
Riblett M.
Tang W.H.
et al.

Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition.

] and suppressing expression of anti-apoptotic (BCL2 and BCL-XL) genes [

31

Hoffman B.
Liebermann D.A.

Apoptotic signaling by c-MYC.

]. However, in cancer cells that overexpress mutated c-MYC, the apoptotic safety mechanism is blocked by inappropriate expression of some anti-apoptotic molecules (BCL2, BCL-XL, and MCL-1) [

32

Meyer N.
Kim S.S.
Penn L.Z.

The Oscar-worthy role of Myc in apoptosis.

,

33

Nieminen A.I.
Partanen J.I.
Klefstrom J.

c-Myc blazing a trail of death: coupling of the mitochondrial and death receptor apoptosis pathways by c-Myc.

,

34

Nilsson J.A.
Cleveland J.L.

Myc pathways provoking cell suicide and cancer.

].

Because impaired apoptosis plays a key role in cancer resistance to therapy, pharmacologic inhibition of anti-apoptotic proteins, especially BCL2, represents an attractive way to force clonal cells to die. Indeed, a number of chemical agents, the so-called BH3 mimetics, which are targeted to anti-apoptotic proteins, have been designed and tested in recent years. These drugs include nonselective inhibitors (AT-101, TW37, apogossypolone [ApoG2], obatoclax [GX15-070], ABT-737) and the BH3-only mimetic, navitoclax (ABT-263) [

35

Kipps T.J.
Eradat H.
Grosicki S.
et al.

A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia.

,

36

Nguyen M.
Marcellus R.C.
Roulston A.
et al.

Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis.

,

37

Nguyen M.
Cencic R.
Ertel F.
et al.

Obatoclax is a direct and potent antagonist of membrane-restricted Mcl-1 and is synthetic lethal with treatment that induces Bim.

,

38

Sun Y.
Wu J.
Aboukameel A.
et al.

Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo.

]. Although navitoclax binds effectively only to BCL2, BCL-XL, and MCL-1, its high affinity to BCL-XL limits its clinical use due to significant thrombocytopenia that restricts dose escalation and safe anticancer administration [

39

Roberts A.W.
Seymour J.F.
Brown J.R.
et al.

Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease.

,

40

Tse C.
Shoemaker A.R.
Adickes J.
et al.

ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.

,

41

Wilson W.H.
O'Connor O.A.
Czuczman M.S.
et al.

Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity.

].

In this review, we focus on the highly selective BCL2 inhibitor venetoclax and its use in hematological malignancies. We present a brief summary of molecular mechanisms, principles of resistance, and main toxicities accompanied by an overview of available clinical studies (Table 1, Table 2, Table 3, Table 4, Table 5, Table 6).

Table 1Results of phase 1 and 2 studies in chronic lymphocytic leukemia

Title	Regimen	EN	N	Condition	ORR% (N)	CR% (N)	PR% (N)	MRD	PFS	OS	Identifier, Phase (Reference)
A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma	Venetoclax	116	116	RR CLL/SLL	79% (92/116)	20% (23/116)	NA	35% (6/17) BM	66% (15th mo)	84% (24th mo)	NCT01328626, Phase 1 (Roberts et al., 2016)
A Phase 2 Open-Label Study of the Efficacy and Safety of ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia (CLL) Subjects With Relapse or Refractory to B-Cell Receptor Signaling Pathway Inhibitor Therapy	Venetoclax	120	64	RR CLL	70% (30/43)	2% (1/43) 0%	67% (29/43)	33% (14/42) PB	72% (12th mo)	90% (12th mo)	NCT02141282. Phase 2 (Jones et al., 2016a)
			43	Ibrutinib arm	57% (10/21)		47% (10/21)
			21	Idelalisib arm	57% (10/21)		47% (10/21)
A Study of the Efficacy of ABT-199 in Subjects With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia With the 17p Deletion	Venetoclax	158	107	RR CLL/SLL	79% (85/107)	8% (8/107)	77% (77/107)	33% (6/18) BM	72% (12th mo)	87% (12th mo)	NCT01889186, Phase 2 (Stilgenbauer et al., 2016a)
A Phase 1b Study Evaluating the Safety and Tolerability of ABT-199 in Combination With Rituximab in Subjects With Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma	Venetoclax	50	49	RR CLL	86% (42/49)	51% (25/49)	35% (17/49)	57% (28/49) BM	89% (24th mo)	NA	NCT01682616, Phase 1 (Seymour et al., 2017a)
	Rituximab	50	49	RR CLL	86% (42/49)	51% (25/49)	35% (17/49)	57% (28/49) BM	89% (24th mo)	NA	NCT01682616, Phase 1 (Seymour et al., 2017a)
CLARITY: Assessment of VenetoCLAx (ABT-199) in combination with IbRutInib in relapsed/refracTory Chronic LymphocYtic Leukaemia	Venetoclax	54	38	RR CLL	100% (38/38)	47% (18/38)	53% (20/38)	37% (15/38) PB	NA	NA	ISCRTN: 13751862, Phase 2 (Hillmen et al., 2017)
	Venetoclax							32% (12/38) BM
	Ibrutinib							32% (12/38) BM
Venetoclax and Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL)	Venetoclax	78	14	RR CLL	100% (14/14)	64% (9/14)	35% (5/14)	NA	NA	NA	NCT02756897, Phase 2 (Jain et al., 2017)
	Ibrutinib	78	14	RR CLL	100% (14/14)	64% (9/14)	35% (5/14)	NA	NA	NA	NCT02756897, Phase 2 (Jain et al., 2017)
A Study of Venetoclax in Combination With Rituximab Compared With Bendamustine in Combination With Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia	Venetoclax	389	194	RR CLL	93% (180/194)	27% (52/194)	67% (129/194)	84% (163/194) PB	84.9% (24th mo)	NA	NCT02005471, Phase 3 (Seymour et al., 2017b)
	Rituximab		194		93% (180/194)	27% (52/194)	67% (129/194)	84% (163/194) PB	84.9% (24th mo)
	Bendamustin		194		68% (132/194)	8% (16/194)	60% (116/194)	23% (45/194) PB	36.3% (24th mo)
	Rituximab		194		68% (132/194)	8% (16/194)	60% (116/194)	23% (45/194) PB	36.3% (24th mo)
A Study of Venetoclax in Combination With Bendamustine + Rituximab or Bendamustine + Obinutuzumab in Participants With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia (CLL)	Venetoclax	100	30	RR CLL	96% (26/27)	26% (7/27)	70% (19/27)	76% (16/21) ^a Not otherwise specified.	NA	NA	NCT01671904, Phase 1 (Stilgenbauer et al., 2016b)
	Bendamustin
	Rituximab
Bcl-2 Inhibitor GDC-0199 in Combination With Obinutuzumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or Previously Untreated Chronic Lymphocytic Leukemia	Venetoclax	68	10	RR CLL	100% (10/10)	20% (2/10)	80% (8/10)	40% (4/10) BM	NA	NA	NCT02427451, Phase 1/2 (Jones et al., 2016b)
	Ibrutinib
	Obinutuzumab
Sequential Regimen of Bendamustine-Debulking Followed by ABT-199 and GA101-Induction and -Maintenance in CLL (CLL2-BAG)	Venetoclax	66	29	RR CLL	93% (27/29)	10% (3/29)	83% (24/29)	97% (33/34) PB	NA	NA	NCT02758665, Phase 2 (Cramer et al., 2017)
	Bendamustin
	Obinutuzumab

BM = bone marrow; EN = estimated enrollment; N = number of patients; MRD = minimal residual disease; NA = not available; PB = peripheral blood; SLL = small lymphocytic lymphoma.

Update data were presented at EHA 2017. MRD in peripheral blood evaluated in an entire cohort of 158 patients (RR and untreated).

a Not otherwise specified.

Open table in a new tab

Table 2Results of phase 1 and 2 studies in CLL

Title	Regimen	EN	N	Condition	ORR% (N)	CR% (N)	PR% (N)	MRD	PFS	OS	Identifier, Phase (Reference)
A Study of the Efficacy of ABT-199 in Subjects With Relapsed/Refractory or Previously ND Chronic Lymphocytic Leukemia With the 17p Deletion	Venetoclax	158	5	ND CLL	80% (4/5)	40% (2/5)	NA	27% (42/158) PB	100% (12th mo)	100% (12th mo)	NCT01889186, Phase 2 (Stilgenbauer et al., 2017)
A Study of Venetoclax in Combination With Obinutuzumab in Participants With Chronic Lymphocytic Leukemia	Venetoclax	82	32	ND CLL	100% (32/32)	56% (17/32)	44% (14/32)	100% (32/32) PB 65% (20/32) BM	100% (12th mo)	NA	NCT01685892, Phase 1 (Flinn et al., 2017)
	Obinutuzumab	82	32	ND CLL	100% (32/32)	56% (17/32)	44% (14/32)	100% (32/32) PB 65% (20/32) BM	100% (12th mo)	NA	NCT01685892, Phase 1 (Flinn et al., 2017)
A Study to Compare the Efficacy and Safety of Obinutuzumab + Venetoclax (GDC-0199) Versus Obinutuzumab + Chlorambucil in Participants With Chronic Lymphocytic Leukemia	Venetoclax	445	12	ND CLL	100% (12/12)	66% (8/12)	NA	100% (12/12) PB	NA		NCT02242942, Phase 3 (Fischer et al., 2016)
	Obinutuzumab
	Chlorambucil
	Obinutuzumab
Venetoclax and Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL)	Venetoclax	78	16	ND CLL	100% (16/16)	56% (9/16)	44% (7/16)	NA	NA	NA	NCT02756897, Phase 2 (Jain et al., 2017)
	Ibrutinib	78	16	ND CLL	100% (16/16)	56% (9/16)	44% (7/16)	NA	NA	NA	NCT02756897, Phase 2 (Jain et al., 2017)
A Study of Venetoclax in Combination With Bendamustine + Rituximab or Bendamustine + Obinutuzumab in Participants With Relapsed/Refractory or Previously ND Chronic Lymphocytic Leukemia (CLL)	Venetoclax	100	17	ND CLL	100% (14/14)	43% (6/14)	57% (8/14)	67% (6/9) ^a Not otherwise specified.	NA	NA	NCT01671904, Phase 1 (Stilgenbauer et al., 2016b)
	Bendamustin
	Rituximab
	Venetoclax		8	ND CLL	100% (7/7)	43% (3/7)	57% (4/7)	50% (2/4) ^a Not otherwise specified.	NA	NA
	Bendamustin
	Obinutuzumab
Bcl-2 Inhibitor GDC-0199 in Combination With Obinutuzumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or Previously ND Chronic Lymphocytic Leukemia	Venetoclax	68	23	ND CLL	100% (23/23)	50% (12/24)	46% (11/23)	58% (14/23)	NA	NA	NCT02427451, Phase 1/2 (Rogers, et al., 2017)
	Ibrutinib
	Obinutuzumab
Sequential Regimen of Bendamustine-Debulking Followed by ABT-199 and GA101-Induction and -Maintenance in CLL (CLL2-BAG)	Venetoclax	66	34	ND CLL	100% (34/34)	9% (3/34)	91% (31/34)	12% (4/34) BM	NA	NA	NCT02758665, Phase 2 (Cramer et al. , 2017)
	Bendamustin
	Obinutuzumab

SLL = small lymphocytic lymphoma, NA = not available, EN = estimated enrollment, N = number of patients, MRD = minimal residual disease, PB = peripheral blood, BM = bone marrow, ND = newly diagnosed.

Update data were presented at EHA 2017. MRD in peripheral blood evaluated in an entire cohort of 158 patients (RR and ND).

a Not otherwise specified.

Open table in a new tab

Table 3Ongoing phase 2 and 3 clinical trials in RR and ND CLL

Title	Regimen	EN	Condition	Identifier
A Study Venetoclax in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia in the Presence of 17p Deletion	Venetoclax	70	RR CLL	NCT02966756
	Venetoclax	70	RR CLL	Phase 2
A Study Evaluating Venetoclax in Subjects With Chronic Lymphocytic Leukemia Whose Cancer Has Come Back or Who Had No Response to Previous Cancer Treatments Including Subjects Missing Part of Their Chromosome 17, or TP53 Gene Mutation; or Who Received Prior Treatment With a B-Cell Receptor Inhibitor	Venetoclax	200	RR CLL	NCT02980731
	Venetoclax	200	RR CLL	Phase 3
A Study of Venetoclax (GDC-0199; ABT-199) in Combination With Obinutuzumab in Participants With Chronic Lymphocytic Leukemia	Venetoclax	81	RR CLL	NCT01685892
	Obinutuzumab	81	RR CLL	Phase 1
Venetoclax and Ibrutinib in Patients With Relapsed/Refractory CLL or SLL	Venetoclax	20	RR CLL/SLL	NCT03045328
	Ibrutinib	20	RR CLL/SLL	Phase 2
Ibrutinib Plus Venetoclax in Patients With Treatment-naive Chronic Lymphocytic Leukemia /Small Lymphocytic Lymphoma	Venetoclax	150	ND CLL/SLL	NCT02910583
	Ibrutinib	150	ND CLL/SLL	Phase 2
Sequential Regimen of Bendamustine-Debulking Followed by ABT-199 and GA101-Induction and -Maintenance in CLL (CLL2-BAG)	Venetoclax	66	RR CLL	NCT02401503
	Venetoclax		ND CLL	Phase 2
	Bendamustin
	Obinutuzumab
Bcl-2 Inhibitor GDC-0199 in Combination With Obinutuzumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or Previously ND Chronic Lymphocytic Leukemia	Venetoclax	68	RR CLL ^a MRD was evaluated either from bone marrow or peripheral blood.	NCT02427451
	Ibrutinib		ND CLL	Phase 1
	Obinutuzumab		ND CLL	Phase 1
Trial of Ibrutinib Plus Venetoclax Plus Obinutuzumab in Patients With CLL (CLL2-GiVe)	Venetoclax	40	ND CLL	NCT02758665
	Ibrutinib			Phase 2
	Obinutuzumab			Phase 2
Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab + Venetoclax (RVe) Versus Obinutuzumab (GA101) + Venetoclax (GVe) Versus Obinutuzumab + Ibrutinib + Venetoclax (GIVe) in Fit Patients With Previously ND Chronic Lymphocytic leukemia (CLL) Without Del (17p) or TP53 Mutation (GAIA)	FCR	920	ND CLL	NCT02950051
	BR			Phase 3
	Venetoclax
	Rituximab
	Venetoclax
	Obinutuzumab
	Venetoclax
	Ibrutinib
	Obinutuzumab

SLL = small lymphocytic lymphoma, EN = estimated enrollment, N = number of patients, ND = newly diagnosed.

a MRD was evaluated either from bone marrow or peripheral blood.

Open table in a new tab

Table 4Results of phase 1 and 2 clinical trials in NHL, MM, and AML

Title	Regimen	EN	N	Condition	ORR% (N)	CR% (N)	PR% (N)	PFS (median)	OS (1-year)	Identifier, Phase (Reference)
A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma	Venetoclax	106	106	RR NHL	44% (47/106)	13% (14/106)	31% (33/106)	6 m	70%	NCT01328626, Phase 1 (Davids et al., 2017)
			106	RR NHL	44% (47/106)	13% (14/106)	31% (33/106)	14 m	82%
			28	MCL	75% (21/28)	21% (6/28)	54% (15/28)	11 m	100%
			28	MCL	75% (21/28)	21% (6/28)	54% (15/28)	1 m	32%
			29	FL	38% (11/29)	14% (4/29)	24% (7/29)	NA	NA
			29	FL	38% (11/29)	14% (4/29)	24% (7/29)	NA	NA
			34	DLBCL	18% (6/34)	12% (4/34)	6% (2/34)	NA	NA
			7	RT	43% (3/7)	0%	43% (3/7)
			4	WM	100% (4/4)	0%	100% (4/4)
			3	MZL	67% (2/3)	0%	67% (2/3)
A Safety and Pharmacokinetics Study of GDC-0199 (ABT-199) in Patients With Non-Hodgkin's Lymphoma	Venetoclax	248	21	NHL RR/Untreated	86% (18/21)	67% (14/21)	14% (3/21)	NA	NA	NCT02055820, Phase 1 (Zelenetz et al., 2016)
	R-CHOP		21		86% (18/21)	67% (14/21)	14% (3/21)
	Venetoclax		21		81% (17/21)	62% (13/21)	19% (4/21)
	G-CHOP		21		81% (17/21)	62% (13/21)	19% (4/21)
ABT-199 & Ibrutinib in Mantle Cell Lymphoma (AIM) (AIM)	Venetoclax	24	23	RR MCL	71% (17/24)	63% (15/24)	17% (4/24)	NA	NA	NCT02471391, Phase 2 (Tam et al., 2017)
ABT-199 & Ibrutinib in Mantle Cell Lymphoma (AIM) (AIM)	Ibrutinib	24	1	ND MCL	71% (17/24)	63% (15/24)	17% (4/24)	NA	NA	NCT02471391, Phase 2 (Tam et al., 2017)
Study Evaluating ABT-199 in Subjects With Relapsed or Refractory MM	Venetoclax	84	66	RR MM	21% (14/66)	6% (4/66)	15% (10/66)	NA	NA	NCT01794520, Phase 1 (Kumar et al., 2016)
	Venetoclax
	Dexamethasone
A Study Evaluating ABT-199 in Multiple Myeloma Subjects Who Are Receiving Bortezomib and Dexamethasone as Standard Therapy	Venetoclax	66	66	RR MM	68% (44/65)	17% (11/66)	51% (33/66)	NA	NA	NCT01794507, Phase 1 (Moreau et al., 2016)
	Bortezomib
	Dexamethasone
A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia (AML)	Venetoclax	91	61	Elderly ND AML	61% (37/61)	62% (38/61)	2% (1/61)	NA	46%	NCT02287233, Phase 1/2 (Wei et al., 2017)
	LD-Cytarabine	91	61	Elderly ND AML	61% (37/61)	62% (38/61)	2% (1/61)	NA	46%	NCT02287233, Phase 1/2 (Wei et al., 2017)
Phase 1b Acute Myelogenous Leukemia (AML) Study With ABT-199 + Decitabine or Azacitidine (Chemo Combo)	Venetoclax	260	145	Elderly ND AML	68% (97/145)	NA	NA	17.5 m	NA	NCT02203773, Phase 1 (DiNardo et al., 2017)
	5-Azacitidine
	Venetoclax
	Decitabine

EN = estimated enrollment, LD = low-dose, ND = newly diagnosed, N = number of patients.

Open table in a new tab

Table 5Ongoing clinical trials in NHL, MM, and AML

Title	Regimen	EN	Condition	Identifier
Non-Hodgkin lymphoma
A Study Evaluating the Safety and Efficacy of GDC-0199 Plus Bendamustine + Rituximab (BR) in Comparison With BR or GDC-0199 Plus Rituximab in Participants With Relapsed and Refractory Follicular Non-Hodgkin's Lymphoma (fNHL)	Venetoclax	165	RR FL	NCT02187861
	Venetoclax			Phase 2
	Rituximab
	Venetoclax
	BR
	BR
Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma	Venetoclax	41	RR FL	NCT02956382
	Ibrutinib	41	RR FL	Phase 2
Combination of Obinutuzumab and Venetoclax in Relapsed or Refractory DLBCL	Venetoclax	21	RR DLBCL	NCT02987400
	Obinutuzumab	21	RR DLBCL	Phase 2
Study of Venetoclax in Combination With Carfilzomib and Dexamethasone in Subjects With Relapsed or Refractory MM	Venetoclax	40	RR MM	NCT02899052
	Carfilzomib			Phase 2
	Dexamethasone			Phase 2
Study of Ibrutinib Combined With Venetoclax in Subjects With Mantle Cell Lymphoma (SYMPATICO)	Venetoclax	287	RR MCL	NCT03112174
	Venetoclax			Phase 3
	Ibrutinib
	Ibrutinib
MM
A Study Evaluating Venetoclax (ABT-199) in Multiple Myeloma Subjects Who Are Receiving Bortezomib and Dexamethasone as Standard Therapy	Venetoclax	240	RR MM	NCT02755597
	Bortezomib			Phase 3
	Dexamethasone
	Placebo
	Bortezomib
	Dexamethasone
Acute myeloid leukemia
A Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment Naïve Subjects With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy	Venetoclax	400	Elderly	NCT02993523
	5-Azacitidine		ND AML	Phase 3
	Placebo
	5-Azacitidine
A Study of Venetoclax in Combination With Low Dose Cytarabine Versus Low Dose Cytarabine Alone in Treatment Naïve Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy	Venetoclax	175	Elderly	NCT03069352
	LD-Cytarabine		ND AML	Phase 3
	Placebo
	LD-Cytarabine
Study of the BCL-2 Inhibitor Venetoclax in Combination With Standard Intensive Acute Myeloid Leukemia (AML) Induction/Consolidation Therapy With FLAG-IDA in Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML)	Venetoclax	56	ND or RR AML	NCT03214562
	FLAG-IDA	56	ND or RR AML	Phase 1/2
A Study of Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients Aged >/=60 Years With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy	Venetoclax	140	Elderly	NCT02670044
	cobimetinib		RR AML	Phase 1/2
	Venetoclax
	Idasanutlin

BR = bendamustin plus rituximab, ND = newly diagnosed, LD = low dose, FLAG-IDA = fludarabine, cytosinearabinoside, idarubicine, EN = estimated enrollment.

Open table in a new tab

Table 6Chemotherapeutic and targeted agents, monoclonal antibodies, and combined regimens

Chemical name	Agent	Pharmacology	Regimen
Rituximab	mAb, anti-CD20	Induction of CDC, ADCC	FCR, BR, R-CHOP, RClb
Obinutuzumab	mAb, anti-CD20	Induction of direct cell death, ADCC, ADCP, CDC	R-CHOP, G-CHOP
Cyclophosphamide	Alkylating agent	Inhibition of DNA synthesis	R-CHOP, G-CHOP
Chlorambucil	Alkylating agent	Inhibition of DNA synthesis	RClb
Bendamustine	Alkylating agent	Inhibition of DNA and RNA synthesis, Induction of apoptosis, activation of p53	BR
Doxorubicin	Anthracycline antibiotic	Inhibition of DNA and RNA synthesis	R-CHOP, G-CHOP
Cytarabine	Antimetabolite—pyrimidine analogue	Inhibition of DNA polymerase	LDAC
Fludarabine	Antimetabolite—purine analogue	Inhibition of DNA polymerase and ribonucleotide reductase	FCR
5-azacytidine	Antimetabolite—pyrimidine analogue, demethylation agent	Hypomethylation of DNA, impairment of trna	5-Aza
Decitabine	Antimetabolite -cytidine analogue, demethylation agent	Hypomethylation of DNA, arrest of DNA synthesis	Decitabine
Vincristine	Vinca alkaloid	Arrest tumor cells in metaphase	R-CHOP, G-CHOP
Dexamethasone	Synthetic glucocorticoid	Inhibition of DNA synthesis	VD
Prednisone	Synthetic glucocorticoid	Inhibition of DNA synthesis	R-CHOP, G-CHOP
Ibrutinib	B-cell receptor inhibitor	Inhibition of Bruton's tyrosine kinase	Ibrutinib
Idelalisib	B-cell receptor inhibitor	Inhibition of Phosphatidylinositol 3-kinase	Idelalisib
Venetoclax	Inhibitor of anti-apoptotic proteins	BCL2 inhibitor	Venetoclax
Bortezomib	Proteasome inhibitor	Inhibition of the 26S proteasome	VD

R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, G-CHOP = obinutuzumab, cyclophosphamide, doxorubicin, vincristine, prednisone, FCR = fludarabine, cyclophosphamide, rituximab, RClb = rituximab, chlorambucil, BR = bendamustin, rituximab, LDAC = low-dose cytarabine, VD = bortezomib, dexamethasone, 5-Aza = 5-azacytidine, CDC = complement-dependent cytotoxicity, ADCC = antibody-dependent cellular cytotoxicity, ADCP = antibody-dependent cellular phagocytosis, mAb = monoclonal antibody.

Open table in a new tab

Venetoclax: mechanism of action

Venetoclax (ABT-199, GDC-0199, Venclexta™) is a unique, small, and highly selective orally bioavailable molecule that was designed to target specifically the BH3 domain of BCL2 [

42

Souers A.J.
Leverson J.D.
Boghaert E.R.
et al.

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.

]. As a BH3 mimetic, venetoclax displays a high affinity to the BH3-binding groove of BCL2 and is able to displace pro-apoptotic BH3-only proteins (e.g., BIM) bound to BCL2. Therefore, free BH3-only proteins can activate apoptotic effectors (BAX and BAK) or inhibit other anti-apoptotic members (MCL-1). Therefore, venetoclax triggers and restores apoptosis in tumor cells by releasing pro-apoptotic proteins from BCL2 [

43

Konopleva M.
Contractor R.
Tsao T.
et al.

Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.

] (Fig. 1).

Figure 1In cancer cells, the anti-apoptotic protein BCL22 sequesters and blocks the function of BH3-only pro-apoptotic proteins (e.g., BIM) and therefore prevents apoptosis. The BH3-only mimetic compound venetoclax displaces and reactivates pro-apoptotic proteins bound to the BH3-binding groove of BCL2. Consequently, released pro-apoptotic proteins associate with the apoptotic effectors BAX and BAK and induce permeabilization of the mitochondrial outer membrane. Cytochrome c released from mitochondria then activates caspases and triggers cell death.
View Large Image
Figure Viewer
Download Hi-res image
Download (PPT)

Venetoclax is highly bound to plasma proteins (>99%), with a terminal half-life of 16–19 hours [

44

Roberts A.W.
Davids M.S.
Pagel J.M.
et al.

Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia.

,

45

Salem A.H.
Agarwal S.K.
Dunbar M.
Enschede S.L.H.
Humerickhouse R.A.
Wong S.L.

Pharmacokinetics of venetoclax, a novel BCL-2 inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or non-Hodgkin lymphoma.

]. Peak concentrations have been observed after 4–5 hours and have been delayed by approximately 2 hours when taken with a meal (high-fat meal) [

46

Salem A.H.
Agarwal S.K.
Dunbar M.
et al.

Effect of low- and high-fat meals on the pharmacokinetics of venetoclax, a selective first-in-class BCL-2 inhibitor.

]. Venetoclax is metabolized by CYP3A4 and CYP3A5 and it is a substrate for the P-glycoprotein efflux pump [

45

Salem A.H.
Agarwal S.K.
Dunbar M.
Enschede S.L.H.
Humerickhouse R.A.
Wong S.L.

Pharmacokinetics of venetoclax, a novel BCL-2 inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or non-Hodgkin lymphoma.

,

47

Agarwal S.K.
Hu B.
Chien D.
Wong S.L.
Salem A.H.

Evaluation of rifampin's transporter inhibitory and CYP3A inductive effects on the pharmacokinetics of venetoclax, a BCL-2 inhibitor: results of a single- and multiple-dose study.

]. Concomitant therapy with strong CYP3A inhibitors or P-glycoprotein inhibitors should be avoided, but if they are necessary, then venetoclax reduction is required (≥75% and 50% dose reduction in concomitant use of CYP3A and P-glycoprotein inhibitors). There is only minimal excretion of the intact drug in urine [

45

Salem A.H.
Agarwal S.K.
Dunbar M.
Enschede S.L.H.
Humerickhouse R.A.
Wong S.L.

Pharmacokinetics of venetoclax, a novel BCL-2 inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or non-Hodgkin lymphoma.

] and its clearance does not appear to be affected in patients with mild to moderate renal or hepatic impairment [

48

Freise K.J.
Jones A.K.
Eckert D.
et al.

Impact of venetoclax exposure on clinical efficacy and safety in patients with relapsed or refractory chronic lymphocytic leukemia.

]. However, it has not been studied in patients with severe abnormalities of kidney or liver functions.

Chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia arising from clonal mature B lymphocytes with a characteristic immunophenotype [

49

Ginaldi L.
De Martinis M.
Matutes E.
Farahat N.
Morilla R.
Catovsky D.

Levels of expression of CD19 and CD20 in chronic B cell leukaemias.

]. Although it is an indolent malignancy, its clinical course is variable and prognosis is predicted according to present genetic lesions. More than 80% of CLL cases have classified genomic aberrations, including the most frequent deletions (del)13q (55%), del11q (18%), del17p (8%), and trisomy 12 (12–16%) [

21

Döhner H.
Stilgenbauer S.
Benner A.
et al.

Genomic aberrations and survival in chronic lymphocytic leukemia.

].

Investigation of the BCL2 protein has revealed that nearly all patients have increased BCL2 expression in CLL cells [

50

Hanada M.
Delia D.
Aiello A.
Stadtmauer E.
Reed J.C.

bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia.

,

51

O'Brien S.
Moore J.O.
Boyd T.E.
et al.

Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia.

,

52

Schena M.
Larsson L.G.
Gottardi D.
et al.

Growth- and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells.

]. Translocations such as t(14;18)(q32;q21), t(2;18)(p11;q21.3), and t(18;22)(q21.3;q11) are rarely detected [

53

Dyer M.J.
Zani V.J.
Lu W.Z.
et al.

BCL2 translocations in leukemias of mature B cells.

]. Another reason for BCL2 overexpression is the loss of the tumor suppressor genes microRNA 15 (miR15) and miR16, which are located on the 13q14 chromosome region. miR15 and miR16 interact directly with and inhibit BCL2 and several other oncogenes (e.g., MCL1 and BMl1). Therefore, del 13q14 results in the loss of miR15 and miR16 function and enables increase of BCL2 protein in 50% of CLL patients [

17

Calin G.A.
Dumitru C.D.
Shimizu M.
et al.

Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.

,

19

Pekarsky Y.
Croce C.M.

Role of miR-15/16 in CLL.

,

54

Cimmino A.
Calin G.A.
Fabbri M.
et al.

miR-15 and miR-16 induce apoptosis by targeting BCL2.

].

In April 2016, the U.S. Food and Drug Administration approved venetoclax as monotherapy for the treatment of relapsed/refractory (RR) CLL with del17p. The overall response rate (ORR) in the initial phase 1 study in patients with RR CLL/SLL (median of three previous therapies) was achieved by 79% (92/116) and complete remission (CR) occurred in 20% (23/116). Almost no differences were observed in the subgroup of patients with del17p (ORR and CR were 71% [22/31] and 16% [5/31], respectively) Progression-free survival (PFS) at 15 months was estimated to be 66% (median PFS was 16 months for CLL with del17p and median PFS was not reached for CLL with unmutated chromosome 17) and the 2-year overall survival (OS) for all cohorts was 84%. Compared with other options for RR CLL, 68% and 63% of patients responded to bendamustin plus rituximab (BR) and ibrutinib, respectively, and 83% with del17p response to ibrutinib monotherapy. Clinical tumor lysis syndrome (TLS) occurred in three cases, with one death after step-up to 1200 mg per day. Other most common serious adverse events (AEs) (grade 3–4) were neutropenia, febrile neutropenia, pneumonia, upper respiratory tract infection, and immune thrombocytopenia [

44

Roberts A.W.
Davids M.S.
Pagel J.M.
et al.

Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia.

]. In a phase 2 study, 107 patients with RR CLL (median of two previous therapies) with del17p received venetoclax in monotherapy. Response occurred in 79% (85/107), with 8% (8/107) achieving CR. One-year PFS and OS were 72% and 87%, respectively [

55

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.

]. Another phase 2 study assessed the efficacy of venetoclax monotherapy in the treatment of patients who relapsed after, or were refractory to, a B-cell receptor inhibitor (idelalisib or ibrutinib). In arm A (prior ibrutinib for a median of 17 months), 70% (30/43) of patients responded to the administered drug and 2% (1/43) achieved CR; 57% (10/21) patients in arm B (prior idelalisib for a median of 8 months) responded with partial remission (PR) as the best response. One-year PFS and OS were 72% and 90%, respectively, for all patients. The majority of both arms were refractory to ibrutinib (91%) or idelalisib (67%). Hematological toxicity (neutropenia, anemia, and thrombocytopenia), febrile neutropenia, and pneumonia were the most common grade 3–4 AEs [

56

Jones J.
Choi M.Y.
Mato A.R.
et al.

Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib.

].

Venetoclax in combination with rituximab was investigated in a phase 1 study in RR CLL (median of two previous therapies) and the combination regimen was effective in 86% (42/49) of patients, with 51% (25/49) obtaining CR. The 2-year estimated PFS and OS were 82% and 89%, respectively. Toxicity appeared to be similar to venetoclax in monotherapy, including two clinical significant TLS cases, one of which ended in death [

57

Seymour J.F.
Ma S.
Brander D.M.
et al.

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.

]. Promising outcomes were obtained by untreated and RR CLL patients (median of one previous therapy) who were administered obinutuzumab, ibrutinib, and venetoclax. At the time of data analysis, 10 RR patients had completed eight cycles (ORR and CR were 100% [10/10] and 20% [2/10], respectively) [

56

Jones J.
Choi M.Y.
Mato A.R.
et al.

Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib.

] and 32 untreated patients completed six cycles (ORR and CR were 100% [32/32] and 56% [17/32], respectively) [

58

Rogers K.A.
Huang Y.
Stark A.
Jones J.A.

Initial results of the phase 2 treatment-naïve cohort in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax in CLL.

Google Scholar

]. Observed toxicities for the combination were consistent with those reported for the single agents, with neutropenia, lymphopenia, hypertension, and fatigue as the most common AEs and no cases of TLS [

56

Jones J.
Choi M.Y.
Mato A.R.
et al.

Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib.

]. Untreated and RR CLL (median of one previous therapy) were enrolled in a phase 1 study of standard chemoimmunotherapy: BR combined with venetoclax. In the group of untreated and RR CLL, ORR reached 100% (14/14) and 96% (26/27) with 43% (6/14) and 26% (7/27) of CR, respectively. In the same study, bendamustin plus obinutuzumab (BG) and venetoclax were administered to seven untreated CLL patients with similar outcomes to BR plus venetoclax (ORR 100%, CR 43% [3/7]). Hematologic toxicity was the most serious across all groups and diarrhea with fatigue appeared most often as a nonhematologic toxicity [

59

Stilgenbauer S.
Morschhauser F.
Wendtner C.M.
et al.

Phase Ib study (GO28440) of venetoclax with bendamustine/rituximab or bendamustine/obinutuzumab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia.

Google Scholar

]. Outcomes of a phase 2 study with the same combination (BG plus venetoclax) were presented at the European Haematology Association (EHA) 2017 meeting. Responses were similar to the phase 1 study (ORR 100% [34/34] and 93% [27/29], CR 9% [3/34] and 10% [3/29] for untreated and RR CLL, respectively). More AEs occurred in the RR cohort than in untreated patients [

60

Cramer P.
von Tresckow J.
Bahlo J.
et al.

Bendamustine (B), followed by obinutuzumab (G, GA101) and venetoclax (A, ABT-199) in patients with chronic lymphocytic leukemia (CLL): CLL2-BAG Phase-II-trial of the German CLL study group (GCLLSG) EHA Learning Center.

Google Scholar

]. A randomized phase 3 trial (CLL14) compares the efficacy and safety of obinutuzumab and venetoclax with obinutuzumab and chlorambucil in patients with previously untreated CLL with coexisting medical conditions (CIRS > 6). Response was obtained by all patients, with 66% (8/12) of patients obtaining CR and neither progression nor death at 15 months of treatment monitored [

61

Fischer K.
Al-Sawaf O.
Fink A.-M.
Dixon M.
Bahlo J.
Hallek M.

Safety and efficacy of venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting medical conditions: final results of the run-in phase of the randomized CLL14 Trial (BO25323.

Google Scholar

]. Early results of phase 2 study in RR CLL (median of two previous therapies) suggest a potent synergy between ibrutinib and venetoclax (ORR and CR were 100% [38/38] and 47% [18/38], respectively) with acceptable toxicity and TLS only in two patients thus far [

62

Hillmen P.
Munir T.
Rawstron A.
et al.

Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY Study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy.

Google Scholar

]. Similar results were achieved in RR patients (ORR and CR were 100% [14/14] and 64% [9/14], respectively) and untreated patients (ORR and CR were 100% [19/19] and 56% [9/16], respectively) in another trial with the same combination [

63

Jain N.
Thompson P.A.
Ferrajoli A.
et al.

Combined venetoclax and ibrutinib for patients with previously untreated high-risk CLL, and relapsed/refractory CLL: a phase II trial.

Google Scholar

].

There is an ongoing phase 3 trial comparing a combination regimen of venetoclax plus monoclonal antibody (rituximab or obinutuzumab) or venetoclax, ibrutinib plus obinutuzumab with standard chemoimmunotherapy, BR and FCR (fludarabine, cyclophosphamide, and rituximab). All available results of completed and ongoing clinical trials are summarized in Table 1, Table 2, Table 3.

Mantle cell lymphoma

Mantle cell lymphoma (MCL) is usually represented as an aggressive B-cell lymphoma developing from naive B cells [

64

Swerdlow S.H.
Campo E.
Pileri S.A.
et al.

The 2016 revision of the World Health Organization classification of lymphoid neoplasms.

]. It is associated with translocation t(11;14)(q13;q32), resulting in overexpression of cyclin D1 in 70–95% of cases [

65

Ives Aguilera N.S.
Bijwaard K.E.
Duncan B.
et al.

Differential expression of cyclin D1 in mantle cell lymphoma and other non-Hodgkin's lymphomas.

,

66

Leroux D.
Marc'hadour F.L.
Gressin R.
et al.

Non-Hodgkin's lymphomas with t (11;14) (q13;q32): a subset of mantle zone/intermediate lymphocytic lymphoma?.

,

67

Vandenberghe E.
De Wolf Peeters C.
Wlodarska I.
et al.

Chromosome 11q rearrangements in B non-Hodgkin's lymphoma.

]. Despite the presence of this aberration, additional genetic changes (loss of tumor suppressor genes TP53, ATM, and CDKN2A or gain of oncogenes BCL2, C-MYC, SYK) are usually required for malignant transformation [

68

Ghielmini M.
Zucca E.

How I treat mantle cell lymphoma.

].

Nearly all (95%) clonal cells are BCL2 positive in MCL [

65

Ives Aguilera N.S.
Bijwaard K.E.
Duncan B.
et al.

Differential expression of cyclin D1 in mantle cell lymphoma and other non-Hodgkin's lymphomas.

]. Benz et al. identified amplification of the 18q21–22 locus in several cases and also pointed out the presence of del13q14 that was shown to be responsible for BCL2 activation in CLL [

69

Bentz M.
Plesch A.
Bullinger L.
et al.

t (11;14)-positive mantle cell lymphomas exhibit complex karyotypes and share similarities with B-cell chronic lymphocytic leukemia.

]. Gain of c-MYC, which is involved in oncogenesis, might contribute to BCL2 overexpression as well [

70

Hemann M.T.
Bric A.
Teruya-Feldstein J.
et al.

Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants.

].

In an initial phase 1 study of RR non-Hodgkin's lymphoma (NHL) (106 patients), the cohort of RR MCL (median of three previous therapies) was one of the best responding groups achieving ORR and CR in 75% (21/28) and 21% (6/28), respectively. One-year OS was demonstrated in 82% and median PFS was 14 months. The most common grade 3–4 toxicity was hematological (anemia, neutropenia, and thrombocytopenia) and only a few cases of hyponatremia and infections (lower respiratory tract infection and influenza) occurred during treatment. No clinical TLS was observed [

71

Davids M.S.
Roberts A.W.
Seymour J.F.
et al.

Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma.

]. The combination of venetoclax and ibrutinib was investigated in a phase 2 study in RR MCL (95%, median of two previous therapies, 30% failed to autologous stem cell transplantation) and untreated MCL (5%). ORR and CR were achieved in 71% (17/24) and 63% (15/24) of all patients and estimates of PFS and OS were 74% and 81%, respectively, at 8 months. TLS occurred in two cases with high tumor burden, leading to revision of the protocol (venetoclax starting dose from 50 to 20 mg per day) [

72

Tam C.S.L.
Roberts A.W.
Anderson M.A.
et al.

Combination ibrutinib (Ibr) and venetoclax (Ven) for the treatment of mantle cell lymphoma (MCL): primary endpoint assessment of the phase 2 AIM study.

Google Scholar

]. A phase 3 trial comparing venetoclax plus ibrutinib with ibrutinib or venetoclax monotherapy is ongoing (Table 5).

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma morphologically classified by the diffuse growth of mature neoplastic large B lymphoid cells [

73

Campo E.
Swerdlow S.H.
Harris N.L.
Pileri S.
Stein H.
Jaffe E.S.

The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.

]. It comprises several distinct histologic, immunophenotypic, and genetic subgroups. The most common aberrations involve mutations of the BCL6 (30%), BCL2 (20–30%), and c-MYC (5–22%) genes [

74

Kramer M.H.
Hermans J.
Wijburg E.
et al.

Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma.

,

75

Li S.
Lin P.
Young K.H.
Kanagal-Shamanna R.
Yin C.C.
Medeiros L.J.

MYC/BCL2 double-hit high-grade B-cell lymphoma.

,

76

Saito M.
Gao J.
Basso K.
et al.

A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma.

]. Translocation t(14;18)(q32;q21) and amplification of 18q21-23 are responsible for BCL-2 overexpression in 20–30% and 21% of DLBCL, respectively [

18

Monni O.
Joensuu H.
Franssila K.
Knuutila S.

DNA copy number changes in diffuse large B-cell lymphoma–comparative genomic hybridization study.

,

20

Tsujimoto Y.
Finger L.R.
Yunis J.
Nowell P.C.
Croce C.M.

Cloning of the chromosome breakpoint of neoplastic B cells with the t (14;18) chromosome translocation.

]. Double-hit DLBCL is a subgroup with poor clinical outcome that harbors concurrent gene rearrangement of c-MYC and the BCL2, BCL6, or BCL3 proto-oncogene. It represents less than 10% of DLBCL, with the most frequent MYC/BCL2 subtype carrying translocation of c-MYC and t(14;18)(q32;q21) [

77

Aukema S.M.
Siebert R.
Schuuring E.
et al.

Double-hit B-cell lymphomas.

].

In a phase 1 study, venetoclax monotherapy was administered to 34 patients with RR DLBCL (median of three previous therapies). The drug was effective in 18% (6/34) and 12% (4/34) of patients reached CR. However, the responses did not last long and were the shortest among all types of RR NHL. Median PFS was 1 month and 1-year OS was achieved by 12%. Venetoclax was well tolerated and no TLS was observed [

71

Davids M.S.
Roberts A.W.
Seymour J.F.
et al.

Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma.

].

Preliminary data of combination therapy, venetoclax plus R-CHOP/G-CHOP (rituximab/obinutuzumab, cyclophosphamide, doxorubicin, vincristine and prednisone) were published at ASH 2016. Patients (24 follicular lymphoma [FL], 17 DLBCL, five marginal zone lymphoma [MZL], 10 others) with untreated disease (91%) or RR disease (9%, one previous therapy) were enrolled. Demonstrated results were presented for all NHL (untreated and RR) types together and they were nearly the same in both cohorts (R-CHOP and G-CHOP). Patients treated with venetoclax plus R-CHOP achieved ORR and CR in 86% (18/21) and 67% (14/21) of patients, respectively, and in the arm with venetoclax plus G-CHOP, ORR and CR were 81% (17/21) and 62% (13/21), respectively. Toxicity seemed to be higher than in venetoclax monotherapy and mainly presented as neutropenia, febrile neutropenia, and thrombocytopenia without TLS [

78

Zelenetz A.D.
Salles G.A.
Mason K.D.
et al.

Results of a phase Ib Study of venetoclax plus R- or G-CHOP in patients with B-cell non-Hodgkin lymphoma.

].

FL

FL represents an indolent lymphoproliferative disease arising from malignant germinal center B cells (centrocytes and centroblasts) [

79

Kridel R.
Mottok A.
Farinha P.
et al.

Cell of origin of transformed follicular lymphoma.

] undergoing histologic transformation (typically to DLBCL) in 30–40% of cases [

80

Montoto S.
Fitzgibbon J.

Transformation of indolent B-cell lymphomas.

]. Translocation t(14;18)(q32;q21) is present in 80–90% cases [

81

Horsman D.E.
Gascoyne R.D.
Coupland R.W.
Coldman A.J.
Adomat S.A.

Comparison of cytogenetic analysis, southern analysis, and polymerase chain reaction for the detection of t (14; 18) in follicular lymphoma.

], but other aberrations might be caused by various genes, including c-MYC and TP53 [

82

Lossos I.S.
Alizadeh A.A.
Diehn M.
et al.

Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes.

].

In a phase 1 study of RR NHL, venetoclax in monotherapy was given to 29 patients with RR FL (median of three previous therapies). Treatment was successful in 38% (11/29) and 14% (4/29) of CRs were observed. All patients were alive in the first year and the estimated median PFS was 11 months. Toxicity was acceptable and similar to all groups/types of NHL [

71

Davids M.S.
Roberts A.W.
Seymour J.F.
et al.

Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma.

].

Combination of venetoclax plus standard immunochemotherapy (R-CHOP/G-CHOP) was investigated in a phase 1 study in 24 patients with untreated or RR FL (one previous therapy). Preliminary results were published for the whole cohort of NHL together. ORR and CR were 86% (18/21) and 67% (14/21) versus 81% (17/21) and 62% (13/21), respectively, in venetoclax plus R-CHOP versus enetoclax plus G-CHOP. Most common grade 3–4 AEs (neutropenia, febrile neutropenia, and thrombocytopaenia) occurred more frequently than in venetoclax monotherapy [

78

Zelenetz A.D.
Salles G.A.
Mason K.D.
et al.

Results of a phase Ib Study of venetoclax plus R- or G-CHOP in patients with B-cell non-Hodgkin lymphoma.

]. Finally, several studies with rituximab, ibrutinib, bendamustine, and rituximab were designed to find the best combination for venetoclax (Table 5).

MZL

MZL is an indolent lymphoma that arises from memory B cells that are present in the marginal zone of lymphoid tissue. Chromosomal changes such as trisomy 3, trisomy 18, and t(11;18)(q21;q21) are commonly seen in the extranodal subtype and other specific mutations such as t(1;14)(p22;q32), t(14;18)(q32;q21), t(3;14)(p14;q32) and del17p13 are recorded only rarely [

83

Braggio E.
Dogan A.
Keats J.J.
et al.

Genomic analysis of marginal zone and lymphoplasmacytic lymphomas identified common and disease-specific abnormalities.

].

Several subtypes of MZL are BCL2 positive (nodal and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue), whereas others (splenic) are negative [

84

Ortolani C.

Flow cytometry of hematological malignancies.

], but little is known about the pathogenesis of BCL2 expression in MZL. In the initial study for RR NHL, venetoclax has shown efficacy in 67% (2/3) of patients, with PR as the best response. To correctly interpret outcomes of venetoclax treatment, a bigger cohort of patients must be assessed [

71

Davids M.S.
Roberts A.W.
Seymour J.F.
et al.

Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma.

].

Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is a B-cell neoplasm manifested by accumulation of the monoclonal immunoglobulin M secreted by lymphoplasmacytic cells. Malignancy is associated with somatic mutations of MYD88 and CXCR4 in 90% and 30% of cases, respectively [

85

Hunter Z.R.
Xu L.
Yang G.
et al.

The genomic landscape of Waldenström macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis.

,

86

Treon S.P.
Xu L.
Yang G.
et al.

MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.

].

In several in vitro experiments, overexpressed BCL2 was detected in malignant cells [

87

Chng W.J.
Schop R.F.
Price-Troska T.
et al.

Gene-expression profiling of Waldenström macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma.

,

88

Hatjiharissi E.
Mitsiades C.S.
Bryan C.T.
et al.

Comprehensive molecular characterization of malignant and microenvironmental cells in Waldenstrom's macroglobulinemia by gene expression profiling.

Google Scholar

]. Subsequently, venetoclax demonstrated effective induction of apoptosis alone and in combination with either ibrutinib or idelalisib ex vivo (including WM cells with CXCR4 mutation), so it is speculated that it will be able to overcome the resistance of CXCR4-mutated WM in vivo as well [

89

Cao Y.
Yang G.
Hunter Z.R.
et al.

The BCL2 antagonist ABT-199 triggers apoptosis, and augments ibrutinib and idelalisib mediated cytotoxicity in CXCR4 wild-type and CXCR4 WHIM mutated Waldenstrom macroglobulinaemia cells.

]. All four RR WM patients (median of four previous therapies) responded to venetoclax monotherapy, with PR as the best response. Toxicity was the same as in the whole group of NHL [

71

Davids M.S.
Roberts A.W.
Seymour J.F.
et al.

Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma.

].

Multiple myeloma

Multiple myeloma (MM) is a genetically heterogeneous malignant disorder caused by the proliferation and accumulation of clonal plasma cells and is almost always associated with the presence of monoclonal immunoglobulin in the serum and/or urine [

90

Jelinek T.
Hajek R.

PD-1/PD-L1 inhibitors in multiple myeloma: the present and the future.

,

91

Jelinek T.
Hajek R.

Monoclonal antibodies: a new era in the treatment of multiple myeloma.

].

MM is a heterogeneous disease due to its dependence on anti-apoptotic proteins such as BCL2, BCL_XL_L, or MCL-1 and it is currently not known what proportion of MM patients are likely to be BCL2 dependent [

92

Touzeau C.
Ryan J.
Guerriero J.
et al.

BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics.

]. Nevertheless, it has been demonstrated in MM cell lines and primary patient samples that venetoclax is highly effective in a specific subset of MM with translocation t(11;14), mainly due to the higher BCL2/MCL-1 mRNA ratio. Interestingly, venetoclax remains active in this subgroup of MM even if the high-risk 17p deletion is present [

93

Touzeau C.
Dousset C.
Le Gouill S.
et al.

The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t (11;14) multiple myeloma.

,

94

Touzeau C.
Le Gouill S.
Mahé B.
et al.

Deep and sustained response after venetoclax therapy in a patient with very advanced refractory myeloma with translocation t (11;14).

]. Moreover, it has been shown that this drug works synergistically with dexamethasone and is able to increase the expression of BCL2 and BIM, so MM cells become more sensitive to venetoclax [

95

Matulis S.M.
Gupta V.A.
Nooka A.K.
et al.

Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax.

].

In a phase 1 clinical trial with venetoclax monotherapy, 66 RR MM patients with a median of five previous therapies were enrolled overall. The ORR for all patients was 21% (14/66), with 15% (10/66) reaching very good partial response (VGPR, decrease of more than 90% of M-protein) or better. In the subset of MM patients with t(11;14), ORR was 40% (12/30), with 27% (8/30) achieving VGPR or better. Conversely, in patients without t(11;14), almost no responses were observed (ORR: 6%) [

96

Kumar S.
Vij R.
Kaufman J.L.
et al.

Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study.

]. In another phase 1b trial, the combination of venetoclax with bortezomib and dexamethasone was investigated in the cohort of 66 RRMM patients with a median of three previous therapies. The ORR was 67% for all patients (44/66), with 42% (28/66) of patients reaching VGPR or better. The ORR for patients with or without t(11;14) was 78% versus 65% and with or without del(17p) was 47% versus 73%, respectively. Venetoclax alone or in combination had an acceptable safety profile in both of these phase 1 trials, with the most common AEs grade 3/4 being thrombocytopenia, anemia, neutropenia, and infectious complications [

97

Moreau P.
Chanan-Khan A.A.
Roberts A.W.
et al.

Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma.

]. There is an ongoing phase 3 clinical trial comparing bortezomib and dexamethasone plus venetoclax versus bortezomib and dexamethasone plus placebo (Table 5).

Acute myeloid leukemia

Acute myeloid leukemia (AML) is a biologically heterogeneous clonal disorder of undifferentiated myeloid precursors resulting in impaired hematopoiesis and bone marrow failure [

98

Jelinek T.
Mihalyova J.
Kascak M.
Duras J.
Hajek R.

PD-1/PD-L1 inhibitors in haematological malignancies: update 2017.

,

99

Papaemmanuil E.
Gerstung M.
Bullinger L.
et al.

Genomic classification and prognosis in acute myeloid leukemia.

].

AML cells are dependent on BCL2 for survival [

43

Konopleva M.
Contractor R.
Tsao T.
et al.

Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.

]. Overexpression of this anti-apoptotic protein is also implicated in chemotherapy resistance, even though the mechanism of overexpression has not yet been fully described [

100

Saygin C.
Carraway H.E.

Emerging therapies for acute myeloid leukemia.

]. Importantly, venetoclax spares normal hematopoietic stem cells that are more dependent on MCL-1 for their survival [

101

Opferman J.T.
Iwasaki H.
Ong C.C.
et al.

Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells.

,

102

Pan R.
Hogdal L.J.
Benito J.M.
et al.

Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia.

]. The first evidence of venetoclax efficacy was proposed by Pan et al., who demonstrated selective blast killing in AML cell lines, primary patient samples, and murine primary xenografts by this agent [

102

Pan R.
Hogdal L.J.
Benito J.M.
et al.

Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia.

].

Preclinical studies revealed that patients with mutated isocitrate dehydrogenase proteins 1 and 2 (IDH 1/2, approximately 15% of AML) are more likely to respond to BCL2 inhibition by venetoclax [

103

Chan S.M.
Thomas D.
Corces-Zimmerman M.R.
et al.

Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia.

]. In the first clinical trial investigating venetoclax monotherapy (800 mg daily) in 32 high-risk RR AML patients, the ORR was 19%. However, 38% (12/32) had IDH 1/2 mutations, of whom 33% (4/12) reached CR or CR with incomplete blood count recovery (CRi), confirming this preclinical finding. Common AEs grade 3/4 included nausea, vomiting, diarrhea, febrile neutropenia, and hypokalemia [

104

Konopleva M.
Pollyea D.A.
Potluri J.
et al.

Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia.

]. Preclinical investigation (by RNA interference drug modifier screens) identified the potential synergistic role of BCL2 family protein inhibitors with 5-azacytidine (5-Aza). Preliminary results of the phase 1 clinical trial investigating the combination of venetoclax plus either 5-Aza or decitabine in newly diagnosed >65-year-old AML patients ineligible for intensive chemotherapy were presented at ASH 2017. Overall, 145 patients were enrolled in four arms (comparing 400 or 800 mg doses of venetoclax with each hypomethylating agent), with the ORR being 67% (97/145).The median OS in all patients was 17.5 months. The emerging clinical and exposure response data demonstrated that 400 mg venetoclax has the best benefit-risk profile. A phase 3 study of 400 mg venetoclax combined with AZA is under way. The most frequent grade 3/4 AEs were hematologic toxicities and febrile neutropenia [

105

DiNardo C.D.
Pollyea D.A.
Jonas B.A.
et al.

Updated safety and efficacy of venetoclax with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia.

Google Scholar

]. Another logical combination of venetoclax is with low-dose cytarabine (LDAC); this is considered as a current standard of care in the elderly AML patient population, with an expected ORR of maximum 20%. Sixty-one patients were enrolled in a phase 1/2 study with 600 mg venetoclax; 62% (38/61) of these patients achieved CR/CRi with a median duration of CR/CRi of 14.9 months. Treatment-emergent grade 3/4 AEs (in ≥20% of 61 patients) were thrombocytopenia (59%), neutropenia (46%), febrile neutropenia (36%), and anemia (28%). One case (2%) of TLS occurred [

106

Wei A.
Strickland S.A.
Roboz G.J.
et al.

Phase 1/2 study of venetoclax with low-dose cytarabine in treatment-naive, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes.

Google Scholar

]. These promising results led to the initiation of randomized phase 3 trials that are currently ongoing. One compares venetoclax plus 5-Aza versus 5-Aza alone; the other one compares venetoclax plus LDAC versus LDAC alone (Table 5).

Conclusions

The intrinsic apoptotic pathway deregulated due to the overexpression of anti-apoptotic proteins is found in a variety of tumor types. It has been demonstrated that the blockade of these proteins leading to the release of pro-apoptotic proteins might restart the process of cell suicide in malignant cells. To date, the most effective molecule is venetoclax, the BH3-only mimetic and the first selective BCL2 inhibitor. It has been approved for RR CLL patients with del17p in monotherapy. However, expanded indications may be assumed in this malignancy. FL was another lymphoproliferative disease with expected efficacy according to a high rate of t(14;18)(q32;q21) in malignant cells (80–90%). Nevertheless, the results of venetoclax monotherapy are not that promising, with responses in less than half of RR FL [

71

Davids M.S.
Roberts A.W.
Seymour J.F.
et al.

Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma.

]. Current research identifies BCL2-positive DLBCL (BCG and ABC subtypes) as DLBCL with inferior prognosis [

107

Szafer-Glusman E.
Peale F.V.
Lei G.
et al.

BCL2 expression identifies a population with unmet medical need in previously untreated (1L) patients with DLBCL.

Google Scholar

,

108

Tsuyama N.
Sakata S.
Baba S.
et al.

BCL2 expression in DLBCL: reappraisal of immunohistochemistry with new criteria for therapeutic biomarker evaluation.

], but it is still not clear why venetoclax, even in combination with standard care (R-CHOP), does not improve outcomes in these patients [

78

Zelenetz A.D.
Salles G.A.
Mason K.D.
et al.

Results of a phase Ib Study of venetoclax plus R- or G-CHOP in patients with B-cell non-Hodgkin lymphoma.

]. Conversely, RR MCL, MZL, and WM have achieved interesting outcomes, even though the final conclusion requires bigger cohorts and longer follow-up [

71

Davids M.S.
Roberts A.W.
Seymour J.F.
et al.

Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma.

]. Venetoclax is also active in MM patients, especially in those with translocation t(11;14), and represents an available biomarker predicting the efficacy of this drug. Quite striking results were obtained in elderly AML patients, in whom venetoclax in combination with LDAC or hypomethylating agents (5-Aza or decitabine) induced approximately 60–70% of responses (taking into account that, in the current standard of care, LDAC does not induce more than 20% of responses), resulting in the initiation of phase 3 clinical trials.

The venetoclax toxicity profile was found to be acceptable across all studies. Initially, there was a concern about TLS, but this is well manageable with the recommended prophylactic procedures. Typically, it has occurred in CLL with two deaths demonstrated to date (venetoclax monotherapy at 1200 mg and venetoclax plus rituximab at 50 mg) [

44

Roberts A.W.
Davids M.S.
Pagel J.M.
et al.

Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia.

,

57

Seymour J.F.
Ma S.
Brander D.M.
et al.

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.

]. To mitigate the risk, a dose ramp-up period (initial dose of 20 mg in CLL and 50 mg in NHL with dose escalation every week during the first months), along with prophylactic hydration and urate lowering therapy, is recommended [

109

Coiffier B.
Altman A.
Pui C.-H.
Younes A.
Cairo M.S.

Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review.

]. Relatively frequent hematological toxicity might be explained by the presence of anti-apoptotic members in the immature stages of hematopoietic cells during their maturation. Anti-apoptotic proteins let immature cells survive and differentiate into mature forms [

110

Leverson J.D.
Phillips D.C.
Mitten M.J.
et al.

Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.

,

111

Motoyama N.
Kimura T.
Takahashi T.
Watanabe T.
Nakano T.

bcl-x prevents apoptotic cell death of both primitive and definitive erythrocytes at the end of maturation.

,

112

Socolovsky M.
Fallon A.E.
Wang S.
Brugnara C.
Lodish H.F.

Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X (L) induction.

,

113

Villunger A.
O'Reilly L.A.
Holler N.
Adams J.
Strasser A.

FAS ligand, Bcl-2, granulocyte colony-stimulating factor, and p38 mitogen-activated protein kinase.

], but this process is interrupted prematurely when anti-apoptotic inhibitors are administered. Grade of cytopenia depends on both the selectivity of the inhibitor and the ratio of protein members (BCL/MCL-1 and BCL2/BCL-XL). For instance, it has been proven that venetoclax does not induce limiting thrombocytopenia because megakaryopoesis is controlled by the BCL-XL protein [

114

Zhang H.
Nimmer P.M.
Tahir S.K.
et al.

Bcl-2 family proteins are essential for platelet survival.

].

Despite promising results in preclinical tests and initial trials with venetoclax, there are already signs of resistance [

44

Roberts A.W.
Davids M.S.
Pagel J.M.
et al.

Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia.

]. Therefore, it is of high importance to establish additional prognostic markers that can predict the sensitivity to venetoclax and further explore potential resistance mechanisms, which will be likely diverse in individual groups of patients. Given the high venetoclax specificity to BCL2, upregulated BCL-XL and MCL1 can sequester proapoptotic protein BIM and lead to resistance [

115

Choudhary G.S.
Al-Harbi S.
Mazumder S.
et al.

MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies.

]. Preclinical data indicate that BCL2/BCL-XL and BCL2/MCL1 ratios could be used in response prediction and thus should be included in routine clinical pipelines. Interestingly, low expression of miR-377 was inversely correlated with high expression of BCL-XL and might also be of potential prognostic importance [

116

Al-Harbi S.
Choudhary G.S.
Ebron J.S.
et al.

miR-377-dependent BCL-xL regulation drives chemotherapeutic resistance in B-cell lymphoid malignancies.

]. Additional mechanisms of venetoclax resistance include increased BCL2 phosphorylation [

117

Song T.
Chai G.
Liu Y.
Yu X.
Wang Z.
Zhang Z.

Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding.

] and mutations in BH3 domain of BCL2 [

5

Huang D.C.S.
Hahne M.
Schroeter M.
et al.

Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-xL.

], which displace BIM from BCL2 or prevent inhibitor binding. The complexity of venetoclax resistance in B-cell malignancies has been broadly described in other studies [

118

Bodo J.
Zhao X.
Durkin L.
et al.

Acquired resistance to venetoclax (ABT-199) in t (14;18) positive lymphoma cells.

,

119

Vogler M.
Butterworth M.
Majid A.
et al.

Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia.

] and additional mechanisms can be uncovered by modern screening approaches [

120

Oppermann S.
Ylanko J.
Shi Y.
et al.

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells.

].

The ratio of different anti-apoptotic proteins within malignant cells has an impact on venetoclax resistance. The combination of different molecules such as some of the B-cell receptor inhibitors is being used to try to solve this issue. For example, ibrutinib (a Bruton's tyrosine kinase inhibitor) mobilizes lymphocytes expressing BCL-XL and A1 (dominantly) from lymph nodes into the peripheral blood. In circulation, clonal cells lose protecting microenvironment signals, reduce BCL-XL and A1, and increase BCL2 protein expression [

119

Vogler M.
Butterworth M.
Majid A.
et al.

Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia.

,

121

Cervantes-Gomez F.
Lamothe B.
Woyach J.A.
et al.

Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia.

,

122

Hillmen P.
Rawstron A.
Munir T.
et al.

The initial report of the bloodwise tap clarity study combining ibrutinib and venetoclax in relapsed, refractory cll shows acceptable safety and promising early indications of efficacy.

Google Scholar

]. In MM, the overexpressed MCL-1 protein may be reduced by proteasome inhibitors and synergized with venetoclax activity [

123

Punnoose E.A.
Leverson J.D.
Peale F.
et al.

Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models.

]. Various other kinase inhibitors such as entospletinib (GS-9973), sunitinib (SU11248), cerdulatinib (PRT062070), CC-115 (TORK and DNA-PK inhibitor), and inhibitors of cyclin-dependent kinases (CDK2, CDK9), are able to block MCL-1 and might become the right partners for venetoclax treatment [

120

Oppermann S.
Ylanko J.
Shi Y.
et al.

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells.

,

124

Bojarczuk K.
Sasi B.K.
Gobessi S.
et al.

BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199.

,

125

Choudhary G.S.
Tat T.T.
Misra S.
et al.

Cyclin E/Cdk2-dependent phosphorylation of Mcl-1 determines its stability and cellular sensitivity to BH3 mimetics.

,

126

Flynn J.
Jones J.
Johnson A.J.
et al.

Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia.

,

127

Hamlin P.A.
Flinn I.
Wagner-Johnston N.
et al.

Clinical and correlative results of a phase 1 study of cerdulatinib (PRT062070) a dual SYK/JAK inhibitor in patients with relapsed/refractory B cell malignancies.

Google Scholar

,

128

Thijssen R.
ter Burg J.
Garrick B.
et al.

Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia.

]. A therapeutic challenge is double-hit DLBCL expressing BCL2 but also other anti-apoptotic proteins (e.g., MCL-1 and BCL-XL) that have been effectively blocked by combination of venetoclax plus carfilzomib, 5-Aza, or BR101801 (PI3K and DNA-PK inhibitor) in some in vitro studies [

129

Crombie J.
Lossos C.
Sarosiek K.
et al.

Dynamic BH3 profiling reveals novel therapeutic strategies for the treatment of double-hit lymphoma.

Google Scholar

,

130

Jung H.S.
Kim N.H.
Wang J.
et al.

Combination of BR101801 and venetoclax demonstrates synergistic activity in DLBCL cell lines harboring double hit and double expressor alterations.

Google Scholar

,

131

Mavis C.
Torka P.
Zeccola A.
et al.

Pre-clinical development of targeted therapies for double hit (DH) diffuse large B-cell lymphoma (DLBCL).

Google Scholar

].

In conclusion, venetoclax is a targeted drug with a novel mechanism of action that has already demonstrated highly promising activity in a variety of hematological malignancies. Due to its effect on the restoration of the apoptotic pathway, it can also be used successfully in patients with high-risk genetic features and nonfunctional p53. Taking all this and its low toxicity into consideration, venetoclax might become an important part of the treatment armamentarium against a substantial number of blood cancers.

Conflict of interest

The authors declare no competing financial interests.

Acknowledgments

The authors thank Shira Timilsina, M.D., for English language editing and Michal Kupka, M.D., for illustrations.

This work was supported by grants from the Ministry of Health (DRO-FNOs/2017) and the Ministry of Health [17-30089A); the Institutional Development Plan of University of Ostrava [IRP201550), SGS18/PrF/2017–2018; and Strengthening International Cooperation in Science, Research and Education (project ID: 01211/2016/RRC).

References

- Fink S.L.
- Cookson B.T.
Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells.
Infect Immun. 2005; 73: 1907-1916
View in Article
- Kerr J.F.
- Wyllie A.H.
- Currie A.R.
Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.
Br J Cancer. 1972; 26: 239-257
View in Article
- Cory S.
- Adams J.M.
The Bcl2 family: regulators of the cellular life-or-death switch.
Nat Rev Cancer. 2002; 2: 647-656
View in Article
- Hanahan D.
- Weinberg R.A.
The hallmarks of cancer.
Cell. 2000; 100: 57-70
View in Article
- Huang D.C.S.
- Hahne M.
- Schroeter M.
- et al.
Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-xL.
Proc Natl Acad Sci USA. 1999; 96: 14871-14876
View in Article
- Strasser A.
- Harris A.W.
- Huang D.C.
- Krammer P.H.
- Cory S.
Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis.
EMBO J. 1995; 14: 6136-6147
View in Article
- Guicciardi M.E.
- Gores G.J.
Life and death by death receptors.
FASEB J. 2009; 23: 1625-1637
View in Article
- Chen L.
- Willis S.N.
- Wei A.
- et al.
Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.
Mol Cell. 2005; 17: 393-403
View in Article
- Chittenden T.
BH3 domains: intracellular death-ligands critical for initiating apoptosis.
Cancer Cell. 2002; 2: 165-166
View in Article
- Czabotar P.E.
- Lessene G.
- Strasser A.
- Adams J.M.
Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.
Nat Rev Mol Cell Biol. 2014; 15: 49-63
View in Article
- Huang D.C.
- Strasser A.
BH3-Only proteins-essential initiators of apoptotic cell death.
Cell. 2000; 103: 839-842
View in Article
- Willis S.N.
- Chen L.
- Dewson G.
- et al.
Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins.
Genes Dev. 2005; 19: 1294-1305
View in Article
- Willis S.N.
- Fletcher J.I.
- Kaufmann T.
- et al.
Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.
Science. 2007; 315: 856-859
View in Article
- Gazzaniga P.
- Gradilone A.
- Vercillo R.
- et al.
bcl-2/bax mRNA expression ratio as prognostic factor in low-grade urinary bladder cancer.
Int J Cancer. 1996; 69: 100-104
View in Article
- Jiang S.-X.
- Sato Y.
- Kuwao S.
- Kameya T.
Expression of bcl-2 oncogene protein is prevalent in small cell lung carcinomas.
J Pathol. 1995; 177: 135-138
View in Article
- Joensuu H.
- Pylkkänen L.
- Toikkanen S.
Bcl-2 protein expression and long-term survival in breast cancer.
Am J Pathol. 1994; 145: 1191-1198
View in Article
- PubMed
- Google Scholar
- Calin G.A.
- Dumitru C.D.
- Shimizu M.
- et al.
Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.
Proc Natl Acad Sci USA. 2002; 99: 15524-15529
View in Article
- Monni O.
- Joensuu H.
- Franssila K.
- Knuutila S.
DNA copy number changes in diffuse large B-cell lymphoma–comparative genomic hybridization study.
Blood. 1996; 87: 5269-5278
View in Article
- Pekarsky Y.
- Croce C.M.
Role of miR-15/16 in CLL.
Cell Death Differ. 2015; 22: 6-11
View in Article
- Tsujimoto Y.
- Finger L.R.
- Yunis J.
- Nowell P.C.
- Croce C.M.
Cloning of the chromosome breakpoint of neoplastic B cells with the t (14;18) chromosome translocation.
Science. 1984; 226: 1097-1099
View in Article
- Döhner H.
- Stilgenbauer S.
- Benner A.
- et al.
Genomic aberrations and survival in chronic lymphocytic leukemia.
N Engl J Med. 2000; 343: 1910-1916
View in Article
- Edelmann J.
- Holzmann K.
- Miller F.
- et al.
High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations.
Blood. 2012; 120: 4783-4794
View in Article
- Toshiyuki M.
- Reed J.C.
Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.
Cell. 1995; 80: 293-299
View in Article
- Nakano K.
- Vousden K.H.
PUMA, a novel proapoptotic gene, is induced by p53.
Mol Cell. 2001; 7: 683-694
View in Article
- Yu J.
- Wang Z.
- Kinzler K.W.
- Vogelstein B.
- Zhang L.
PUMA mediates the apoptotic response to p53 in colorectal cancer cells.
Proc Natl Acad Sci USA. 2003; 100: 1931-1936
View in Article
- Petros A.M.
- Gunasekera A.
- Xu N.
- Olejniczak E.T.
- Fesik S.W.
Defining the p53 DNA-binding domain/Bcl-x (L)-binding interface using NMR.
FEBS Lett. 2004; 559: 171-174
View in Article
- Zilfou J.T.
- Lowe S.W.
Tumor suppressive functions of p53.
Cold Spring Harb Perspect Biol. 2009; 1: a001883
View in Article
- Dansen T.B.
- Whitfield J.
- Rostker F.
- Brown-Swigart L.
- Evan G.I.
Specific requirement for Bax, not Bak, in Myc-induced apoptosis and tumor suppression in vivo.
J Biol Chem. 2006; 281: 10890-10895
View in Article
- Egle A.
- Harris A.W.
- Bouillet P.
- Cory S.
Bim is a suppressor of Myc-induced mouse B cell leukemia.
Proc Natl Acad Sci USA. 2004; 101: 6164-6169
View in Article
- Nikiforov M.A.
- Riblett M.
- Tang W.H.
- et al.
Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition.
Proc Natl Acad Sci USA. 2007; 104: 19488-19493
View in Article
- Hoffman B.
- Liebermann D.A.
Apoptotic signaling by c-MYC.
Oncogene. 2008; 27: 6462-6472
View in Article
- Meyer N.
- Kim S.S.
- Penn L.Z.
The Oscar-worthy role of Myc in apoptosis.
Semin Cancer Biol. 2006; 16: 275-287
View in Article
- Nieminen A.I.
- Partanen J.I.
- Klefstrom J.
c-Myc blazing a trail of death: coupling of the mitochondrial and death receptor apoptosis pathways by c-Myc.
Cell Cycle. 2007; 6: 2464-2472
View in Article
- Nilsson J.A.
- Cleveland J.L.
Myc pathways provoking cell suicide and cancer.
Oncogene. 2003; 22: 9007-9021
View in Article
- Kipps T.J.
- Eradat H.
- Grosicki S.
- et al.
A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia.
Leuk Lymphoma. 2015; 56: 2826-2833
View in Article
- Nguyen M.
- Marcellus R.C.
- Roulston A.
- et al.
Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis.
Proc Natl Acad Sci USA. 2007; 104: 19512-19517
View in Article
- Nguyen M.
- Cencic R.
- Ertel F.
- et al.
Obatoclax is a direct and potent antagonist of membrane-restricted Mcl-1 and is synthetic lethal with treatment that induces Bim.
BMC Cancer. 2015; 15: 568
View in Article
- Sun Y.
- Wu J.
- Aboukameel A.
- et al.
Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo.
Cancer Biol Ther. 2008; 7: 1418-1426
View in Article
- Roberts A.W.
- Seymour J.F.
- Brown J.R.
- et al.
Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease.
J Clin Oncol. 2012; 30: 488-496
View in Article
- Tse C.
- Shoemaker A.R.
- Adickes J.
- et al.
ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.
Cancer Res. 2008; 68: 3421-3428
View in Article
- Wilson W.H.
- O'Connor O.A.
- Czuczman M.S.
- et al.
Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity.
Lancet Oncol. 2010; 11: 1149-1159
View in Article
- Souers A.J.
- Leverson J.D.
- Boghaert E.R.
- et al.
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.
Nat Med. 2013; 19: 202-208
View in Article
- Konopleva M.
- Contractor R.
- Tsao T.
- et al.
Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.
Cancer Cell. 2006; 10: 375-388
View in Article
- Roberts A.W.
- Davids M.S.
- Pagel J.M.
- et al.
Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia.
N Engl J Med. 2016; 374: 311-322
View in Article
- Salem A.H.
- Agarwal S.K.
- Dunbar M.
- Enschede S.L.H.
- Humerickhouse R.A.
- Wong S.L.
Pharmacokinetics of venetoclax, a novel BCL-2 inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or non-Hodgkin lymphoma.
J Clin Pharmacol. 2017; 57: 484-492
View in Article
- Salem A.H.
- Agarwal S.K.
- Dunbar M.
- et al.
Effect of low- and high-fat meals on the pharmacokinetics of venetoclax, a selective first-in-class BCL-2 inhibitor.
J Clin Pharmacol. 2016; 56: 1355-1361
View in Article
- Agarwal S.K.
- Hu B.
- Chien D.
- Wong S.L.
- Salem A.H.
Evaluation of rifampin's transporter inhibitory and CYP3A inductive effects on the pharmacokinetics of venetoclax, a BCL-2 inhibitor: results of a single- and multiple-dose study.
J Clin Pharmacol. 2016; 56: 1335-1343
View in Article
- Freise K.J.
- Jones A.K.
- Eckert D.
- et al.
Impact of venetoclax exposure on clinical efficacy and safety in patients with relapsed or refractory chronic lymphocytic leukemia.
Clin Pharmacokinet. 2017; 56: 515-523
View in Article
- Ginaldi L.
- De Martinis M.
- Matutes E.
- Farahat N.
- Morilla R.
- Catovsky D.
Levels of expression of CD19 and CD20 in chronic B cell leukaemias.
J Clin Pathol. 1998; 51: 364-369
View in Article
- Hanada M.
- Delia D.
- Aiello A.
- Stadtmauer E.
- Reed J.C.
bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia.
Blood. 1993; 82: 1820-1828
View in Article
- O'Brien S.
- Moore J.O.
- Boyd T.E.
- et al.
Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia.
J Clin Oncol. 2007; 25: 1114-1120
View in Article
- Schena M.
- Larsson L.G.
- Gottardi D.
- et al.
Growth- and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells.
Blood. 1992; 79: 2981-2989
View in Article
- Dyer M.J.
- Zani V.J.
- Lu W.Z.
- et al.
BCL2 translocations in leukemias of mature B cells.
Blood. 1994; 83: 3682-3688
View in Article
- PubMed
- Google Scholar
- Cimmino A.
- Calin G.A.
- Fabbri M.
- et al.
miR-15 and miR-16 induce apoptosis by targeting BCL2.
Proc Natl Acad Sci USA. 2005; 102: 13944-13949
View in Article
- 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: 768-778
View in Article
- Jones J.
- Choi M.Y.
- Mato A.R.
- et al.
Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib.
Blood. 2016; 128: 637
View in Article
- Crossref
- Google Scholar
- Seymour J.F.
- Ma S.
- Brander D.M.
- et al.
Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.
Lancet Oncol. 2017; 18: 230-240
View in Article
- Rogers K.A.
- Huang Y.
- Stark A.
- Jones J.A.
Initial results of the phase 2 treatment-naïve cohort in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax in CLL.
(Available at)
https://ash.confex.com/ash/2017/webprogram/Paper107539.html
(Cited 2018 Jan 9)
View in Article
- Google Scholar
- Stilgenbauer S.
- Morschhauser F.
- Wendtner C.M.
- et al.
Phase Ib study (GO28440) of venetoclax with bendamustine/rituximab or bendamustine/obinutuzumab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia.
Blood. 2016; 128: 4393
View in Article
- Google Scholar
- Cramer P.
- von Tresckow J.
- Bahlo J.
- et al.
Bendamustine (B), followed by obinutuzumab (G, GA101) and venetoclax (A, ABT-199) in patients with chronic lymphocytic leukemia (CLL): CLL2-BAG Phase-II-trial of the German CLL study group (GCLLSG) EHA Learning Center.
(Available at)
https://learningcenter.ehaweb.org/eha/2017/22nd/181751/paula.cramer.bendamustine.28b29.followed.by.obinutuzumab.28g.ga10129.and.html?f=m3e1181
(Cited 2017 Jun 17)
View in Article
- Google Scholar
- Fischer K.
- Al-Sawaf O.
- Fink A.-M.
- Dixon M.
- Bahlo J.
- Hallek M.
Safety and efficacy of venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting medical conditions: final results of the run-in phase of the randomized CLL14 Trial (BO25323.
(Available at)
https://ash.confex.com/ash/2016/webprogram/Paper94946.html
(Cited 2017 Feb 9)
View in Article
- Google Scholar
- Hillmen P.
- Munir T.
- Rawstron A.
- et al.
Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY Study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy.
Blood. 2017; 130: 428
View in Article
- Google Scholar
- Jain N.
- Thompson P.A.
- Ferrajoli A.
- et al.
Combined venetoclax and ibrutinib for patients with previously untreated high-risk CLL, and relapsed/refractory CLL: a phase II trial.
Blood. 2017; 130: 429
View in Article
- Google Scholar
- Swerdlow S.H.
- Campo E.
- Pileri S.A.
- et al.
The 2016 revision of the World Health Organization classification of lymphoid neoplasms.
Blood. 2016; 127: 2375-2390
View in Article
- Ives Aguilera N.S.
- Bijwaard K.E.
- Duncan B.
- et al.
Differential expression of cyclin D1 in mantle cell lymphoma and other non-Hodgkin's lymphomas.
Am J Pathol. 1998; 153: 1969-1976
View in Article
- Leroux D.
- Marc'hadour F.L.
- Gressin R.
- et al.
Non-Hodgkin's lymphomas with t (11;14) (q13;q32): a subset of mantle zone/intermediate lymphocytic lymphoma?.
Br J Haematol. 1991; 77: 346-353
View in Article
- Vandenberghe E.
- De Wolf Peeters C.
- Wlodarska I.
- et al.
Chromosome 11q rearrangements in B non-Hodgkin's lymphoma.
Br J Haematol. 1992; 81: 212-217
View in Article
- Ghielmini M.
- Zucca E.
How I treat mantle cell lymphoma.
Blood. 2009; 114: 1469-1476
View in Article
- Bentz M.
- Plesch A.
- Bullinger L.
- et al.
t (11;14)-positive mantle cell lymphomas exhibit complex karyotypes and share similarities with B-cell chronic lymphocytic leukemia.
Genes Chromosomes Cancer. 2000; 27: 285-294
View in Article
- Hemann M.T.
- Bric A.
- Teruya-Feldstein J.
- et al.
Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants.
Nature. 2005; 436: 807-811
View in Article
- Davids M.S.
- Roberts A.W.
- Seymour J.F.
- et al.
Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma.
J Clin Oncol. 2017; 35: 826-833
View in Article
- Tam C.S.L.
- Roberts A.W.
- Anderson M.A.
- et al.
Combination ibrutinib (Ibr) and venetoclax (Ven) for the treatment of mantle cell lymphoma (MCL): primary endpoint assessment of the phase 2 AIM study.
J Clin Oncol. 2017; 35: 7520
View in Article
- Google Scholar
- Campo E.
- Swerdlow S.H.
- Harris N.L.
- Pileri S.
- Stein H.
- Jaffe E.S.
The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.
Blood. 2011; 117: 5019-5032
View in Article
- Kramer M.H.
- Hermans J.
- Wijburg E.
- et al.
Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma.
Blood. 1998; 92: 3152-3162
View in Article
- Li S.
- Lin P.
- Young K.H.
- Kanagal-Shamanna R.
- Yin C.C.
- Medeiros L.J.
MYC/BCL2 double-hit high-grade B-cell lymphoma.
Adv Anat Pathol. 2013; 20: 315-326
View in Article
- Saito M.
- Gao J.
- Basso K.
- et al.
A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma.
Cancer Cell. 2007; 12: 280-292
View in Article
- Aukema S.M.
- Siebert R.
- Schuuring E.
- et al.
Double-hit B-cell lymphomas.
Blood. 2011; 117: 2319-2331
View in Article
- Zelenetz A.D.
- Salles G.A.
- Mason K.D.
- et al.
Results of a phase Ib Study of venetoclax plus R- or G-CHOP in patients with B-cell non-Hodgkin lymphoma.
Blood. 2016; 128: 3032
View in Article
- PubMed
- Google Scholar
- Kridel R.
- Mottok A.
- Farinha P.
- et al.
Cell of origin of transformed follicular lymphoma.
Blood. 2015; 126: 2118-2127
View in Article
- Montoto S.
- Fitzgibbon J.
Transformation of indolent B-cell lymphomas.
J Clin Oncol. 2011; 29: 1827-1834
View in Article
- Horsman D.E.
- Gascoyne R.D.
- Coupland R.W.
- Coldman A.J.
- Adomat S.A.
Comparison of cytogenetic analysis, southern analysis, and polymerase chain reaction for the detection of t (14; 18) in follicular lymphoma.
Am J Clin Pathol. 1995; 103: 472-478
View in Article
- Lossos I.S.
- Alizadeh A.A.
- Diehn M.
- et al.
Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes.
Proc Natl Acad Sci USA. 2002; 99: 8886-8891
View in Article
- Braggio E.
- Dogan A.
- Keats J.J.
- et al.
Genomic analysis of marginal zone and lymphoplasmacytic lymphomas identified common and disease-specific abnormalities.
Mod Pathol. 2012; 25: 651-660
View in Article
- Ortolani C.
Flow cytometry of hematological malignancies.
John Wiley & Sons, New York2011
View in Article
- Hunter Z.R.
- Xu L.
- Yang G.
- et al.
The genomic landscape of Waldenström macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis.
Blood. 2014; 123: 1637-1646
View in Article
- Treon S.P.
- Xu L.
- Yang G.
- et al.
MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.
N Engl J Med. 2012; 367: 826-833
View in Article
- Chng W.J.
- Schop R.F.
- Price-Troska T.
- et al.
Gene-expression profiling of Waldenström macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma.
Blood. 2006; 108: 2755-2763
View in Article
- Hatjiharissi E.
- Mitsiades C.S.
- Bryan C.T.
- et al.
Comprehensive molecular characterization of malignant and microenvironmental cells in Waldenstrom's macroglobulinemia by gene expression profiling.
Blood. 2007; 110: 3174
View in Article
- Google Scholar
- Cao Y.
- Yang G.
- Hunter Z.R.
- et al.
The BCL2 antagonist ABT-199 triggers apoptosis, and augments ibrutinib and idelalisib mediated cytotoxicity in CXCR4 wild-type and CXCR4 WHIM mutated Waldenstrom macroglobulinaemia cells.
Br J Haematol. 2015; 170: 134-138
View in Article
- Jelinek T.
- Hajek R.
PD-1/PD-L1 inhibitors in multiple myeloma: the present and the future.
Oncoimmunology. 2016; 5: e1254856
View in Article
- Jelinek T.
- Hajek R.
Monoclonal antibodies: a new era in the treatment of multiple myeloma.
Blood Rev. 2016; 30: 101-110
View in Article
- Touzeau C.
- Ryan J.
- Guerriero J.
- et al.
BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics.
Leukemia. 2016; 30: 761-764
View in Article
- Touzeau C.
- Dousset C.
- Le Gouill S.
- et al.
The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t (11;14) multiple myeloma.
Leukemia. 2014; 28: 210-212
View in Article
- Touzeau C.
- Le Gouill S.
- Mahé B.
- et al.
Deep and sustained response after venetoclax therapy in a patient with very advanced refractory myeloma with translocation t (11;14).
Haematologica. 2017; 102: e112-e114
View in Article
- Matulis S.M.
- Gupta V.A.
- Nooka A.K.
- et al.
Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax.
Leukemia. 2016; 30: 1086-1093
View in Article
- Kumar S.
- Vij R.
- Kaufman J.L.
- et al.
Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study.
Blood. 2016; 128: 488
View in Article
- Moreau P.
- Chanan-Khan A.A.
- Roberts A.W.
- et al.
Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma.
Blood. 2016; 128: 975
View in Article
- Crossref
- Google Scholar
- Jelinek T.
- Mihalyova J.
- Kascak M.
- Duras J.
- Hajek R.
PD-1/PD-L1 inhibitors in haematological malignancies: update 2017.
Immunology. 2017; 152: 357-371
View in Article
- Papaemmanuil E.
- Gerstung M.
- Bullinger L.
- et al.
Genomic classification and prognosis in acute myeloid leukemia.
N Engl J Med. 2016; 374: 2209-2221
View in Article
- Saygin C.
- Carraway H.E.
Emerging therapies for acute myeloid leukemia.
J Hematol Oncol. 2017; 10: 93
View in Article
- Opferman J.T.
- Iwasaki H.
- Ong C.C.
- et al.
Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells.
Science. 2005; 307: 1101-1104
View in Article
- Pan R.
- Hogdal L.J.
- Benito J.M.
- et al.
Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia.
Cancer Discov. 2014; 4: 362-375
View in Article
- Chan S.M.
- Thomas D.
- Corces-Zimmerman M.R.
- et al.
Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia.
Nat Med. 2015; 21: 178-184
View in Article
- Konopleva M.
- Pollyea D.A.
- Potluri J.
- et al.
Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia.
Cancer Discov. 2016; 6: 1106-1117
View in Article
- DiNardo C.D.
- Pollyea D.A.
- Jonas B.A.
- et al.
Updated safety and efficacy of venetoclax with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia.
Blood. 2017; 130: 2628
View in Article
- Google Scholar
- Wei A.
- Strickland S.A.
- Roboz G.J.
- et al.
Phase 1/2 study of venetoclax with low-dose cytarabine in treatment-naive, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes.
Blood. 2017; 130: 890
View in Article
- Google Scholar
- Szafer-Glusman E.
- Peale F.V.
- Lei G.
- et al.
BCL2 expression identifies a population with unmet medical need in previously untreated (1L) patients with DLBCL.
Blood. 2017; 130: 418
View in Article
- Google Scholar
- Tsuyama N.
- Sakata S.
- Baba S.
- et al.
BCL2 expression in DLBCL: reappraisal of immunohistochemistry with new criteria for therapeutic biomarker evaluation.
Blood. 2017; 130: 489-500
View in Article
- Coiffier B.
- Altman A.
- Pui C.-H.
- Younes A.
- Cairo M.S.
Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review.
J Clin Oncol. 2008; 26: 2767-2778
View in Article
- Leverson J.D.
- Phillips D.C.
- Mitten M.J.
- et al.
Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.
Sci Transl Med. 2015; 7: 279ra40
View in Article
- Motoyama N.
- Kimura T.
- Takahashi T.
- Watanabe T.
- Nakano T.
bcl-x prevents apoptotic cell death of both primitive and definitive erythrocytes at the end of maturation.
J Exp Med. 1999; 189: 1691-1698
View in Article
- Socolovsky M.
- Fallon A.E.
- Wang S.
- Brugnara C.
- Lodish H.F.
Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X (L) induction.
Cell. 1999; 98: 181-191
View in Article
- Villunger A.
- O'Reilly L.A.
- Holler N.
- Adams J.
- Strasser A.
FAS ligand, Bcl-2, granulocyte colony-stimulating factor, and p38 mitogen-activated protein kinase.
J Exp Med. 2000; 192: 647-658
View in Article
- Zhang H.
- Nimmer P.M.
- Tahir S.K.
- et al.
Bcl-2 family proteins are essential for platelet survival.
Cell Death Differ. 2007; 14: 943-951
View in Article
- Choudhary G.S.
- Al-Harbi S.
- Mazumder S.
- et al.
MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies.
Cell Death Dis. 2015; 6: e1593
View in Article
- Al-Harbi S.
- Choudhary G.S.
- Ebron J.S.
- et al.
miR-377-dependent BCL-xL regulation drives chemotherapeutic resistance in B-cell lymphoid malignancies.
Mol Cancer. 2015; 14: 185
View in Article
- Song T.
- Chai G.
- Liu Y.
- Yu X.
- Wang Z.
- Zhang Z.
Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding.
Br J Pharmacol. 2016; 173: 471-483
View in Article
- Bodo J.
- Zhao X.
- Durkin L.
- et al.
Acquired resistance to venetoclax (ABT-199) in t (14;18) positive lymphoma cells.
Oncotarget. 2016; 7: 70000-70010
View in Article
- Vogler M.
- Butterworth M.
- Majid A.
- et al.
Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia.
Blood. 2009; 113: 4403-4413
View in Article
- Oppermann S.
- Ylanko J.
- Shi Y.
- et al.
High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells.
Blood. 2016; 128: 934-947
View in Article
- Cervantes-Gomez F.
- Lamothe B.
- Woyach J.A.
- et al.
Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia.
Clin Cancer Res. 2015; 21: 3705-3715
View in Article
- Hillmen P.
- Rawstron A.
- Munir T.
- et al.
The initial report of the bloodwise tap clarity study combining ibrutinib and venetoclax in relapsed, refractory cll shows acceptable safety and promising early indications of efficacy.
(Available at)
https://learningcenter.ehaweb.org/eha/2017/22nd/182057/peter.hillmen.the.initial.report.of.the.bloodwise.tap.clarity.study.combining.html?f=m3
(Cited 2017 Aug 19)
View in Article
- Google Scholar
- Punnoose E.A.
- Leverson J.D.
- Peale F.
- et al.
Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models.
Mol Cancer Ther. 2016; 15: 1132-1144
View in Article
- Bojarczuk K.
- Sasi B.K.
- Gobessi S.
- et al.
BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199.
Blood. 2016; 127: 3192-3201
View in Article
- Choudhary G.S.
- Tat T.T.
- Misra S.
- et al.
Cyclin E/Cdk2-dependent phosphorylation of Mcl-1 determines its stability and cellular sensitivity to BH3 mimetics.
Oncotarget. 2015; 6: 16912-16925
View in Article
- Flynn J.
- Jones J.
- Johnson A.J.
- et al.
Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia.
Leukemia. 2015; 29: 1524-1529
View in Article
- Hamlin P.A.
- Flinn I.
- Wagner-Johnston N.
- et al.
Clinical and correlative results of a phase 1 study of cerdulatinib (PRT062070) a dual SYK/JAK inhibitor in patients with relapsed/refractory B cell malignancies.
Blood. 2015; 126: 3929
View in Article
- Google Scholar
- Thijssen R.
- ter Burg J.
- Garrick B.
- et al.
Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia.
Blood. 2016; 128: 574-583
View in Article
- Crombie J.
- Lossos C.
- Sarosiek K.
- et al.
Dynamic BH3 profiling reveals novel therapeutic strategies for the treatment of double-hit lymphoma.
Blood. 2017; 130: 2764
View in Article
- Google Scholar
- Jung H.S.
- Kim N.H.
- Wang J.
- et al.
Combination of BR101801 and venetoclax demonstrates synergistic activity in DLBCL cell lines harboring double hit and double expressor alterations.
Blood. 2017; 130: 4114
View in Article
- Google Scholar
- Mavis C.
- Torka P.
- Zeccola A.
- et al.
Pre-clinical development of targeted therapies for double hit (DH) diffuse large B-cell lymphoma (DLBCL).
Blood. 2017; 130: 1542
View in Article
- Google Scholar

Article info

Publication history

Published online: February 22, 2018

Accepted: February 5, 2018

Received in revised form: January 31, 2018

Received: November 13, 2017

Identification

DOI: https://doi.org/10.1016/j.exphem.2018.02.002

Copyright

User license

Elsevier user license |

How you can reuse Information Icon

ScienceDirect

Access this article on ScienceDirect

Toggle Thumbstrip

Property	Value
Status
Version
Ad File
Disable Ads Flag
Environment
Moat Init
Moat Ready
Contextual Ready
Contextual URL
Contextual Initial Segments
Contextual Used Segments
AdUnit
SubAdUnit
Custom Targeting
Ad Events
Invalid Ad Sizes

Latest

For Authors

Collections

Special Issues

Society

Journal Information

Access

Contact

Follow Us

Venetoclax: A new wave in hematooncology

Highlights

Venetoclax: mechanism of action

Chronic lymphocytic leukemia

Mantle cell lymphoma

Diffuse large B-cell lymphoma

FL

MZL

Waldenström macroglobulinemia

Multiple myeloma

Acute myeloid leukemia

Conclusions

Conflict of interest

Acknowledgments

References

Article info

Publication history

Identification

Copyright

User license

ScienceDirect

Related Articles

Venetoclax: A new wave in hematooncology

Highlights

Venetoclax: mechanism of action

Chronic lymphocytic leukemia

Mantle cell lymphoma

Diffuse large B-cell lymphoma

FL

MZL

Waldenström macroglobulinemia

Multiple myeloma

Acute myeloid leukemia

Conclusions

Conflict of interest

Acknowledgments

References

Article info

Publication history

Identification

Copyright

User license

Permitted

For non-commercial purposes:

Not Permitted

ScienceDirect

Related Articles