BCL2 and MCL1 are commonly expressed prosurvival (antiapoptotic) proteins in hematologic cancers and play important roles in their biology either through dysregulation or by virtue of intrinsic importance to the cell-of-origin of the malignancy. A new class of small-molecule anticancer drugs, BH3 mimetics, now enable specific targeting of these proteins in patients. BH3 mimetics act by inhibiting the prosurvival BCL2 proteins to enable the activation of BAX and BAK, apoptosis effectors that permeabilize the outer mitochondrial membrane, triggering apoptosis directly in many cells and sensitizing others to cell death when combined with other antineoplastic drugs. Venetoclax, a specific inhibitor of BCL2, is the first approved in class, demonstrating striking single agent activity in chronic lymphocytic leukemia and in other lymphoid neoplasms, as well as activity against acute myeloid leukemia (AML), especially when used in combination. Key insights from the venetoclax experience include that responses occur rapidly, with major activity as monotherapy proving to be the best indicator for success in combination regimens. This emphasizes the importance of adequate single-agent studies for drugs in this class. Furthermore, secondary resistance is common with long-term exposure and often mediated by genetic or adaptive changes in the apoptotic pathway, suggesting that BH3 mimetics are better suited to limited duration, rather than continuous, therapy. The success of venetoclax has inspired development of BH3 mimetics targeting MCL1. Despite promising preclinical activity against MYC-driven lymphomas, myeloma, and AML, their success may particularly depend on their tolerability profile given physiological roles for MCL1 in several nonhematologic tissues.

The regulatory approvals for venetoclax herald the arrival of a new class of small-molecule cancer therapeutics that target prosurvival proteins that protect against apoptosis. Venetoclax, a potent and selective inhibitor of the intracellular protein BCL2, has received US Food and Drug Administration (FDA) approval for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Fast on its heels in development are similarly acting drugs that target either BCL2 or proteins with comparable prosurvival function, particularly MCL1. This review focuses on key areas relevant to clinical use and development of these BH3 mimetic drugs. Underpinning preclinical data will be only selectively touched on, given previous comprehensive reviews. Neither have we attempted to summarize all early-phase trial data in hematologic diseases given the currently rapidly changing trial landscape. Rather, we distil principles that have been established and identify major questions that the field needs to address to enable BCL2 and MCL1 inhibitors to achieve maximum clinical impact.

The development this new class of antineoplastics required a deep understanding of the intrinsic (mitochondrial) pathway to apoptosis.1-5 The pathway is orchestrated by the BCL2 network, a family of partially homologous cytoplasmic proteins, best considered as 3 functional subfamilies. Pivotal in this are the effectors of mitochondrial apoptosis: BAX and BAK.

Within a cell, BAX/BAK are kept inert by the direct and indirect actions of prosurvival family members. These proteins (BCL2, MCL1, BCLxL, BCLw, and BCL2A1) act to prevent BAX/BAK-driven apoptosis, thereby maintaining cellular viability. Physiologic stresses (eg, lack of growth signals, oncogenic stresses, DNA damage) trigger increased expression of the BH3-only proteins, the third subfamily in the network. These BH3-only proteins (eg, BIM, BAD, NOXA) act to initiate apoptosis by binding tightly to prosurvival BCL2 proteins. If present in sufficient amounts, the BH3-only proteins overwhelm the capacity of prosurvival proteins to hold BAX/BAK in check, thus allowing these effectors to oligomerize and form activated pores that damage the mitochondrial outer membrane. Certain BH3-only proteins have also been reported to activate BAX/BAK directly; however, BAX/BAK-driven apoptosis can proceed even in the complete absence of any BH3-only protein.6 

BAX/BAK-driven mitochondria outer membrane permeabilization (MOMP) commits a cell toward apoptosis undermining normal mitochondrial function, including energy production, and allowing the leakage of mitochondrial contents, including cytochrome c, which trigger proteolytic enzymes (caspases) causing cellular demolition.

Most normal cells rely on multiple prosurvival BCL2 proteins to maintain their viability although in some cell types particular prosurvival proteins predominate. For example, mature B lymphocytes are highly reliant on BCL2, whereas MCL1 plays a central role in plasma cells.7 This is exaggerated by overexpression of specific prosurvival proteins in certain neoplasms, such as BCL2 in CLL. Regardless, once the action of the prosurvival proteins is blocked by the BH3-only proteins, BAX and BAK are freed to drive apoptosis. Conversely, mitochondrial apoptosis cannot proceed in the absence of BAX and BAK.

A cardinal feature of this cellular life-death switch is that it is underpinned by protein–protein interactions, distinct from enzymatic reactions such as phosphorylation by kinases (eg, BCR-ABL, FLT3, BTK). To initiate apoptosis, the killer BH3 domain of the BH3-only proteins engages a large, poorly defined groove on the prosurvival proteins. Unlike enzymes such as protein kinases that bind their substrates via small binding interfaces (akin to a “lock-and-key”), the BH3:prosurvival groove interactions use an “induced-fit” mechanism mediated largely by hydrophobic interactions.8 Moreover, multiple molecular interactions are required for tight binding across the large protein-protein interfaces.

Small molecules have been developed to mimic the action of the BH3-only proteins, hence BH3 mimetics. Such small-molecule entities have been generated to preferentially bind ≥1 prosurvival proteins: cells reliant on BCL2 will be highly sensitive to a BCL2-selective inhibitor. By mimicking the action of the BH3-only proteins, a selective chemical inhibitor will induce BAX/BAK-mediated mitochondrial apoptosis unless other prosurvival proteins are present in sufficient amounts to restrain endogenous apoptosis effectors (Figure 1).

Figure 1.

Regulation of the intrinsic (mitochondrial) pathway to apoptosis by the BCL2 protein family and mechanism of action of BH3 mimetics in normal cells and selected hematologic neoplasms. (A) In most normal cells, multiple prosurvival BCL2 proteins act to maintain their survival by preventing the activation of the cell death effectors BAX and BAK. Cellular stresses upregulate the BH3-only proteins (eg, BIM, BAD, PUMA, NOXA) that act by binding to BCL2 or its prosurvival relatives (MCL1, BCLxL, BCLw, BCL2A1). These interactions between BH3-only proteins and prosurvival proteins can be specific (eg, BAD only binds BCL2, BCLxL, and BCLW with high affinity; NOXA only binds MCL1 and BCL2A1) or more encompassing (eg, BIM and PUMA will bind all prosurvival proteins with high affinity).121 Tight binding of the BH3-only proteins blocks the ability of the prosurvival BCL2 proteins to hold BAX/BAK in check. The threshold for apoptosis is determined largely by the relative abundance of the key players and this varies according to cell lineage and microenvironmental cues. In many hematologic cancers, oncogenic stress-induced BH3-only protein activity means that the threshold for inducing apoptosis is low with the malignant cell being “primed for death” in some instances.2 (B) BCL2 expression is often dysregulated in CLL with high levels of expression and the leukemic cells are heavily reliant on BCL2.17,30,122 Hence, CLL cells are susceptible to the selective inhibition of BCL2 with venetoclax (in red). Inhibition of BCL2 by venetoclax allows activated BAX/BAK oligomers to form on the mitochondrial outer membrane, permeabilizing it and thereby compromising normal mitochondrial function (eg, reduced ATP production), as well as triggering the leakage of intramitochondrial molecules (eg, cytochrome c; green). These trigger the activation of proteolytic caspases that lead to cellular demolition. Because BAX/BAK are essential to drive MOMP, they are required for the action of venetoclax and all true BH3 mimetics. (C) In normal plasma cells and in many cases of multiple myeloma, especially relapsed disease, the predominant survival protein expressed is MCL1.7,117,123 Hence, MCL1 inhibition (in green) could well prove to be effective for this plasma cell malignancy. However, as indicated by the red asterisk, some subtypes of multiple myeloma are also highly susceptible to BCL2 inhibition (see Figure 2). (D) In AML, the degree of dependence on BCL2 or on MCL1 varies, with some subtypes being more BCL2 reliant than others (see Figure 2). Overall, both BCL2 and MCL1 appear to play prominent prosurvival roles in most AML cases. Loss of oxidative phosphorylation and energy production after MOMP is a prominent effect of venetoclax in AML cells.91,124 Professional illustration by Somersault18:24.

Figure 1.

Regulation of the intrinsic (mitochondrial) pathway to apoptosis by the BCL2 protein family and mechanism of action of BH3 mimetics in normal cells and selected hematologic neoplasms. (A) In most normal cells, multiple prosurvival BCL2 proteins act to maintain their survival by preventing the activation of the cell death effectors BAX and BAK. Cellular stresses upregulate the BH3-only proteins (eg, BIM, BAD, PUMA, NOXA) that act by binding to BCL2 or its prosurvival relatives (MCL1, BCLxL, BCLw, BCL2A1). These interactions between BH3-only proteins and prosurvival proteins can be specific (eg, BAD only binds BCL2, BCLxL, and BCLW with high affinity; NOXA only binds MCL1 and BCL2A1) or more encompassing (eg, BIM and PUMA will bind all prosurvival proteins with high affinity).121 Tight binding of the BH3-only proteins blocks the ability of the prosurvival BCL2 proteins to hold BAX/BAK in check. The threshold for apoptosis is determined largely by the relative abundance of the key players and this varies according to cell lineage and microenvironmental cues. In many hematologic cancers, oncogenic stress-induced BH3-only protein activity means that the threshold for inducing apoptosis is low with the malignant cell being “primed for death” in some instances.2 (B) BCL2 expression is often dysregulated in CLL with high levels of expression and the leukemic cells are heavily reliant on BCL2.17,30,122 Hence, CLL cells are susceptible to the selective inhibition of BCL2 with venetoclax (in red). Inhibition of BCL2 by venetoclax allows activated BAX/BAK oligomers to form on the mitochondrial outer membrane, permeabilizing it and thereby compromising normal mitochondrial function (eg, reduced ATP production), as well as triggering the leakage of intramitochondrial molecules (eg, cytochrome c; green). These trigger the activation of proteolytic caspases that lead to cellular demolition. Because BAX/BAK are essential to drive MOMP, they are required for the action of venetoclax and all true BH3 mimetics. (C) In normal plasma cells and in many cases of multiple myeloma, especially relapsed disease, the predominant survival protein expressed is MCL1.7,117,123 Hence, MCL1 inhibition (in green) could well prove to be effective for this plasma cell malignancy. However, as indicated by the red asterisk, some subtypes of multiple myeloma are also highly susceptible to BCL2 inhibition (see Figure 2). (D) In AML, the degree of dependence on BCL2 or on MCL1 varies, with some subtypes being more BCL2 reliant than others (see Figure 2). Overall, both BCL2 and MCL1 appear to play prominent prosurvival roles in most AML cases. Loss of oxidative phosphorylation and energy production after MOMP is a prominent effect of venetoclax in AML cells.91,124 Professional illustration by Somersault18:24.

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BH3 mimetics are therefore defined by their ability to kill cells by apoptosis in a strictly BAX/BAK-dependent manner.3 BH3 mimetics targeting BCL2 (±BCLxL) or MCL1 that have progressed into clinical trials are listed in Table 1. Other than venetoclax and navitoclax, it can be appreciated that the clinical development of other BH3 mimetics is only in the earliest stages. Navitoclax9 was the first potent BCL2 inhibitor to enter clinical trials and demonstrated moderate single-agent activity in patients with relapsed CLL and indolent B-cell lymphomas.10-13 However, acute reduction in platelet count is a direct legacy of its cotargeting of BCLxL, as survival of platelets is highly dependent on BCLxL.14 Consequently, thrombocytopenia proved to be the dose-limiting toxicity, precluding full exploration of BCL2 inhibition. Navitoclax remains in clinical development only for hematologic diseases where targeting of BCLxL or both BCL2 and BCLxL, is anticipated to be beneficial, such as myelofibrosis and acute lymphoblastic leukemia (ALL), respectively.15,16

Table 1.

BCL2-targeting or MCL1-targeting bone fide BH3 mimetics currently in clinical trials

State of developmentCharacteristics
Target moleculeDeveloperFDA approvedDevelopmental phaseHeme malignancyTarget Ki* (nM)BAX/BAK dependentRoute
BCL2        
 Venetoclax (ABT-199)17  Abbvie /Genentech CLL, AML MM, NHL, AML, CLL <<1 ✓ Oral 
 S655487   S55746125  Servier  1
Multiple
CLL, AML 
NR
∼1 
NR
✓ 
IV
Oral 
 BGB-11417126  Beigene  Multiple <<1 NR Oral 
 APG-2575127  Ascentage  CLL, AML, NHL, T-PLL <<1 ✓ Oral 
 FCN-338128  Fochon  CLL, SLL NR NR Oral 
BCL2/BCLxL        
 Navitoclax (ABT-263)9  Abbvie  Myelofibrosis <1/<1 ✓ Oral 
 AZD0466129,130 Astra Zeneca  Multiple NR ✓ IV 
 Pelcitoclax (APG-1252)131,132 Ascentage  1/2 Myelofibrosis <1/<1 ✓ IV 
MCL1        
 AMG 17619,
AMG 39720  
Amgen  AML, MM
Multiple 
<<1
<<1 
✓ IV
Oral 
 S64315 (MIK665)21  Servier/Novartis  AML, MM, NHL <<1 ✓ IV 
 AZD599122  Astra Zeneca  Multiple <1 ✓ IV 
 ABBV-467 Abbvie  MM NR NR IV 
 PRT1419 Prelude  MDS, AML, NHL, MM NR NR Oral 
State of developmentCharacteristics
Target moleculeDeveloperFDA approvedDevelopmental phaseHeme malignancyTarget Ki* (nM)BAX/BAK dependentRoute
BCL2        
 Venetoclax (ABT-199)17  Abbvie /Genentech CLL, AML MM, NHL, AML, CLL <<1 ✓ Oral 
 S655487   S55746125  Servier  1
Multiple
CLL, AML 
NR
∼1 
NR
✓ 
IV
Oral 
 BGB-11417126  Beigene  Multiple <<1 NR Oral 
 APG-2575127  Ascentage  CLL, AML, NHL, T-PLL <<1 ✓ Oral 
 FCN-338128  Fochon  CLL, SLL NR NR Oral 
BCL2/BCLxL        
 Navitoclax (ABT-263)9  Abbvie  Myelofibrosis <1/<1 ✓ Oral 
 AZD0466129,130 Astra Zeneca  Multiple NR ✓ IV 
 Pelcitoclax (APG-1252)131,132 Ascentage  1/2 Myelofibrosis <1/<1 ✓ IV 
MCL1        
 AMG 17619,
AMG 39720  
Amgen  AML, MM
Multiple 
<<1
<<1 
✓ IV
Oral 
 S64315 (MIK665)21  Servier/Novartis  AML, MM, NHL <<1 ✓ IV 
 AZD599122  Astra Zeneca  Multiple <1 ✓ IV 
 ABBV-467 Abbvie  MM NR NR IV 
 PRT1419 Prelude  MDS, AML, NHL, MM NR NR Oral 

Trial data from ClinicalTrials.gov (accessed 2 January 2021). The most advanced trial phase is listed. References are provided where publication has disclosed the chemical structure and function of the compound. NR, not reported.

*

Ki measures the affinity for the target in a competition assay. As Ki is measured relative to a competitor and the competitors and assay formats are not uniform across drugs, direct comparison of Ki values between the drugs listed is precluded. Therefore, approximations are provided based on cited specific published data. A Ki of 1 nM or less reflects tight binding to the target and potency in competing with BH3-containing proteins.

To avoid the on-target thrombocytopenia associated with navitoclax, venetoclax was designed to be a BCL2-specific inhibitor. No naturally occurring BH3-only proteins inhibit BCL2 exclusively. Venetoclax binds and inhibits BCL2 with picomolar affinity and displays greater than 100-fold selectivity for BCL2 over BCLxL and >1000-fold for MCL1.17 The demonstration that a single prosurvival protein can be inhibited and have important clinical activity turbo-charged drug discovery and development of this class. Similarly, MCL1 can now be selectively targeted by potent BH3 mimetics.18-22 

CLL

Dependence on BCL2 is high and relatively uniformly so in CLL. BCL2 is required but not essential for normal B-cell development, and mature B cells normally express high levels of BCL2.23 CLL cells in all patients express high levels of BCL2 and typically much lower levels of MCL1 or BCLxL.23-27 CLL bearing del(13q) have loss of mir15/16, negative regulators of BCL2 expression, with enhanced levels of BCL2 expression.28,29 In vitro, CLL cells are highly sensitive to BCL2-selective inhibition (Figures 1 and 2).17,30,31

Figure 2.

Summary of key preclinical and clinical characteristics of hematologic cancers where BCL2 inhibitors demonstrate clinical activity. At the single cell level, high vulnerability to BCL2 inhibition (left) is typically observed when BCL2 expression is constitutively high, and there is relatively minor expression of other prosurvival proteins.17,133 These BCL2-dependent cells reflect the near totality of cells among populations where CRs can readily be induced with monotherapy (eg, CLL,11,17,27,30,31,41 some MCL,103,105 t(11;14) myeloma and myeloma with heightened BCL2:BCLxl expression,96,97,123IDH-mutant AML69,80). For these cell populations, BH3 mimetics like venetoclax strike the bullseye. More commonly (right), cells are not BCL2 dependent, and BCL2 is not the bullseye. Rather these cells are vulnerable to BCL2 inhibition when a wave (depicted as green lines) of secondary inhibition of other prosurvival proteins by displaced BH3-only proteins134 is initiated, resulting in antagonism of other prosurvival proteins and BCL2. In these partially BCL2-dependent cells, BCL2 inhibitor monotherapy may be insufficient to kill cells with these characteristics (moderate and variable BCL2 expression, relatively higher levels of MCL1 or BCLxL), but some cells will die, whereas others suffer sublethal injury consequent on BAX/BAK-dependent mitochondrial depolarization and reduced energy production.53,91 Additional stressors will be required to maximize apoptosis and achieve high response rates in diseases in which the majority of cells are affected in this manner. This includes most myeloma,97 AML,67,69,135 ALL,16 and many B-cell lymphomas.17,105,136 Adapted137 with permission. Professional illustration by Somersault18:24.

Figure 2.

Summary of key preclinical and clinical characteristics of hematologic cancers where BCL2 inhibitors demonstrate clinical activity. At the single cell level, high vulnerability to BCL2 inhibition (left) is typically observed when BCL2 expression is constitutively high, and there is relatively minor expression of other prosurvival proteins.17,133 These BCL2-dependent cells reflect the near totality of cells among populations where CRs can readily be induced with monotherapy (eg, CLL,11,17,27,30,31,41 some MCL,103,105 t(11;14) myeloma and myeloma with heightened BCL2:BCLxl expression,96,97,123IDH-mutant AML69,80). For these cell populations, BH3 mimetics like venetoclax strike the bullseye. More commonly (right), cells are not BCL2 dependent, and BCL2 is not the bullseye. Rather these cells are vulnerable to BCL2 inhibition when a wave (depicted as green lines) of secondary inhibition of other prosurvival proteins by displaced BH3-only proteins134 is initiated, resulting in antagonism of other prosurvival proteins and BCL2. In these partially BCL2-dependent cells, BCL2 inhibitor monotherapy may be insufficient to kill cells with these characteristics (moderate and variable BCL2 expression, relatively higher levels of MCL1 or BCLxL), but some cells will die, whereas others suffer sublethal injury consequent on BAX/BAK-dependent mitochondrial depolarization and reduced energy production.53,91 Additional stressors will be required to maximize apoptosis and achieve high response rates in diseases in which the majority of cells are affected in this manner. This includes most myeloma,97 AML,67,69,135 ALL,16 and many B-cell lymphomas.17,105,136 Adapted137 with permission. Professional illustration by Somersault18:24.

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Efficacy

Venetoclax was first approved by the FDA as monotherapy for relapsed or refractory del(17p) CLL in April 2016. It now has multiple listings internationally for relapsed/refractory disease in combination with rituximab and for unfit patients with newly diagnosed CLL in combination with obinutuzumab. Monotherapy studies in relapsed/refractory disease indicated an immediate reduction in CLL burden in almost all patients. Objective responses occurred in 79% of patients, complete remissions (CRs) in 20% and undetectable measurable residual disease (uMRD) in up to 30%32-34 with acceptable toxicity.35 Indeed, the dose-limiting toxicity (DLT) was biochemical tumor lysis, with several patients experiencing severe or fatal clinical tumor lysis syndrome (TLS).32 Patients with high burden disease or reduced renal function were at highest risk. This necessitated introduction of a standard 4-week ramp-up phase commencing at 20 mg/day and rising incrementally each week to the target dose of 400 mg/day. In patients, apoptosis of CLL cells was readily detectable within 6 to 8 hours of dosing,31 consistent with the rapid induction observed in vitro and the timing of peak plasma venetoclax concentrations (6 hours).32 Importantly, venetoclax is highly active after prior therapy with chemo-immunotherapy, BTK inhibitors, or phosphatidylinositol 3-kinase inhibitors.32,34,36,37

Apparently higher CR (51%) and uMRD (57%) rates were observed in early-phase trials combining rituximab with venetoclax,38 prompting this combination to be compared in a randomized trial against bendamustine-rituximab in relapsed/refractory CLL. Venetoclax-rituximab demonstrated superior efficacy and safety; respective hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were 0.17 and 0.48, with a number-needed-to treat (NNT) of 2 for PFS at 2 years.39,40 Despite its now uniform adoption as the standard venetoclax regimen for relapsed/refractory CLL, in the absence of a randomized comparison vs venetoclax monotherapy, the evidence for additive benefit from rituximab is modest and confined to improvement in CR rate in a multivariable analysis of pooled trial data.41 Uncontrolled real-world data analyses of PFS do not suggest additive benefit,42 and it seems most probable that venetoclax is delivering the majority of the observed clinical efficacy.

In first-line treatment of patients unfit for fludarabine-based regimens, venetoclax-obinutuzumab proved superior to chlorambucil-obinutuzumab with respect to PFS (HR, 0.31; NNT of 3 at 3 years), with similar toxicity and OS.43 As previously observed for fludarabine-cyclophosphamide-rituximab chemo-immunotherapy, the durability of benefit with venetoclax-based regimens correlated with achievement of deeper responses (measured either by CR or uMRD rate).38,40,41,44 In the salvage setting, the probability of achieving uMRD with continuing venetoclax plateaus around 2 years34,40,41,44 and earlier in the first-line setting.44 This has provided a rational basis for the introduction of regimens with fixed-duration venetoclax (2 years for relapsed/refractory, 1 year for first-line) in registration studies rather than continuous use which may not provide additional benefit.45 

Biomarkers

However, long-term follow-up data indicate an ongoing risk of relapse with these venetoclax-based regimens, and it seems improbable that these treatments are curative. Accumulated trial data now enable analyses of which factors either modify the response to venetoclax and/or predict for particular benefit from the use of venetoclax-based regimens over chemo-immunotherapy and/or are prognostic with venetoclax-based regimens. In relapsed CLL, the validated genetic biomarkers most relevant to clinical practice are del(17p), TP53 mutation, and immunoglobulin heavy chain variable region (IGHV) mutational status.46,Table 2 summarizes the key findings from randomized trials. Other factors have been associated with relatively reduced response rates or inferior duration of response compared with their absence (bulky lymphadenopathy >10 cm; refractoriness to ibrutinib; NOTCH1 mutations) in multivariable analyses of pooled data from single arm trials,41 but these have not yet been confirmed in prospective trials.

Table 2.

Treatment effect modifiers for venetoclax in CLL, myeloma, and AML

Disease line, regimenBiomarkerImprovements in treatment outcomes vs control arm (in comparison with absence of marker)Predict benefit vs control arm?Prognostic with Ven?
   Chemo-Ab (Chl-Obin or Benda-R) → Ven-Ab    
CLL Name Status CR uMRD
(<10–4) 
2-y PFS 3-y PFS CR and uMRD PFS  
First line43,44,47
Ven-Obin 
del(17p) Present
Absent 
7% → 44%
(24% → 50%) 
7% → 71%
38% → 76% 
23% → 65%
(∼71% → 91%) 
12% → 49%
(>50% → ∼84%) 
Yes ↑↑ Yes ↑ Yes ↓ 
Relapsed39,48
Ven-R 
 Present
Absent 
NR 5%* → 60%
(20%* → 76%) 
28% → 82%
(41% → 86%) 
0% → 40%
(∼30% → 80%) 
Yes ↑↑ Yes ↑↑ Yes ↓ 
First line TP53 mut Present
Absent 
5% → 48%
(25% → 50%) 
21 → 65
(37% → 77%) 
37% → 73%
(∼73% → 93%) 
35% → 60%
(53% → 85%) 
Yes ↑↑ Yes ↑ Yes ↓ 
Relapsed  Present
Absent 
NR 5% → 57%
(20% → 66%) 
HR 0.19
(HR 0.15) 
∼10% → 63%
(∼25% → 80%) 
Yes ↑↑ Yes ↑ Yes ↓ 
First line Unmutated IGHV Unmutated
Mutated 
15% → 61%
(16% → 64%) 
28% → 79%
(43% → 74%) 
51% → 89%
(86% → 90%) 
34% → 81%
(75% → 87%) 
Yes ↑↑ Yes ↑↑ Probably ↓ 
Relapsed  Unmutated
Mutated 
NR 15% → 61%
(16% →64%) 
HR 0.16
HR (0.11) 
NR Yes ↑↑ Yes ↑ NR 
   Pbo-BortDex → Ven-BortDex    
Myeloma Name Status ≥vGPR uMRD
(<10–5) 
PFS Survival HR ≥vGPR & PFS OS  
Relapsed99 
Ven-BD 
t(11;14) Present
Absent 
27% → 75%
(38% → 58%) 
0% → 25%
(1% → 12%) 
HR 0.11
(HR 0.67) 
0.34
(2.5) 
Yes ↑↑ No Yes ↑ 
 High BCL2§ First quartile
Fourth quartile 
28% → 71%
(40% → 52%) 
0% → 18%
(2% →11%) 
HR 0.24
(HR 0.76) 
1.0
(>2.0) 
Yes ↑↑ No Yes ↑ 
   Pbo-Aza → Ven-Aza    
AML Name Status CR/Cri ΔCR/Cri 2-y OS HR OS CR OS  
First line74 
Ven-Aza 
IDH1/2 mut Present
Absent 
11% → 75%
32% → 66% 
+64%
+34% 
14% → 52%
(14% → 41%) 
0.34 Yes ↑↑ Yes ↑↑ Yes ↑ 
 TP53 mut Present
Absent 
0% → 55%
31% → 68% 
+55%
+37% 
7% → 11%
27% → 49% 
0.76 Yes ↑↑ No Yes ↓ 
Disease line, regimenBiomarkerImprovements in treatment outcomes vs control arm (in comparison with absence of marker)Predict benefit vs control arm?Prognostic with Ven?
   Chemo-Ab (Chl-Obin or Benda-R) → Ven-Ab    
CLL Name Status CR uMRD
(<10–4) 
2-y PFS 3-y PFS CR and uMRD PFS  
First line43,44,47
Ven-Obin 
del(17p) Present
Absent 
7% → 44%
(24% → 50%) 
7% → 71%
38% → 76% 
23% → 65%
(∼71% → 91%) 
12% → 49%
(>50% → ∼84%) 
Yes ↑↑ Yes ↑ Yes ↓ 
Relapsed39,48
Ven-R 
 Present
Absent 
NR 5%* → 60%
(20%* → 76%) 
28% → 82%
(41% → 86%) 
0% → 40%
(∼30% → 80%) 
Yes ↑↑ Yes ↑↑ Yes ↓ 
First line TP53 mut Present
Absent 
5% → 48%
(25% → 50%) 
21 → 65
(37% → 77%) 
37% → 73%
(∼73% → 93%) 
35% → 60%
(53% → 85%) 
Yes ↑↑ Yes ↑ Yes ↓ 
Relapsed  Present
Absent 
NR 5% → 57%
(20% → 66%) 
HR 0.19
(HR 0.15) 
∼10% → 63%
(∼25% → 80%) 
Yes ↑↑ Yes ↑ Yes ↓ 
First line Unmutated IGHV Unmutated
Mutated 
15% → 61%
(16% → 64%) 
28% → 79%
(43% → 74%) 
51% → 89%
(86% → 90%) 
34% → 81%
(75% → 87%) 
Yes ↑↑ Yes ↑↑ Probably ↓ 
Relapsed  Unmutated
Mutated 
NR 15% → 61%
(16% →64%) 
HR 0.16
HR (0.11) 
NR Yes ↑↑ Yes ↑ NR 
   Pbo-BortDex → Ven-BortDex    
Myeloma Name Status ≥vGPR uMRD
(<10–5) 
PFS Survival HR ≥vGPR & PFS OS  
Relapsed99 
Ven-BD 
t(11;14) Present
Absent 
27% → 75%
(38% → 58%) 
0% → 25%
(1% → 12%) 
HR 0.11
(HR 0.67) 
0.34
(2.5) 
Yes ↑↑ No Yes ↑ 
 High BCL2§ First quartile
Fourth quartile 
28% → 71%
(40% → 52%) 
0% → 18%
(2% →11%) 
HR 0.24
(HR 0.76) 
1.0
(>2.0) 
Yes ↑↑ No Yes ↑ 
   Pbo-Aza → Ven-Aza    
AML Name Status CR/Cri ΔCR/Cri 2-y OS HR OS CR OS  
First line74 
Ven-Aza 
IDH1/2 mut Present
Absent 
11% → 75%
32% → 66% 
+64%
+34% 
14% → 52%
(14% → 41%) 
0.34 Yes ↑↑ Yes ↑↑ Yes ↑ 
 TP53 mut Present
Absent 
0% → 55%
31% → 68% 
+55%
+37% 
7% → 11%
27% → 49% 
0.76 Yes ↑↑ No Yes ↓ 

The table summarizes the randomized trial data for genetic markers with the most robust evidence informing treatment effect modification: either abrogation of previously established negative treatment effect modification by venetoclax or the presence of novel positive treatment effect modification with venetoclax therapy. In CLL, the established negative treatment effect modifiers for chemo-immunotherapy (del(17p), TP53 mutations and unmutated IGHV status) do not affect responsiveness to venetoclax, and their presence predicts major benefit from use of venetoclax over chemo-immunotherapy, but they remain negatively prognostic. In multiple myeloma, the presence of either t(11;14) or high BCL2 RNA expression is a strong positive treatment effect modifier, with the magnitude of response and PFS benefits for venetoclax significantly exceeding that seen in marker-negative myeloma. In AML, the presence of mutations in IDH1 or IDH2 is a strong positive treatment effect modifier with the magnitude of benefits for venetoclax significantly exceeding that seen in marker-negative AML. Although TP53 mutations in AML are associated with magnified benefit with respect CR/CRi rate, improved survival has not been shown; the presence of TP53 mutations is associated with a lower CR/CRi rate with venetoclax and a negative prognosis compared with AML with normal TP53. ∼, estimated from Kaplan-Meier plots;

Aza, azacytidine; BD, bortezomib + dexamethasone; Benda, bendamustine; Chl, chlorambucil; CRi, CR, including with hematologic incomplete recovery; HR, hazard ratio for progression vs control, included when actual rates were not provided, and italicized when not statistically significantly different from control therapy; NR, not reported; Obin, obinutuzumab; Pbo, placebo; R, rituximab; Ven, venetoclax.

*

Includes data for either del(17p) or TP53 mutated cases for control treatment arm, as del(17p) data alone were not reported.

All data in these comparisons include either del(17p) or TP53 mutations.

PFS: HR, 1.96; 95% CI, 0.92-4.17.

§

High BCL2 RNA expression.

Absence of a marker includes patients with unknown status.

Abnormalities of TP53 function are known negative response-effect modifiers for DNA-damaging therapy in CLL (and other hematologic malignancies), characterized by consistent associations with inferior CR, uMRD, PFS, and OS rates in trials and mechanistic studies in model systems.46 With venetoclax ± anti-CD20 antibodies, no negative effect is observed for overall response, CR, or MRD clearance rates or with CLL killing in vitro.31,39,43,47,48 However, the presence of a TP53 abnormality before therapy is associated with an increased rate of relapse, compared with CLL with normal TP53, and remains prognostic.41,47,48 The magnitude of benefit for venetoclax-based regimens over chemo-immunotherapy is greater for patients with TP53-aberrant CLL than observed for those with TP53 wild-type CLL.47,48 Similarly, patients with unmutated IGHV CLL have inferior outcomes with chemo-immunotherapy compared with those whose CLL has mutated IGHV. Although unmutated IGHV is a negative treatment effect modifier for chemo-immunotherapy, it is not for venetoclax-based regimens, and its presence predicts for major benefit from the use of venetoclax.41,47 Both mutated and unmutated IGHV CLL have similar rates and depths of response. However, unmutated IGHV may remain a negative prognostic factor (compared with mutated IGHV; Table 2), in long-term follow-up of approved venetoclax-based regimens.47 

Resistance

Robust data are also emerging about the molecular basis for treatment failure in CLL (Table 3). Early progression (within the first year) is uncommon and closely associated with complex karyotype and Richter transformation in heavily pretreated patients.49,50 Secondary resistance in patients receiving continuous venetoclax can be caused by several independently occurring mechanisms (Table 3; Figure 3). These include mutations in BCL2 (eg, Gly101Val), overexpression of MCL1, and overexpression of BCLxL.51-54 All have been validated functionally, with each reducing the intrinsic sensitivity of CLL cells to venetoclax by 1.5 to 3 logs in both patient cells and model systems. BCL2 mutations reduce binding of the drug but retain pro-survival function of the protein.51,55 Heightened expression of MCL1 or BCLxL provides cells with sufficient alternative prosurvival function to avoid apoptosis in the presence of venetoclax. It is common for relapse to be polyclonal, with independent mechanisms evident in different subclones. For example, as well as the 2 more common BCL2 mutations (Gly101Val and Asp104Tyr), 6 other BCL2 mutations have been described, with many patients demonstrating several independent subclones, each characterized by a different mutation.56 How the BCL2 mutations are generated remains unknown. The great majority have never been observed outside the context of secondary venetoclax resistance. MCL1 overexpression can be the consequence of amplification of the MCL1 locus on chromosome 1q21 but can also occur in the absence of gene amplification.53 The presumed epigenetic mechanisms leading to MCL1 overexpression in those circumstances and BCLxL overexpression in other patients’ cells remain to be elucidated. With most patients treated with venetoclax now completing time-limited therapy in objective response and early data suggesting that re-exposure to the drug induces secondary responses in 12 of 17 cases reported in 2 prospective studies to date,45,48 further studies are required to understand whether the landscape of resistance will be different with repeat exposure.

Table 3.

Clinical, genetic, and epigenetic alterations associated with venetoclax resistance in patients, classified by class and tier of supportive evidence

ClassGene or gene productCLLMantle cell lymphomaAML
Clinical High bulk41   Tier 3   
 BTKi clinical resistance41   Tier 3   
 Prior azacitidine75     Tier 3 
 Monocytic lineage86     Tier 2 
Cytogenetic Complex karyotype48,74  Tier 1*  Tier 2 
 del9p138    Tier 1  
Mutations/CNV Apoptosis TP53 mut/loss (incl del17p)41,47,81,82 Tier 2  Tier 2 
  BCL2 mut51,52,54,56 Tier 1   
  MCL1 amp53  Tier 1   
  BAX mut84,85 Tier 1  Tier 2 
 Signaling Notch1 mut (activating)41  Tier 2   
  Activated growth factor49,81 Braf; Tier 2  FLT3; Tier 1
Ras; Tier 2 
 Cell cycle CDKN2A/B mut/loss49  Tier 1*   
  BTG1 mut49  Tier 2   
 Epigenetic regulator SWI/SNF family mut/loss138   Tier1  
Expression Apoptosis ↓BCL2138   Tier 1  
  ↑BCLxL51,78,82,86,138 Tier 1 Tier 1 Tier 1 
  ↑MCL153,86 Tier 1  Tier 1 
  ↑BCL2A1139,140 Tier 1  Tier 1 
  ↓PUMA78    Tier 2 
  ↓NOXA82,88   Tier 2 
 Mitochondrial metabolism AMPK53  Tier 1  Tier 1 
ClassGene or gene productCLLMantle cell lymphomaAML
Clinical High bulk41   Tier 3   
 BTKi clinical resistance41   Tier 3   
 Prior azacitidine75     Tier 3 
 Monocytic lineage86     Tier 2 
Cytogenetic Complex karyotype48,74  Tier 1*  Tier 2 
 del9p138    Tier 1  
Mutations/CNV Apoptosis TP53 mut/loss (incl del17p)41,47,81,82 Tier 2  Tier 2 
  BCL2 mut51,52,54,56 Tier 1   
  MCL1 amp53  Tier 1   
  BAX mut84,85 Tier 1  Tier 2 
 Signaling Notch1 mut (activating)41  Tier 2   
  Activated growth factor49,81 Braf; Tier 2  FLT3; Tier 1
Ras; Tier 2 
 Cell cycle CDKN2A/B mut/loss49  Tier 1*   
  BTG1 mut49  Tier 2   
 Epigenetic regulator SWI/SNF family mut/loss138   Tier1  
Expression Apoptosis ↓BCL2138   Tier 1  
  ↑BCLxL51,78,82,86,138 Tier 1 Tier 1 Tier 1 
  ↑MCL153,86 Tier 1  Tier 1 
  ↑BCL2A1139,140 Tier 1  Tier 1 
  ↓PUMA78    Tier 2 
  ↓NOXA82,88   Tier 2 
 Mitochondrial metabolism AMPK53  Tier 1  Tier 1 

The strength of evidence for a clinically important role of an associated marker in venetoclax resistance is categorized into tiers: tier 1, proven mechanism and associated with resistance in multiple patients; tier 2, plausible mechanism and observed in some patients; tier 3, associated with resistance in multiple patients, but no mechanism established. Where a molecular marker is associated with primary resistance to venetoclax, the tier is in bold. Markers associated with secondary resistance are recorded in normal font. Consistent with expectations arising from our knowledge of the regulation of apoptosis, genetic or epigenetic alterations in BCL2 family expression are common causes of secondary resistance to venetoclax.

BTKi, Bruton tyrosine kinase inhibitor; CK, complex karyotype; CNV, copy number variation.

*

Associated with Richter transformation.

del(9p) and SWI/SNF family mutations are causative of resistance when they co-occur.

Figure 3.

Direct and indirect alterations to apoptosis regulators explain many of the proven mechanisms of clinical resistance to venetoclax. The graphic highlights the interrelations between validated genetic and epigenetic mechanisms of venetoclax resistance observed in patients (tier 1 mechanisms listed in Table 3 with references) and their convergence on the expression or function of BCL2 family proteins and/or on mitochondria. Genetic aberrations in BCL2 family members such as amplifications affecting MCL1, coding mutations in BCL2 (*such as encode BCL2 Gly101Val) that alter venetoclax binding, or nonsense mutations (eg, BAX) may occur. Alternatively, genetic changes in their regulators (eg, TP53, del9p, members of the SWI/SNF complex) may alter their expression indirectly (epigenetic changes [Δ]). TP53 loss or mutation (in green) can indirectly reduce sensitivity to venetoclax by reducing expression of BH3-only proteins (eg, PUMA, NOXA) and/or by increasing the threshold for BAX/BAK-induced permeabilization of the outer mitochondrial membrane.83 Activated signaling in various growth factor pathways (in blue; eg, via kinase mutations) can indirectly increase expression of other prosurvival proteins or increase mitochondrial metabolism.

Figure 3.

Direct and indirect alterations to apoptosis regulators explain many of the proven mechanisms of clinical resistance to venetoclax. The graphic highlights the interrelations between validated genetic and epigenetic mechanisms of venetoclax resistance observed in patients (tier 1 mechanisms listed in Table 3 with references) and their convergence on the expression or function of BCL2 family proteins and/or on mitochondria. Genetic aberrations in BCL2 family members such as amplifications affecting MCL1, coding mutations in BCL2 (*such as encode BCL2 Gly101Val) that alter venetoclax binding, or nonsense mutations (eg, BAX) may occur. Alternatively, genetic changes in their regulators (eg, TP53, del9p, members of the SWI/SNF complex) may alter their expression indirectly (epigenetic changes [Δ]). TP53 loss or mutation (in green) can indirectly reduce sensitivity to venetoclax by reducing expression of BH3-only proteins (eg, PUMA, NOXA) and/or by increasing the threshold for BAX/BAK-induced permeabilization of the outer mitochondrial membrane.83 Activated signaling in various growth factor pathways (in blue; eg, via kinase mutations) can indirectly increase expression of other prosurvival proteins or increase mitochondrial metabolism.

Close modal

BTK inhibitors (BTKi) are the other class of targeted novel drugs that have revolutionized care in CLL. Like venetoclax, they are highly effective as monotherapy and against TP53-aberrant disease.57,58 Unlike venetoclax, they are not rapidly cytotoxic; rather CLL cells die of neglect because of blockade of B-cell receptor and chemokine receptor signaling.58 Indefinite continuous rather than fixed-duration therapy appears required. Preclinical data indicate synergy between BTKi and BCL2 inhibition, and circulating CLL cells from patients taking ibrutinib are sensitized to in vitro killing by venetoclax.59-61 Together with the largely nonoverlapping toxicity profiles, these findings made exploration of the combination of BTKi and venetoclax logical in CLL (and mantle cell lymphoma [MCL]). Phase 1/2 trials indicate 90% to 100% rates of response and very high levels of CRs (50% to 88%) and uMRD (60% to 70%) in both the first-line and relapsed settings.62,63 Phase 3 trials comparing various combinations of venetoclax with a BTKi ± anti-CD20 antibody are ongoing, including randomized studies vs chemoimmunotherapy in fit patients.

AML

AML is a more heterogeneous disease than CLL, representing neoplastic transformation of either hematopoietic stem cells (HSCs) or myeloid progenitor cells. BCL2 expression varies across its spectrum and can be heterogeneous even within a patient’s leukemic cell population. Genetic evidence indicates that BCL2 is not essential for HSC or progenitor cell function, whereas MCL1 is required for HSC function64 and for expansion of AML in model systems.65 Nevertheless, ABT-737 had in vitro activity against primary patient samples.66 Subsequent studies revealed venetoclax and ABT-737 to be equipotent in killing AML cells, supporting the dominant prosurvival role played by BCL2.67 Venetoclax was also shown to induce apoptosis more effectively in leukemic compared with normal CD34+ HSCs and progenitor cells, suggesting a therapeutic window.68 In the first study of venetoclax monotherapy in relapsed/refractory AML, CRs were observed in 19%.69 These responses, however, were not durable, in contrast to those seen in CLL.

Combination therapy is therefore necessary, and the first regimens trialed were those incorporating conventional treatments for patients unfit for intensive induction therapy. Azacitidine can enhance venetoclax activity against AML through TP53-independent NOXA induction after activation of the integrated stress response pathway,70 whereas genotoxic drugs do so through TP53-mediated upregulation of NOXA and PUMA.67,71

Efficacy

In November 2018, venetoclax was granted accelerated approval for use in adults with newly diagnosed AML ≥ 75 years of age or with comorbidities precluding intensive chemotherapy. Phase 1b/2 studies had shown that venetoclax in combination with either low-dose cytarabine or hypomethylating agents produced high rates of CR (54%-67%) in patients with a median age of 74 years.72,73 These remissions were achieved rapidly and with low early (30-day) mortality (3% to 6%), consistent with the profile expected for a low-intensity therapy. In October 2020, venetoclax was granted full approval after 2 confirmatory phase 3 trials, conducted in the same unfit patient population, demonstrated a significant survival benefit over placebo for the addition of venetoclax to azacitidine (VIALE-A; HR 0.66, NNT of ∼5 at 2 years) or to low-dose cytarabine (VIALE-C).74,75 In VIALE-C, improvement in survival was only significant after a post hoc longer-term follow-up analysis. Therefore, venetoclax-azacitidine has been widely adopted as the preferred first line therapy for older and unfit AML patients. In these patients, the major toxicities relate to myelosuppression which is increased and can be prolonged.

Biomarkers

With the graduation of venetoclax into the routine management of AML, a current priority is the identification of clinically relevant correlates of response and resistance to guide patient selection and inform design of new drug combinations aimed at subverting drug resistance or salvaging patients with disease progression.

However, biomarkers of primary response to venetoclax in AML are not straightforward to delineate, as AML has diverse genetics, and the drug has not been widely used as monotherapy. Two clinical studies have examined bone marrow blast responses to venetoclax monotherapy. In relapsed/refractory AML, blast reductions were greatest in AML bearing IDH, SRSF2, or ZRSR2 mutations.76 In previously untreated AML, a 7-day prephase of venetoclax monotherapy suppressed marrow blasts most effectively in NPM1, IDH, and SRSF2 mutant AML.77 Preclinical studies have suggested the presence of a HOX gene expression signature,78,MLL-X fusion, RAD21, GATA2, or WT1 mutations to correspond with venetoclax sensitivity.78,79 It has yet to be determined, however, how these entities perturb AML biology in favor of venetoclax responsiveness, and they have not been studied prospectively in trials. Importantly, the presence of either IDH1 or IDH2 canonical mutations is a bone fide treatment effect modifier in the context of venetoclax-azacitidine treatment. Consistent with preclinical discoveries and early signals from the phase 1 study, IDH-mutant AML is relatively highly susceptible to BCL2 inhibition compared with other AMLs and compared with azacitidine therapy alone (Table 2).69,74,80

Resistance

In terms of secondary venetoclax resistance, longitudinal studies have identified some factors associated with adaptive resistance (Table 3). Selection of clones enriched for FLT3-ITD or mutant TP53 has been found at the time of AML relapse.81 The addition of exogenous growth factors reduces sensitivity to venetoclax in vitro and activating mutations in growth factor signaling pathways (eg, FLT3-ITD) appear to drive expression of prosurvival proteins, including MCL1, which can mediate resistance to venetoclax and other cytotoxic drugs.81 Unlike in CLL, BCL2 mutations impairing venetoclax affinity have not been reported in patients with relapsed AML. Loss-of-function CRISPR (clustered regularly interspaced short palindromic repeats) screens have identified TP53 and BAX as candidate loss-of-function routes to venetoclax resistance, but exactly how TP53 dysfunction achieves this remains uncertain.82 In part, it is explained by recent data demonstrating that TP53 loss impairs BAX/BAK activation, conferring a competitive advantage for subclones with aberrant TP53 during ongoing BCL2 (or MCL1) inhibition.83 This appears particularly important when BH3 mimetic concentrations are suboptimal and resolves the apparent disconnect between similarly high response rates in TP53-aberrant and TP53-sufficient AML and CLL but inferior long-term benefit in TP53-aberrant leukemias. Emergent BAX mutations have been identified recently in patients with AML relapsing after venetoclax and also in the myeloid compartment of patients with clonal hematopoiesis receiving venetoclax for treatment of CLL.84,85 Higher constitutive expression of MCL1 in monocytes may also result in lineage-associated adaptive resistance during venetoclax therapy (Table 3).86 Other reported associations with venetoclax resistance in AML in vitro include increased expression of alternative prosurvival proteins, such as BCLxL, MCL1, BCL2A1, downregulation of proapoptotic BH3-only members PUMA or NOXA, or activating mutations affecting other kinases in the MAPK pathway, such as RAS or PTPN11.78,82,87,88 However, whether these lesions do cause resistance in patients in vivo is currently unknown.

Previous studies have identified MCL1 to be amplified or overexpressed in AML and models conditionally targeting MCL1 have confirmed its prosurvival role in certain subsets of AML, including MLL-X–driven disease.65 Xenograft model systems demonstrated synergistic antileukemic activity in vivo when venetoclax was combined with an inducible vector targeting MCL1.67 Although a subset of primary AML samples also appear sensitive to MCL1 inhibition with BH3 mimetics, monotherapy activity in vitro against primary AML is generally modest.18,89 However, combined targeting of BCL2 and MCL1 (using S63845,18 AMG176,19 AZD5991,22 or VU66101390) has been reported by 4 independent groups to be synergistic against AML, including TP53-aberrant AML,83 confirming the importance of these 2 prosurvival targets in sustaining survival of a diverse spectrum of leukemic blasts (Figures 1 and 2). Although toxicity from dual inhibition may be a barrier, to date, lethal damage to normal tissues in these models has not been observed, perhaps suggesting that clinical development of such combinations may be feasible.19,89

Other opportunities to improve venetoclax efficacy in AML relate to the apparent reliance of leukemic stem and progenitor cells (LSPCs) on glycolytic metabolism as an energy source.91 Following BAX/BAK-induced MOMP, the oxidative phosphorylation pathway is disrupted, including in cells incompletely committed to apoptosis (Figure 1). Adding drugs that compromise amino acid metabolism92 or transportation of fatty acids into the cell can deprive AML of alternative energy sources to compensate for the effect of venetoclax-azacitidine on oxidative phosphorylation in LSPCs.93 In fit patients with poor prognosis AML, venetoclax is now being combined with more intensive cytotoxic regimens. Preliminary data indicate higher initial response rates but also more pronounced hematopoietic toxicity, particularly with repetitive cycles of therapy.77 

Multiple myeloma

Neoplastic plasma cells not only typically express high levels of BCL2 but commonly express BCLxL and MCL1.94 Indeed, MCL1 is required for normal plasma cell development.7 In vitro testing of primary cells indicate broad activity of BCL2 inhibitors against myeloma, with marked sensitivity observed for myeloma bearing t(11;14).94-96 BCL2 inhibition as treatment of patients with myeloma remains experimental. Although durable remissions in the t(11;14) subset have been observed with venetoclax monotherapy,97 combination therapy appears necessary in most patients.98 The most advanced combination, venetoclax with bortezomib-dexamethasone, has been investigated in a placebo-controlled randomized trial in relapsed/refractory disease.99 Venetoclax substantially improved PFS but not OS, at a cost of increased morbidity and some excess mortality in patients with myeloma progression (Table 4). Increased risk of infections was an important contributor to this excess toxicity and current trials in multiple myeloma include specific recommendations on how this risk can be mitigated. t(11;14) is clearly a positive response-effect modifier (Table 2). Ongoing trials are required to identify how this drug can be incorporated into well tolerated regimens with enhanced efficacy.

Table 4.

Published phase 2 or 3 data in other hematologic malignancies

Disease phase (n)Regimen (dose)ComparatorEfficacy*SafetyComment
Relapsed multiple myeloma      
 Phase 399 (n = 291) Ven-BortD 800 mg daily Pbo-BortD Median PFS: 22m vs 11m; HR 0.63 (0·44–0·90) ↑ Neutropenia;
↑ Mortality related to infection 
↑ Efficacy without excess mortality in t(11;14) subgroup 
Relapsed follicular lymphoma      
 Phase 2141 (n = 163) Ven-R;
Ven-BR
800 mg daily 
BR CMR/CR rate
VR: 17%
VBR: 75%
BR: 69% 
↑ Toxicity with VBR; and ↓ BR dose intensity when combined with Ven No benefit from adding Ven to BR 
First-line diffuse large B-cell lymphoma      
 Phase 2142 (N = 206) Ven-R-CHOP
800 mg 10d 
R-CHOP CR rate:
69% vs 63%; NS
2-y PFS: 80% vs 67%; HR 0.61 (0.43-0.87) 
↑ Grade 3/4 AEs (86% vs 66%), principally neutropenia Scheduling needs optimization;
↑ Incremental efficacy if BCL2 IHC+Ven (exploratory) 
Relapsed mantle-cell lymphoma      
 Phase 2143 (n = 24Ven-Ibr
400 mg daily 
Nil CR at 16 wk 42%
CMR rate 71% 
33% G3/4 neutropenia
17% G3/4 tcp 
Dose adjustments for either Ven or Ibr common 
 Phase 1/2144 (n = 24) Obin-Ven-Ibr
400 mg daily§ 
Nil CMR rate 67% 33% G4 neutropenia
12% G4 tcp 
Dose adjustments for either Ven or Ibr common 
Disease phase (n)Regimen (dose)ComparatorEfficacy*SafetyComment
Relapsed multiple myeloma      
 Phase 399 (n = 291) Ven-BortD 800 mg daily Pbo-BortD Median PFS: 22m vs 11m; HR 0.63 (0·44–0·90) ↑ Neutropenia;
↑ Mortality related to infection 
↑ Efficacy without excess mortality in t(11;14) subgroup 
Relapsed follicular lymphoma      
 Phase 2141 (n = 163) Ven-R;
Ven-BR
800 mg daily 
BR CMR/CR rate
VR: 17%
VBR: 75%
BR: 69% 
↑ Toxicity with VBR; and ↓ BR dose intensity when combined with Ven No benefit from adding Ven to BR 
First-line diffuse large B-cell lymphoma      
 Phase 2142 (N = 206) Ven-R-CHOP
800 mg 10d 
R-CHOP CR rate:
69% vs 63%; NS
2-y PFS: 80% vs 67%; HR 0.61 (0.43-0.87) 
↑ Grade 3/4 AEs (86% vs 66%), principally neutropenia Scheduling needs optimization;
↑ Incremental efficacy if BCL2 IHC+Ven (exploratory) 
Relapsed mantle-cell lymphoma      
 Phase 2143 (n = 24Ven-Ibr
400 mg daily 
Nil CR at 16 wk 42%
CMR rate 71% 
33% G3/4 neutropenia
17% G3/4 tcp 
Dose adjustments for either Ven or Ibr common 
 Phase 1/2144 (n = 24) Obin-Ven-Ibr
400 mg daily§ 
Nil CMR rate 67% 33% G4 neutropenia
12% G4 tcp 
Dose adjustments for either Ven or Ibr common 

AE, adverse events; B, bendamustine; Bort, bortezomib; CMR, complete metabolic response (no PET evidence of active lymphoma, but may have residual structural abnormalities); D, dexamethasone; G, grade; Ibr, ibrutinib; IHC+, positive immunohistochemistry for BCL2; Obin, obinutuzumab; Pbo, placebo; R, rituximab; tcp, thrombocytopenia; Ven, venetoclax.

*

Primary end point of the trial.

Indirect comparison with covariate-adjusted controls from GOYA trial.

Includes 1 first-line patient with TP53 aberration.

§

Six of 24 patients received either 600 or 800 mg daily of venetoclax.

Lymphoma

B-cell lymphomas by virtue of their lineage commonly express BCL2.100 Overexpression is driven in some through translocation (eg, t[14;18]),101 in follicular lymphoma and some double-hit lymphomas, gene amplification (eg, some diffuse large B-cell lymphomas [DLBCL]),102 or epigenetic dysregulation (eg, MCL).103 High-level MCL1 expression is common in MYC-driven lymphomas such as Burkitt lymphoma.104 

BCL2 inhibition as treatment of patients with lymphoma remains experimental. Early-phase trials established modest single agent activity in MCL, follicular lymphoma, and Waldenström macroglobulinemia, but minimal activity in DLBCL.105 Various combination regimens, rational for each disease, are being tested in ongoing trials. Published results for completed phase 2 trials are summarized in Table 4. The results of randomized trials of R-CHOP (rituximab-cyclophosphamide-doxorubicin hydrochloride-vincristine sulphate-prednisone), with or without venetoclax for first-line high risk DLBCL and ibrutinib, with or without venetoclax, in relapsed MCL are awaited with interest.

Other diseases

Single-agent activity has also been observed in small series of patients with diseases with high levels of BCL2 expression: blastic plasmacytoid dendritic cell neoplasm,106 prolymphocytic leukemia,107 and t(11;14) light chain amyloidosis.108 In relapsed acute lymphoblastic leukemia, venetoclax in combination with navitoclax (to inhibit BCLxL) and nonmyelotoxic chemotherapy is being explored, with a phase 1b study reporting a high response rate.109 

What should we expect from MCL1 inhibitors?

As listed in Table 1, there are multiple specific MCL1i in early-stage clinical development. Based on preclinical data and lessons learned from selective BCL2 inhibition with venetoclax, several predictions can be made for selective MCL1i undergoing clinical trials. First, apoptosis of susceptible cells is likely to be rapid, with biological activity evident within hours after exposure. TLS can be anticipated to occur occasionally, especially in patients with bulky or proliferative forms of myeloma, lymphoma, or acute leukemia. Second, "on target" hematopoietic toxicities, including neutropenia, monocytopenia, and depletion of plasma cells (with consequent hypogammaglobulinemia), are likely to occur in patients receiving antitumoral doses.19,110 Gene ablation models have also highlighted the biologically important role played by MCL1 in cardiomyocyte,111,112 neuronal,113 hepatocyte,114,115 and intestinal cell survival.116 Consequently, collateral toxicities that should be anticipated in clinical trials include biochemical derangement of liver and cardiac enzymes and gastrointestinal symptoms. Patients should be screened for pretreatment hepatic and/or cardiac abnormalities and monitored closely for evidence of biochemical damage after commencing therapy. As MCL1i are likely to be less well tolerated than BCL2i, intermittent schedules (eg, weekly or bi weekly) are being explored in initial first-in-human trials. Third, objective responses with monotherapy should be observed in myeloma,18,19,117 AML,18,19,22,65,90 and MYC-driven lymphomas,18,104 but these may not be durable. Although some exceptional responders are likely to be seen, at this point, no putative biomarkers have been validated. Candidate biomarkers of response include amplification of MCL1 on chromosome 1q21118 and monocytic differentiation in AML.86,119

Analogous to venetoclax in various blood cancers (CLL, AML), aberrant TP53 is unlikely to diminish response to MCL1i but durability of benefit is likely to be reduced.83 Consequently, combination therapy will be required.18,19,22,90 As with venetoclax, potential partners should be tailored to specific diseases and can be anticipated to include monoclonal antibodies , tyrosine kinase inhibitors (TKIs), hypomethylating agents, and conventional cytotoxics. Furthermore, once tolerable monotherapy regimens demonstrating biological activity without DLTs are established, it seems appropriate to commence assessment of novel combinations. Based on a narrower therapeutic window than venetoclax, it is probable that MCL1i will most likely succeed if efficacy only requires brief bursts of exposure to maximal tolerated doses.

To date, the only clinical trial data reported for MCL1 inhibition are preliminary results from the first 26 patients with relapsed refractory myeloma enrolled to the first-in-human trial of intravenous AMG-176. Emergent side effects were mostly hematologic (neutropenia and anemia) and gastrointestinal (nausea and diarrhea). An antitumor effect was reported in 3 patients (1 CR and 2 partial responses).120 Enrollment to another trial investigating the orally administered MCL1 inhibitor AMG-397 in various blood malignancies was placed on clinical hold after a cardiac toxicity signal was seen. Clinical trial data from all MCL1i are awaited to determine how appropriate patient selection and dosing schedules can result in identification of a safe and efficacious clinical pathway for these new BH3 mimetic drugs.

For highly susceptible diseases (eg, CLL with BCL2 inhibition), the outstanding questions relate to (1) the optimum duration of treatment: is this for a fixed duration or adapted to the tempo and depth of MRD clearance, and (2) whether triplet regimens combining venetoclax with BTKi and monoclonal antibodies add substantially to durability of disease clearance? The latter question also applies for mantle cell lymphoma. Long term, it is conceivable that combinations of BCL2i and BTKi may be curative for some patients with CLL. For less susceptible diseases (eg, BCL2-expressing DLBCL), the critical question is whether routine addition of venetoclax adds to the cure fraction currently achievable with chemo-immunotherapy alone. This question is also of great interest in patients with AML suitable for standard intensive chemotherapy. BH3 mimetics have long promised to augment efficacy when combined with DNA-damaging cytotoxics in preclinical models, and it seems these 2 clinical settings will inform us as to whether the inevitable increase in hematologic toxicity is outweighed by substantially higher proportions of patients with durable responses. In AML, another important question is whether treatment should continue until disease progression or whether limited-duration therapy should be considered, similar to CLL. This is especially pertinent in subgroups such as IDH-mutated leukemia and where MRD is absent.

As outlined above, the immediate research imperative for MCL1 inhibitors is definition of safe and biologically active regimens with preliminary evidence of efficacy in relapsed and refractory disease settings. The field is expecting that some clinically important dose-limiting toxicities will emerge necessitating use of submaximal doses in combination regimens in order to limit exposure at peak concentrations while maximizing clinical efficacy. Priorities for phase 2 exploration should be guided by where the preliminary clinical data suggest the greatest impact may be, with likely candidate areas including relapsed AML, first-line AML bearing highly unfavorable genomic features, multiply relapsed MYC-driven lymphomas, and relapsed myeloma bearing amplifications of chromosome 1q21 (containing the MCL1 locus).

The potential of BH3 mimetics as anticancer drugs is only beginning to emerge. These rapidly acting, non-DNA, damaging cytotoxics may fill key gaps in our current armamentaria against hematologic malignancies. Lessons learned thus far form sound principles for future therapeutic endeavors. The small, potential risk of tumor lysis syndrome, as well as bone marrow and other organ toxicity, mandates that new combinations are carefully tested in clinical trials. As long as therapeutic safety margins can be maintained, BH3 mimetic agents have the potential to further improve clinical outcomes in multiple hematologic malignancies.

The authors thank their many long-term collaborators for advice and important contributions to the generation of knowledge included in this review.

Academic research in the A.W.R., A.H.W., and D.C.S.H. laboratories has been supported over the last 20 years by grants from the National Health and Medical Research Council of Australia , the Leukemia and Lymphoma Society, Cancer Council of Victoria, Victorian Cancer Agency, Australian Cancer Research Foundation, Leukaemia Foundation of Australia, the Snowdome Foundation, and the Medical Research Future Fund.

Contribution: A.W.R., A.H.W., and D.C.S.H. conceived, reviewed the literature, and wrote the manuscript.

Conflict-of-interest disclosure: A.W.R. and D.C.S.H. are employees and A.H.W. is a former employee of the Walter and Eliza Hall Institute, which receives milestone and royalty payments related to venetoclax; each receives a share of these royalties from the Institute. A.W.R. has received research funding to his institutions from Abbvie, Janssen, and Servier for investigator-initiated clinical trials or laboratory research. A.H.W. has served on advisory boards for Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, Celgene-BMS, Macrogenics, Agios, and Gilead; receives research funding to the institution from Novartis, Abbvie, Servier, Celgene-BMS, Astra Zeneca, and Amgen; and serves on speaker bureaus for Abbvie, Novartis, and Celgene. D.C.S.H. has received research funding from Genentech and Servier.

Correspondence: Andrew Roberts, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; e-mail: roberts@wehi.edu.au.

1.
Cory
S
,
Adams
JM
.
The Bcl2 family: regulators of the cellular life-or-death switch
.
Nat Rev Cancer.
2002
;
2
(
9
):
647
-
656
.
2.
Letai
AG
.
Diagnosing and exploiting cancer’s addiction to blocks in apoptosis
.
Nat Rev Cancer.
2008
;
8
(
2
):
121
-
132
.
3.
Lessene
G
,
Czabotar
PE
,
Colman
PM
.
BCL-2 family antagonists for cancer therapy
.
Nat Rev Drug Discov.
2008
;
7
(
12
):
989
-
1000
.
4.
Davids
MS
,
Letai
A
.
Targeting the B-cell lymphoma/leukemia 2 family in cancer
.
J Clin Oncol.
2012
;
30
(
25
):
3127
-
3135
.
5.
Merino
D
,
Kelly
GL
,
Lessene
G
,
Wei
AH
,
Roberts
AW
,
Strasser
A
.
BH3-mimetic drugs: blazing the trail for new cancer medicines
.
Cancer Cell.
2018
;
34
(
6
):
879
-
891
.
6.
Huang
K
,
O’Neill
KL
,
Li
J
, et al
.
BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis
.
Cell Res.
2019
;
29
(
11
):
942
-
952
.
7.
Peperzak
V
,
Vikström
I
,
Walker
J
, et al
.
Mcl-1 is essential for the survival of plasma cells [correction published in Nat Immunol. 2013;14:877]
.
Nat Immunol.
2013
;
14
(
3
):
290
-
297
.
8.
Hinds
MG
,
Smits
C
,
Fredericks-Short
R
, et al
.
Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets
.
Cell Death Differ.
2007
;
14
(
1
):
128
-
136
.
9.
Tse
C
,
Shoemaker
AR
,
Adickes
J
, et al
.
ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor
.
Cancer Res.
2008
;
68
(
9
):
3421
-
3428
.
10.
Wilson
WH
,
O’Connor
OA
,
Czuczman
MS
, 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
(
12
):
1149
-
1159
.
11.
Roberts
AW
,
Seymour
JF
,
Brown
JR
, 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
(
5
):
488
-
496
.
12.
Roberts
AW
,
Advani
RH
,
Kahl
BS
, et al
.
Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20+ lymphoid malignancies
.
Br J Haematol.
2015
;
170
(
5
):
669
-
678
.
13.
Kipps
TJ
,
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
(
10
):
2826
-
2833
.
14.
Mason
KD
,
Carpinelli
MR
,
Fletcher
JI
, et al
.
Programmed anuclear cell death delimits platelet life span
.
Cell.
2007
;
128
(
6
):
1173
-
1186
.
15.
Waibel
M
,
Solomon
VS
,
Knight
DA
, et al
.
Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors
.
Cell Rep.
2013
;
5
(
4
):
1047
-
1059
.
16.
Khaw
SL
,
Suryani
S
,
Evans
K
, et al
.
Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia
.
Blood.
2016
;
128
(
10
):
1382
-
1395
.
17.
Souers
AJ
,
Leverson
JD
,
Boghaert
ER
, et al
.
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
.
Nat Med.
2013
;
19
(
2
):
202
-
208
.
18.
Kotschy
A
,
Szlavik
Z
,
Murray
J
, et al
.
The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
.
Nature.
2016
;
538
(
7626
):
477
-
482
.
19.
Caenepeel
S
,
Brown
SP
,
Belmontes
B
, et al
.
AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies
.
Cancer Discov.
2018
;
8
(
12
):
1582
-
1597
.
20.
Caenepeel
S
,
Karen
R
,
Belmontes
B
, et al
.
Discovery and preclinical evaluation of AMG 397, a potent, selective and orally bioavailable MCL1 inhibitor [abstract]
.
Cancer Res.
2020
;
80
(
16 suppl
):
6218
-
6218
. Abstract 6218.
21.
Szlavik
Z
,
Csekei
M
,
Paczal
A
, et al
.
Discovery of S64315, a potent and selective Mcl-1 inhibitor
.
J Med Chem.
2020
;
63
(
22
):
13762
-
13795
.
22.
Tron
AE
,
Belmonte
MA
,
Adam
A
, et al
.
Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia
.
Nat Commun.
2018
;
9
(
1
):
5341
.
23.
Schena
M
,
Larsson
LG
,
Gottardi
D
, et al
.
Growth- and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells
.
Blood.
1992
;
79
(
11
):
2981
-
2989
.
24.
Hanada
M
,
Delia
D
,
Aiello
A
,
Stadtmauer
E
,
Reed
JC
.
bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia
.
Blood.
1993
;
82
(
6
):
1820
-
1828
.
25.
Robertson
LE
,
Plunkett
W
,
McConnell
K
,
Keating
MJ
,
McDonnell
TJ
.
Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome
.
Leukemia.
1996
;
10
(
3
):
456
-
459
.
26.
Mason
KD
,
Khaw
SL
,
Rayeroux
KC
, et al
.
The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia
.
Leukemia.
2009
;
23
(
11
):
2034
-
2041
.
27.
Del Gaizo Moore
V
,
Brown
JR
,
Certo
M
,
Love
TM
,
Novina
CD
,
Letai
A
.
Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737
.
J Clin Invest.
2007
;
117
(
1
):
112
-
121
.
28.
Calin
GA
,
Dumitru
CD
,
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
(
24
):
15524
-
15529
.
29.
Cimmino
A
,
Calin
GA
,
Fabbri
M
, et al
.
miR-15 and miR-16 induce apoptosis by targeting BCL2 [published correction appears in Proc Natl Acad Sci USA. 2006;103(7):2464]
.
Proc Natl Acad Sci USA.
2005
;
102
(
39
):
13944
-
13949
.
30.
Vogler
M
,
Dinsdale
D
,
Dyer
MJ
,
Cohen
GM
.
ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets
.
Br J Haematol.
2013
;
163
(
1
):
139
-
142
.
31.
Anderson
MA
,
Deng
J
,
Seymour
JF
, et al
.
The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism
.
Blood.
2016
;
127
(
25
):
3215
-
3224
.
32.
Roberts
AW
,
Davids
MS
,
Pagel
JM
, et al
.
Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia
.
N Engl J Med.
2016
;
374
(
4
):
311
-
322
.
33.
Stilgenbauer
S
,
Eichhorst
B
,
Schetelig
J
, et al
.
Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study
.
Lancet Oncol.
2016
;
17
(
6
):
768
-
778
.
34.
Stilgenbauer
S
,
Eichhorst
B
,
Schetelig
J
, et al
.
Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial [published correction appears in J Clin Oncol. 2019;37(25):2299]
.
J Clin Oncol.
2018
;
36
(
19
):
1973
-
1980
.
35.
Davids
MS
,
Hallek
M
,
Wierda
W
, et al
.
Comprehensive safety analysis of venetoclax monotherapy for patients with relapsed/refractory chronic lymphocytic leukemia
.
Clin Cancer Res.
2018
;
24
(
18
):
4371
-
4379
.
36.
Jones
JA
,
Mato
AR
,
Wierda
WG
, et al
.
Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial
.
Lancet Oncol.
2018
;
19
(
1
):
65
-
75
.
37.
Coutre
S
,
Choi
M
,
Furman
RR
, et al
.
Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy
.
Blood.
2018
;
131
(
15
):
1704
-
1711
.
38.
Seymour
JF
,
Ma
S
,
Brander
DM
, et al
.
Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study
.
Lancet Oncol.
2017
;
18
(
2
):
230
-
240
.
39.
Seymour
JF
,
Kipps
TJ
,
Eichhorst
B
, et al
.
Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia
.
N Engl J Med.
2018
;
378
(
12
):
1107
-
1120
.
40.
Kater
AP
,
Seymour
JF
,
Hillmen
P
, et al
.
Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study
.
J Clin Oncol.
2019
;
37
(
4
):
269
-
277
.
41.
Roberts
AW
,
Ma
S
,
Kipps
TJ
, et al
.
Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables
.
Blood.
2019
;
134
(
2
):
111
-
122
.
42.
Mato
AR
,
Roeker
LE
,
Eyre
TA
, et al
.
A retrospective comparison of venetoclax alone or in combination with an anti-CD20 monoclonal antibody in R/R CLL
.
Blood Adv.
2019
;
3
(
10
):
1568
-
1573
.
43.
Fischer
K
,
Al-Sawaf
O
,
Bahlo
J
, et al
.
Venetoclax and obinutuzumab in patients with CLL and coexisting conditions
.
N Engl J Med.
2019
;
380
(
23
):
2225
-
2236
.
44.
Al-Sawaf
O
,
Zhang
C
,
Tandon
M
, et al
.
Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial
.
Lancet Oncol.
2020
;
21
(
9
):
1188
-
1200
.
45.
Ma S, Seymour JF, Brander DM, et al. Efficacy of venetoclax plus rituximab for relapsed CLL: 5-year follow-up of continuous or limited-duration therapy. Blood.
2021
;
138
(
10
):
836
-
846
.
46.
Stilgenbauer
S
.
Prognostic markers and standard management of chronic lymphocytic leukemia
.
Hematology Am Soc Hematol Educ Program.
2015
;
2015
:
368
-
377
.
47.
Tausch
E
,
Schneider
C
,
Robrecht
S
, et al
.
Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax
.
Blood.
2020
;
135
(
26
):
2402
-
2412
.
48.
Kater
AP
,
Wu
JQ
,
Kipps
T
, et al
.
Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study
.
J Clin Oncol.
2020
;
38
(
34
):
4042
-
4054
.
49.
Herling
CD
,
Abedpour
N
,
Weiss
J
, et al
.
Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia
.
Nat Commun.
2018
;
9
(
1
):
727
.
50.
Anderson
MA
,
Tam
C
,
Lew
TE
, et al
.
Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax
.
Blood.
2017
;
129
(
25
):
3362
-
3370
.
51.
Blombery
P
,
Anderson
MA
,
Gong
JN
, et al
.
Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia
.
Cancer Discov.
2019
;
9
(
3
):
342
-
353
.
52.
Tausch
E
,
Close
W
,
Dolnik
A
, et al
.
Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia
.
Haematologica.
2019
;
104
(
9
):
e434
-
e437
.
53.
Guièze
R
,
Liu
VM
,
Rosebrock
D
, et al
.
Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies
.
Cancer Cell.
2019
;
36
(
4
):
369
-
384.e13
.
54.
Lucas
F
,
Larkin
K
,
Gregory
CT
, et al
.
Novel BCL2 mutations in venetoclax-resistant, ibrutinib-resistant CLL patients with BTK/PLCG2 mutations
.
Blood.
2020
;
135
(
24
):
2192
-
2195
.
55.
Birkinshaw
RW
,
Gong
JN
,
Luo
CS
, et al
.
Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
.
Nat Commun.
2019
;
10
(
1
):
2385
.
56.
Blombery
P
,
Thompson
ER
,
Nguyen
T
, et al
.
Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax
.
Blood.
2020
;
135
(
10
):
773
-
777
.
57.
Byrd
JC
,
Furman
RR
,
Coutre
SE
, et al
.
Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib
.
Blood.
2015
;
125
(
16
):
2497
-
2506
.
58.
Burger
JA
,
Wiestner
A
.
Targeting B cell receptor signalling in cancer: preclinical and clinical advances
.
Nat Rev Cancer.
2018
;
18
(
3
):
148
-
167
.
59.
Axelrod
M
,
Ou
Z
,
Brett
LK
, et al
.
Combinatorial drug screening identifies synergistic co-targeting of Bruton’s tyrosine kinase and the proteasome in mantle cell lymphoma
.
Leukemia.
2014
;
28
(
2
):
407
-
410
.
60.
Cervantes-Gomez
F
,
Lamothe
B
,
Woyach
JA
, et al
.
Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia
.
Clin Cancer Res.
2015
;
21
(
16
):
3705
-
3715
.
61.
Deng
J
,
Isik
E
,
Fernandes
SM
,
Brown
JR
,
Letai
A
,
Davids
MS
.
Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia
.
Leukemia.
2017
;
31
(
10
):
2075
-
2084
.
62.
Jain
N
,
Keating
M
,
Thompson
P
, et al
.
Ibrutinib and venetoclax for first-line treatment of CLL
.
N Engl J Med.
2019
;
380
(
22
):
2095
-
2103
.
63.
Hillmen
P
,
Rawstron
AC
,
Brock
K
, et al
.
Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study [published correction appears in J Clin Oncol. 2020;38(14):1644]
.
J Clin Oncol.
2019
;
37
(
30
):
2722
-
2729
.
64.
Opferman
JT
,
Iwasaki
H
,
Ong
CC
, et al
.
Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells
.
Science.
2005
;
307
(
5712
):
1101
-
1104
.
65.
Glaser
SP
,
Lee
EF
,
Trounson
E
, et al
.
Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia
.
Genes Dev.
2012
;
26
(
2
):
120
-
125
.
66.
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
(
5
):
375
-
388
.
67.
Teh
TC
,
Nguyen
NY
,
Moujalled
DM
, et al
.
Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1
.
Leukemia.
2018
;
32
(
2
):
303
-
312
.
68.
Vo
T-T
,
Ryan
J
,
Carrasco
R
, et al
.
Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML
.
Cell.
2012
;
151
(
2
):
344
-
355
.
69.
Konopleva
M
,
Pollyea
DA
,
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
(
10
):
1106
-
1117
.
70.
Jin
S
,
Cojocari
D
,
Purkal
JJ
, et al
.
5-Azacitidine induces NOXA to prime AML cells for venetoclax-mediated apoptosis
.
Clin Cancer Res.
2020
;
26
(
13
):
3371
-
3383
.
71.
Niu
X
,
Zhao
J
,
Ma
J
, et al
.
Binding of released Bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells
.
Clin Cancer Res.
2016
;
22
(
17
):
4440
-
4451
.
72.
DiNardo
CD
,
Pratz
KW
,
Letai
A
, et al
.
Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study
.
Lancet Oncol.
2018
;
19
(
2
):
216
-
228
.
73.
Wei
AH
,
Strickland
SA
Jr
,
Hou
JZ
, et al
.
Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study
.
J Clin Oncol.
2019
;
37
(
15
):
1277
-
1284
.
74.
DiNardo
CD
,
Jonas
BA
,
Pullarkat
V
, et al
.
Azacitidine and venetoclax in previously untreated acute myeloid leukemia
.
N Engl J Med.
2020
;
383
(
7
):
617
-
629
.
75.
Wei
AH
,
Montesinos
P
,
Ivanov
V
, et al
.
Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial
.
Blood.
2020
;
135
(
24
):
2137
-
2145
.
76.
Chyla
B
,
Daver
N
,
Doyle
K
, et al
.
Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia
.
Am J Hematol.
2018
;
93
(
8
):
E202
-
E205
.
77.
Chua
CC
,
Roberts
AW
,
Reynolds
J
, et al
.
Chemotherapy and venetoclax in elderly acute myeloid leukemia trial (CAVEAT): a phase Ib dose-escalation study of venetoclax combined with modified intensive chemotherapy
.
J Clin Oncol.
2020
;
38
(
30
):
3506
-
3517
.
78.
Kontro
M
,
Kumar
A
,
Majumder
MM
, et al
.
HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia
.
Leukemia.
2017
;
31
(
2
):
301
-
309
.
79.
Bisaillon
R
,
Moison
C
,
Thiollier
C
, et al
.
Genetic characterization of ABT-199 sensitivity in human AML
.
Leukemia.
2020
;
34
(
1
):
63
-
74.
80.
Chan
SM
,
Thomas
D
,
Corces-Zimmerman
MR
, et al
.
Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia
.
Nat Med.
2015
;
21
(
2
):
178
-
184
.
81.
DiNardo
CD
,
Tiong
IS
,
Quaglieri
A
, et al
.
Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML
.
Blood.
2020
;
135
(
11
):
791
-
803
.
82.
Nechiporuk
T
,
Kurtz
SE
,
Nikolova
O
, et al
.
The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells
.
Cancer Discov.
2019
;
9
(
7
):
910
-
925
.
83.
Thijssen
R
,
Diepstraten
ST
,
Moujalled
D
, et al
.
Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias
.
Blood.
2021
;
137
(
20
):
2721
-
2735
.
84.
Moujalled
DM
,
Brown
FC
,
Pomilio
G
, et al
.
Acquired mutations in BAX confer resistance to BH3 mimetics in acute myeloid leukemia
.
Blood.
2020
;
136
(
suppl 1
):
7
-
8
.
85.
Blombery
P
,
Thompson
ER
,
Chen
X
, et al
.
BAX-mutated clonal hematopoiesis in patients on long-term venetoclax for relapsed/refractory chronic lymphocytic leukemia
.
Blood.
2020
;
136
(
suppl 1
):
9
-
10
.
86.
Pei
S
,
Pollyea
DA
,
Gustafson
A
, et al
.
Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia
.
Cancer Discov.
2020
;
10
(
4
):
536
-
551
.
87.
Zhang
H
,
Nakauchi
Y
,
Köhnke
T
, et al
.
Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia
.
Nat Can.
2020
;
1
(
8
):
826
-
839
.
88.
Chen
X
,
Glytsou
C
,
Zhou
H
, et al
.
Targeting mitochondrial structure sensitizes acute myeloid leukemia to venetoclax treatment
.
Cancer Discov.
2019
;
9
(
7
):
890
-
909
.
89.
Moujalled
DM
,
Pomilio
G
,
Ghiurau
C
, et al
.
Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia
.
Leukemia.
2019
;
33
(
4
):
905
-
917
.
90.
Ramsey
HE
,
Fischer
MA
,
Lee
T
, et al
.
A novel MCL1 inhibitor combined with venetoclax rescues venetoclax-resistant acute myelogenous leukemia
.
Cancer Discov.
2018
;
8
(
12
):
1566
-
1581
.
91.
Lagadinou
ED
,
Sach
A
,
Callahan
K
, et al
.
BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells
.
Cell Stem Cell.
2013
;
12
(
3
):
329
-
341
.
92.
Jones
CL
,
Stevens
BM
,
Pollyea
DA
, et al
.
Nicotinamide metabolism mediates resistance to venetoclax in relapsed acute myeloid leukemia stem cells
.
Cell Stem Cell.
2020
;
27
(
5
):
748
-
764
.
93.
Stevens
BM
,
Jones
CL
,
Pollyea
DA
, et al
.
Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells.
Nature Can.
2020
;
1
(
20
):
1176
1187
.
94.
Punnoose
EA
,
Leverson
JD
,
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
(
5
):
1132
-
1144
.
95.
Bodet
L
,
Gomez-Bougie
P
,
Touzeau
C
, et al
.
ABT-737 is highly effective against molecular subgroups of multiple myeloma
.
Blood.
2011
;
118
(
14
):
3901
-
3910
.
96.
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
(
1
):
210
-
212
.
97.
Kumar
S
,
Kaufman
JL
,
Gasparetto
C
, et al
.
Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma
.
Blood.
2017
;
130
(
22
):
2401
-
2409
.
98.
Moreau
P
,
Chanan-Khan
A
,
Roberts
AW
, et al
.
Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM
.
Blood.
2017
;
130
(
22
):
2392
-
2400
.
99.
Kumar
SK
,
Harrison
SJ
,
Cavo
M
, et al
.
Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial
.
Lancet Oncol.
2020
;
21
(
12
):
1630
-
1642
.
100.
Nakayama
K
,
Nakayama
K
,
Negishi
I
, et al
.
Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice
.
Science.
1993
;
261
(
5128
):
1584
-
1588
.
101.
Tsujimoto
Y
,
Cossman
J
,
Jaffe
E
,
Croce
CM
.
Involvement of the bcl-2 gene in human follicular lymphoma
.
Science.
1985
;
228
(
4706
):
1440
-
1443
.
102.
Wessendorf
S
,
Schwaenen
C
,
Kohlhammer
H
, et al
.
Hidden gene amplifications in aggressive B-cell non-Hodgkin lymphomas detected by microarray-based comparative genomic hybridization
.
Oncogene.
2003
;
22
(
9
):
1425
-
1429
.
103.
Touzeau
C
,
Dousset
C
,
Bodet
L
, et al
.
ABT-737 induces apoptosis in mantle cell lymphoma cells with a Bcl-2high/Mcl-1low profile and synergizes with other antineoplastic agents
.
Clin Cancer Res.
2011
;
17
(
18
):
5973
-
5981
.
104.
Grabow
S
,
Kelly
GL
,
Delbridge
AR
, et al
.
Critical B-lymphoid cell intrinsic role of endogenous MCL-1 in c-MYC-induced lymphomagenesis
.
Cell Death Dis.
2016
;
7
(
3
):
e2132
.
105.
Davids
MS
,
Roberts
AW
,
Seymour
JF
, et al
.
Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma
.
J Clin Oncol.
2017
;
35
(
8
):
826
-
833
.
106.
Montero
J
,
Stephansky
J
,
Cai
T
, et al
.
Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL2 and sensitive to venetoclax
.
Cancer Discov.
2017
;
7
(
2
):
156
-
164
.
107.
Boidol
B
,
Kornauth
C
,
van der Kouwe
E
, et al
.
First-in-human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia
.
Blood.
2017
;
130
(
23
):
2499
-
2503
.
108.
Premkumar
VJ
,
Lentzsch
S
,
Pan
S
, et al
.
Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis
.
Blood Cancer J.
2021
;
11
(
1
):
10
.
109.
Pullarkat
VA
,
Lacayo
NJ
,
Jabbour
E
, et al
.
Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma
.
Cancer Discov.
2021
;
11
(
6
):
1440
-
1453
.
110.
Brennan
MS
,
Chang
C
,
Tai
L
, et al
.
Humanized Mcl-1 mice enable accurate preclinical evaluation of MCL-1 inhibitors destined for clinical use
.
Blood.
2018
;
132
(
15
):
1573
-
1583
.
111.
Wang
X
,
Bathina
M
,
Lynch
J
, et al
.
Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction
.
Genes Dev.
2013
;
27
(
12
):
1351
-
1364
.
112.
Thomas
RL
,
Roberts
DJ
,
Kubli
DA
, et al
.
Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure
.
Genes Dev.
2013
;
27
(
12
):
1365
-
1377
.
113.
Arbour
N
,
Vanderluit
JL
,
Le Grand
JN
, et al
.
Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage
.
J Neurosci.
2008
;
28
(
24
):
6068
-
6078
.
114.
Hikita
H
,
Takehara
T
,
Shimizu
S
, et al
.
Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver
.
Hepatology.
2009
;
50
(
4
):
1217
-
1226
.
115.
Vick
B
,
Weber
A
,
Urbanik
T
, et al
.
Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes
.
Hepatology.
2009
;
49
(
2
):
627
-
636
.
116.
Healy
ME
,
Boege
Y
,
Hodder
MC
, et al
.
MCL1 is required for maintenance of intestinal homeostasis and prevention of carcinogenesis in mice
.
Gastroenterology.
2020
;
159
(
1
):
183
-
199
.
117.
Gong
JN
,
Khong
T
,
Segal
D
, et al
.
Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1
.
Blood.
2016
;
128
(
14
):
1834
-
1844
.
118.
Beroukhim
R
,
Mermel
CH
,
Porter
D
, et al
.
The landscape of somatic copy-number alteration across human cancers
.
Nature.
2010
;
463
(
7283
):
899
-
905
.
119.
Kuusanmäki
H
,
Leppä
A-M
,
Pölönen
P
, et al
.
Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia
.
Haematologica.
2020
;
105
(
3
):
708
-
720
.
120.
Spencer
A
,
Rosenberg
AS
,
Jakubowiak
A
, et al
.
A phase 1, first-in-human study of AMG 176, a selective MCL-1 inhibitor, in patients with relapsed or refractory multiple myeloma
.
Clin Lymphoma Myeloma Leuk.
2019
;
19
(
10
):
e53
-
e54
.
121.
Chen
L
,
Willis
SN
,
Wei
A
, et al
.
Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function
.
Mol Cell.
2005
;
17
(
3
):
393
-
403
.
122.
Mason
KD
,
Vandenberg
CJ
,
Scott
CL
, et al
.
In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas
.
Proc Natl Acad Sci USA.
2008
;
105
(
46
):
17961
-
17966
.
123.
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
(
3
):
761
-
764
.
124.
Jones
CL
,
Stevens
BM
,
D’Alessandro
A
, et al
.
Inhibition of amino acid metabolism selectively targets human leukemia stem cells [published correction appears in Cancer Cell. 2019;35(2):P333-P335]
.
Cancer Cell.
2018
;
34
(
5
):
724
-
740.e4
.
125.
Casara
P
,
Davidson
J
,
Claperon
A
, et al
.
S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth
.
Oncotarget.
2018
;
9
(
28
):
20075
-
20088
.
126.
Hu
N
,
Guo
Y
,
Xue
H
, et al
.
Abstract 3077: preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in haematological tumor models
.
Cancer Res.
2020
;
80
(
16 Supplement
):
3077
-
3077
.
127.
Luo
Q
,
Pan
W
,
Zhou
S
, et al
.
A novel BCL-2 inhibitor APG-2575 exerts synthetic lethality with BTK or MDM2-p53 inhibitor in diffuse large B-cell lymphoma
.
Oncol Res.
2020
;
28
(
4
):
331
-
344
.
128.
Lin
S
,
Zhao
X
,
Liu
H
, et al
.
FCN-338, a novel and selective Bcl-2 inhibitor, exhibits potent anti-tumor activity in B-cell lymphoma
.
Cancer Res.
2019
;
79
(
13 suppl
):
2497
-
2497
.
129.
Balachander
SB
,
Criscione
SW
,
Byth
KF
, et al
.
AZD4320, a dual inhibitor of Bcl-2 and Bcl-xL, induces tumor regression in hematologic cancer models without dose-limiting thrombocytopenia
.
Clin Cancer Res.
2020
;
26
(
24
):
6535
-
6549
.
130.
Balachander
SB
,
Tabatabai
A
,
Wen
S
, et al
.
Abstract 56: AZD0466, a nanomedicine of a potent dual Bcl-2/Bcl-xL inhibitor, exhibits anti-tumor activity in a range of hematological and solid tumor models
.
Cancer Res.
2020
;
80
(
16 suppl
):
56
-
56
.
131.
Yi
H
,
Qiu
M-Z
,
Yuan
L
, et al
.
Bcl-2/Bcl-xl inhibitor APG-1252-M1 is a promising therapeutic strategy for gastric carcinoma
.
Cancer Med.
2020
;
9
(
12
):
4197
-
4206
.
132.
Bai
L
,
Chen
J
,
McEachern
D
, et al
.
BM-1197: a novel and specific Bcl-2/Bcl-xL inhibitor inducing complete and long-lasting tumor regression in vivo
.
PLoS One.
2014
;
9
(
6
):
e99404
.
133.
van Delft
MF
,
Wei
AH
,
Mason
KD
, et al
.
The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized
.
Cancer Cell.
2006
;
10
(
5
):
389
-
399
.
134.
Roberts
AW
,
Huang
D
.
Targeting BCL2 with BH3 mimetics: basic science and clinical application of venetoclax in chronic lymphocytic leukemia and related B cell malignancies
.
Clin Pharmacol Ther.
2017
;
101
(
1
):
89
-
98
.
135.
Pollyea
DA
,
Stevens
BM
,
Jones
CL
, et al
.
Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia
.
Nat Med.
2018
;
24
(
12
):
1859
-
1866
.
136.
Cao
Y
,
Yang
G
,
Hunter
ZR
, 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
(
1
):
134
-
138
.
137.
Roberts
AW
.
Therapeutic development and current uses of BCL-2 inhibition
.
Hematology Am Soc Hematol Educ Program.
2020
;
2020
:
1
-
9
.
138.
Agarwal
R
,
Chan
YC
,
Tam
CS
, et al
.
Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma
.
Nat Med.
2019
;
25
(
1
):
119
-
129
.
139.
Marques-Piubelli
ML
,
Schlette
EJ
,
Khoury
JD
, et al
.
Expression of BCL2 alternative proteins and association with outcome in CLL patients treated with venetoclax
.
Leuk Lymphoma.
2021
;
62
(
5
):
1129
-
1135.
140.
Zhang
H
,
Nakauchi
Y
,
Köhnke
T
, et al
.
Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia
.
Nat Can.
2020
;
1
(
8
):
826
-
839
.
141.
Zinzani
PL
,
Flinn
IW
,
Yuen
SLS
, et al
.
Venetoclax-rituximab with or without bendamustine vs bendamustine-rituximab in relapsed/refractory follicular lymphoma
.
Blood.
2020
;
136
(
23
):
2628
-
2637
.
142.
Morschhauser
F
,
Feugier
P
,
Flinn
IW
, et al
.
A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma [published correction appears in Blood. 2021;137(13):1844]
.
Blood.
2021
;
137
(
5
):
600
-
609
.
143.
Tam
CS
,
Anderson
MA
,
Pott
C
, et al
.
Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma
.
N Engl J Med.
2018
;
378
(
13
):
1211
-
1223
.
144.
Le Gouill
S
,
Morschhauser
F
,
Chiron
D
, et al
.
Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial
.
Blood.
2021
;
137
(
7
):
877
-
887
.
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