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A protein that stops cells from self-destructing. Venetoclax removes that protection and has transformed leukaemia treatment. This dossier gathers the 2 products (2 approved), 69 trials, 12 pathways and 5 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
BCL-2 is an anti-apoptotic BH3-domain protein, overexpressed via t(14;18) in follicular lymphoma.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Chronic lymphocytic leukaemia | >90% | BCL-2 overexpression | Wikipedia | |
| Diffuse large B-cell lymphoma | 30-40% | BCL2 translocation/overexpression | ~90% in follicular lymphoma t(14;18) | Wikipedia |
| Acute myeloid leukaemia | n/a | Dependency, not a prevalence threshold | Wikipedia |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| G101V 101 | Resistance | not sourced | Reduces venetoclax affinity about 180-fold; found in a subset of CLL relapsing on continuous venetoclax, often subclonal. Sonrotoclax is reported to retain activity against it. | Blombery et al., Cancer Discov 2019 | ||
| D103Y / F104L 103 | Resistance | not sourced | Additional BH3-groove mutations co-occurring with G101V. | Blombery et al., Cancer Discov 2019 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: COSMIC: BCL2.
| Modality | Approved |
|---|---|
| Small molecule 2 |
| Trial | Setting | Result | Products | ||
|---|---|---|---|---|---|
| 3 | - | A Phase 3, Randomized, Open-Label Study Evaluating the Safety and Efficacy of Magrolimab in Combination With Azacitidine Versus Physician's Choice of Venetoclax in Combination With Azacitidine or Intensive Chemotherapy in Previously Untreated Patients With TP53 Mutant Acute Myeloid Leukemia | - | ||
| 3 | - | A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Magrolimab Versus Placebo in Combination With Venetoclax and Azacitidine in Newly Diagnosed, Previously Untreated Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy | - | ||
SYMPATICO NCT03112174 | 3 | Positive | Relapsed or refractory mantle cell lymphoma after one to five prior lines: ibrutinib with venetoclax or with placebo (double-blind), after a safety run-in for tumour lysis syndrome, plus an open-label treatment-naive arm of the combination in patients with TP53 mutation | Median progression-free survival 31.9 months with ibrutinib plus venetoclax against 22.1 months with ibrutinib plus placebo (hazard ratio 0.629, p 0.0024); complete response 69.2 percent in treatment-naive TP53-mutated disease. | |
VERONA NCT04401748 | 3 | Negative | Untreated higher-risk myelodysplastic syndromes: azacitidine with venetoclax or placebo | Venetoclax added to azacitidine did not significantly improve overall survival in untreated higher-risk myelodysplastic syndromes. | |
AMPLIFY NCT03836261 | 3 | Positive | Fit, previously untreated CLL without del(17p)/TP53: fixed-duration acalabrutinib + venetoclax (AV) or + obinutuzumab (AVO) vs FCR/BR chemoimmunotherapy | 3-year PFS 76.5% (AV) / 83.1% (AVO) vs 66.5%. | |
CLL13 / GAIA NCT02950051 | 3 | Positive | Fit, previously untreated CLL without del(17p)/TP53: chemoimmunotherapy (FCR/BR) vs venetoclax-rituximab vs venetoclax-obinutuzumab vs venetoclax-obinutuzumab-ibrutinib | 5-year PFS 81.3% (GIV), 69.8% (GV), 57.4% (RV), 50.7% (CIT). | |
SEQUOIA NCT03336333 | 3 | Positive | Previously untreated CLL/SLL unsuitable for FCR: zanubrutinib vs bendamustine-rituximab (cohort 1); zanubrutinib in del(17p) (arm C); zanubrutinib + venetoclax (arm D) | PFS HR 0.42 vs BR; 5-year PFS 72.2% in del(17p). | |
GLOW NCT03462719 | 3 | Positive | Previously untreated CLL, age ≥65 or with comorbidities, no del(17p)/TP53: fixed-duration ibrutinib + venetoclax vs chlorambucil + obinutuzumab | PFS HR 0.216; OS HR 0.487 (4-year). | |
VIALE-A NCT02993523 | 3 | Positive | Newly diagnosed AML unfit for intensive chemotherapy: venetoclax + azacitidine vs placebo + azacitidine | OS 14.7 vs 9.6 months, HR 0.66; CR 36.7% vs 17.9%. | |
CLL14 NCT02242942 | 3 | Positive | Previously untreated CLL with coexisting conditions: 12 months of venetoclax + obinutuzumab vs chlorambucil + obinutuzumab | 6-year PFS 53.1% vs 21.7%; HR 0.40. | |
MURANO NCT02005471 | 3 | Positive | Relapsed or refractory chronic lymphocytic leukaemia: two years of venetoclax with six cycles of rituximab against six cycles of bendamustine and rituximab | Venetoclax plus rituximab greatly lengthened progression-free survival compared with bendamustine-rituximab, with high rates of undetectable minimal residual disease; approved in June 2018. | |
| 3 | Active | A Phase 3, Multicenter, Randomized, Open Label Study of Venetoclax and Dexamethasone Compared With Pomalidomide and Dexamethasone in Subjects With t(11;14)-Positive Relapsed or Refractory Multiple Myeloma | - | ||
| 3 | Active | A Phase III Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma | - | ||
| 3 | Recruiting | A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Nemtabrutinib (MK-1026) Plus Venetoclax Versus Venetoclax Plus Rituximab in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least 1 Prior Therapy (BELLWAVE-010) | - | ||
| 3 | Recruiting | A Phase 3, Open-Label, Randomized Study of BGB-16673 Compared to Investigator's Choice (Idelalisib Plus Rituximab or Bendamustine Plus Rituximab or Venetoclax Plus Rituximab Retreatment) in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Previously Exposed to Both BTK and BCL2 Inhibitors | - | ||
| 3 | Recruiting | A Prospective, Open-Label, Phase IIb/III Study to Evaluate the Risk of TLS and Optimization of the Initiation of Venetoclax in Combination With Obinutuzumab or Acalabrutinib With Different Ramp- Up Periods in Previously Untreated Subjects With CLL | - | ||
| 3 | Recruiting | A Phase 3 Randomized, Open-Label, Multicenter Study of Sonrotoclax Plus Anti-CD20 Antibody Therapies Versus Venetoclax Plus Rituximab in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma | - | ||
| 3 | Recruiting | A Phase 3, Open-Label, Randomized Study of Sonrotoclax (BGB-11417) Plus Zanubrutinib (BGB-3111) Compared With Venetoclax Plus Acalabrutinib in Patients With Previously Untreated Chronic Lymphocytic Leukemia | - | ||
| 3 | Recruiting | A Phase 3 Randomized Double-Blind Multicenter Study of Sonrotoclax Plus Zanubrutinib Versus Placebo Plus Zanubrutinib in Patients With Relapsed/Refractory Mantle Cell Lymphoma | - | ||
| 3 | Active | A Phase 3 Open-Label, Randomized Study of Fixed Duration Pirtobrutinib (LOXO-305) Plus Venetoclax and Rituximab Versus Venetoclax and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-322) | - | ||
| 3 | Active | An Extension Study of Venetoclax for Subjects Who Have Completed a Prior Venetoclax Clinical Trial | - | ||
CELESTIAL-TNCLL NCT06073821 | 3 | Active | Previously untreated CLL/SLL: fixed-duration sonrotoclax + zanubrutinib vs venetoclax + obinutuzumab | - | |
| 3 | Active | A Randomized, Open-Label Study of the Efficacy and Safety of Galinpepimut-S (GPS) Maintenance Monotherapy Compared to Investigator's Choice of Best Available Therapy in Subjects With Acute Myeloid Leukemia Who Have Achieved Complete Remission After Second-Line Salvage Therapy | - | ||
| 3 | Recruiting | Phase 3 Randomized, Double-blind, Placebo-controlled Studies Assessing Ziftomenib in Combination With Either Standard of Care Nonintensive (Venetoclax+Azacitidine) or Intensive (7+3) Therapy in Patients With Untreated NPM1 Mutated or KMT2A Rearranged Acute Myeloid Leukemia | - | ||
| 2/3 | - | Phase 2/3 Randomized Study to Assess the Efficacy and Safety of Ublituximab in Combination With Umbralisib and Venetoclax (U2-V) Compared to Ublituximab and Umbralisib (U2) in Subjects With Chronic Lymphocytic Leukemia (CLL) | - | ||
| 2/3 | Recruiting | A Multi-phase, Pharmacokinetics, Safety, and Efficacy Study of ASTX030 (Azacitidine and Cedazuridine) as Monotherapy in Subjects With Myeloid Neoplasm or in Combination With Venetoclax in Subjects With AML (AZTOUND Study) | - | ||
| 2/3 | Recruiting | A Phase II/III Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics and Preliminary Efficacy of BL-M11D1 for Injection in Combination With Cytarabine + Daunorubicin or Venetoclax + Azacitidine in Patients With Acute Myeloid Leukemia | - | ||
| 2/3 | Recruiting | A Randomized Phase 2/3 Study Evaluating the Safety and Efficacy of Pivekimab Sunirine (PVEK) in Combination With Venetoclax and Azacitidine in Adult Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML) Ineligible to Receive Intensive Chemotherapy | - | ||
Beat AML Master Trial NCT03013998 | platform | Recruiting | Newly diagnosed acute myeloid leukaemia in patients aged 60 and over: cytogenetic and genomic results returned within seven days assign each patient to a mutation-defined sub-study of targeted therapy, alone or with azacitidine or venetoclax | Genomic assignment within seven days was feasible; patients treated on Beat AML sub-studies had median overall survival of 12.8 months against 3.9 months for those choosing standard care (non-randomised comparison). | |
myeloMATCH NCT05564390 | platform | Recruiting | Newly diagnosed AML and MDS: genomic screening at diagnosis assigns patients to tiered, biomarker-defined sub-studies from induction through MRD-guided consolidation and maintenance | - |
Substituting the cysteine the drug binds covalently leaves the kinase active and makes inhibition reversible, so the drug no longer holds.
The kinase-dead L528W substitution and the gatekeeper T474I change the pocket rather than the covalent cysteine, so they defeat reversible inhibitors too.
R665W and L845F make B-cell receptor signalling autonomous below the kinase, so blocking BTK above them achieves nothing.
The valine substitution at glycine 101 reduces BCL-2 affinity for venetoclax about 180-fold, so the drug can no longer displace the pro-apoptotic proteins while BCL-2 keeps working.
A cell that needed BCL-2 can be made to need its relatives instead, which is the main reason venetoclax has not repeated its chronic lymphocytic leukaemia result in follicular and large B-cell lymphoma.
The B-cell receptor is the survival switch of B cells. Signals from it pass through BTK to free NF-kappa-B, which keeps the cell alive. B-cell cancers hold it on; BTK inhibitors, proteasome inhibitors and lenalidomide each cut the line at a different point.
Which nodes have drugs →KEGG's basal cell carcinoma map is the Hedgehog pathway: loss of the brake PTCH1 or activation of SMO leaves GLI transcription factors permanently on. Hedgehog inhibitors (vismodegib, sonidegib) shut this down in advanced disease.
Which nodes have drugs →Even when a drug wipes out 99% of a tumour, a few cells survive without any resistance mutation: they go quiet, stop dividing, and wait. These persisters are the seed of relapse. They are hard to kill precisely because they are not doing much, but they have their own weaknesses.
Which nodes have drugs →Immune cells kill by touch: they present FAS ligand or TRAIL to a target cell, whose death receptors then trigger self-destruction from the outside in. Tumours cut this wire by deleting the receptors or over-producing decoys and blockers.
Which nodes have drugs →Cells can die in several programmed ways. Beyond the classic apoptosis, ferroptosis kills through iron-driven fat oxidation, and drug-resistant, mesenchymal cancer cells turn out to be unusually prone to it.
Which nodes have drugs →Intrinsic apoptosis is the cell's self-destruct switch. BCL-2 holds it shut; BAX and BAK pull it open. Venetoclax pries BCL-2 off so the switch can fire.
Which nodes have drugs →This KEGG map collects the small RNA molecules (microRNAs) that are switched up or down in nine common cancers and shows which oncogenes and tumour suppressors they silence. It matters because a single microRNA can dial down dozens of genes at once, so losing or gaining one reshapes whole signalling routes.
Which nodes have drugs →When a cell divides, a scaffold of microtubules (the spindle) pulls one copy of each chromosome to each side. A checkpoint holds the split until every chromosome is hooked on. Taxanes and vinca alkaloids freeze the spindle so the cell is stuck at this checkpoint until it dies.
Which nodes have drugs →KEGG's small cell lung cancer map shows a tumour with both master brakes removed, RB1 and TP53, plus amplified MYC pushing the cell cycle and PTEN loss and BCL2 keeping cells alive. Chemotherapy with PD-L1 antibodies and the DLL3 T-cell engager tarlatamab are the current answers.
Which nodes have drugs →To make a good antibody, a B cell has to deliberately damage its own DNA and keep dividing while it does. The germinal centre is where that happens, under strict time limits. Most B-cell lymphomas are cells that went through it and did not come out.
Which nodes have drugs →p53 is the cell's emergency coordinator: DNA damage, oncogene stress or lack of oxygen switch it on, and it then pauses division, orders repairs, or triggers suicide or permanent retirement, while MDM2 keeps it off in healthy cells. About half of cancers mutate p53 outright, and sarcomas, gliomas, melanomas and retinoblastomas silence it instead by amplifying MDM2 or MDM4.
Which nodes have drugs →Cancer cells run a few genes (MYC, their lineage factors, their fusion oncogenes) at extreme volume from giant control regions called super-enhancers. The amplifiers, BRD4, CDK7, CDK9 and Mediator, are the same in every cell, but cancers are unusually dependent on them, and that dependence is druggable.
Which nodes have drugs →No companion diagnostic in the registry measures this target.
No model entry for this target yet; check the cancer entries on the models page.
Why unresolved. CLL14 and AMPLIFY show long treatment-free remissions after one or two years; measurable-residual-disease kinetics predict relapse but retreatment strategies and the role of newer BCL2 inhibitors are unsettled.
What would answer it. Long-term follow-up with MRD-guided retreatment trials and comparison of sonrotoclax with venetoclax.
Query for this target: (TITLE:"BCL-2" OR ABSTRACT:"BCL-2" OR TITLE:"BCL2" OR ABSTRACT:"BCL2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about BCL-2, not a curated reading list.
The dossier as machine-readable JSON, at /api/v1/dossiers/bcl2.json: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/bcl2.json. Licence CC BY-NC 4.0.