^
Contact us  to learn more about
our Premium Content:  News alerts, weekly reports and conference planners
BIOMARKER:

BCL2 mutation

i
Other names: BCL2, Bcl-2, PPP1R50, B-cell CLL/lymphoma 2
Entrez ID:
12h
Therapeutic targeting of apoptosis in chronic lymphocytic leukemia. (PubMed, Semin Hematol)
In contrast, relapsed CLL that arises while being off therapy after a period of time-limited venetoclax-based regimens maintains sensitivity to re-treatment with venetoclax for the majority of patients. Novel strategies related to therapeutic targeting of apoptosis include next-generation BCL-2 inhibitors with improved potency and pharmacokinetic profiles, direct targeting of anti-apoptotic BH3 family proteins beyond BCL-2 such as MCL-1, and indirect targeting of MCL-1 through mechanisms such as small molecule cyclin-dependent kinase 9 inhibitors.
Journal • IO biomarker
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus) • CDK9 (Cyclin Dependent Kinase 9)
|
TP53 mutation • BCL2 mutation
|
Venclexta (venetoclax)
1m
Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy. (PubMed, Nat Commun)
Leukemia drug venetoclax is currently the only approved selective BCL-2 inhibitor...Furthermore, we identify a single-residue discrepancy between BCL-2 D111 and BCL-XL A104 as a molecular "switch" that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-XL by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
BCL2 mutation • BCL2L1 mutation
|
Venclexta (venetoclax)
3ms
Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy. (PubMed, Blood)
In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.
Preclinical • Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2)
|
BCL2 mutation • BCL2 G101V
|
Venclexta (venetoclax)
4ms
SOHO State of the Art Updates and Next Questions: Understanding and Overcoming Venetoclax Resistance in Hematologic Malignancies. (PubMed, Clin Lymphoma Myeloma Leuk)
However, with resistant patients' subsets targeted combination therapies are becoming an increasingly attractive option. We explore the incorporation of non-BCL-2 inhibitors, next-generation BCL-2 and multi-protein agents, other inhibitors most prominently FLT-3 inhibitors in addition to Venetoclax, and other novel approaches for resolving Venetoclax resistance.
Review • Journal • IO biomarker
|
TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • ASXL1 (ASXL Transcriptional Regulator 1)
|
TP53 mutation • FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • ASXL1 mutation • BCL2 mutation • MTOR mutation
|
Venclexta (venetoclax)
4ms
Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies. (PubMed, J Clin Invest)
Additionally, we provide evidence that anti-apoptotic BCL-2 family protein phosphorylation alters the apoptotic protein interactome, thereby changing the profile of functional dependence on these pro-survival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs re-wired these dependences, thus restoring sensitivity to venetoclax in a panel of venetoclax resistant lymphoid cell lines, resistant mouse model, and paired patient samples pre-venetoclax and at time of progression.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1)
|
BCL2 mutation
|
Venclexta (venetoclax)
4ms
Rituximab With or Without Yttrium Y-90 Ibritumomab Tiuxetan in Treating Patients With Untreated Follicular Lymphoma (clinicaltrials.gov)
P3, N=20, Completed, Mayo Clinic | Active, not recruiting --> Completed | Trial completion date: Jan 2026 --> Nov 2023
Trial completion • Trial completion date • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • B2M (Beta-2-microglobulin)
|
BCL2 mutation
|
Rituxan (rituximab) • Zevalin (ibritumomab tiuxetan)
5ms
Distinct Circulating Genomic Features of Classical Hodgkin Lymphoma of Older Adults (ASH 2023)
Older cHL patients exhibit unique genomic characteristics compared to younger counterparts, including more prevalent H2 tumor genetic subtype and EBV positivity. Identifying of a high-risk subgroup of older cHL underscores the importance of ctDNA levels and EBV status. We envision future trials of personalized biomarker driven treatment strategies could therapeutically target this risk, including by PD1 blockade.
Clinical • PD(L)-1 Biomarker • IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • KMT2D (Lysine Methyltransferase 2D) • B2M (Beta-2-microglobulin) • PAX5 (Paired Box 5) • GNA13 (G Protein Subunit Alpha 13) • STAT6 (Signal transducer and activator of transcription 6)
|
TP53 mutation • BCL2 mutation
5ms
Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 5-Year Follow-up Data (ASH 2023)
5 pts have started subsequent therapy (acalabrutinib, n=4; ibrutinib, n=1; all are clinically responding); 1 pt has not yet started therapy. We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 5-year PFS of 90.1%. The 5-year PFS for pts with del(17p)/TP53 mutation is 86.1%. Retreatment with BTK inhibitor appears effective for pts with disease relapse.
Clinical • IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • Chr del(11q) • TP53 mutation + Chr del(17p) • BCL2 mutation
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Calquence (acalabrutinib)
5ms
Enriched Signalling Pathways in Venetoclax-Relapsed Chronic Lymphocytic Leukemia (CLL) Cells and Targeting Using a Protac-Based Bcl-2/Bcl-Xl Degrader (ASH 2023)
Venetoclax is a specific inhibitor of Bcl-2, the key protein which protects CLL cells from intrinsic apoptosis, whereas the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib kills CLL cells via blockade of B-cell receptor (BCR) signalling. In conclusion, WH25244 is a PROTAC-based Bcl-2/Bcl-xL degrader with the potential to overcome venetoclax-resistant CLL dependent on Bcl-xL and mutant Bcl-2. Relative to its precursor, navitoclax, it shows increased potency against CLL cells and decreased toxicity against platelets in vitro, due to its VHL-dependent activity and minimal expression of VHL in platelets.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • MAP3K8 (Mitogen-Activated Protein Kinase Kinase Kinase 8) • ANXA5 (Annexin A5)
|
BCL2 expression • BCL2 mutation • MCL1 expression • BCL2 G101V • BCL2L1 mutation
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • navitoclax (ABT 263)
5ms
Emergence of Highly-Plastic B Cell States Cooperates with Early Immune Microenvironment Remodeling to Drive Follicular Lymphomagenesis (ASH 2023)
In conclusion, our results provide a high-resolution view of events spanning FL progression and indicate a major role of early TME remodeling in establishing a suitable niche for progression. Early intervention aimed to target the B cell-tumor microenvironment interactions driving intra-tumoral heterogeneity may represent a promising therapeutic avenue against early disease and prevention of FL recurrence.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • CD8 (cluster of differentiation 8) • KMT2D (Lysine Methyltransferase 2D) • CD4 (CD4 Molecule)
|
BCL2 overexpression • KMT2D mutation • BCL2 expression • BCL2 mutation
5ms
Multilayer Profiling of MRD in Patients with Relapsed/Refractory CLL Treated with Venetoclax-Based Regimens in a Real-World Setting (ASH 2023)
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. JCO 2019, 7(4):269-277
Real-world evidence • Clinical • IO biomarker • Real-world
|
BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • SF3B1 (Splicing Factor 3b Subunit 1) • IGLL5 (Immunoglobulin Lambda Like Polypeptide 5) • NXF1 (Nuclear RNA Export Factor 1) • ZMYM3 (Zinc Finger MYM-Type Containing 3)
|
TP53 mutation • BRAF mutation • BCL2 mutation
|
clonoSEQ
|
Venclexta (venetoclax) • Rituxan (rituximab)
5ms
Genomic Evolution and Resistance during Pirtobrutinib Therapy in Covalent BTK-Inhibitor (cBTKi) Pre-Treated Chronic Lymphocytic Leukemia Patients: Updated Analysis from the BRUIN Study (ASH 2023)
BTK Cysteine 481 substitution is known to contribute to cBTKi acquired resistance to ibrutinib, acalabrutinib, and zanubrutinib. Despite this cohort representing the first relapsing CLL patients from BRUIN and presenting with frequent baseline BTK mutations, response to pirtobrutinib was high, with an ORR of 83%, and substantial clearance of BTK C481 clones. At progression, the majority of pts (56%) either acquired non-BTK mutations or did not acquire any resistance mutations in this targeted panel, suggesting alternative resistance mechanisms. A smaller group of patients (44%) displayed emergence of non-C481 clones, particularly gatekeeper T474 and kinase-impaired L528W mutations.
Clinical • IO biomarker
|
TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • SF3B1 (Splicing Factor 3b Subunit 1) • PLCG2 (Phospholipase C Gamma 2)
|
TP53 mutation • PIK3CA mutation • ATM mutation • SF3B1 mutation • BTK C481S • BCL2 mutation • PLCG2 mutation • BTK mutation • BTK C481 • BTK T474I
|
Imbruvica (ibrutinib) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Jaypirca (pirtobrutinib)
5ms
Pre-Clinical Study on the Dual BCL2/BCL-XL Inhibitor AZD0466 for the Treatment of Chronic Lymphocytic Leukemia (ASH 2023)
To evaluate if combination treatment of AZD0466 with BTK inhibitors would improve efficacy, we transplanted murine Eµ-TCL1 tumors into syngeneic recipient mice and randomized them for treatment with vehicle, ibrutinib (30mg/kg in drinking water), acalabrutinib (25mg/kg, p.o. QD), AZD0466 (70mg/kg, i.v., QW) and combination of AZD0466 with ibrutinib or acalabrutinib. Moreover, AZD4320 was highly efficacious in MAVER-1 and MINO cell line models where resistance to venetoclax mediated by BCL-XL upregulation was modelled by an in vitro dose escalation method. In summary, our pre-clinical study shows that the dual BCL2/BCL-XL inhibitor could represent an important treatment option for venetoclax resistance mediated by specific BCL2 mutations or BCL-XL upregulation and that its efficacy could be further improved upon combination treatment with BTKi.
Preclinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • IGH (Immunoglobulin Heavy Locus) • BCL2L1 (BCL2-like 1) • CD5 (CD5 Molecule) • ANXA5 (Annexin A5)
|
BCL2 expression • BCL2 mutation • BCL2 G101V • BCL2 D103Y • BCL2L1 mutation
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Calquence (acalabrutinib) • AZD0466 • AZD4320
7ms
Acquisition of venetoclax resistance is characterized by higher expression of anti-apoptotic regulators, less mitochondrial priming, and broader resistance to anti-MM agents. (IMW 2023)
The Bellini study demonstrated that combination therapy of BH3-mimetic venetoclax with velcade improves progression-free survival (PFS) and response rates in this subgroup of MM patients...Simultaneous inhibition of MCL1 (via S63845) or BCL-XL (via A155463) and BCL2 (via venetoclax) increased BIM release and enhanced cell death in the resistant clones compared to single agents, with combination index (CI) values < 0.3 in all doses tested. In conclusion, we report that resistance to Venetoclax in in vitro models of MM evolves from the outgrowth of persister clones with a shift in mitochondrial dependency that confers broad resistance to all anti-tumor agents, including standard-of-care myeloma drugs.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2)
|
BCL2 expression • BCL2 mutation • MCL1 expression
|
Venclexta (venetoclax) • bortezomib • S63845
7ms
Follicular Lymphoma and Diffuse Large B-cell Lymphoma with BCL2 and IRF4 Rearrangements in Adult Patients. (PubMed, Hum Pathol)
Both lacked mutations involving IRF4 and NF-kB pathway genes that are frequently detected in large B-cell lymphoma with IRF4 rearrangement, and one case showed DLBCL-EZH2 type mutations, including KMT2D and BCL2 mutations, similar to 2 previously reported DLBCL with BCL2 and IRF4 rearrangements. Adults with FL and FL/DLBCL with BCL2 and IRF4 rearrangements display clinicopathologic and mutational features more akin to FL and DLBCL and should not be characterized as large B-cell lymphoma with IRF4 rearrangement.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6) • KMT2D (Lysine Methyltransferase 2D) • IRF4 (Interferon regulatory factor 4) • MME (Membrane Metalloendopeptidase)
|
KMT2D mutation • EZH2 mutation • BCL2 mutation • BCL2 rearrangement • IRF4 mutation
8ms
Single-cell transcriptomic analysis of CLL cells at ibrutinib plus venetoclax relapse and targeting using BCL-2/BCL-xL PROTACs PZ18753b and WH25244 (IWCLL 2023)
Knowing that BCL-xL inhibition in the clinic has been limited by platelet toxicity, PROTACs PZ18753b and WH25244 were synthesized from navitoclax (BCL-2/BCL-xL dual inhibitor) linked to a VHL E3 ligase ligand to target Bcl-2 and Bcl-xL for degradation, with improved specificity to cancer cells while sparing platelets. PZ18753b and WH25244 have preclinical efficacy in baseline CLL and can degrade, both, Bcl-xL and mutant Bcl-2 proteins, which are known to confer venetoclax resistance. This translational study supports the development of novel therapeutics for the treatment of CLL subgroups with adverse clinical prognosis and will open new frontiers as we better understand the biology of this disease.
IO biomarker • Omic analysis
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • IGH (Immunoglobulin Heavy Locus) • BCL2L1 (BCL2-like 1) • IL2 (Interleukin 2) • BCL2A1 (BCL2 Related Protein A1) • IL5 (Interleukin 5) • MAP3K8 (Mitogen-Activated Protein Kinase Kinase Kinase 8) • ANXA5 (Annexin A5)
|
BCL2 overexpression • IGH mutation • BCL2 expression • BCL2 mutation • MCL1 expression • BCL2 G101V • BCL2L1 mutation • TS 12
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • navitoclax (ABT 263)
8ms
Characterizing Specificities of Chronic Lymphoid Leukemia Harboring a BCL2 Rearrangement, an update from the FILO group (IWCLL 2023)
Ex vivo drug treatments included: BCL2i (inhibitor): venetoclax; MCL-1i: AZD5991, S63845 and BCLXLi: A133. The genomic landscape of BCL2-R CLL is characterized by a high frequency of trisomy 12, subclonal NOTCH and RAS pathway mutations, as well as BCL2 and MLL2 mutations. Protein expression, BH3 profiling and viability assays data are consistent with nearly exclusive dependence on Bcl-2.
IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • SF3B1 (Splicing Factor 3b Subunit 1) • KMT2D (Lysine Methyltransferase 2D) • BCL2L1 (BCL2-like 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • CREBBP (CREB binding protein) • BIRC3 (Baculoviral IAP repeat containing 3) • BCL2L11 (BCL2 Like 11) • EP300 (E1A binding protein p300) • MLL2 (Myeloid/lymphoid or mixed-lineage leukemia 2) • ANXA5 (Annexin A5)
|
TP53 mutation • BRAF mutation • NOTCH1 mutation • RAS mutation • KMT2D mutation • EZH2 mutation • MYD88 L265P • BCL2 expression • BCL2 mutation • MCL1 expression • BCL2 G101V • MLL2 mutation • BCL2 rearrangement • TS 12
|
Venclexta (venetoclax) • S63845 • AZD5991
8ms
Venetoclax as an Alternative and Effective Treatment in Central Nervous System Involvement of Chronic Lymphocytic Leukemia: Monocentric Experience (IWCLL 2023)
This report highlights the successful use of a venetoclax-based regimen in CLL patients with CNS involvement. It presents a case of primary ibrutinib-resistant CNS involvement in CLL, responding to second-line therapy with venetoclax-rituximab. Additionally, it discusses a case of CNS relapse after venetoclax treatment discontinuation, with a response to resuming venetoclax.
IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • IGH (Immunoglobulin Heavy Locus) • B2M (Beta-2-microglobulin)
|
BCL2 mutation
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab)
8ms
Unveiling the Spectrum of Genetic Alterations in Relapsed/Refractory CLL Patients on Targeted Inhibitors: A Prospective Unicentric Study (IWCLL 2023)
With regard to treatment, 56% received Brutone tyrosine kinase (BTK) inhibitors, others received Bcl-2 inhibitor venetoclax (31%) or PI3K inhibitor idelalisib (13%). This interim analysis points to the dynamic and complex nature of genomic alterations in CLL, with implications for disease progression and therapeutic responses. Our findings highlight the importance of longitudinal genomic monitoring to uncover evolving mutational profiles and their clinical implications.
Clinical • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • ATM (ATM serine/threonine kinase) • NOTCH1 (Notch 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • IGH (Immunoglobulin Heavy Locus) • TET2 (Tet Methylcytosine Dioxygenase 2) • ETV6 (ETS Variant Transcription Factor 6) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • WT1 (WT1 Transcription Factor) • BCOR (BCL6 Corepressor) • BIRC3 (Baculoviral IAP repeat containing 3) • CARD11 (Caspase Recruitment Domain Family Member 11) • PLCG2 (Phospholipase C Gamma 2) • STAG2 (Stromal Antigen 2) • IKZF3 (IKAROS Family Zinc Finger 3) • DDX41 (DEAD-Box Helicase 41) • GATA2 (GATA Binding Protein 2) • POT1 (Protection of telomeres 1) • NFKBIE (NFKB Inhibitor Epsilon) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)
|
TP53 mutation • KRAS mutation • ATM mutation • Chr del(11q) • BCL2 mutation • STAG2 mutation • BTK mutation
|
Venclexta (venetoclax) • Zydelig (idelalisib)
8ms
Recurrent Genomic Alterations in the Apoptotic Machinery in Patients With CLL Treated With Venetoclax Monotherapy Following Treatment With BCRi (IWCLL 2023)
Patients previously treated with B-cell receptor pathway inhibitors (BCRi), such as ibrutinib and idelalisib, have lower response rates to Ven; those who are refractory to prior BCRi have a significantly higher risk of relapse than those who are not refractory [1]. With extended follow-up, Ven demonstrated durable responses in patients with CLL who progressed on BCRi, irrespective of BTK mutation status. BCL-2 resistance mutations were detected in 19.1% (13/68) of patients, generally at low VAF. These acquired mutations were detectable in patients with prolonged Ven exposure, supporting further exploration of strategies focused on time-limited Ven exposure.
Clinical • IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • BTK (Bruton Tyrosine Kinase)
|
TP53 mutation • BCL2 mutation • BCL2 G101V • BTK mutation • BTK C481
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Zydelig (idelalisib)
10ms
Relationship between BCL2 mutations and follicular lymphoma outcome in the chemoimmunotherapy era. (PubMed, Blood Cancer J)
Among 97 FL patients who did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF ≥20% were associated with increased transformation risk (HR 3.01, 95% CI 1.04-8.78, p = 0.043) and a trend toward shorter event-free survival (EFS, median 20 months with mutations versus 54 months without, p = 0.052)...Across the entire population, nonsynonymous BCL2 mutations at VAF ≥20% were associated with decreased EFS (HR 1.55, 95% CI 1.02-2.35, p = 0.043 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.82, 95% CI 1.05-3.17, p = 0.034). Thus, high VAF nonsynonymous BCL2 mutations remain prognostic even in the chemoimmunotherapy era.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6) • PAX5 (Paired Box 5) • PIM1 (Pim-1 Proto-Oncogene)
|
BCL2 mutation
|
Rituxan (rituximab)
11ms
CLONAL EVOLUTION WITH BCL-2 AMPLIFICATION DURING VENETOCLAX TREATMENT (EHA 2023)
After the first induction cycle with the 7+3 scheme (cytarabine + idarubicin), refractoriness was observed, in addition to the appearance of 6% of nuclei with BCL2 amplification by FISH, while maintaining the TP53 variant (confirmed by PCR). A new therapeutic scheme was initiated with decitabine 10- venetoclax... Clonal evolution of the leukemia was evidenced by the acquisition of BCL2 amplification alongside changes in the karyotype after antineoplastic treatment, and particularly following venetoclax administration, while maintaining the primary TP53 pathogenic variant.The increasing use of targeted therapies is improving remission and survival rates in most hematologic neoplasms, but it is also leading to the emergence of therapy-related clonal selections, as seen in this case, which could cause resistant relapses or even refractoriness. Understanding the mechanisms responsible for these phenomena would help to understand their relevance in the evolution of these patients.
IO biomarker
|
TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
TP53 mutation • BCL2 overexpression • BCL2 mutation • MCL1 expression • BCL2 G101V • BCL2 D103Y • BCL2 amplification • BCL2L1 mutation
|
Venclexta (venetoclax) • cytarabine • decitabine • idarubicin hydrochloride
11ms
GENETIC MARKERS AND OUTCOME OF CLL PATIENTS IN COMBINED TIME-LIMITED TREATMENT WITH ANTI-CD20 ANTIBODY + IBRUTINIB, IDELALISIB OR VENETOCLAX IN THE GCLLSG CLL2-BAG, -BCG, -BIG AND -BIO PHASE-II TRIALS (EHA 2023)
Four phase-2 trials of the German CLL Study Group evaluated time-limited combination regimens in treatment-naïve or relapsed/refractory CLL: BAG (venetoclax-obinutuzumab), BCG (idelalisib- obinutuzumab), BIG (ibrutinib-obinutuzumab) and BIO (ibrutinib-ofatumumab), with or without initial debulking with bendamustine. Genetic risk factors such as the IGHV mutation status remain significant prognostic factors for PFS in the context of time-limited treatment with targeted drugs. Acquisition of high-risk markers was rare and resistance mutations were only acquired in 2 of 44 cases. Chronic lymphocytic leukemia, ibrutinib, Prognostic factor, Venetoclax
Clinical • P2 data • IO biomarker
|
BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • SF3B1 (Splicing Factor 3b Subunit 1) • IGH (Immunoglobulin Heavy Locus) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • BIRC3 (Baculoviral IAP repeat containing 3) • POT1 (Protection of telomeres 1) • NFKBIE (NFKB Inhibitor Epsilon)
|
TP53 mutation • Chr del(17p) • Chr del(11q) • SF3B1 mutation • IGH mutation • BCL2 mutation
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Gazyva (obinutuzumab) • Zydelig (idelalisib) • bendamustine • Arzerra (ofatumumab)
11ms
HDAC INHIBITORS RESTORE SENSITIVITY TO VENETOCLAX AND NAVITOCLAX IN AML CELLS RESULTING IN THE IRREVERSIBLE DNA DAMAGE (EHA 2023)
Background: The BCL-2 inhibitor venetoclax, in combination with hypomethylating agents (HMA) or low dose cytarabine, has been introduced to clinical practice as an alternative for AML patients unfit for intensive chemotherapy... We demonstrate that sensitivity to venetoclax and navitoclax correlates with sensitivity to the HDAC inhibitors belinostat, panobinostat and vorinostat in samples from AML patients with relapsed disease (N = 53)...We demonstrated that small doses of HDAC inhibitors, non-toxic as a single agent, can resensitize AML cells to venetoclax and navitoclax by induction of irreversible DNA damage.
IO biomarker
|
TP53 (Tumor protein P53) • BCL2L1 (BCL2-like 1) • HDAC2 (Histone deacetylase 2) • ANXA5 (Annexin A5) • HDAC3 (Histone Deacetylase 3) • HDAC4 (Histone Deacetylase 4)
|
TP53 mutation • BCL2 mutation
|
Venclexta (venetoclax) • cytarabine • Zolinza (vorinostat) • navitoclax (ABT 263) • Farydak (panobinostat) • Beleodaq (belinostat)
11ms
Pirtobrutinib and Venetoclax in Waldenström Macroglobulinemia (clinicaltrials.gov)
P2, N=42, Recruiting, Dana-Farber Cancer Institute | Not yet recruiting --> Recruiting | Initiation date: Aug 2023 --> May 2023
Enrollment open • Trial initiation date • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • BTK (Bruton Tyrosine Kinase) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 mutation • CXCR4 mutation • BCL2 mutation • BTK mutation • MYD88 wild-type
|
Venclexta (venetoclax) • Jaypirca (pirtobrutinib)
12ms
Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax. (PubMed, Int J Mol Sci)
To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax-rituximab combination therapy. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.
Journal • Real-world evidence • IO biomarker • Real-world
|
BCL2 (B-cell CLL/lymphoma 2)
|
BCL2 mutation • BCL2 G101V • BCL2 D103Y
|
Venclexta (venetoclax) • Rituxan (rituximab)
1year
FCN-683, a novel second-generation BCL-2 inhibitor, is highly potent, selective and efficacious against clinically relevant venetoclax-resistant mutations (AACR 2023)
Preferable safety profiles of FCN-683 were shown with no potential hERG inhibitory effect and less drug-drug interaction potential, as evidenced by no inhibitory effect (IC50 >50 μM) on CYP2C9 enzyme compared with VEN (IC50 1.05 μM). Together, FCN-683 is highly potent, selective and highly efficacious against a variety of clinically relevant VEN-resistance BCL-2 mutations in vitro and in vivo and exhibits favorable PK and safety profiles, highlighting its therapeutic potential to become an effective therapeutic approach for VEN-naïve or -resistant BCL-2-addicted B-cell malignancies.
Clinical • IO biomarker
|
BCL2L1 (BCL2-like 1)
|
BCL2 expression • BCL2 mutation • BCL2 G101V
|
Venclexta (venetoclax) • FCN-683
1year
L105, a next generation of Bcl-2 inhibitor, overcomes Bcl-2 mutation and exhibits superior antitumor activity (AACR 2023)
L105 showed great potency on wild type and acquisition resistance mutations of Bcl-2, excellent oral bioavailability, and superior preclinical anti-tumor activities and safety profiles. It may provide new thoughts on treatment for a wide range of Bcl-2-dependent and Venetoclax-resistant hematological cancers.
IO biomarker
|
BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3)
|
BCL2 overexpression • BCL2 mutation • BCL2 G101V
|
Venclexta (venetoclax) • L105
1year
Next-generation sequencing (NGS) and cytokine assessment from a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) - associations with survival endpoints (AACR 2023)
Mutation status was associated with improvements in PFS in FL pts with mutant BCL2 or mutant EZH2 treated with C+R. iNHL pts with low plasma levels of IL2 levels treated with C+R showed a significant improvement in OS.
Combination therapy • P3 data • Clinical • IO biomarker • Next-generation sequencing
|
PTEN (Phosphatase and tensin homolog) • BCL2 (B-cell CLL/lymphoma 2) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • IL2 (Interleukin 2)
|
EZH2 mutation • BCL2 mutation • IL2-L • PTEN positive
|
TruSight Oncology 500 Assay
|
Rituxan (rituximab) • Aliqopa (copanlisib)
1year
Pirtobrutinib and Venetoclax in Waldenström Macroglobulinemia (clinicaltrials.gov)
P2, N=42, Not yet recruiting, Dana-Farber Cancer Institute
New P2 trial • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • BTK (Bruton Tyrosine Kinase) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 mutation • CXCR4 mutation • BCL2 mutation • BTK mutation • MYD88 wild-type
|
Venclexta (venetoclax) • Jaypirca (pirtobrutinib)
1year
Polypharmacological BCL-2/HDAC dual inhibitor strategy to mitigate MCL-1 upregulation in venetoclax resistance (ACS-Sp 2023)
Therefore, we have designed and synthesized dual BCL-2/HDAC inhibitors to target HDAC1, as well as other dual inhibitors to target HDAC6. It is hypothesized that our polypharmacological approach will be comparable with the corresponding polypharmacy approach in cells but superior in vivo; our progress will be presented.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
BCL2 mutation • MCL1 expression
|
Venclexta (venetoclax)
1year
Impact of BCL2 Mutations to BCL2 Protein Expression in B-Cell Lymphoma (USCAP 2023)
The presence of BCL2 mutations correlates with BCL2 translocations suggesting an AID-induced mechanism. The epitopes recognized by the antibodies are often affected by mutations in that region, therefore may lead to false negative IHC results using the 124/Ventana clone. Given the clinical significance of BCL2 expression in diagnosis and prognostication of FL and DLBCL, it is recommended that alternative antibodies, such as the E17 clone, be used to prevent false negative BCL2 protein expression.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • IGH (Immunoglobulin Heavy Locus)
|
BCL2 overexpression • BCL2 expression • BCL2 positive • BCL2 mutation • MYC translocation + BCL2 translocation • BCL2 translocation
over1year
NX-2127-001, a First-in-Human Trial of NX-2127, a Bruton's Tyrosine Kinase-Targeted Protein Degrader, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and B-Cell Malignancies (ASH 2022)
All have previously received a BTKi and 76.5% had also received venetoclax. Double- and emerging triple-refractory CLL (patients who progressed on cBTKi, ncBTKi, and a BCL2 inhibitor) represents a major unmet medical need with no approved therapeutic options and poor survival. These patients may thus benefit from the interruption of BTK kinase-independent scaffolding signaling. In this first-in-human, first-in-class study of a BTK degrader, clinical responses and benefit were observed in heavily pretreated (median 6 prior therapies) patients with CLL who have poor prognostic factors, including those with BTK mutations resistant to cBTKi and ncBTKi, BCL2 mutations and those who were previously treated with both BTKi and BCL2 inhibitors.
Clinical • P1 data • IO biomarker
|
TP53 (Tumor protein P53) • BTK (Bruton Tyrosine Kinase) • IGH (Immunoglobulin Heavy Locus) • IKZF1 (IKAROS Family Zinc Finger 1) • IKZF3 (IKAROS Family Zinc Finger 3)
|
TP53 mutation • BCL2 mutation • BTK mutation • BTK C481
|
Venclexta (venetoclax) • NX-2127
over1year
Discovery of HZ-L105, a Next Generation of Bcl-2 Inhibitor, Overcomes Bcl-2 Mutation and Exhibits Superior Antitumor Activity (ASH 2022)
In summary, HZ-L105 as a next generation Bcl-2 inhibitor, showed great potency on wild type and acquisition resistance mutations of Bcl-2 in vitro, excellent oral bioavailability, superior anti-tumor activities on preclinical xenograft model, and safety profiles,. It may provide new thoughts on treatment for a wide range of Bcl-2-dependent and Venetoclax-resistant hematological cancers.
IO biomarker
|
BCL2L1 (BCL2-like 1)
|
BCL2 mutation • BCL2 G101V
|
Venclexta (venetoclax)
over1year
Follicular Lymphoma Transcriptional Signatures Identify Heterogenous Biological Subtypes with Distinct Clinical Outcomes (ASH 2022)
To evaluate the prognostic significance of these 4 signatures, we performed signature recovery on two independent FL datasets annotated with mature clinical data (both with OS, one with failure free survival (FFS), which identified heterogeneous survival outcomes between transcriptional subtypes (Figure 1) and highlighted the potential predictive value of the signatures for treatment naïve patients initiating frontline therapy with rituximab and chemotherapy...In summary, our analyses uncovered genetic subtypes of FL with distinct biological and clinical features, providing a potential framework for advancing precision medicine strategies in FL. These results suggest the possibility of using transcriptional signatures and/or their surrogates as novel biomarkers to guide front-line risk-adapted therapy.
Clinical • Clinical data • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • CD79B (CD79b Molecule) • PRDM15 (PR/SET Domain 15) • BTG2 (BTG Anti-Proliferation Factor 2)
|
BCL2 mutation
|
Rituxan (rituximab)
over1year
Crebbp Mutations Are Associated with Shorter Time to Progression in Limited-Stage Follicular Lymphoma Treated with Radiation (ASH 2022)
In conclusion, we found an association between CREBBP mutations and shorter time to progression in limited-stage FL treated with RT. To our knowledge, this represents a novel genetic prognostic finding in limited-stage FL. Further studies with larger sample sizes are required to confirm the association.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • KMT2D (Lysine Methyltransferase 2D) • CREBBP (CREB binding protein) • TNFRSF14 (TNF Receptor Superfamily Member 14) • STAT6 (Signal transducer and activator of transcription 6) • TNFRSF18 (TNF Receptor Superfamily Member 18)
|
KMT2D mutation • CREBBP mutation • BCL2 mutation
over1year
Targeting Venetoclax Resistant CLL Using a Protac-Based BCL-2/BCL-XL Degrader (ASH 2022)
Treatment for chronic lymphocytic leukemia (CLL) is primarily based upon the use of small molecules targeting Bruton's tyrosine kinase (BTK; ibrutinib, acalabrutinib) or BCL-2 (venetoclax)...The efficacy of WH2544 and PZ18753b in treating naïve CLL cells fell in between that of venetoclax and navitoclax...In conclusion, our results suggest that venetoclax refractory CLL cells retain survival dependency on BCL-2 and BCL-xL proteins to evade apoptosis. This vulnerability can be therapeutically exploited using the BCL-2/BCL-xL dual targeting PROTACs PZ18753b and WH2544 in CLL.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BTK (Bruton Tyrosine Kinase) • BCL2L1 (BCL2-like 1) • ANXA5 (Annexin A5)
|
BCL2 overexpression • BCL2 expression • BCL2 mutation • BCL2 G101V
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Calquence (acalabrutinib) • navitoclax (ABT 263)
over1year
Lisaftoclax in Combination with Alrizomadlin Overcomes Venetoclax Resistance in Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia: Preclinical Studies. (PubMed, Clin Cancer Res)
Lisaftoclax in combination with alrizomadlin overcomes venetoclax resistance mediated by various mechanisms, including BCL-2 mutations. In addition, we posit further, putative molecular mechanisms. Our data rationalize clinical development of this treatment combination in patients with diseases that are insensitive or resistant to venetoclax.
Preclinical • Journal • Combination therapy • IO biomarker
|
MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
TP53 wild-type • BCL2 mutation • MCL1 expression
|
Venclexta (venetoclax) • alrizomadlin (APG-115) • lisaftoclax (APG-2575)
over1year
MUTATIONAL STATUS OF CHONDROSARCOMA BASED ON TARGETED NEXT-GENERATION SEQUENCING ANALYSIS (CTOS 2022)
Mutational status analysis suggests that the pathogenesis of high-grade ChS and progression of diseases may be related to tumor growth and cell proliferation (PI3K-AKT-mTOR, RAS-RAF-MEK-ERK), regulation of cell cycle, and apoptosis (p53 signaling), and chondrocyte differentiation (Hedgehog pathway) signaling pathways. Moreover, methylation of histones may play also an important role in high-grade ChS, but not in the mesenchymal subtype.
Next-generation sequencing • Tumor Mutational Burden • IO biomarker
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • MSI (Microsatellite instability) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • BCL2 (B-cell CLL/lymphoma 2) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • mTOR (Mechanistic target of rapamycin kinase) • PTCH1 (Patched 1) • EPHB1 (EPH Receptor B1) • HNF1A (HNF1 Homeobox A) • TAF1 (TATA-Box Binding Protein Associated Factor 1)
|
TP53 mutation • PIK3CA mutation • IDH1 mutation • IDH2 mutation • ARID1A mutation • PTCH1 mutation • BCL2 mutation • MTOR mutation
over1year
Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis. (PubMed, Front Oncol)
Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • B2M (Beta-2-microglobulin) • STAT6 (Signal transducer and activator of transcription 6)
|
LDH elevation • BCL2 mutation • EZH2 Y646
almost2years
B-cell lymphoma-2 (BCL2) downregulation is a useful feature -supporting a neoplastic phenotype in mature T-cell lymphomas. (PubMed, Hum Pathol)
BCL2 downregulation is pervasive among many T-cell lymphoproliferations and unrelated to any mutations. There is utility for BCL2 immunostaining in some challenging situations as discussed in manuscript.
Journal • IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • STAT5B (Signal Transducer And Activator Of Transcription 5B)
|
TP53 mutation • BCL2 expression • BCL2 mutation
almost2years
SINGLE-CELL MULTIOMICS ANALYSES REVEAL COMPLEX INTRA-PATIENT HETEROGENEITY IN RELAPSED CLL FOLLOWING VENETOCLAX THERAPY (EHA 2022)
Given the multiple ways a CLL population in a patient can become resistant to ongoing VEN, it seems unlikely that simply adding other drugs at relapse will be durably effective in most patients. The data pinpoint NF-ΚB activation as a biomarker for in vivo VEN-resistance and provide a specific biological rationale for ceasing VEN in deep response, as is currently being used in time-limited and explored in response-directed regimens.
Clinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2)
|
BCL2 mutation • MCL1 expression • MCL1 amplification
|
Venclexta (venetoclax)