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BIOMARKER:

BCR-ABL1 E255V

i
Other names: BCR, BCR Activator Of RhoGEF And GTPase, BCR, RhoGEF And GTPase Activating Protein, Breakpoint Cluster Region Protein, Renal Carcinoma Antigen NY-REN-26, Breakpoint Cluster Region, D22S11, BCR1, BCR/FGFR1 Chimera Protein, FGFR1/BCR Chimera Protein, D22S662, ALL, CML, PHL, ABL proto-oncogene 1, ABL, c-ABL, JTK7, p150, ABL1
Entrez ID:
12ms
Getting to Know the Molecular Landscape of R/R Chronic Myeloid Leukemia: NGS-Based Profiling of Myeloid Mutations Beyond BCR/ABL (ASH 2023)
This study shows us that there are more mutations associated with therapeutic failure in patients with CML in addition to those in the ABL domain. Knowing these mutations can support the diagnosis, prognosis, establish target therapies and even guide the decision of a bone marrow transplant. Studies with larger populations are required to corroborate the data presented here to generate correlations the clinical and prognostic relevance of myeloid mutations, both at the time of treatment failure and perhaps at diagnosis.
Next-generation sequencing
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TP53 (Tumor protein P53) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • WT1 (WT1 Transcription Factor)
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TP53 mutation • ATM mutation • DNMT3A mutation • SF3B1 mutation • BCR-ABL1 Y253H • BCR-ABL1 E255V
12ms
The Promising Third-Generation TKI Olverembatinib in Adult BCR: : ABL1-Positive Acute Lymphoblastic Leukemia with T315I Mutation and Relapsed/Refractory Disease (ASH 2023)
As for the 23-year-old female pt with CML-LBP, dasatinib was switched to olverembatinib when T315I, E255K, and E255V mutations were detected...At present, the patient maintained in CR, and blinatumomab will be used for MRD clearance before allo-HSCT...In addition, bridging allo-HSCT after deeper molecular remission could further improve survival. The safety profiles were manageable, but there is still a need to explore the optimal dose in elderly pts.
Clinical
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase)
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BCR-ABL1 E255K • BCR-ABL1 E255V • ABL1 T315I • ABL1 E255K • BCR-ABL1 T315I + ABL1 E255V
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dasatinib • Blincyto (blinatumomab) • Nailike (olverembatinib)
1year
Tgrx-678, a Novel Allosteric Inhibitor of BCR-ABL1, Demonstrates Preclinical Anti-Leukemia Activity, High Oral Bioavailability and Synergism with Ponatinib to Suppress the Highly Resistant Compound Mutations (ASH 2023)
ABL1 is subject to auto-inhibition mediated by myristoylation-triggered conformational change, which can be exploited to overcome resistance, as validated by allosteric inhibitors such as GNF2, GNF5 and asciminib. Furthermore, TGRX-678 and ponatinib synergize to overcome the clinically challenging resistance conferred by T315M or T315I-inclusive compound mutations. This data warrant further clinical investigation of TGRX-678 for the treatment of resistant or refractory CML patients.
Preclinical
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase)
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BCR-ABL1 T315I • BCR-ABL1 E255K • BCR-ABL1 Y253H • BCR-ABL1 E255V • BCR-ABL1 G250E • ABL1 T315I • BCR-ABL1 Q252H • ABL1 E255K • ABL1 G250E • ABL1 Y253H • BCR-ABL1 T315M • BCR-ABL1 Y253H + BCR-ABL1 T315I
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Iclusig (ponatinib) • Scemblix (asciminib) • TGRX-678
over1year
Dose optimisation of ponatinib in chronic phase chronic myeloid leukemia. (PubMed, Expert Rev Hematol)
Based on pharmacological findings and international guidelines on chronic myeloid leukemia and cardiovascular risk management, as well as on the most recent data collected in real-life studies and in a randomized phase II trial, we propose a decision-tree of dose selection of the drug. We distinguish (1) highly resistant patients according to poor previous response to second generation tyrosine kinase inhibitors (complete hematologic response or less) or to mutationnal status (T315I, E255V, alone or within compound mutations), requiring a starting daily dose of 45 mg, reduced to 15 or 30 mg according to the patient's profile, preferentially upon major molecular achievement (3-log reduction or MR3, BCR:ABL1 ≤0.1%); (2) less resistant patients justifying an initial dose of 30 mg, reduced to 15 mg upon MR2 (BCR:ABL1 ≤1%) or preferentially MR3 in patients with a favorable safety profile; (3) intolerant patients to be treated by 15 mg.
Journal
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ABL1 (ABL proto-oncogene 1)
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BCR-ABL1 E255V • ABL1 T315I
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Iclusig (ponatinib)
2years
A Phase II Study of Flumatinib with Chemotherapy for Newly Diagnosed Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia in Adults:Preliminary Results from RJ-ALL2020.2A Trial (ASH 2022)
It has been demonstrated better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL...Once the diagnosis is confirmed, combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is administered promptly...Central nervous system (CNS) prophylaxis is regularly performed by intrathecal injection of methotrexate, cytarabine, and dexamethasone after remission induction course...Conclusion The combination of the second-generation TKI flumatinib and chemotherapy is quite effective and safe in Chinese adult pts with newly diagnosed Ph/BCR-ABL1+ ALL. This clinical trial is still ongoing, and the long-term follow-up data will be further investigated.
Clinical • P2 data
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase)
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BCR-ABL1 E255K • BCR-ABL1 Y253H • BCR-ABL1 E255V • ABL1 T315I • ABL1 E255K • ABL1 Y253H
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imatinib • cytarabine • vincristine • prednisone • dexamethasone • idarubicin hydrochloride • Hansoh Xinfu (flumatinib)
almost3years
P-Loop mutations-Negative prognosticators in tyrosine kinase inhibitors resistant chronic myeloid leukemia patients. (PubMed, Int J Lab Hematol)
The presence of P-Loop domain mutations negatively impacted the prognosis of the disease in terms of disease advancement and overall survival. So, the timely performance of the BCR-ABL1 mutational analysis and the modifications in the treatment plan based on the mutation identified would help in a better outcome of the disease.
Journal
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase)
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BCR-ABL1 Y253H • BCR-ABL1 E255V • BCR-ABL1 G250E • BCR-ABL1 Y253F • BCR-ABL1 mutation • ABL1 G250E • ABL1 Y253H
4years
[VIRTUAL] Phase 1 Trial of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI): Activity in CML Chronic Phase Patients Failing TKI Therapies Including Ponatinib (ASH 2020)
Vodobatinib was evaluated over 9 escalating doses. Comparable and promising efficacy was noted in both PT (50% CCyR) and PN (67% CCyR) groups, meriting further study of vodobatinib as a potential new agent for treatment of previously treated CP-CML.
Clinical • P1 data
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase)
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BCR-ABL1 F317L • BCR-ABL1 Y253H • BCR-ABL1 E255V • ABL1 T315I • ABL1 F317L • ABL1 Y253H
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Iclusig (ponatinib)