BCR-ABL1

BCR-ABL1 is a fusion gene that results from a translocation between chromosomes 9 and 22, known as the Philadelphia chromosome. This fusion produces the BCR-ABL1 tyrosine kinase protein, which plays a pivotal role in the development of hematologic cancers, particularly chronic myeloid leukemia (CML) and, to a lesser degree, acute lymphoblastic leukemia (ALL). 

Understanding and monitoring BCR-ABL1 levels aids in diagnosing, monitoring, and adjusting treatment for these cancers. 

What is BCR-ABL1?

The BCR-ABL1 fusion gene is a genetic abnormality caused by the translocation of the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9, resulting in the Philadelphia chromosome. 

This fusion produces the BCR-ABL1 protein, a tyrosine kinase that promotes uncontrolled cell proliferation, a key feature of chronic myelogenous leukemia (CML) and certain cases of acute lymphoblastic leukemia (ALL). 

The presence of BCR-ABL1 is essential for diagnosing these cancers and monitoring treatment responses, particularly with tyrosine kinase inhibitors (TKIs). 

BCR-ABL1 quantification, typically performed using real-time quantitative PCR (RT-qPCR), helps assess disease burden and track therapeutic effectiveness, including monitoring minimal residual disease (MRD).

Clinical Significance of the BCR-ABL1 Fusion Gene and Protein

The clinical importance of measuring BCR-ABL1 levels is that it helps doctors track the progress of chronic myelogenous leukemia (CML) and how well treatment is working, especially when using tyrosine kinase inhibitors (TKIs).

By measuring BCR-ABL1 mRNA levels using a method called real-time quantitative PCR (RT-qPCR), doctors can see how well the treatment is working at the molecular level. 

Key milestones, like Major Molecular Response (MMR), show a significant reduction in BCR-ABL1 levels. Achieving deeper molecular responses, such as MR4 or MR4.5, is linked to better long-term results and can help doctors decide whether to stop treatment or consider treatment-free remission (TFR). 

Standardizing BCR-ABL1 testing with reference panels and certified materials ensures that test results are consistent across different labs, making it easier to monitor the disease accurately and provide the best care for patients.

Who Should Get BCR-ABL1 Tested?

BCR-ABL1 testing is recommended in several clinical scenarios:

• Symptomatic Individuals: patients presenting with fatigue, unexplained weight loss, recurrent infections, or easy bruising should undergo BCR-ABL1 testing to assess for CML or ALL.
• Diagnosed Patients: in individuals diagnosed with CML or ALL, BCR-ABL1 testing is used for both initial confirmation and ongoing monitoring.
• High-Risk Populations: individuals with a family history of hematologic malignancies or those exposed to chemical or other toxins may consider BCR-ABL1 testing for early detection.
• Treatment Monitoring: for patients undergoing treatment for CML or ALL, regular BCR-ABL1 testing is crucial to monitor response to therapy and detect relapse at an early stage.

Test Procedure and Interpretation

BCR-ABL1 genetic testing is usually performed through polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) techniques. These methods detect and quantify the presence of the BCR-ABL1 fusion gene in blood or bone marrow samples.

No special patient preparation is generally required. However, it's important to follow specific laboratory instructions related to timing (e.g., whether fasting is necessary) or medication adjustments before testing.

Normal Reference Ranges

In patients with CML or ALL, BCR-ABL1 levels are often detectable. The reference range can vary based on disease stage and treatment regimen.

For patients in remission, BCR-ABL1 levels are typically very low or undetectable.

For healthy individuals, BCR-ABL1 levels should be undetectable.

The International Standard for BCR-ABL1 Interpretation

The development of an international standard for interpreting BCR-ABL1 results has become important. The normal reference range for the BCR-ABL1 test on the International Scale (IS) is reported as:

• 0% BCR-ABL1 at diagnosis (baseline), which is the reference point for the measurement of therapeutic responses.

• ≤0.1% IS indicates a Major Molecular Response (MMR)

• ≤0.0032% IS indicates a Complete Molecular Response (CMR)

The International Scale (IS) is used to standardize BCR-ABL1 test results, making it possible to compare results across different laboratories and clinical settings. 

The IS values are necessary for monitoring treatment response and determining whether the patient is achieving key molecular response milestones like MMR and CMR, which correlate with better long-term outcomes.

Clinical Implications of Elevated Levels

Elevated BCR-ABL1 levels typically indicate active disease or disease progression in CML and ALL. High levels can also suggest treatment resistance, particularly to tyrosine kinase inhibitors (TKIs), and may require adjustments in therapy, such as changing the type of TKI or intensifying treatment. 

Additionally, elevated levels may signal minimal residual disease (MRD), meaning a small number of cancerous cells remain, increasing the risk of relapse. These elevated levels necessitate careful monitoring and possible modifications to the treatment regimen to address disease activity or resistance.

Clinical Implications of Decreased Levels

Low or undetectable BCR-ABL1 levels generally indicate an effective treatment response, suggesting the disease is in remission and possibly reflecting a deep molecular response (DMR). 

In some cases, these levels may even suggest the potential for treatment-free remission (TFR), where the patient can maintain remission without ongoing therapy. 

However, even with low levels, ongoing monitoring is essential to detect early signs of relapse and ensure sustained remission. Regular testing also helps inform long-term treatment decisions, weighing the benefits of continuing therapy against the possibility of treatment discontinuation.

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