BCR-ABL

BCR-ABL testing is ordered to detect the Philadelphia (Ph) chromosome and BCR-ABL gene sequence. It is used to help diagnose chronic myelogenous leukemia (CML) and a type of acute lymphocytic leukemia (ALL) in which the BCR-ABL gene sequence is present (BCR-ABL positive), to monitor response to treatment, and to monitor for disease recurrence.

A chromosome analysis, the qualitative BCR-ABL molecular genetic test, and/or FISH may be ordered to help establish the initial diagnosis of CML or Ph-positive ALL. It is often performed along with other tests if a doctor suspects that a patient has leukemia and is trying to diagnose or rule out CML and Ph-positive ALL. The chromosomal analysis and FISH can also help to determine what percentage of patient's blood or bone marrow cells are affected.

The qualitative BCR-ABL test can also help determine the breakpoint variant of BCR-ABL that is being produced. The size and weight of the BCR-ABL protein produced depends upon where the break in chromosome 22 occurred. In CML, the breakpoint in BCR is almost always in the major breakpoint cluster region (M-BCR), leading to the production of BCR-ABL protein of a larger size (p210). Breaks in the minor breakpoint cluster region (m-BCR) leads to a shorter fusion protein (p190), which is most frequently associated with Ph-positive ALL. Knowing whether a patient has a break in the major or minor BCR is important because the quantitative BCR-ABL molecular genetic test may be set up to measure a specific variant, p210 or p190, but not both.

The quantitative BCR-ABL molecular test is ordered once the BCR-ABL gene sequence has been detected and the breakpoint variant established. It may be ordered at the time of the initial diagnosis to establish a baseline value and then used periodically to monitor the person's response to treatment and, if the person achieves remission, to monitor for recurrence.

BCR-ABL testing is ordered when a doctor suspects that a person has CML or Ph-positive ALL. Initial testing may be indicated when a person has nonspecific symptoms such as fatigue, weight loss, joint or bone pain, and/or an enlarged spleen or as a follow-up to abnormal findings on a CBC. Early in the disease, a person may have few or no symptoms. As time passes and normal blood cells are crowded out of the bone marrow and the number of abnormal leukemic cells increases, a person may experience anemia, prolonged bleeding, and recurrent infections.

Once CML or Ph chromosome-positive ALL has been diagnosed, BCR-ABL quantitative genetic testing is ordered periodically (typically every 3 months) to monitor the response to treatment and monitor for recurrence. If treatment resistance or disease recurrence occurs, the BCR-ABL kinase domain mutation analysis should be performed to guide further treatment.

If a person has abnormal white blood cells in the bone marrow and has the Ph chromosome and BCR-ABL gene sequence, then that person has CML or Ph-positive ALL. Of those who have CML, 90-95% have the Ph chromosome by cytogenetics and 100% have BCR-ABL gene by FISH and/or qualitative BCR-ABL molecular testing. About 25% of adult ALL and 3% of childhood ALL are positive for the Ph chromosome and/or BCR-ABL gene sequence.

A small percentage of patients with CML will have the BCR-ABL gene sequence but not the Ph chromosome. These cases either have variant translocations that involve a third or even a fourth chromosome in addition to 9 and 22, or have a hidden translocation involving 9 and 22 that can not be identified by routine chromosomal analysis. Since the treatment for BCR-ABL-related leukemias specifically targets the tyrosine kinase protein produced, these patients can still be monitored with quantitative BCR-ABL molecular testing.

In general, if the amount of BCR-ABL in the blood or bone marrow decreases over time, then the person is responding to treatment. If the quantity of BCR-ABL drops below the test's detection level and the person's blood cell counts are normal, then the patient is considered to be in remission. If BCR-ABL levels rise, then it indicates disease progression or recurrence. It may also indicate that the person has become resistant to imatinib, the first-generation tyrosine kinase inhibitor. Additional genetic testing is often performed to detect the development of BCR-ABL kinase domain mutations associated with imatinib resistance. If a patient is determined to be resistant to imatinib, a different tyrosine kinase inhibitor may be given.

If a patient with ALL is not positive for the Ph chromosome and BCR-ABL gene sequence, then that person will not be given a tyrosine kinase inhibitor drug and BCR-ABL molecular testing cannot be used to monitor the patient.

Recognition of disease progression and transformation is important for prognosis and treatment. CML goes through three phases:

• Chronic phase—most patients with CML are diagnosed in chronic phase, which usually has an insidious onset. The chronic phase may last for several years. This is the phase when there are few or no symptoms and also the time period when treatment is most successful.
• Accelerated phase—changes include but are not limited to increasing white blood cell (WBC) counts, additional cytogenetic changes, an increase in blasts in blood and/or bone marrow (but less than 20%) and lack of therapeutic response to standard treatment
• Blast phase—when blasts equal or are greater than 20% of the blood white cells and/or of the nucleated (containing a nucleus) cells in the bone marrow, or when there is blast proliferation outside the bone marrow

Both blood and bone marrow are often evaluated as part of the initial diagnosis, but the majority of follow-up monitoring is performed on blood samples. There is significant test variability among laboratories using different test platforms. Therefore, for a given patient, the quantitative BCR-ABL molecular testing should be done by the same laboratory or referred to a laboratory that follows universal reporting criteria. Rising and falling levels of BCR-ABL are usually more important than a single test result.