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BCR-ABL1 Gene Rearrangement, Quantitative PCRTest code(s) 91065
Question 1. How does Quest Diagnostics perform PCR testing for the BCR-ABL1 fusion gene found in chronic myelogenous leukemias (CML) and acute lymphoblastic leukemias (ALL) that bear the t(9;22) Philadelphia (Ph) chromosome?
For new patients, Quest Diagnostics will test for both the P210 isoform (e13a2 and e14a2 transcripts) and the P190 isoform (e1a2 fusion). Once a BCR-ABL1 fusion is detected, subsequent samples from the patient will be tested for the indicated isoform(s) only.
Question 2. What types of samples can be tested?
International guidelines1 recommend that CML testing be performed using peripheral blood only. Ph-positive ALL can be assessed using either peripheral blood (6-10 mL) or bone marrow aspirate samples (1-3 mL). While lavender-top EDTA collection tubes are preferred, yellow-top citrate or green-top heparin tubes will be accepted.
Question 3. How are the results reported for P210- and P190-positive cases?
The level of the BCR-ABL1 fusion transcript is expressed as a percent of the ABL1 gene transcript level. For the P210 transcript, this ratio is further normalized to the international scale (IS) and reported as BCR-ABL1/ABL1 % (IS). The IS is a standardized correction factor that enables direct comparison of results from different laboratories regardless of differences in methodology. The universal baseline is defined as 100% (IS). A 3-log decrease, indicated by a % (IS) value of 0.1%, is indicative of the major molecular response (MMR) level with transcript levels below the MMR being the target for optimal CML therapy.
No IS currently exists for the P190 isoform, so P190-positive cases are reported asBCR-ABL/ABL1 % with no further normalization.
Question 4. What are the major differences between the old BCR-ABL1PCR tests and the new BCR-ABL1 PCR test (test code 91065)?
Effective 08.07.2012, the test was renamed to BCR-ABL1 Gene Rearrangement, Quantitative PCR and a new test code (91065) was assigned. All the previous BCR-ABL1 PCR codes (15052X, 15101X and 17853X) have been retired. With the new test,
- It is no longer necessary to order transcript subtyping as that is done automatically for new patients.
- The log-reduction method of reporting has been replaced by the BCR-ABL1/ABL1 % (IS), as described above.
- There is now a graphical trending report available via Care360 (see your sales representative for further information on how to get this report).
Question 5. How do the values in the new assay compare to those in the old assay?
Although not precisely equivalent due to changes in the assay design, a BCR-ABL1/ABL1 value of 10% (IS) in the new assay roughly correlates to a 1-log reduction in the old assay; a 1% (IS) correlates to a 2-log reduction; and a 0.1% (IS) correlates to a 3-log reduction.
Question 6. Is the Leumeta® (plasma-based) test code for BCR-ABL1 still available?
No. As described above, peripheral blood is now the recommended standard specimen type for CML monitoring. In Ph-positive ALL, either bone marrow aspirate or peripheral blood can be tested.
Question 7. Why do discordances between BCR-ABL1 PCR and FISH occur?
Cases that are PCR-positive and FISH-negative are common, since FISH is a less-sensitive technique. However, approximately 1% to 3% of CML and Ph-positive ALL cases will have an altered fusion transcript (usually missing exon A2 of ABL1) that cannot be detected using this PCR assay. In those cases, FISH can be used to monitor patients. FISH can also be used to monitor patients with the very rare P230 BCR-ABL1 isoform, which is not reliably detected by this PCR assay.
Question 8. What does a value >100% (IS) mean?
This signifies that the amount of BCR-ABL1 transcript is greater than the universally established average level at diagnosis. For the purposes of the trending report, values above 100% are plotted at the100% line.
Question 9. What are the causes of treatment failure in CML?
Lack of initial response to tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (Gleevec®) is called primary resistance and is most commonly related to inadequate drug levels or pharmacodynamic factors although all causes are not yet known.
The most frequent cause of secondary resistance to TKIs is a mutation in the ABL1 kinase domain. Such mutations can be detected using the ABL kinase domain mutation test (test code 16029X). Another cause of secondary resistance is acquisition of additional cytogenetic changes; these can be detected using a bone marrow aspirate chromosome study (test code 14600X).
Extra copies of the Ph chromosome can mediate both primary and secondary partial TKI resistance. Extra copies can be detected using the BCR-ABL1 FISH test (test code 12070X).
Question 10. What degree of increase in BCR-ABL1 transcript suggests secondary resistance?
Therapeutic response to initial treatment is indicated by a drop in the BCR-ABL1 level. A subsequent 5- to 10-fold increase in the % (IS) level suggests developing drug resistance, which is usually due to an ABL1 mutation or clonal evolution. Overt hematologic or cytogenetic relapse and emergence of blast phase are others indicators of secondary resistance.
For patients in the first year of treatment, a repeat PCR test is indicated to confirm the increase in BCR-ABL1 transcript prior to a drug resistance workup.
- Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108:28-37.