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Monitoring response to therapy in patients with known e1/a2 bcr/abl (p190) fusion forms
mRNA transcribed from BCR/ABL (fusion of the breakpoint cluster region gene [BCR]at chromosome 22q11 to the Abelson gene [ABL] at chromosome 9q23) is detected in all chronic myelogenous leukemia (CML) patients and a subset of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients. Although breakpoints in the BCR and ABL genes may occur in a variety of locations, splicing of the primary RNA transcripts result in only 8 fusion site variants (e1/a2, e6/a2, e13/a2, e14/a2, e19/a2, and e1/a3, e13/a3, e14/a3), which incorporate the entire sequence of the exons on both sides of the fusion site. The e1/a2 and e1/a3 fusion forms produce a 190-kDa protein designated p190. This bcr/abl protein form is found in approximately 75% of childhood ALL patients and approximately 50% of adult ALL patients, with the majority arising from e1/a2 mRNA. The p190 is also the predominant fusion form in a small subset of CML patients, although the vast majority of CML cases contain the p210 protein, typically from e13/a2 or e14/a2 mRNA fusions. Other fusion forms are very rare.
Quantitative reverse-transcription PCR (qRT-PCR) is the most sensitive method for monitoring bcr/abl levels during treatment. This test detects mRNA coding for the most common p190 fusion form (e1/a2).
The presence or absence of the BCR/ABL mRNA (bcr/abl) fusion form producing the p190 fusion protein is reported. If positive, the level is reported as the ratio of bcr/abl (p190) to abl with conversion to a percentage (ie, bcr/abl (p190) as a percentage of total abl).
An interpretive report will be provided.
This test detects only the e1/a2 bcr/abl (p190) fusion form. Other fusion forms are not detected by this assay, including those containing the BCR e13 and e14 exons, which code for the p210 protein commonly found in chronic myeloid leukemia (CML).
This test should not be used to monitor patients carrying bcr/abl fusion forms coding for the p210 protein, which includes most CML patients; BCRAB / BCR/ABL, p210, mRNA Detection, Reverse Transcription-PCR (RT-PCR), Quantitative, Monitoring Chronic Myelogenous Leukemia (CML) should be ordered for this purpose.
This test should not be used to screen for bcr/abl fusions at the time of diagnosis; BADX / BCR/ABL, mRNA, Detection, Reverse Transcription-PCR (RT-PCR), Qualitative, Diagnostic Assay should be ordered for this purpose.
The precision of this assay at very low bcr/abl levels is less reliable, such that inter-run variation can be more variable. If the results are being used to make major therapeutic decisions, significant changes during monitoring should be verified with a subsequent specimen.
Results of this assay cannot be directly compared with results generated from other PCR assays, including identical assays performed in other laboratories. Monitoring should be performed using the same method and laboratory for each subsequent specimen.
The results of this assay cannot be directly compared with bcr/abl results obtained using FISH technology. FISH measures DNA alleles and this PCR-based assay measures mRNA transcripts. Because a single DNA allele can produce many mRNA transcripts, the values are not directly comparable.
Blood is the specimen of choice for monitoring. While most patients show similar bcr/abl levels in blood and bone marrow drawn at the same time, some patients have a consistent difference in the levels in blood and bone marrow such that altering specimen types during monitoring can lead to confusion.
Assay precision does not appear to be significantly affected by specimen transport or moderate delays in processing. However, in specimen with very low levels of bcr/abl, these conditions may cause sufficient RNA degradation to produce false-negative results. Thus, specimen should be shipped as quickly as possible and specimens >3 days old at the time of receipt will be considered unacceptable.
1. Hughes TP, Kaeda J, Branford S, et al: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003;349:1423-1432
2. Radich JP, Gooley T, Bryant E, et al: The significance of BCR/ABL molecular detection in chronic myeloid leukemia patients "late," 18 months or more after transplantation. Blood 2001;98:1701-1707
3. Olavarria E, Kanfer E, Szydlo R, et al: Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplant for chronic myeloid leukemia. Blood 2001;97:1560-1565