2012/11/13 12:02

Major and minor BCR-ABL1

  • Diagnose chronic myelogenous leukemia (CML)

  • Identify acute lymphoblastic leukemia (ALL) with t(9;22) BCR/ABL1 rearrangement (Ph+ ALL)

  • Select treatment in patients with ALL

  • Monitor the effectiveness of therapy

  • Monitor minimal residual disease (MRD)

  • Predict disease progression

Clinical Background

The BCR-ABL1 fusion gene is formed by a translocation between chromosomes 9 and 22 [t(9;22)], which also results in an abnormally short chromosome 22 (the Philadelphia chromosome; Ph). The fusion gene is present in virtually all individuals with CML and is the hallmark diagnostic feature of the disease.1 It is also present in some adults (~25%) and children (2-4%) with ALL.2

The BCR-ABL1 rearrangement results in the production of a fusion protein with constitutive tyrosine kinase activity, which is thought to play a role in the development of leukemia. In almost all CML cases the major breakpoint cluster region of the BCR gene rearranges with the ABL1 gene to create either the e13a2 or e14a2 fusion transcript, which in turn produces the P210 fusion protein. In most children with Ph+ ALL, the minor breakpoint cluster region rearranges with ABL1 to create the e1a2 fusion transcript, which in turn produces the P190 fusion protein. Adults with Ph+ ALL may have either the P190 or the P210 protein.3

The BCR-ABL1 Gene Rearrangement, Quantitative PCR test can measure the two P210 transcripts (e13a2 and e14a2) as well as the P190 transcript (e1a2). For P210 transcripts, results are standardized to the international scale (IS), allowing direct comparison across different laboratories regardless of method variations.

Tyrosine kinase inhibitors (TKIs) are the first-line treatment for CML and are part of the recommended treatment regimens for Ph+, but not Ph-, ALL.4

Method

BCR-ABL1 fusion transcripts are amplified by real-time reverse transcription-polymerase chain reaction. The ABL1 gene is amplified as an internal control for sample RNA quality and as a reference for relative quantitation. The assay has a linear range of 10 to 106 RNA copies.

Results Reported

  • The type of BCR-ABL1 transcript (P210 or P190) will be identified, if present, the first time a patient is tested. In subsequent testing on the same patient, reporting will be limited to the transcript initially identified.

  • For samples harboring the P210 transcript, results will be expressed as the BCR-ABL1/ABL1 % (IS) value: (BCR-ABL1/ABL1 ratio) x 100 x correction factor. A BCR-ABL1/ABL1 % (IS) value of 100% represents the level at diagnosis in most patients, which is similar to the universal baseline used in the landmark International Randomized Study of Interferon and STI571 (IRIS) trial.5

  • For P190, results will be expressed as the percent ratio: (BCR-ABL1/ABL1 ratio) x 100.

To help monitor changes in the fusion transcript over time, a graphical trending report can be ordered through Care360 or by speaking with your sales representative.


Interpretive Information

Diagnosis

Along with characteristic cell morphology findings, presence of the P210 BCR-ABL transcript is consistent with CML. Presence of the P190 transcript, or the P210 transcript together with lymphoid blasts, is consistent with Ph+ ALL.

Monitoring

The quantity of transcript detected in the initial test serves as a baseline for serial monitoring. An increasing BCR-ABL1/ABL1 percent ratio over time suggests an increase in tumor burden, while a decreasing ratio suggests a favorable response to therapy. For P210 and P190 transcripts, a BCR-ABL1/ABL1 ratio of 0 represents a complete molecular response to therapy.

P210

BCR-ABL1/ABL1 % (IS) values ≤0.1% correspond to a 3-log or greater reduction from the baseline, indicating a major molecular response (MMR) in CML patients and thus excellent progression-free survival.5

A 5- to 10-fold increase in the BCR-ABL1/ABL1 IS value in CML patients after initial achievement of a MMR indicates secondary loss of response (resistance) to TKI therapy.4,5 Evaluation of ABL1 kinase domain mutations in such cases, or in those who fail to achieve a MMR initially, can identify the cause of resistance and potentially guide treatment changes.4

Similar associations for P210 IS values have not been established in Ph+ ALL patients.

P190

An increasing BCR-ABL1/ABL1 ratio may indicate a poor initial response or a secondary loss of response to TKI therapy (disease recurrence) in Ph+ ALL patients. Evaluation of ABL1 kinase domain mutations in recurrent Ph+ ALL can help guide changes in TKI therapy.6

 

References

  1. Vardiman JW, Melo JV, Baccarani M, et al. Chronic myelogenous leukemia, BCR-ABL1 positive. In: Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:180-182.

  2. Borowitz MJ, Chan JKC. B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:171-175.

  3. Jones D, Rajyalakshmi L, Cortes J, et al. BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome-positive leukemias. Blood. 2008;112:5190-5192.

  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia. Version 2.2012. http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Updated March 12, 2012. Accessed September 14, 2012.

  5. 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.

  6. Jones D, Thomas D, Yin CC, et al. Kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors. Cancer. 2008;113:985-994.


This reverse-transcription PCR-based assay detects the BCR-ABL1 transcript produced by the t(9;22) chromosomal translocation associated with chronic myelogenous leukemia (CML) and a subset of lymphoblastic leukemias.

For the P190 transcript associated with the minor t(9;22) breakpoint in lymphoblastic leukemia, BCR-ABL1 transcript levels are expressed as a percent ratio of BCR-ABL1 to the normalizing ABL1 transcript.

For the P210 transcript associated with CML, quantitation is further adjusted to the international scale (IS) to allow comparison with other IS-compliant BCR-ABL1 assays. Optimal therapy in CML is associated with transcript levels below the major molecular response (MMR) milestone indicated by a BCR-ABL1/ABL1 % (IS) below 0.1.

Reference Range(s)

BCR-ABL1/ABL1 % 0.000
BCR-ABL1/ABL1 % (IS) 0.000


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