BCR-ABL1 Testing in CML: Understanding Genetic Changes and Treatment Response

Chronic myeloid leukemia is unusual among cancers in that its molecular cause was identified decades ago and that the treatment developed to target that cause has transformed the prognosis of the disease in a way that remains remarkable. The BCR-ABL1 fusion gene, which drives the uncontrolled growth of myeloid cells in CML, is also the target of the tyrosine kinase inhibitors that have made CML a manageable condition for most people diagnosed with it. Understanding the BCR-ABL1 test and what it measures at different stages of the treatment journey helps patients engage meaningfully with clinical decisions rather than receiving them passively.

What the BCR-ABL1 Fusion Gene Is

The genetic hallmark of CML is a reciprocal chromosomal translocation [t(9;22)(q34;q11)] between chromosomes 9 and 22. A segment of chromosome 9 (carrying the ABL1 gene) breaks off and fuses with the BCR gene on chromosome 22.

• Philadelphia Chromosome: The shortened chromosome 22 resulting from this fusion.
• Oncoprotein Function: The BCR-ABL1 fusion gene encodes a chimeric protein with constitutively active tyrosine kinase activity, driving continuous blood cell proliferation.
• Clinical Presence: Beyond CML, this fusion gene is also detected in a subset of Ph+ Acute Lymphoblastic Leukemia (ALL) cases, where it carries distinct prognostic and therapeutic implications.

How the BCR-ABL1 Test Works

The BCR-ABL1 assay utilizes Real-Time Quantitative Reverse Transcription PCR (RT-qPCR) to measure BCR-ABL1 messenger RNA (mRNA) transcripts relative to an internal control gene in a blood or bone marrow sample. Results are reported on the International Scale (% IS), establishing global standardization:

The quantitative BCR-ABL1 test offered by MedGenome is calibrated to the International Scale (IS), ensuring that transcript values directly mirror international NCCN and ELN clinical guidelines.

How the BCR-ABL1 Test Guides Treatment Decisions

The BCR-ABL1 test is performed before treatment begins to establish a baseline, and then at defined intervals through treatment to track response. The response milestones at three, six, and twelve months are the clinical decision points at which the treating team assesses whether the current treatment is working as expected or whether a change is needed.

Treatment guidelines specify what level of response is expected at each milestone. A patient whose BCR-ABL1 level has not fallen to the expected level by three months is at higher risk of treatment failure than one whose response is on track, and this finding prompts assessment of whether the current tyrosine kinase inhibitor is appropriate or whether switching to an alternative drug would produce better results.

The BCR-ABL1 test from Medgenome uses quantitative PCR calibrated to the International Scale, providing results in the standardized format that clinical decision-making in CML requires.

When Mutation Testing Adds to the Picture

When a patient’s BCR-ABL1 level stops falling or begins rising during treatment, mutation analysis of the BCR-ABL1 kinase domain provides additional information about why. Specific mutations in the kinase domain, the most clinically significant of which is the T315I mutation, confer resistance to certain tyrosine kinase inhibitors while remaining susceptible to others. Identifying the specific mutation allows the treating oncologist to select the most appropriate second-line treatment rather than making a blind switch.

The BCR-ABL1 genetic test with kinase domain mutation analysis is the investigation that provides this additional layer of information when standard quantitative monitoring suggests inadequate response or emerging resistance.