Topic Name

Message

If ARUP Consult does not answer your test selection and interpretation questions, or if you would like to suggest ways to improve content or usability, please send a message to the Consult editorial staff.

Please do not include any patient-specific or personal health information (PHI) in your message.

Email Address

An email address is not required, but providing one allows the ARUP Consult editorial staff to respond directly. ARUP will only use your email address to respond to your feedback. See the ARUP privacy policy for more information regarding email use.

CAPTCHA

What code is in the image?

Enter the characters shown in the image.

This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

BCR-ABL1 Mutation Analysis for Tyrosine Kinase Inhibitor Resistance

2008420

BCR-ABL1 Mutation Analysis for Tyrosine Kinase Inhibitor Resistance by Next Generation Sequencing 2008420

Method

Massively Parallel Sequencing

Order only for patients with an established diagnosis of a BCR-ABL1-positive leukemia
Use to determine if a mutation is present that would interfere with response to TKI therapy in Ph+ ALL or CML
- Detects all common mutations, including T315I
- Higher sensitivity than traditional Sanger sequencing techniques
- Offers coverage of SH2, SH3, and kinase domain

BCR-ABL1 mutations may cause resistance to tyrosine kinase inhibitor (TKI) therapy in patients with either chronic myelogenous leukemia (CML) or Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Testing should be performed for patients with an established diagnosis of a BCR-ABL1-positive leukemia to guide treatment decisions.

Disease Overview

Treatment Issues

Chronic Myelogenous Leukemia

CML is characterized by BCR-ABL1 translocations
Initial treatment protocol is TKI therapy
- Imatinib (Gleevec) inhibits tyrosine kinase activity caused by the BCR-ABL1 gene fusion
- Dasatinib (Sprycel) is a dual specific SRC/ABL inhibitor
- Nilotinib (Tasigna) is an imatinib derivative with 30-fold potency compared to imatinib
Resistance to TKI therapy may result from acquired point mutations within the ABL kinase domain, BCR-ABL1 amplification, low bioavailability, and/or quiescent CML stem cells
- Resistance may be overcome with dose adjustments or a change in therapy
- Newer drugs may be useful when resistance develops, including bosutinib (Bosulif) and ponatinib (Iclusig)
Use of massively parallel sequencing (next generation sequencing) improves the ability to detect low-level clones across larger sections of the gene

Acute Lymphoblastic Leukemia

BCR-ABL1 mutations are present in a subset of ALL patients and are more common in adults than children. Detection of mutations in BCR-ABL1 is important in helping to determine potential response to TKI therapy.

Genetics

Gene Fusion

BCR-ABL1

Mutations

>130 mutations
Four regions tested: adenosine triphosphate binding-loop (P-loop), drug-binding sites, catalytic domain, and activation loop

Test Interpretation

Analytical Sensitivity

Variant class: single nucleotide variant (SNV)
Number of variants tested: 396
Positive percent agreement (PPA): 96.3%
PPA, 95% tolerance at 95% reliability: 94.3-98.0%

Results

Result	Interpretation
Detected	Mutation detected in the SH2, SH3, or kinase domain (ABL1 amino acid residues 46-542)
Not amplified	Multiple attempts to amplify the BCR-ABL1 translocation were unsuccessful by PCR
Not detected	No mutation detected
PCR, polymerase chain reaction

Limitations

A negative result does not exclude mutations below the level of detection or outside the sequenced region
Sensitivity of this assay may be limited, and sequencing may not be possible in patient samples containing low tumor burden (ie, low levels of BCR-ABL1 fusion transcript by international scale % or normalized copy number)
Not intended to be used for detection or quantification of BCR-ABL1 fusion transcripts

Feedback