ABL Kinase Domain Mutation Analysis

Point mutations within the ABL1 kinase domain of the BCR-ABL1 fusion gene frequently cause secondary resistance to tyrosine kinase inhibitor (TKI) therapy. Those patients with a longer duration of CML prior to initiation of imatinib therapy are reported to have a higher incidence of detectable mutations compared to patients with an earlier onset of imatinib therapy. In addition, failure to achieve a major cytogenetic response within the first six months of therapy often reflects the presence of a mutation or a high probability that a mutation will subsequently be detected. Biochemical and cellular assays have demonstrated that the different BCR-ABL1 kinase domain mutations result in varying levels of resistance. Presence of kinase domain mutations are associated with poor prognosis and higher risk of disease progression. The different mutations may require differing strategies to overcome resistance, such as dose escalation, combination therapy or transplantation. Candidates for the BCR-ABL1 kinase domain mutation analysis include:

• Response milestones not reached

· Any sign of loss of hematologic response

· Any sign of loss of Complete cytogenetic response (CCyR) or its molecular response correlate-defined as an increase in BCR::ABL1 transcript to >1% International scale [IS]

· 1-log increase in BCR::ABL1 transcript levels and loss of Major Molecular Response (MMR)

• Disease progression to Accelerated Phase (AP-CML) or Blast Phase (BP-CML)

This assay sequences the entire ABL1 kinase domain and will detect all mutations in ABL1 kinase recommended by guidelines including G250E, Y253H, E255K/V, V299L, T315I/A, F317L/V/I/C, A337T, F359V/I/C and P465S.

Please direct any questions regarding this test to oncology customer service at 800-345-4363.

In vitro studies indicate that this analysis has a mutation detection sensitivity of ∼20%. Mutations occurring outside of the analyzed region of the ABL kinase domain will also not be detected by this assay.

This test was developed and its performance characteristics determined by Labcorp. It has not been cleared or approved by the Food and Drug Administration.

Polymerase chain reaction (PCR); direct sequencing; capillary electrophoresis