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ABL Kinase Domain Mutation in CML, Cell-based

Test code(s) 16029

ABL kinase domain mutations may emerge after treatment with tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec®), dasatinib (Sprycel®), and nilotinib (Tasigna®).

The National Comprehensive Cancer Network® (NCCN®)1 recommends ABL mutation testing when there is

  1. Inadequate initial response to TKI therapy
  2. Loss of hematologic or cytogenetic remission
  3. Rise in BCR-ABL1 transcript by 1 log over at least 2 time points, resulting in loss of major molecular remission
  4. Progression to accelerated or blast phase

Mutation testing is not recommended in newly diagnosed chronic phase patients, during routine monitoring, or when there is no evidence of TKI resistance.

Yes. The ABL kinase domain mutation test uses reverse transcription–polymerase chain reaction (RT-PRC) to amplify the BCR1-ABL fusion transcript before sequence analysis of the ABL kinase domain. If the patient’s tumor burden is low, RT-PCR may not generate enough of the BCR-ABL1 transcript for sequence analysis of the ABL kinase domain. Therefore, BCR-ABL1 Gene Rearrangement, Quantitative, PCR (test code 91065) should be performed no more than 2 weeks before ABL kinase domain mutation testing, to ensure adequate BCR1-ABL transcript levels for sequence analysis.

RNA is isolated from blood or bone marrow and reverse transcribed. A first round of PCR selectively amplifies BCR-ABL1 fusion product in CML cells. A second round of PCR then amplifies the ABL kinase domain, which is directly sequenced.  

All of the >90 clinically relevant mutations in the BCR-ABL1 kinase domain are detected in this assay. This includes the pan-resistant T315I mutation.

The resistance pattern varies among the different mutations.2 For example, patients with the T315I mutation can respond to ponatinib3 but not to other FDA-approved tyrosine kinase inhibitors. Patients with V299L, T315A, or F317L/V/I/C mutations may respond to nilotinib therapy, whereas those with Y253H, E255K/V, or F359 V/C/I may respond to dasatinib.

When we report the specific mutation detected, we will provide information about commonly observed kinase inhibitor reactions (response vs resistance) associated with that mutation.

Mutations in the ABL kinase domain play a role in about 50% of CML cases with secondary TKI resistance. Other mechanisms include altered drug transport and metabolism, amplification of the Philadelphia chromosome, and acquisition of additional chromosomal abnormalities. To evaluate the patient for the latter two, consider ordering these tests:

  • FISH, CML/ALL, BCR-ABL, Translocation 9;22 (Test code [12070X])
  • Chromosome Analysis, Hematologic Malignancy (Test code [14600X])

TKIs are combined with chemotherapy to treat lymphoblastic leukemias and lymphomas (ALL/LBL) that have t(9;22)/BCR-ABL rearrangements. ABL kinase domain mutations, particularly T315I, F317L, and Y253H, are frequently present in ALL/LBL patients who lack initial response or who relapse. Identification of the particular resistance-causing mutation(s) can help guide therapy for such patients.4

References

  1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. Version 1.2014. http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed October 11, 2018.
  2. Cortes J, Jabbour E, Kantarjian H, et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood.2007;110:4005-4011.
  3. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome–positive leukemias. New Engl J Med. 2012;367:2075-2088.
  4. Jones D, Kamel-Reid S, Bahler D, et al. Laboratory practice guidelines for detecting and reporting BCR-ABL drug resistance mutations in chronic myelogenous leukemia and acute lymphoblastic leukemia; a report of the Association for Molecular Pathology. J Molec Diag.2009;11:4-11.

 

This FAQ is provided for informational purposes only and is not intended as medical advice. A clinician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

 

Document FAQS.113 Version: 1
Version 1: Effective 05/30/2019 to present
Version 0: Effective 11/21/2013 to 05/30/2019

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