What are the indications for BCR/ABL mutation screening in patients with chronic myelogenous leukemia (CML)?

Updated: May 23, 2021
  • Author: Emmanuel C Besa, MD; Chief Editor: Sara J Grethlein, MD, FACP  more...
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Answer

Patients should be screened for mutations of the BCR/ABL kinase domain whenever there is an indication of loss of response to imatinib at any level. Primary hematologic resistance to imatinib occurs in approximately 5% of patients who fail to achieve complete histologic remission, and 15% show primary cytogenetic resistance in the chronic phase. Secondary or acquired resistance (loss of previous response) is 16% at 42 months and increases to 26% in those previously treated with interferon, and is 73-95% in the accelerated or blast phase.

Quantitative PCR is uniquely sensitive because it is amplifying a chimeric mRNA not found in normal cells. The detection of a single point mutation in the tyrosine kinase domain of BCR-ABL against a background of wild type BCR-ABL is obviously a much more difficult task.

The most common method, direct nucleotide sequencing, can detect an Abl tyrosine kinase domain mutation if it composes 10% to 20% of the total BCR-ABL sampled population. The prevalence of Abl mutations increases with the “disease time”—that is, these mutations are rare in newly diagnosed chronic-phase CML and increase with late chronic-phase and advanced-phase disease (ie, with increasing Sokal score).Thus, Abl mutations occur as part of the natural history of CML, rather than a merely a manifestation of selective pressure from TKI therapy.

Several studies have demonstrated that these mutations are associated with both an increase in loss of cytogenetic response and progression to advanced-phase disease. However, in some cases, particularly in those patients with a low disease burden, mutations can be detected yet remain at a low level and do not cause problems. One should use caution and reason concerning the “2-fold” rule because an increase from a PCR-negative status to a level of 0.0001% would be an infinite increase in BCR-ABL but should not cause much worry.

Thus, screening for mutations would be reasonable in any of the following:

  • Patients with advanced-phase CML
  • Patients with chronic-phase CML who are not achieving cytogenetic milestones
  • Patients with a rising  BCR-ABL level, especially one nearing or passing the MMR

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