Definition and treatment of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia

Abstract

Resistance to tyrosine kinase inhibitors (TKIs) has many facets. The causes of resistance include low patient compliance, low plasma or intracellular drug concentration, BCR-ABL1 mutations, and clonal chromosome abnormalities in Ph+ cells, but in at least 50% of patients the causes are currently unknown. Primary resistance occurs when a predefined response level is not achieved within a prespecified period of time. Not achieving a complete hematologic response (CHR) within 3 months, not achieving a partial cytogenetic response and/or a BCR-ABL1 transcripts level ≤10% (international standard) within 6 months, and not achieving a complete cytogenetic response (CCyR) and/or a BCR-ABL1 transcripts level <1% within 12 months, define primary resistance. Secondary resistance is defined by a loss of CHR, or CCyR, or major molecular response. Resistance to imatinib calls without exceptions for a second-generation TKI. In case of resistance to two TKIs, an allogeneic stem cell transplantation should be considered.

Keywords::

• BCR-ABL1
• chronic myeloid leukemia
• imatinib
• Philadelphia (chromosome)
• tyrosine kinase inhibitors

Financial & competing interests disclosure

M Baccarani has been a consultant for ARIAD, Novartis and BMS, received honoraria from ARIAD, Novartis, BMS, Pfizer and Teva, and been a speaker for ARIAD, Novartis, BMS, Pfizer and Teva. F Castagnetti, G Guglitotta and F Palandri have received honoraria from Novartis and BMS. F Castagnetti and G Guglitotta have acted as consultants for Novartis and BMS. G Rosti has been a consultant for ARIAD, Novartis and BMS, and a speaker for ARIAD, Novartis, BMS, Pfizer and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Monitor very carefully all patients until a complete cytogenetic response and a major molecular response (BCR–ABL1 ≤0.1% on the international scale) will be achieved and confirmed. Monitoring can be performed only with RT-qPCR, using peripheral blood, buffy coat white cells, provided that the laboratory uses a standardized methodology and can express the results as BCR–ABL1% on the international scale.

• In case of primary resistance that corresponds to failure to achieve a prespecified response level within a prespecified time, if the values of cytogenetic and molecular tests are clear and incontestable, change the treatment, but if the values of the same tests are borderline, repeat the tests even monthly and consider the dynamic of the response. Molecular monitoring is expensive, but is useful. Inappropriate treatment is much more expensive and is dangerous.

• To choice second-line treatment, consider all TKIs that are available in your country and make the choice based on BCR–ABL1 mutations, when they are detectable on the side effects of imatinib and on patient comorbidities.

• In patients with high-risk leukemia, low-risk allogeneic stem cell transplantation and resistance to two tyrosine kinase inhibitors consider very strongly stem cell transplantation.