Understanding TKI Therapy and Drug Resistance in Chronic Myelogenous Leukemia

by Dr. C.H. Weaver M.D. updated 4/2019

Most often, resistance is caused by changes (mutations) in the part of the BCR-ABL gene that makes the BCR-ABL protein. Mutations change the shape of the BCR-ABL protein so that certain TKIs can no longer bind to it effectively. This can cause the TKI to stop working. Because each TKI drug works slightly differently, one TKI drug may be able to overcome the resistance from the mutation that another TKI cannot.

Switching to a different TKI may result in a treatment response after CML stops responding or becomes resistant to a prior TKI. For example, many of the second-generation TKIs work against mutations that are resistant to Gleevec®.

  • Iclusig® is an oral, multi-targeted tyrosine-kinase inhibitor that primarily functions as a BCR-ABL inhibitor. It was designed to overcome the T3151 mutation, which is notoriously resistant and difficult to treat.5
  • Bosulif® is a third-generation tyrosine kinase inhibitor that targets both Abl and Src kinases, which are associated with resistance to Gleevec®.6
  • Synribo® (omacetaxine mepesuccinate) works against the T315I mutation and was approved for use in individuals with resistance and/or intolerance to two or more tyrosine kinase inhibitors.7

Follow-up tests and treatment responses

The goal of TKI therapy is to achieve a complete cytogenetic response within 12 months of beginning treatment, to eventually achieve a major molecular response, and to prevent disease progression to an accelerated or blast phase. Most patients on TKI therapy will have a complete hematologic response within 3 months of beginning treatment, and will have a complete cytogenetic response within 6, 12, or 18 months of beginning treatment. Then, BCR-ABL levels usually fall slowly after a complete cytogenetic response is achieved.

Various tests are used to check how well TKI therapy is working or to assess why it isn’t working. The main tests include cytogenetics and QPCR (quantitative polymerase chain reaction). This test is recommended every 3 months as long as the CML is still responding to treatment. Once no copies of the Philadelphia chromosome are detected on bone marrow cytogenetics, QPCR is recommended every 3 months for 3 years.8

BCR-ABL gene mutation analysis is a test that checks for mutations in the BCR-ABL gene which changes the shape of the BCR-ABL protein, affecting how well certain TKI’s work. This test is recommended if the initial treatment response is less than the response goal or milestone for a particular follow-up period.

Can other medicines affect how well TKI’s work?

Certain medications and substances can change the way TKIs work in the body. TKIs are processed and made active in the liver. Other medications and substances may impact how the liver processes TKI’s. For example St. John’s wort and drugs used to treat seizures—may make TKIs less effective. Other can also impact the levels of TKIs in the blood. These medications include

  • Certain antibiotics (drugs that treat infections caused by bacteria)
  • Anti-fungals (drugs that treat infections caused by fungus).
  • Grapefruit juice may also increase TKI levels in the body.
  • Anti-Ulcer Medications that reduce acid in the stomach
    • H2 blockers
    • Proton pump inhibitors.

Patients should always let their treating physician know if they are taking any dietary supplements, over the counter medications, or other prescription drugs.8

Status of Allogeneic Stem Cell Transplant in the TKI Era

Once the standard of care, allogeneic stem cell transplant (SCT) is rarely performed for chronic phase CML because of the success of TKI treatment. Prior to the development of TKI’s and other targeted therapies early allogeneic stem cell transplantation was the treatment of choice for many patients, offering the only potentially curative treatment option. Most transplant centers today only begin considering SCT when patients have failed at least 2 TKI’s. Patients failing TKI’s can still be cured of their CML with allogeneic SCT.9 Go to Allogeneic Stem Cell Transplant to learn about the procedure, donor selection, selecting a transplant center and specific results in CML patients. Patients should discuss the potential role of SCT with their doctor and a transplant physician to best understand its role in their overall management.

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