Understanding TKI Therapy and Drug Resistance in Chronic Myelogenous Leukemia

by Dr. C.H. Weaver M.D. updated 8/2021

Most often, resistance to tyrosine kinase inhibitors (TKI) used to treat chronic myeloid leukemia (CML) 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®.^1-9

• 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.
• Bosulif® is a third-generation tyrosine kinase inhibitor that targets both Abl and Src kinases, which are associated with resistance to Gleevec®.
• 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.

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.

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.

NGS Better Identifies BCR-ABL1 Mutations in CML Than Sanger Sequencing

Results from a multi-center study show that next-generation sequencing (NGS) more accurately illustrates BCR-ABL1 mutation status than Sanger sequencing in patients with CML who are not responding to TKI therapy.

In 1 of 4 reference laboratories, Sanger sequencing and NGS were used to analyze 236 consecutive patients with CML not responding (n = 124) or yielding warning responses (n = 112) to TKI therapy. Among 51 patients deemed negative for mutations by Sanger sequencing, low-level mutations were detectable via NGS. Additional low-level mutations were detected in 29 of 60 patients who tested positive for mutations via Sanger sequencing.

Overall, this meant that mutations that could not be detected via Sanger sequencing were identified in 80 (34%) of 236 patients through NGS; 42 (18%) of these patients had low-level mutations that affected clinical decision-making in some way.¹⁰

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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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References:

1. Silver RT, Talpaz M, Sawyers CL, et al. Four years of follow-up of 1027 patients with late chronic phase (L-CP), accelerated phase (AP), or blast crisis (BC) chronic myeloid leukemia (CML) treated with imatinib in three large phase II trials. Proceedings of the American Society of Hematology. Blood. 2004;104:11a, abstract number 23.
2. Kantarjian H, Talpaz M, O’Brien S, et al. High-Dose Imatinib Mesylate Therapy in Newly Diagnosed Philadelphia Chromosome-Positive Chronic Phase Chronic Myeloid Leukemia. The New England Journal of Medicine 2004;103:2873-2878.
3. Aoki E, Kantarjian H, O’Brien S, et al. High-dose (HD) imatinib provides better responses in patients with untreated early chronic phase (CP) CML. Blood 2006;608a, abstract 2143.
4. Kantarjian H, Talpaz M, O’Brien S, et al. Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia—comparison with historic experience. Cancer2005;103:2099-2108.
5. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New EnglandJournal of Medicine. 2006;354:2531-2541.
6. Cortes J, Kim DW, Guilhot F, et al. Dasatinib (Sprycel®) in patients (pts) with chronic myelogenous leukemia in accelerated phase (AP-CML) that is imatinib-resistant (im-r) or –intolerant (im-i): Updated results of the CA180-005 ‘START-A’ phase II study. Blood 2006;108:613a, abstract 2160.
7. Giles F, Ottmann O, Bhalla K, et al. Update on AMN107 in Leukemia. Proceedings from the 23rd annual Chemotherapy Symposium. New York, NY. November 2005. Abstract #19
8. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.The New England Journal of Medicine. 2006;354:2542-2551.
9. Jabbour E, Kantarjian H, Giles F, et al. Treatment with nilotinib for patients with chronic myeloid leukemia (CML) who failed prior therapy with imatinib and dasatinib. Blood 2006;108:616a, abstract 2171.
10. Blood. 2020;135[8]:534-541.