Caroline Goodner

Introduction. Chronic Myeloid Leukemia is a cancer of the myeloid progenitor cells in the bone marrow that results after a random translocation between chromosomes 9 and 22 forms an oncogenic BCR-ABL gene. This disease began to be successfully treated after the discovery of the drug Imatinib, a tyrosine kinase inhibitor. The tyrosine kinase inhibitor drugs have dramatically increased the survival rate of CML, but recently, there has been an increase in developed resistance. Studies have shown that there are five known mechanisms of resistance, and the most common is a mutation in the kinase domain of the BCR-ABL protein, found in 40-50% of CML patients¹. Methods. Most current studies focus on secondary tyrosine kinase inhibitor resistance, the loss of a therapeutic response after treatment with one drug. One study observed the development of BCR-ABL protein mutations in CML patients treated with first and second generation tyrosine kinase inhibitors to determine the rate of mutation associated with each². Another study tracked 269 cases of CML patients who had developed resistance to Imatinib. These patients were given either an increase in their Imatinib dose or were treated with a second generation tyrosine kinase inhibitor, such as Dasatinib or Nilotinib³. Results. The T315I mutation was shown to occur after treatment with Imatinib, Dasatinib, and Nilotinib, but the mutation was associated with a higher rate of development after treatment with Nilotinib because of a pre-existing P loop mutation in the drug². In patients who develop resistance, increasing the dose of Imatinib achieves a molecular response in 25.7% of patients, treatment with Nilotinib achieves a molecular response in 46.6%, and treatment with Dasatinib achieves a molecular response in 53.8%³. Conclusions. Tyrosine kinase inhibitors dramatically increased the survival rate of CML, which led to the increase in incidence of resistance to these drugs. Studies have furthered the understanding of resistance development and further treatment options. This began the development of alternative treatment methods and testing that showed that most patients who develop secondary resistance to one drug can still be successfully treated with a second tyrosine kinase inhibitor or a higher dosage ^2-4. This finding combined with promising alternative treatment methods suggests a possible future “cure” for CML.

1. Bauer, R., Sanger, J., Peschel, C., Duyster, J., & von Bubnoff, N. (2013). Sequential inhibitor therapy in CML: in vitro simulation elucidates the pattern of resistance mutations after second- and third-line treatment. Clinical Cancer Research, 19(11)2.
2. Ibarra-Hernández, A., Sosa-Quintero, L., Garcés-Ruiz, O., Aguilar-López, L., Rubio-Jurado, B., & Vega-Ruiz A. (2014). Response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia. Servicio de Hematología, 266(9)
3. Chaitanya, P. K., Kumar, K. A., Stalin, B., Sadashivudu, G., & Srinivas, M. L. (2017). The role of mutation testing in patients with chronic myeloid leukemia in chronic phase after Imatinib failure and their outcomes after treatment modification: Single-institutional experience over 13 years. Indian Journal of Medical and Paediatric Oncology, 38(3), 328-333
4. Marce, S., Zamora, L., Cabezon, M., Xicoy, B., Fernandex, C., Grau, J., Navarro, JT., Fernandez de Sevilla, A., Ribera, JM., Feliu, E., Milla, F. (2013). Frequency of ABL gene mutations in chronic myeloid leukemia patients resistant to imatinib and results of treatment switch to second-generation tyrosine kinase inhibitors. 95(9)