Imatinib mesylate, a tyrosine kinase inhibitor, is the first choice in chronic myeloid leukemia treatment. However, resistance to imatinib may develop with time and in some cases, patients may not respond at all to imatinib. Progressive resistance to imatinib therapy is often due to mutations in the BCR/ABL region. Within the scope of our study 124 patients were evaluated via pyrosequencing between 2015 and 2020. In this regard, 32 patients who have a partial response and have no response to imatinib therapy were included in the study. In addition, next-generation sequencing (NGS) analysis was performed on 15 patients who were resistant to imatinib treatment according to the molecular follow-up reports. With pyrosequencing, 5 cases out of a total of 124 were found to be positive. This means that approximately 4.03% of the proportion is positive. But when we examined only 32 patients who have a partial response and have no response to imatinib therapy this rate is rising 15.6%. NGS analysis was performed with 15 patients who have no mutation with pyrosequencing of 32 patients and VUS (Variant of Uncertain Significance) mutation was detected in one. In this study, our aim was to determine the mutations of the BCR/ABL and to evaluate the mutations by NGS and pyrosequencing. Our study is important in terms of comparing the pyrosequencing with NGS mutation rates, drawing attention to the clinical importance of log reduction.
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Faderl S, Talpaz M, Estrov Z, O’brıen S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341(3):164–72.
Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122(4):515–22.
Linev AJ, Ivanov HJ, Zhelyazkov IG, Ivanova H, Goranova-Marinova VS, Stoyanova VK. Mutations associated with imatinib mesylate resistance—review. Folia Med (Plovdiv). 2018;60(4):617–23.
Izzo B, Gottardi EM, Errichiello S, Daraio F, Baratè C, Galimberti S. Monitoring chronic myeloid leukemia: how molecular tools may drive therapeutic approaches. Front Oncol. 2019;9:1–12.
Hantschel O. Chronic myeloid leukemia. HemaSphere. 2019;3(S2):47.
Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Lett. 2007;249(2):121–32.
Yaghmaie M, Yeung CC. Molecular mechanisms of resistance to tyrosine kinase inhibitors. Curr Hematol Malig Rep. 2019;14(5):395–404.
Bavaro L, Martelli M, Cavo M, Soverini S. Mechanisms of disease progression and resistance to tyrosine kinase inhibitor therapy in chronic myeloid leukemia: an update. Int J Mol Sci. 2019;20(24):1–23.
Etienne G, Dulucq S, Huguet F, Schmitt A, Lascaux A, Hayette S, et al. Incidence and outcome of BCR-ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors. Cancer Med. 2019;8(11):5173–82.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–23.
Kang ZJ, Liu YF, Xu LZ, Long ZJ, Huang D, Yang Y, et al. The philadelphia chromosome in leukemogenesis. Chin J Cancer. 2016;35(1):1–15.
Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102(1):276–83.
Wei Y, Hardling M, Olsson B, Hezaveh R, Ricksten A, Stockelberg D, et al. Not all imatinib resistance in CML are BCR-ABL kinase domain mutations. Ann Hematol. 2006;85(12):841–7.
Chien SH, Liu HM, Chen PM, Ko PS, Lin JS, Chen YJ, et al. The landscape of BCR-ABL mutations in patients with Philadelphia chromosome-positive leukaemias in the era of second-generation tyrosine kinase inhibitors. Hematol Oncol. 2020;38(3):390–8.
Baccarani M, Rosti G, Soverini S. Chronic myeloid leukemia: the concepts of resistance and persistence and the relationship with the BCR-ABL1 transcript type. Leukemia. 2019;33(10):2358–64. https://doi.org/10.1038/s41375-019-0562-1.
Mahon FX, Etienne G. Deep molecular response in chronic myeloid leukemia: the new goal of therapy? Clin Cancer Res. 2014;20(2):310–22.
Alikian M, Gale RP, Apperley JF, Foroni L, Alikian M. Molecular techniques for the personalised management of patients with chronic myeloid leukaemia. Biomol Detect Quantif. 2017;11:4–20. https://doi.org/10.1016/j.bdq.2017.01.001.
El Fakih R, Chaudhri N, Alfraih F, Rausch CR, Naqvi K, Jabbour E. Complexity of chronic-phase CML management after failing a second-generation TKI. Leuk Lymphoma. 2019;61(4):776–87.
Machova Polakova K, Kulvait V, Benesova A, Linhartova J, Klamova H, Jaruskova M, et al. Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase. J Cancer Res Clin Oncol. 2015;141(5):887–99.
de Lavallade H, Jackson S, Kizilors A, Etienne G, Huguet F, Guerci-Bresler A, et al. Prospective evaluation of ABL kinase domain mutational analysis by next-generation-sequencing in newly diagnosed CP CML patients undergoing first-line treatment with nilotinib alone or nilotinib + pegylated interferon-α2a in a prospective phase III trial. Blood. 2019;134(Supplement_1):664–664.
Soverini S, Abruzzese E, Bocchia M, Bonifacio M, Galimberti S, Gozzini A, et al. Next-generation sequencing for BCR-ABL1 kinase domain mutation testing in patients with chronic myeloid leukemia: a position paper. J Hematol Oncol. 2019;12(1):1–11.
Soverini S, Bavaro L, de Benedittis C, Martelli M, Iurlo A, Orofino N, et al. Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study. Blood. 2020;135(8):534–41.
Soverini S, Martelli M, Bavaro L, De Benedittis C, Papayannidis C, Sartor C, et al. Next-generation sequencing improves BCR-ABL1 mutation detection in Philadelphia chromosome-positive acute lymphoblastic leukaemia. Br J Haematol. 2021;193(2):271–9.
Koçkan B, Toptaş T, Atagündüz I, Tuğlular AT, Özer A, Akkiprik M. Molecular screening and the clinical impacts of BCR-ABL KD mutations in patients with imatinib-resistant chronic myeloid leukemia. Oncol Lett. 2018;15(2):2419–24.
Braun TP, Eide CA, Druker BJ. Response and resistance to BCR-ABL1-targeted therapies. Cancer Cell. 2020;37(4):530–42.
Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(11):1018–29.
Azad NA, Shah ZA, Pandith AA, Rasool R, Rasool JA, Baba SM, et al. Analysis of ABL kinase domain mutations as a probable cause of imatinib resistance in chronic myeloid leukemia patients of Kashmir. Meta Gene. 2018;17:93–8. https://doi.org/10.1016/j.mgene.2018.05.003.
Fojo T. Multiple paths to a drug resistance phenotype: Mutations, translocations, deletions and amplification of coding genes or promoter regions, epigenetic changes and microRNAs. Drug Resist Updates. 2007;10(1–2):59–67.
Perrotti D, Silvestri G, Stramucci L, Yu J, Trotta R. Cellular and molecular networks in chronic myeloid leukemia: the leukemic stem, progenitor and stromal cell interplay. Curr Drug Targets. 2016;18(4):377–88.
Bixby D, Talpaz M. Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance. Hematol Am Soc Hematol Educ Program. 2009;2009:461–76.
Gorre M, Sashidhar R, Annamaneni S, Digumarti R, et al. Demographic and clinical characteristics of chronic myeloid leukemia patients: a study on confined populations of southern India. Indian J Med Paediatr Oncol. 2019;40(1):70–6.
The results reported in this article were partially presented at the 7th International Congress of Pharmaceutical Chemistry: API Design, Synthesis, Production, and Standardization, on March 14–17, 2019.
Conflict of interest
The authors have no conflicts of interest to disclose.
This study was approved with the decision dated Dec 16th, 2020 and numbered 629 by Erciyes University Clinical Research Ethics Committee.
All participants gave written informed consent in accordance with the Declaration of Helsinki.
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Karasu, N., Akalin, H., Gokce, N. et al. Detection of mutations in CML patients resistant to tyrosine kinase inhibitor: imatinib mesylate therapy. Med Oncol 38, 120 (2021). https://doi.org/10.1007/s12032-021-01571-1
- Fusion gene BCR/ABL
- Imatinib resistance