Skip to main content

Detection of mutations in CML patients resistant to tyrosine kinase inhibitor: imatinib mesylate therapy

Abstract

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Data availability

All data are available upon request.

References

  1. 1.

    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.

    CAS  Article  Google Scholar 

  2. 2.

    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.

    CAS  Article  Google Scholar 

  3. 3.

    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.

    Article  Google Scholar 

  4. 4.

    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.

    Article  Google Scholar 

  5. 5.

    Hantschel O. Chronic myeloid leukemia. HemaSphere. 2019;3(S2):47.

    Article  Google Scholar 

  6. 6.

    Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Lett. 2007;249(2):121–32.

    CAS  Article  Google Scholar 

  7. 7.

    Yaghmaie M, Yeung CC. Molecular mechanisms of resistance to tyrosine kinase inhibitors. Curr Hematol Malig Rep. 2019;14(5):395–404.

    Article  Google Scholar 

  8. 8.

    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.

    Article  Google Scholar 

  9. 9.

    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.

    CAS  Article  Google Scholar 

  10. 10.

    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.

    Article  Google Scholar 

  11. 11.

    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.

    Article  Google Scholar 

  12. 12.

    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.

    CAS  Article  Google Scholar 

  13. 13.

    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.

    CAS  Article  Google Scholar 

  14. 14.

    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.

    CAS  Article  Google Scholar 

  15. 15.

    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.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Mahon FX, Etienne G. Deep molecular response in chronic myeloid leukemia: the new goal of therapy? Clin Cancer Res. 2014;20(2):310–22.

    CAS  Article  Google Scholar 

  17. 17.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    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.

    Article  Google Scholar 

  19. 19.

    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.

    CAS  Article  Google Scholar 

  20. 20.

    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.

    Article  Google Scholar 

  21. 21.

    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.

    Article  Google Scholar 

  22. 22.

    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.

    Article  Google Scholar 

  23. 23.

    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.

    CAS  Article  Google Scholar 

  24. 24.

    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.

    PubMed  Google Scholar 

  25. 25.

    Braun TP, Eide CA, Druker BJ. Response and resistance to BCR-ABL1-targeted therapies. Cancer Cell. 2020;37(4):530–42.

    CAS  Article  Google Scholar 

  26. 26.

    Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(11):1018–29.

    CAS  Article  Google Scholar 

  27. 27.

    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.

    Article  Google Scholar 

  28. 28.

    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.

    CAS  Article  Google Scholar 

  29. 29.

    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.

    Article  Google Scholar 

  30. 30.

    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.

    Article  Google Scholar 

  31. 31.

    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.

    Google Scholar 

Download references

Acknowledgements

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.

Funding

Not applicable.

Author information

Affiliations

Authors

Contributions

MD* developed the theory and concept of the study. HA designed the study. NK produced the first draft and completed the entire manuscript. NG carried out the NGS laboratory studies and performed the statistical analysis. HK analyzed the patient’s data. AY conducted the literature search. MK and SC provided clinical information of patients. MD evaluated the clinical results and contributed to the lettering of the manuscript. All the authors collected patient data and read and approved the final manuscript (*: corresponder).

Corresponding author

Correspondence to Munis Dundar.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to disclose.

Ethical approval

This study was approved with the decision dated Dec 16th, 2020 and numbered 629 by Erciyes University Clinical Research Ethics Committee.

Informed consent

All participants gave written informed consent in accordance with the Declaration of Helsinki.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 16 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

  • CML
  • Fusion gene BCR/ABL
  • T315I
  • Imatinib resistance
  • NGS