Chronic myelogenous leukemia

BCR-ABL1 compound mutants: prevalence, spectrum and correlation with tyrosine kinase inhibitor resistance in a consecutive series of Philadelphia chromosome-positive leukemia patients analyzed by NGS

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Fig. 1: Frequency and type of CMs in Ph+ leukemia patients.

References

  1. 1.

    Shah NP, Skaggs BJ, Branford S, Hughes TP, Nicoll JM, Paquette RL, et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clin Invest. 2007;117:2562–9.

    CAS  Article  Google Scholar 

  2. 2.

    Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT, et al. BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood 2013;121:489–98.

    CAS  Article  Google Scholar 

  3. 3.

    Gibbons DL, Pricl S, Posocco P, Laurini E, Fermeglia M, Sun H, et al. Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy. Proc Natl Acad Sci USA. 2014;111:3550–5.

    CAS  Article  Google Scholar 

  4. 4.

    Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014;26:428–42.

    CAS  Article  Google Scholar 

  5. 5.

    Byrgazov K, Lucini CB, Valent P, Hantschel O, Lion T. BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib. Haematologica. 2018;103:e10–2.

    CAS  Article  Google Scholar 

  6. 6.

    Deininger MW, Hodgson JG, Shah NP, Cortes JE, Kim DW, Nicolini FE, et al. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients. Blood. 2016;127:703–12.

    CAS  Article  Google Scholar 

  7. 7.

    Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118:1208–15.

    CAS  Article  Google Scholar 

  8. 8.

    Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122:872–84.

    CAS  Article  Google Scholar 

  9. 9.

    Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C, et al. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:v69–82.

    CAS  Article  Google Scholar 

  10. 10.

    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;135:534–41.

    Article  Google Scholar 

  11. 11.

    Parker WT, Phillis SR, Yeung DT, Hughes TP, Scott HS, Branford S. Many BCR-ABL1 compound mutations reported in chronic myeloid leukemia patients may actually be artifacts due to PCR-mediated recombination. Blood. 2014;124:153–5.

    CAS  Article  Google Scholar 

  12. 12.

    Schmitt MW, Pritchard JR, Leighow SM, Aminov BI, Beppu L, Kim DS, et al. Single-molecule sequencing reveals patterns of preexisting drug resistance that suggest treatment strategies in philadelphia-positive leukemias. Clin Cancer Res. 2018;24:5321–34.

    CAS  Article  Google Scholar 

  13. 13.

    Soverini S, Rosti G, Iacobucci I, Baccarani M, Martinelli G. Choosing the best second-line tyrosine kinase inhibitor in imatinib-resistant chronic myeloid leukemia patients harboring Bcr-Abl kinase domain mutations: how reliable is the IC(5)(0)? Oncologist. 2011;16:868–76.

    CAS  Article  Google Scholar 

  14. 14.

    Byrgazov K, Lucini CB, Berkowitsch B, Koenig M, Haas OA, Hoermann G, et al. Transposon-mediated generation of BCR-ABL1-expressing transgenic cell lines for unbiased sensitivity testing of tyrosine kinase inhibitors. Oncotarget. 2016;7:78083–94.

    Article  Google Scholar 

  15. 15.

    Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84.

    CAS  Article  Google Scholar 

  16. 16.

    Eide CA, Zabriskie MS, Savage Stevens SL, Antelope O, Vellore NA, Than H, et al. Combining the allosteric inhibitor asciminib with ponatinib suppresses emergence of and restores efficacy against highly resistant BCR-ABL1 mutants. Cancer Cell. 2019;36:431–43 e5.

    CAS  Article  Google Scholar 

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Correspondence to Simona Soverini.

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SS has received speaker fees from Incyte Biosciences. SSi has received honoraria for advisory boards from Incyte Biosciences. AI has received honoraria from Novartis, Pfizer and Incyte Biosciences. MB has received honoraria from Novartis, Incyte Biosciences, Pfizer. PP has received honoraria from Novartis, Incyte Biosciences, Bristol-Myers Squibb, Pfizer. SG has received speaker fees from Pfizer, Novartis, Incyte Biosciences. FA has received honoraria for advisory boards from Incyte Biosciences. FC has received honoraria from Novartis, Bristol‐Myers Squibb, Pfizer, Incyte Biosciences. GG has received honoraria from Novartis and Bristol‐Myers Squibb. GR has received honoraria from Novartis, Bristol-Myers Squibb, Pfizer, Incyte Biosciences. GM has been a consultant and has received speaker fees from Incyte Biosciences, Pfizer. The remaining authors declare that they have no competing interests.

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Soverini, S., Martelli, M., Bavaro, L. et al. BCR-ABL1 compound mutants: prevalence, spectrum and correlation with tyrosine kinase inhibitor resistance in a consecutive series of Philadelphia chromosome-positive leukemia patients analyzed by NGS. Leukemia (2020). https://doi.org/10.1038/s41375-020-01098-w

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