Skip to main content

Advertisement

SpringerLink
Log in

Dose optimization of tyrosine kinase inhibitor therapy in chronic myeloid leukemia

  • Progress in Hematology
  • Chronic myeloid leukemia: the cutting-edge evidence and things we should know
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

The therapeutic outcomes of chronic myeloid leukemia (CML) have improved dramatically since tyrosine kinase inhibitors (TKIs) became available in clinical practice. Life expectancy of patients with CML is now close to that of the general population. Patients with CML who achieve sustained deep molecular response may discontinue TKI therapy. However, most patients still require TKI therapy for long periods without sustained deep molecular response. Given the awareness of increased incidence of arterial occlusive events in patients on TKI therapy, the optimal TKI selection should be based on age, comorbidities, risk classification, and goals of treatment. Dose optimization of TKI therapy reduces the incidence of adverse events while maintaining efficacy in CML.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290–3.

    Article  CAS  Google Scholar 

  2. Morita K, Sasaki K. Current status and novel strategy of CML. Int J Hematol. 2021;113:624–31.

    Article  CAS  Google Scholar 

  3. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917–27.

    Article  CAS  Google Scholar 

  4. Jain P, Kantarjian H, Alattar ML, Jabbour E, Sasaki K, Gonzalez GN, et al. Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials. Lancet Haematol. 2015;2:e118–28.

    Article  Google Scholar 

  5. Sasaki K, Strom SS, O’Brien S, Jabbour E, Ravandi F, Konopleva M, et al. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015;2:e186–93.

    Article  Google Scholar 

  6. Jain P, Kantarjian H, Sasaki K, Jabbour E, Dasarathula J, Nogueras Gonzalez G, et al. Analysis of 2013 European LeukaemiaNet (ELN) responses in chronic phase CML across four frontline TKI modalities and impact on clinical outcomes. Br J Haematol. 2016;173:114–26.

    Article  CAS  Google Scholar 

  7. Sasaki K, Kantarjian HM, Jain P, Jabbour EJ, Ravandi F, Konopleva M, et al. Conditional survival in patients with chronic myeloid leukemia in chronic phase in the era of tyrosine kinase inhibitors. Cancer. 2016;122:238–48.

    Article  CAS  Google Scholar 

  8. Haddad FG, Sasaki K, Issa GC, Garcia-Manero G, Ravandi F, Kadia T, et al. Treatment-free remission in patients with chronic myeloid leukemia following the discontinuation of tyrosine kinase inhibitors. Am J Hematol. 2022. https://doi.org/10.1182/blood-2021-154380.

    Article  Google Scholar 

  9. Sasaki K, Kantarjian HM, O’Brien S, Ravandi F, Konopleva M, Borthakur G, et al. Incidence of second malignancies in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors. Int J Hematol. 2019;109:545–52.

    Article  CAS  Google Scholar 

  10. Sasaki K, Lahoti A, Jabbour E, Jain P, Pierce S, Borthakur G, et al. Clinical safety and efficacy of nilotinib or dasatinib in patients with newly diagnosed chronic-phase chronic myelogenous leukemia and pre-existing liver and/or renal dysfunction. Clin Lymphoma, Myeloma Leuk. 2016;16:152–62.

    Article  Google Scholar 

  11. Jain P, Kantarjian H, Boddu PC, Nogueras-González GM, Verstovsek S, Garcia-Manero G, et al. Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs. Blood Adv. 2019;3:851–61.

    Article  CAS  Google Scholar 

  12. Takaku T. Management of vascular adverse events during tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Rinsho Ketsueki. 2020;61:1018–27.

    Google Scholar 

  13. Sakaida E. What is the best treatment for chronic-phase CML? Rinsho Ketsueki. 2021;62:1012–23.

    Google Scholar 

  14. Iurlo A, Cattaneo D, Bucelli C, Breccia M. Dose optimization of tyrosine kinase inhibitors in chronic myeloid leukemia: a new therapeutic challenge. J Clin Med. 2021;10:1–12.

    Article  Google Scholar 

  15. Réa D, Mauro MJ, Boquimpani C, Minami Y, Lomaia E, Voloshin S, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021;138:2031–41.

    Article  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. Kantarjian HM, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre P, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021;35:440–53.

    Article  CAS  Google Scholar 

  18. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, et al. Final 5-year study results of DASISION: the Dasatinib versus imatinib study in treatment-Naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333–40.

    Article  CAS  Google Scholar 

  19. Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36:231–7.

    Article  CAS  Google Scholar 

  20. Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30:3486–92.

    Article  CAS  Google Scholar 

  21. Cortes JE, Kim D-W, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783–96.

    Article  CAS  Google Scholar 

  22. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, et al. Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393–404.

    Article  CAS  Google Scholar 

  23. Wilson PWF, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–47.

    Article  CAS  Google Scholar 

  24. Perk J, De Backer G, Gohlke H, Graham I, Reiner Ž, Verschuren M, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J. 2012;33:1635–701.

    Article  CAS  Google Scholar 

  25. Rea D, Mirault T, Raffoux E, Boissel N, Andreoli AL, Rousselot P, et al. Usefulness of the 2012 European CVD risk assessment model to identify patients at high risk of cardiovascular events during nilotinib therapy in chronic myeloid leukemia. Leukemia. 2015;29:1206–9.

    Article  CAS  Google Scholar 

  26. Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol. 2015;33:4210–8.

    Article  CAS  Google Scholar 

  27. Dorer DJ, Knickerbocker RK, Baccarani M, Cortes JE, Hochhaus A, Talpaz M, et al. Impact of dose intensity of ponatinib on selected adverse events: multivariate analyses from a pooled population of clinical trial patients. Leuk Res. 2016;48:84–91.

    Article  CAS  Google Scholar 

  28. Cortes J, Apperley J, Lomaia E, Moiraghi B, Undurraga Sutton M, Pavlovsky C, et al. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial. Blood. 2021;138:2042–50.

    Article  CAS  Google Scholar 

  29. Kantarjian HM, Deininger MW, Abruzzese E, Apperley J, Cortes JE, Chuah C, et al. Efficacy and safety of ponatinib (PON) in patients with chronic-phase chronic myeloid leukemia (CP-CML) who failed one or more second-generation (2G) tyrosine kinase inhibitors (TKIs): analyses based on PACE and optic [Abstract]. Blood. 2020;136(43–4):Abstract 647.

    Google Scholar 

  30. Deininger MW, Apperley JF, Arthur CK, Chuah C, Hochhaus A, De Lavallade H, et al. Post hoc analysis of responses to ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) by baseline BCR-ABL1 level and baseline mutation status in the optic trial [abstract]. Blood. 2021;138:307.

    Article  Google Scholar 

  31. Cortes JE, Hochhaus A, Kantarjian HM, Guilhot F, Kota VK, Hughes TP, et al. Impact of dose reductions on 5-year efficacy in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) from DASISION [abstract]. J Clin Oncol. 2017;35(15_suppl):7051.

    Article  Google Scholar 

  32. Naqvi K, Jabbour E, Skinner J, Anderson K, Dellasala S, Yilmaz M, et al. Long-term follow-up of lower dose dasatinib (50 mg daily) as frontline therapy in newly diagnosed chronic-phase chronic myeloid leukemia. Cancer. 2020;126:67–75.

    Article  CAS  Google Scholar 

  33. Murai K, Ureshino H, Kumagai T, Tanaka H, Nishiwaki K, Wakita S, et al. Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2021;8:e902–11.

    Article  Google Scholar 

  34. Hughes TP, Munhoz E, Aurelio Salvino M, Ong TC, Elhaddad A, Shortt J, et al. Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd. Br J Haematol. 2017;179:219–28.

    Article  CAS  Google Scholar 

  35. Hochhaus A, Rosti G, Cross NCP, Steegmann JL, Le Coutre P, Ossenkoppele G, et al. Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study. Leukemia. 2016;30:57–64.

    Article  CAS  Google Scholar 

  36. Castagnetti F, Gugliotta G, Bocchia M, Trawinska MM, Capodanno I, Bonifacio M, et al. Dose optimization in elderly CML patients treated with bosutinib after intolerance or failure of first-line tyrosine kinase inhibitors. Blood. 2019;134:496–496.

    Article  Google Scholar 

  37. Crugnola M, Castagnetti F, Breccia M, Ferrero D, Trawinska MM, Abruzzese E, et al. Outcome of very elderly chronic myeloid leukaemia patients treated with imatinib frontline. Ann Hematol. 2019;98:2329–38.

    Article  CAS  Google Scholar 

  38. Latagliata R, Breccia M, Carmosino I, Cannella L, De Cuia R, Diverio D, et al. “Real-life” results of front-line treatment with Imatinib in older patients (≥65 years) with newly diagnosed chronic myelogenous leukemia. Leuk Res. 2010;34:1472–5.

    Article  CAS  Google Scholar 

  39. Aitken MJL, Benton CB, Issa GC, Sasaki K, Yilmaz M, Short NJ. Two cases of possible familial chronic myeloid leukemia in a family with extensive history of cancer. Acta Haematol. 2021;144:585–90.

    Article  Google Scholar 

  40. Jain P, Kantarjian H, Patel KP, Gonzalez GN, Luthra R, Shamanna RK, et al. Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors. Blood. 2016;127:1269–75.

    Article  CAS  Google Scholar 

  41. Morita K, Kantarjian HM, Sasaki K, Issa GC, Jain N, Konopleva M, et al. Outcome of patients with chronic myeloid leukemia in lymphoid blastic phase and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with hyper-CVAD and dasatinib. Cancer. 2021;127:2641–7.

    Article  CAS  Google Scholar 

  42. Morita K, Jabbour E, Ravandi F, Borthakur G, Khoury JD, Hu S, et al. Clinical outcomes of patients with chronic myeloid leukemia with concurrent core binding factor rearrangement and Philadelphia chromosome. Clin Lymphoma Myeloma Leuk. 2021;21:338–44.

    Article  Google Scholar 

  43. Saxena K, Jabbour E, Issa G, Sasaki K, Ravandi F, Maiti A, et al. Impact of frontline treatment approach on outcomes of myeloid blast phase CML. J Hematol Oncol. 2021;14:1–10.

    Article  Google Scholar 

  44. Maiti A, Franquiz MJ, Ravandi F, Cortes JE, Jabbour EJ, Sasaki K, et al. Venetoclax and BCR-ABL tyrosine kinase inhibitor combinations: outcome in patients with Philadelphia chromosome-positive advanced myeloid leukemias. Acta Haematol. 2020;143:567–73.

    Article  CAS  Google Scholar 

  45. Jain P, Kantarjian HM, Ghorab A, Sasaki K, Jabbour EJ, Nogueras Gonzalez G, et al. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: cohort study of 477 patients. Cancer. 2017;123:4391–402.

    Article  CAS  Google Scholar 

  46. Sasaki K, Kantarjian H, O’Brien S, Ravandi F, Konopleva M, Borthakur G, et al. Prediction for sustained deep molecular response of BCR-ABL1 levels in patients with chronic myeloid leukemia in chronic phase. Cancer. 2018;124:1160–8.

    Article  CAS  Google Scholar 

  47. Haddad F, Kantarjian H, Issa GC, Jabbour E, Sasaki K. Intracranial hypertension associated with BCR-ABL1 tyrosine kinase inhibitors in chronic myeloid leukemia. Leuk Lymphoma. 2022;1:1–4.

    Google Scholar 

  48. Issa GC, Kantarjian HM, Gonzalez GN, Borthakur G, Tang G, Wierda W, et al. Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment. Blood. 2017;130:2084–91.

    Article  CAS  Google Scholar 

  49. Shoukier M, Borthakur G, Jabbour E, Ravandi F, Garcia-Manero G, Kadia T, et al. The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis. Haematologica. 2021;106:2853–8.

    Article  CAS  Google Scholar 

  50. Sasaki K, Jabbour EJ, Ravandi F, Konopleva M, Borthakur G, Wierda WG, et al. The LEukemia Artificial Intelligence Program (LEAP) in chronic myeloid leukemia in chronic phase: a model to improve patient outcomes. Am J Hematol. 2021;96:241–50.

    Article  Google Scholar 

  51. Alfayez M, Richard-Carpentier G, Jabbour E, Vishnu P, Naqvi K, Sasaki K, et al. Sudden blastic transformation in treatment-free remission chronic myeloid leukaemia. Br J Haematol. 2019;187:543–5.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Yoshihiro Umezawa

  2. Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX, 77030, USA

    Koji Sasaki

Authors
  1. Yoshihiro Umezawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koji Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Koji Sasaki.

Ethics declarations

Conflict of interest

YU declares no conflict of interest. KS received honoraria from Otsuka and research funding from Novartis and served on advisory boards of Pfizer Japan, Novartis, and Takeda.

Additional information

Publisher's Note

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

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Umezawa, Y., Sasaki, K. Dose optimization of tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Int J Hematol 117, 24–29 (2023). https://doi.org/10.1007/s12185-022-03431-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-022-03431-8

Keywords

Search

Navigation