Skip to main content

Advertisement

SpringerLink
Log in

Cardiovascular Adverse Events of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: Clinical Relevance, Impact on Outcome, Preventive Measures and Treatment Strategies

  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion Statement

The introduction of TKIs into the therapeutic armamentarium of CML has changed the disease paradigm, increasing long-term survival from 20% to over 80%, with a life expectancy now approaching that of the general population. Although highly effective, TKIs also have a toxicity profile that is often mild to moderate, but sometimes severe, with multiple kinases involved in the development of adverse events (AEs). Among others, cardiovascular AEs observed in TKI-treated CML patients may represent a significant cause of morbidity and mortality, and their pathogenesis is still only partially understood. In view of the recent introduction into daily clinical practice of new TKIs, namely the STAMP inhibitor asciminib, with a distinct safety profile, hematologists now more than ever have the opportunity to select the most suitable TKI for each patient, an aspect that will be fundamental in terms of personalized preventive and therapeutic strategies. Furthermore, physicians should be aware of the feasibility of TKI dose modifications at all stages of the patients’ treatment journey, both at diagnosis for frail or elderly subjects or with multiple comorbidities, and during follow-up for those patients who experience toxicity, as well as to prevent it, with the main objective of reducing side effects while maintaining the response. Consequently, preserving the cardiovascular health of CML patients will likely be a more urgent topic in the near future, with specific measures aimed at controlling cardiovascular risk factors through a multidisciplinary approach involving a panel of healthcare professionals together with the hematologist.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Shawver LK, Slamon D, Ullrich A. Smart drugs: Tyrosine kinase inhibitors in cancer therapy. Cancer Cell. 2002;1:117–23.

    Article  CAS  PubMed  Google Scholar 

  2. Radich JP, Deininger M, Abboud CN, et al. Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2018;16:1108–35.

    Article  Google Scholar 

  3. •• Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019;381:2315–26. The first clinical trial that led to the approval of asciminib for the treatment of chronic myeloid leukemia

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543:733–7.

    Article  CAS  PubMed  Google Scholar 

  5. Hantschel O, Nagar B, Guettler S, et al. A myristoyl/phosphotyrosine switch regulates c-Abl. Cell. 2003;112:845–57.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Branford S, Yeung DT, Ross DM, et al. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood. 2013;121:3818–24.

    Article  CAS  PubMed  Google Scholar 

  8. Hughes T, Boquimpani C, Takahashi N, et al. Durable treatment-free remission after stopping second line nilotinib in patients with chronic myeloid leukemia in chronic phase: ENESTOP 96-wk update. Haematologica. 2017;102:75.

    Google Scholar 

  9. Ross DM, Pagani IS, Shanmuganathan N, et al. Long-term treatment-free remission of chronic myeloid leukemia with falling levels of residual leukemic cells. Leukemia. 2018;32:2572–9.

    Article  CAS  PubMed  Google Scholar 

  10. Ross DM, Hughes TP. Treatment-free remission in patients with chronic myeloid leukaemia. Nat Rev Clin Oncol. 2020;17:493–503.

    Article  PubMed  Google Scholar 

  11. •• Mahon F-X, Réa D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029–35. The first clinical trial to specifically evaluate the feasibility of tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients

    Article  CAS  PubMed  Google Scholar 

  12. Campbell VE, Copland M. Dasatinib for the treatment of chronic phase chronic myeloid leukemia. Clin Pract. 2013;10:415–25.

    Article  CAS  Google Scholar 

  13. Iurlo A, Galimberti S, Abruzzese E, et al. Pleural effusion and molecular response in dasatinib-treated chronic myeloid leukemia patients in a real-life Italian multicenter series. Ann Hematol. 2018;97:95–100.

    Article  CAS  PubMed  Google Scholar 

  14. Emir H, Albrecht-Schgoer K, Huber K, et al. Nilotinib exerts direct pro-atherogenic and antiangiogenic effects on vascular endothelial cells: A potential explanation for drug-induced vasculopathy in CML. Blood. 2013;122:257.

    Article  Google Scholar 

  15. Hiwase DK, Carne L, Ross D, Grigg A, Hughes TP. Hypercholesterolaemia in imatinib intolerant/resistant CML-CP patients treated with nilotinib: A retrospective analysis. Blood. 2013;122:1503.

    Article  Google Scholar 

  16. Cortes JE, Kim DW, Kantarjian HM, 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  PubMed  PubMed Central  Google Scholar 

  17. • Cortes JE, Kim DW, Pinilla-Ibarz J, 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. The clinical trial that confirmed the efficacy and safety profile of ponatinib in the setting of Ph+ leukemias, including chronic myeloid leukemia

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Caocci G, Mulas O, Annunziata M, et al. Long-term mortality rate for cardiovascular disease in 656 chronic myeloid leukaemia patients treated with second- and third-generation tyrosine kinase inhibitors. Int J Cardiol. 2020;301:163–6.

    Article  PubMed  Google Scholar 

  19. Manouchehri A, Kanu E, Mauro MJ, Aday AW, Lindner JR, Moslehi J. Tyrosine Kinase Inhibitors in Leukemia and Cardiovascular Events: From Mechanism to Patient Care. Arterioscler Thromb Vasc Biol. 2020;40:301–8.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pandey AK, Singhi EK, Arroyo JP, et al. Mechanisms of VEGF (vascular endothelial growth factor) inhibitor–associated hypertension and vascular disease. Hypertension. 2017;71:e1-8.

    PubMed  Google Scholar 

  22. Bower H, Björkholm M, Dickman PW, Höglund M, Lambert PC, Andersson TM-L. Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population. J Clin Oncol. 2016;34:2851–7.

    Article  CAS  PubMed  Google Scholar 

  23. Saussele S, Krauss MP, Hehlmann R, et al. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV. Blood. 2015;126:42–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hoffmann VS, Baccarani M, Hasford J, et al. The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries. Leukemia. 2015;29:1336–43.

    Article  CAS  PubMed  Google Scholar 

  25. Aghel N, Delgado DH, Lipton JH. Cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: preventive strategies and cardiovascular surveillance. Vasc Health Risk Manag. 2017;13:293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nodzon L, Fadol A, Tinsley S. Cardiovascular adverse events and mitigation strategies for chronic myeloid leukemia patients receiving tyrosine kinase inhibitor therapy. J Adv Pract Oncol. 2022;13:127–42.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sayegh N, Yirerong J, Agarwal N, et al. Cardiovascular Toxicities Associated with Tyrosine Kinase Inhibitors. Curr Cardiol Rep. 2023;25:269–80.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Milojkovic D, Lyon AR, Mehta P, et al. Cardiovascular risk in chronic myeloid leukaemia: A multidisciplinary consensus on screening and management. Eur J Haematol. 2023;111:201–10.

    Article  CAS  PubMed  Google Scholar 

  29. Smith G, Apperley J, Milojkovic D, et al. A British Society for Haematology guideline on the diagnosis and management of chronic myeloid leukaemia. Br J Haematol. 2020;191:171–93.

    Article  PubMed  Google Scholar 

  30. •• Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84. The latest version of the ELN recommendations for the diagnosis and treatment of chronic myeloid leukemia

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv261.

    Article  CAS  PubMed  Google Scholar 

  32. Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43:4229–361.

    Article  PubMed  Google Scholar 

  33. Cohen MH, Williams G, Johnson JR, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002;8:935–42.

    CAS  PubMed  Google Scholar 

  34. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.

    Article  CAS  PubMed  Google Scholar 

  35. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.

    Article  CAS  PubMed  Google Scholar 

  36. Hochhaus A, O’Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054–61.

    Article  CAS  PubMed  Google Scholar 

  37. Hochhaus A, Larson RA, Guilhot F, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017;376:917–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Atallah E, Durand J-B, Kantarjian H, Cortes J. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood. 2007;110:1233–7.

    Article  CAS  PubMed  Google Scholar 

  39. Kalmanti L, Saussele S, Lauseker M, et al. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015;29:1123–32.

    Article  CAS  PubMed  Google Scholar 

  40. Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908–16.

    Article  PubMed  Google Scholar 

  41. Wolf A, Couttet P, Dong M, et al. Imatinib does not induce cardiotoxicity at clinically relevant concentrations in preclinical studies. Leuk Res. 2010;34:1180–8.

    Article  CAS  PubMed  Google Scholar 

  42. Giles FJ, Mauro MJ, Hong F, et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or nontyrosine kinase therapy: a retrospective cohort analysis. Leukemia. 2013;27:1310–5.

    Article  CAS  PubMed  Google Scholar 

  43. Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J. 2007;30:104–9.

    Article  CAS  PubMed  Google Scholar 

  44. Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125:2128–37.

    Article  CAS  PubMed  Google Scholar 

  45. Fox LC, Cummins KD, Costello B, et al. The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia. Blood Adv. 2017;1:802–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shah NP, Kantarjian HM, Kim D-W, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008;26:3204–12.

    Article  CAS  PubMed  Google Scholar 

  47. Shah NP, Rousselot P, Schiffer C, et al. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016;91:869–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lilly MB, Ottmann OG, Shah NP, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study. Am J Hematol. 2010;85:164–70.

    Article  CAS  PubMed  Google Scholar 

  49. Saglio G, Hochhaus A, Goh YT, et al. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer. 2010;116:3852–61.

    Article  CAS  PubMed  Google Scholar 

  50. Kantarjian H, Cortes J, Kim D-W, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009;113:6322–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ottmann O, Saglio G, Apperley JF, et al. Long-term efficacy and safety of dasatinib in patients with chronic myeloid leukemia in accelerated phase who are resistant to or intolerant of imatinib. Blood Cancer J. 2018;8:88.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–70.

    Article  CAS  PubMed  Google Scholar 

  53. Cortes JE, Saglio G, Kantarjian HM, 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  PubMed  PubMed Central  Google Scholar 

  54. Cortes JE, Jiang Q, Wang J, et al. Dasatinib vs. imatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: the DASCERN randomized study. Leukemia. 2020;34:2064–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in Imatinib-Resistant CML and Philadelphia Chromosome-Positive ALL. N Engl J Med. 2006;354:2542–51.

    Article  PubMed  Google Scholar 

  56. Aichberger KJ, Herndlhofer S, Schernthaner GH, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol. 2011;86:533–9.

    Article  CAS  PubMed  Google Scholar 

  57. Le Coutre P, Rea D, Abruzzese E, et al. Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst. 2011;103:1347–8.

    Article  PubMed  Google Scholar 

  58. Levato L, Cantaffa R, Kropp MG, Magro D, Piro E, Molica S. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in chronic myeloid leukemia: A single institution study. Eur J Haematol. 2013;90:531–2.

    Article  CAS  PubMed  Google Scholar 

  59. Rosti G, Palandri F, Castagnetti F, et al. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood. 2009;114:4933–8.

    Article  CAS  PubMed  Google Scholar 

  60. Gugliotta G, Castagnetti F, Breccia M, et al. Treatment-free remission in chronic myeloid leukemia patients treated front-line with nilotinib: 10-year follow-up of the GIMEMA CML 0307 study. Haematologica. 2022;107:2356–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cortes JE, Jones D, O’Brien S, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010;28:392–7.

    Article  CAS  PubMed  Google Scholar 

  62. Masarova L, Cortes JE, Patel KP, et al. Long-Term Results of a Phase 2 Trial of Nilotinib 400 mg Twice Daily in Newly Diagnosed Patients With Chronic-Phase Chronic Myeloid Leukemia. Cancer. 2020;126:1448–59.

    Article  CAS  PubMed  Google Scholar 

  63. Saglio G, Kim D-W, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–9.

    Article  CAS  PubMed  Google Scholar 

  64. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26:2197–203.

    Article  CAS  PubMed  Google Scholar 

  65. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kantarjian HM, Hughes TP, Larson RA, 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  PubMed  PubMed Central  Google Scholar 

  67. Cortes JE, Jean Khoury H, Kantarjian H, et al. Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib. Am J Hematol. 2016;91:606–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118:4567–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica. 2018;103:1298–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Brümmendorf TH, Cortes JE, de Souza CA, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2015;168:69–81.

    Article  PubMed  Google Scholar 

  71. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J Hematol. 2014;89:947–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cortes JE, Gambacorti-Passerini C, Deininger MW, 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  PubMed  Google Scholar 

  73. Brümmendorf TH, Cortes JE, Milojkovic D, et al. Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial. Leukemia. 2022;36:1825–33.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783–96.

    Article  CAS  PubMed  Google Scholar 

  75. Lipton JH, Chuah C, Guerci-Bresler A, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17:612–21.

    Article  CAS  PubMed  Google Scholar 

  76. Dorer DJ, Knickerbocker RK, Baccarani 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  PubMed  Google Scholar 

  77. Cortes J, Apperley J, Lomaia E, 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  PubMed  PubMed Central  Google Scholar 

  78. Iurlo A, Cattaneo D, Malato A, et al. Low-dose ponatinib is a good option in chronic myeloid leukemia patients intolerant to previous TKIs. Am J Hematol. 2020;95:E260–3.

    Article  CAS  PubMed  Google Scholar 

  79. Schoepfer J, Jahnke W, Berellini G, et al. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J Med Chem. 2018;61:8120–35.

    Article  CAS  Google Scholar 

  80. Mauro MJ, Hughes TP, Kim D-W, et al. Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results. Leukemia. 2023;37:1048–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Réa D, Mauro MJ, Boquimpani C, 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  PubMed  PubMed Central  Google Scholar 

  82. Hochhaus A, Réa D, Boquimpani C, et al. Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL. Leukemia. 2023;37:617–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Breccia M, Piciocchi A, Abruzzese E, et al. Italian Physicians’ Perceptions about the Role of Asciminib in Later Lines Chronic Myeloid Leukemia in Clinical Practice: A GIMEMA Survey. J Clin Med. 2023;12:5267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42:3227–337.

    Article  PubMed  Google Scholar 

  85. Tini G, Sarocchi M, Tocci G, et al. Arterial hypertension in cancer: The elephant in the room. Int J Cardiol. 2019;281:133–9.

    Article  PubMed  Google Scholar 

  86. Romanens M, Sudano I, Adams A, Schober EA. Sonographic assessment of carotid atherosclerosis: preferred risk indicator for future cardiovascular events? Swiss Med Wkly. 2019;149:w20142.

    PubMed  Google Scholar 

  87. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111–88.

    Article  PubMed  Google Scholar 

  88. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020;27:593–603.

    Article  PubMed  Google Scholar 

  89. Preiss D, Tobert JA, Hovingh GK, Reith C. Lipid-Modifying Agents, From Statins to PCSK9 Inhibitors: JACC Focus Seminar. J Am Coll Cardiol. 2020;75:1945–55.

    Article  CAS  PubMed  Google Scholar 

  90. Caocci G, Mulas O, Capodanno I, et al. Low low-density lipoprotein (LDL), cholesterol and triglycerides plasma levels are associated with reduced risk of arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life. A Campus CML study. Blood Cancer J. 2020;10:66.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Caocci G, Mulas O, Capodanno I, et al. Low-density lipoprotein (LDL) levels and risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib. Ann Hematol. 2021;100:2005–14.

    Article  CAS  PubMed  Google Scholar 

  92. Iurlo A, Orsi E, Cattaneo D, et al. Effects of first- and second-generation tyrosine kinase inhibitor therapy on glucose and lipid metabolism in chronic myeloid leukemia patients: a real clinical problem? Oncotarget. 2015;6:33944–51.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39:3021–104.

    Article  PubMed  Google Scholar 

  94. Mulas O, Caocci G, Stagno F, et al. Renin angiotensin system inhibitors reduce the incidence of arterial thrombotic events in patients with hypertension and chronic myeloid leukemia treated with second- or third-generation tyrosine kinase inhibitors. Ann Hematol. 2020;99:1525–30.

    Article  CAS  PubMed  Google Scholar 

  95. Breccia M, Pregno P, Spallarossa P, et al. Identification, prevention and management of cardiovascular risk in chronic myeloid leukaemia patients candidate to ponatinib: an expert opinion. Ann Hematol. 2017;96:549–58.

    Article  CAS  PubMed  Google Scholar 

  96. Marquis-Gravel G, Roe MT, Harrington RA, Muñoz D, Hernandez AF, Jones WS. Revisiting the Role of Aspirin for the Primary Prevention of Cardiovascular Disease. Circulation. 2019;140:1115–24.

    Article  CAS  PubMed  Google Scholar 

  97. Caocci G, Mulas O, Annunziata M, et al. Cardiovascular toxicity in patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors in the real-life practice: Identification of risk factors and the role of prophylaxis. Am J Hematol. 2018;93:E159–61.

    Article  PubMed  Google Scholar 

  98. Caocci G, Mulas O, Bonifacio M, et al. Recurrent arterial occlusive events in patients with chronic myeloid leukemia treated with second- and third-generation tyrosine kinase inhibitors and role of secondary prevention. Int J Cardiol. 2019;288:124–7.

    Article  PubMed  Google Scholar 

  99. Caocci G, Mulas O, Abruzzese E, et al. Arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life practice are predicted by the Systematic Coronary Risk Evaluation (SCORE) chart. Hematol Oncol. 2019;37:296–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 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;10:515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hematology Division, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milano, Italy

    Alessandra Iurlo MD, PhD, Daniele Cattaneo MD, Cristina Bucelli MD & Francesco Passamonti MD

  2. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Daniele Cattaneo MD & Francesco Passamonti MD

  3. Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino - Italian IRCCS Cardiology Network, Genova, Italy

    Paolo Spallarossa MD

Authors
  1. Alessandra Iurlo MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniele Cattaneo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristina Bucelli MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paolo Spallarossa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco Passamonti MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors wrote the paper and gave their final approval.

Corresponding author

Correspondence to Alessandra Iurlo MD, PhD.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iurlo, A., Cattaneo, D., Bucelli, C. et al. Cardiovascular Adverse Events of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: Clinical Relevance, Impact on Outcome, Preventive Measures and Treatment Strategies. Curr. Treat. Options in Oncol. 24, 1720–1738 (2023). https://doi.org/10.1007/s11864-023-01149-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11864-023-01149-1

Keywords

Search

Navigation