Skip to main content

Advertisement

SpringerLink
Log in

Chronic myelogenous leukemia

Cardiovascular events in chronic myeloid leukemia clinical trials. Is it time to reassess and report the events according to cardiology guidelines?

  • Review Article
  • Published:
Leukemia Submit manuscript

Abstract

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). Although these treatments have changed the natural course of CML and many other cancers, they may cause cardiovascular and/or metabolic complications. In this review, we discuss how overlooking the main drivers of cardiovascular events (CVEs) and lack of standard definitions for cardiovascular adverse events might have affected these event rates in CML trials. Methodological limitations that affect the available data are discussed, with an emphasis on the future direction of cardiovascular safety research in trials of investigational drugs in cancer treatment.

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

Similar content being viewed by others

References

  1. Bower H, Bjorkholm M, Dickman PW, Hoglund M, Lambert PC, Andersson TM. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34:2851–7. http://www.ncbi.nlm.nih.gov/pubmed/27325849.

    Article  CAS  Google Scholar 

  2. Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol. 2015;33:4210–8. http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2015.62.4718.

    Article  CAS  Google Scholar 

  3. Moslehi JJ. Cardiovascular toxic effects of targeted cancer therapies. N Engl J Med. 2016;375:1457–67. http://www.ncbi.nlm.nih.gov/pubmed/27732808.

    Article  CAS  Google Scholar 

  4. Li W, Croce K, Steensma DP, McDermott DF, Ben-Yehuda O, Moslehi J. Vascular and metabolic implications of novel targeted cancer therapies. J Am Coll Cardiol. 2015;66:1160–78. http://www.ncbi.nlm.nih.gov/pubmed/26337996.

    Article  Google Scholar 

  5. 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. http://doi.wiley.com/10.1111/ejh.12096.

    Article  CAS  Google Scholar 

  6. Kim TD, le Coutre P, Schwarz M, Grille P, Levitin M, Fateh-Moghadam S, et al. Clinical cardiac safety profile of nilotinib. Haematologica. 2012;97:883–9. http://www.ncbi.nlm.nih.gov/pubmed/22271904.

    Article  CAS  Google Scholar 

  7. ICLUSIG® (ponatinib). http://www.iclusig.com/hcp/.

  8. 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. http://www.ncbi.nlm.nih.gov/pubmed/24180494.

    Article  CAS  Google Scholar 

  9. Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, 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. http://linkinghub.elsevier.com/retrieve/pii/S1470204516000802.

    Article  CAS  Google Scholar 

  10. Johnson CB, Davis MK, Law A, Sulpher J. Shared risk factors for cardiovascular disease and cancer: implications for preventive health and clinical care in oncology patients. Can J Cardiol. 2016;32:900–7. http://linkinghub.elsevier.com/retrieve/pii/S0828282X16300526.

    Article  Google Scholar 

  11. CTCAE Files. https://evs.nci.nih.gov/ftp1/CTCAE/About.html

  12. Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, et al. ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials. J Am Coll Cardiol. 2015;66:403–69. http://linkinghub.elsevier.com/retrieve/pii/S0735109714074841.

    Article  Google Scholar 

  13. Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, et al.Cardiovascular and stroke endpoint definitions for clinical trials. Circulation. 2018;137:961–72. http://www.ncbi.nlm.nih.gov/pubmed/29483172.

    Article  Google Scholar 

  14. Pocock SJ, Clayton TC, Stone GW. Design of major randomized trials. J Am Coll Cardiol. 2015;66:2757–66. http://www.ncbi.nlm.nih.gov/pubmed/26700838.

    Article  Google Scholar 

  15. Schroll JB, Maund E, Gøtzsche PC. Challenges in coding adverse events in clinical trials: a systematic review. PLoS One. 2012;7:e41174.

    Article  CAS  Google Scholar 

  16. Giles FJ, Mauro MJ, Hong F, Ortmann C-E, McNeill C, Woodman RC, et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia [Internet]. 2013;27:1310–5. http://www.nature.com/doifinder/10.1038/leu.2013.69.

    Article  CAS  Google Scholar 

  17. Kim TD, Rea D, Schwarz M, Grille P, Nicolini FE, Rosti G, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia. 2013;27:1316–21. http://www.ncbi.nlm.nih.gov/pubmed/23459449.

    Article  CAS  Google Scholar 

  18. Sivendran S, Latif A, McBride RB, Stensland KD, Wisnivesky J, Haines L, et al. Adverse event reporting in cancer clinical trial publications. J Clin Oncol. 2014;32:83–9. http://ascopubs.org/doi/10.1200/JCO.2013.52.2219.

    Article  Google Scholar 

  19. Vaduganathan M, Prasad V. Cardiovascular risk assessment in oncological clinical trials: is there a role for centralized events adjudication?. Eur J Heart Fail. 2016;18:128–32. http://doi.wiley.com/10.1002/ejhf.457.

    Article  Google Scholar 

  20. Fda. Guidance for industry diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008. http://www.fda.gov/cder/guidance/index.htm.

  21. Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365:699–708. http://www.nejm.org/doi/10.1056/NEJMoa1105819.

    Article  CAS  Google Scholar 

  22. D'Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: the Framingham heart study. Circulation. 2008;117:743–53. http://www.ncbi.nlm.nih.gov/pubmed/18212285.

    Article  Google Scholar 

  23. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet (London, England). 2004;364:937–52. http://linkinghub.elsevier.com/retrieve/pii/S0140673604170189.

    Article  Google Scholar 

  24. The World Health Organization MONICA Project (monitoring trends and determinants in cardiovascular disease): a major international collaboration. WHO MONICA Project Principal Investigators. J Clin Epidemiol. 1988;41:105–14. http://www.ncbi.nlm.nih.gov/pubmed/3335877.

  25. Sigurdsson E, Thorgeirsson G, Sigvaldason H, Sigfusson N. Prevalence of coronary heart disease in Icelandic men 1968–1986. The Reykjavik Study. Eur Heart J. 1993;14:584–91. http://www.ncbi.nlm.nih.gov/pubmed/8508850.

    Article  CAS  Google Scholar 

  26. Liu J, Fox CS, Hickson D, Sarpong D, Ekunwe L, May WD, et al. Pericardial adipose tissue, atherosclerosis, and cardiovascular disease risk factors: the Jackson Heart Study. Diabetes Care. 2010;33:1635–9. http://www.ncbi.nlm.nih.gov/pubmed/20413524.

    Article  CAS  Google Scholar 

  27. Le Coutre P, Rea D, Abruzzese E, Dombret H, Trawinska MM, Herndlhofer S, et al. Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst. 2011;103:1347–8. https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/djr292.

    Article  Google Scholar 

  28. Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim D-W, Issaragrisil S, 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. http://www.ncbi.nlm.nih.gov/pubmed/26837842.

    Article  CAS  Google Scholar 

  29. Aghel N, Lipton JH, Atenafu EG, Kim DDH, Delgado DH. Cardiovascular events after exposure to nilotinib in chronic myeloid leukemia: long-term follow-up. Clin Lymphoma Myeloma Leuk. 2017;17:870–878.e1.

    Article  Google Scholar 

  30. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics’2017 update: a report from the American Heart Association. Circulation. 2017;135:e146–603.

    Article  Google Scholar 

  31. Steg PG, Bhatt DL, Wilson PWF, D’Agostino R, Ohman EM, Röther J, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007;297:1197. http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.297.11.1197.

    Article  CAS  Google Scholar 

  32. Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, Mahoney EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304:1350. http://www.ncbi.nlm.nih.gov/pubmed/20805624.

    Article  CAS  Google Scholar 

  33. Jernberg T, Hasvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J. 2015;36:1163–70. https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehu505

    Article  Google Scholar 

  34. Abu-Assi E, López-López A, González-Salvado V, Redondo-Diéguez A, Peña-Gil C, Bouzas-Cruz N, et al. The risk of cardiovascular events after an acute coronary event remains high, especially during the first year, despite revascularization. Rev Esp Cardiol (Engl Ed). 2016;69:11–8. http://linkinghub.elsevier.com/retrieve/pii/S1885585715002704

    Article  Google Scholar 

  35. Jabbour E, Makenbaeva D, Lingohr-Smith M, Lin J. Use of real-world claim databases to assess prevalence of comorbid conditions relevant to the treatment of chronic myelogenous leukemia based on national comprehensive network treatment guidelines. Clin Lymphoma Myeloma Leuk. 2015;15:797–802.e1. http://www.ncbi.nlm.nih.gov/pubmed/26603185.

    Article  Google Scholar 

  36. Fowkes FGR, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382:1329–40. http://www.ncbi.nlm.nih.gov/pubmed/23915883.

    Article  Google Scholar 

  37. Hiatt WR, Goldstone J, Smith SC, McDermott M, Moneta G, Oka R, et al. Atherosclerotic Peripheral Vascular Disease Symposium II: nomenclature for vascular diseases. Circulation. 2008;118:2826–9. http://circ.ahajournals.org/cgi/doi/10.1161/CIRCULATIONAHA.108.191171.

    Article  Google Scholar 

  38. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res. 2015;116:1509–26. http://www.ncbi.nlm.nih.gov/pubmed/25908725.

    Article  CAS  Google Scholar 

  39. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation. 2004;110:738–43. http://www.ncbi.nlm.nih.gov/pubmed/15262830.

    Article  Google Scholar 

  40. Poredos P, Jug B. The prevalence of peripheral arterial disease in high risk subjects and coronary or cerebrovascular patients. Angiology. 2007;58:309–15. http://ang.sagepub.com/cgi/doi/10.1177/0003319707302494.

    Article  Google Scholar 

  41. Subherwal S, Patel MR, Chiswell K, Tidemann-Miller BA, Jones WS, Conte MS, et al. Clinical trials in peripheral vascular disease: pipeline and trial designs: an evaluation of the ClinicalTrials.gov database. Circulation. 2014;130:1812–9. http://circ.ahajournals.org/cgi/doi/10.1161/CIRCULATIONAHA.114.011021.

    Article  CAS  Google Scholar 

  42. Howard DPJ, Banerjee A, Fairhead JF, Hands L, Silver LE, Rothwell PM, et al. Population-based study of incidence, risk factors, outcome, and prognosis of ischemic peripheral arterial events: implications for prevention. Circulation. 2015;132:1805–15. http://circ.ahajournals.org/lookup/doi/10.1161/CIRCULATIONAHA.115.016424.

    Article  Google Scholar 

  43. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. Circulation. 2012;126:2020–35. http://circ.ahajournals.org/cgi/doi/10.1161/CIR.0b013e31826e1058.

    Article  Google Scholar 

  44. 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. http://www.nejm.org/doi/10.1056/NEJMoa1609324%0A. http://www.ncbi.nlm.nih.gov/pubmed/28273028.

    Article  CAS  Google Scholar 

  45. 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. http://ascopubs.org/doi/10.1200/JCO.2015.64.8899.

    Article  CAS  Google Scholar 

  46. Kantarjian H, Pasquini R, Lévy V, Jootar S, Holowiecki J, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily. Cancer. 2009;115:4136–47. http://www.ncbi.nlm.nih.gov/pubmed/19536906.

    Article  CAS  Google Scholar 

  47. Wang J, Shen Z-X, Saglio G, Jin J, Huang H, Hu Y, et al. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood. 2015;125:2771–8. http://www.ncbi.nlm.nih.gov/pubmed/25766724.

    Article  CAS  Google Scholar 

  48. 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. http://www.ncbi.nlm.nih.gov/pubmed/28699641.

    Article  CAS  Google Scholar 

  49. Cortes JE, De Souza CA, Ayala M, Lopez JL, Bullorsky E, Shah S, et al. Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial. Lancet Haematol. 2016;3:e581–91. http://linkinghub.elsevier.com/retrieve/pii/S2352302616301673.

    Article  Google Scholar 

  50. Cortes JE, Kim D-W, 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. http://ascopubs.org/doi/10.1200/JCO.2011.38.7522.

    Article  CAS  Google Scholar 

  51. Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim D-W, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2017;36:231–237. http://www.ncbi.nlm.nih.gov/pubmed/29091516.

    Article  Google Scholar 

  52. Aichberger KJ, Herndlhofer S, Schernthaner G-H, Schillinger M, Mitterbauer-Hohendanner G, Sillaber C, 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  Google Scholar 

  53. Quintás-Cardama A, Kantarjian H, Cortes J. Nilotinib-associated vascular events. Clin Lymphoma Myeloma Leuk. 2012;12:337–40. http://www.ncbi.nlm.nih.gov/pubmed/22633167.

    Article  Google Scholar 

  54. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075–88. http://www.ncbi.nlm.nih.gov/pubmed/23190221.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Work for this project is supported by our patients through the Friends for Life Fund, Princess Margaret Hospital Foundation.

Author information

Author notes

  1. These authors contributed equally: Diego Hernan Delgado, Jeffrey Howard Lipton.

Authors and Affiliations

  1. Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada

    Nazanin Aghel & Diego Hernan Delgado

  2. Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada

    Jeffrey Howard Lipton

Authors
  1. Nazanin Aghel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diego Hernan Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey Howard Lipton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nazanin Aghel.

Ethics declarations

Conflict of interest

DHD has received a grant from Novartis. JHL has received honoraria, been on the advisory boards, and has received research funding from Novartis, BMS, Pfizer, and Ariad. NA declares that she has no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aghel, N., Delgado, D.H. & Lipton, J.H. Cardiovascular events in chronic myeloid leukemia clinical trials. Is it time to reassess and report the events according to cardiology guidelines?. Leukemia 32, 2095–2104 (2018). https://doi.org/10.1038/s41375-018-0247-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0247-1

  • Springer Nature Limited

Search

Navigation