A new paradigm of cardiohematological monitoring in patients with chronic myeloid leukemia taking tyrosine kinase inhibitors

Main Article Content

N. A. Lopina
І. S. Dyagil
I. V. Dmitrenko
D. S. Hamov
D. O. Lopin


Currently, significant progress has been achieved in patients with oncohematological diseases treatment, including chronic myeloid leukemia (CML). This is primarily associated with the development of targeted therapy named tyrosine kinase inhibitors (TKI) – imatinib, nilotinib, bosutinib, dasatinib, ponatinib, etc.). Along with the increased survival of patients with CML, special attention has recently been paid to cardiovascular complications in this group of patients due to the prevalence of cardiovascular diseases in the general population and the toxicity profile of targeted drugs. The article is devoted to the discussion of the cardiovascular risk-reducing strategy in patients with CML. The components of cardiovascular risk in patients with CML are described in detail, and current studies confirm the increased cardiovascular risk in this group of patients compared to the general population, which requires the widespread introduction of cardiovascular prophylaxis for patients with CML. The pathophysiology of the TKI effects on the cardiovascular system are presented, the profiles of cardiovascular toxicity of TKI are considered. The article proposes to implement two concepts in the strategy of cardiovascular prophylaxis in patients with CML – before the start of TKI therapy and during the TKI treatment. The article presents diagnostic measures before the TKI prescribing and for monitoring the TKI therapy, discusses the features of the TKI choice depending on concomitant conditions and diseases. Emphasis is made on the necessity of the risk stratification in patients with CML in accordance with general population algorithms, lifestyle modifications, statin therapy with the achievement of the targeted levels of cardiovascular markers in patients with CML. The article also presents unresolved issues of clinical recommendations and ways to further implement the strategy.

Article Details


chronic myeloid leukemia, tyrosine kinase inhibitors, cardiovascular diseases, cardiovascular risk, strategy for cardiovascular events prevention, statins


Hehlmann R. Innovation in hematology. Perspectives: CML 2016. Haematologica. 2016;101(6):657–9. doi: https://doi.org/10.3324/haematol.2016.142877

Barber MC, Mauro MJ, Moslehi J, Cardiovascular care of patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitor (TKI) therapy. Hematology Am Soc Hematol Educ Program. 2017;1:110–4. doi: https://doi.org/10.1182/asheducation-2017.1.110.

Smith G, Apperley J, Milojkovic D, Cross NCP, Foroni L, Byrne J, Goringe A, Rao A, Khorashad J, de Lavallade H, Mead AJ, Osborne W, Plummer C, Jones G, Copland M. A British Society for Haematology Guideline on the diagnosis and management of chronic myeloid leukaemia. Brit J Haematol. 2020;2:171–93. doi: https://doi.org/10.1111/bjh.16971.

Seguro FS, Silva CMPDC, Moura CMB, Conchon M, Fogliatto L, Funke VAM, Abdo A, Macedo AVS, Santos MHHD, Saraiva JFK. Recommendations for the management of cardiovascular risk in patients with chronic myeloid leukemia on tyrosine kinase inhibitors: risk assessment, stratification, treatment and monitoring. Hematology, Transfusion and Cell Therapy. 2021;43(2):191–200. doi: https://doi.org/10.1016/j.htct.2020.04.009.

Coutinho AD, Makenbaeva D, Farrelly E, Landsman-Blumberg PB, Lenihan D. Elevated cardiovascular disease risk in patients with chronic myelogenous leukemia seen incommunity-based oncology practices in the United States. Clin Lymphoma, Myeloma & Leukemia. 2017;17(10):676–83. doi: https://doi.org/10.1016/j.clml.2017.06.011

Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, Flinn IW, Kurokawa M, Moiraghi B, Yu R, Blakesley RE, Gallagher NJ, Saglio G, Kantarjian HM Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;10:2197–203. doi: https://doi.org/10.1038/leu.2012.134.

Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre PD, Etienne G, Dorlhiac-Llacer PE, Clark RE, Flinn IW, Nakamae H, Donohue B, Deng W, Dalal D, Menssen HD, Kantarjian HM. 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(5):1044–54. doi: https://doi.org/10.1038/leu.2016.5.

Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. New Engl J Med. 2013;369(19):1783–96. doi: https://doi.org/10.1056/NEJMoa1306494.

Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Lustgarten S, Rivera VM, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Shah NP, Kantarjian HM. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393–404. doi: https://doi.org/10.1182/blood-2016-09-739086.

Cortes JE, Jimenez CA, Mauro MJ, Geyer A, Pinilla-Ibarz J, Smith BD. Pleural effusion in dasatinib-treated patients with chronic myeloid leukemia in chronic phase: Identification and Management. Clin Lymphoma, Myeloma and Leukemia. 2017;17(2):78–82. doi: https://doi.org/10.1016/j.clml.2016.09.012.

Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, Clark RE, Cortes JE, Deininger MW, Guilhot F, Hjorth-Hansen H, Hughes TP, Janssen JJWM, Kan­­­tarjian HM, Kim DW, Larson RA, Lipton JH, Mahon FX, Mayer J, Nicolini F, Niederwieser D, Pane F, Radich JP, Rea D, Richter J, Rosti G, Rousselot P, Saglio G, Saußele S, Soverini S, Steegmann JL, Turkina A, Zaritskey A, Hehlmann R. European Leukemia Net 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966–84. doi: https://doi.org/10.1038/s41375-020-0776-2.

Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, Shah NP, Chuah C, Casanova L, Bradley-Garelik B, Manos G, Hochhaus A. Final 5-year study results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncology. 2016;34(20):2333–40. doi:https://doi.org/10.1200/JCO.2015.64.8899.

Jain P, Kantarjian H, Boddu PC, Nogueras-González GM, Verstovsek S, Garcia-Manero G, Borthakur G, Sasaki K, Kadia TM, Sam P, Ahaneku H, O’Brien S, Estrov Z, Ravandi F, Jabbour E, Cortes JE. Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs. Blood Adv. 2019 Mar 26;3(6):851–61. doi: https://doi.org/10.1182/bloodadvances.2018025874.

Yang YC, Huang RY, Tsai HJ, Li PC, Yang YH, Hsieh KP. Cardiovascular events in patients with chronic myeloid leukaemia treated with tyrosine kinase inhibitors in Taiwan: a nationwide population-based study. Eur J Preventive Cardiol. 2021;28:zwab043. doi: https://doi.org/10.1093/eurjpc/zwab043.

Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet. 2014; 15;383(9921):999–1008. doi: https://doi.org/10.1016/S0140-6736(13)61752-3.

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. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40(2):301–8. doi: https://doi.org/10.1161/ATVBAHA.119.313353.

Ito Y, Miyamoto T, Chong Y, Maki T, Akashi K, Kamimura T. Nilotinib exacerbates diabetes mellitus by decreasing secretion of endogenous insulin. Intern J Hematology. 2013; 97:135–8. doi: https://doi.org/10.1007/s12185-012-1222-7.

Pandey AK, Singhi EK, Arroyo JP, Ikizler TA, Gould ER, Brown J, Beckman JA, Harrison DG, Moslehi J. Mechanisms of VEGF (vascular endothelial growth factor) inhibitor – associated hypertension and vascular disease. Hypertension. 2017;71:e1–e8. doi: https://doi.org/10.1161/HYPERTENSIONAHA.117.10271.

Moslehi JJ. Cardiovascular toxic effects of targeted cancer therapies. New Engl J Med. 2016;375:1457–67. doi: https://doi.org/10.1056/NEJMra1100265

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

Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, Benetos A, Biffi A, Boavida JM, Capodanno D, Cosyns B, Crawford C, Davos CH, Desormais I, Di Angelantonio E, Franco OH, Halvorsen S, Hobbs FDR, Hollander M, Jankowska EA, Michal M, Sacco S, Sattar N, Tokgozoglu L, Tonstad S, Tsioufis KP, van Dis I, van Gelder IC, Wanner C, Williams B; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: Developed by the Task Force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies With the special contribution of the European Association of Preventive Cardiology (EAPC). Eur Heart J. 2021;42(34):3227–337. https://doi.org/10.1093/eurheartj/ehab484.

Glodkowska-Mrowka E, Mrowka P, Basak GW, Niesiobedzka-Krezel J, Seferynska I, Wlodarski PK, Jakobisiak M, Stoklosa T. Statins inhibit ABCB1 and ABCG2 drug transporter activity in chronic myeloid leukemia cells and potentiate antileukemic effects of imatinib. Exp Hematol. 2014;42(6):439-47. doi: https://doi.org/10.1016/j.exphem.2014.02.006.

Jang HJ, Woo YM, Naka K, Park JH, Han HJ, Kim HJ, Kim SH, Ahn JS, Kim T, Kimura S, Zarabi S, Lipton JH, Minden MD, Jung CW, Kim HJ, Kim JW, Kim DDH. Statins enhance the molecular response in chronic myeloid leukemia when combined with tyrosine kinase inhibitors. Cancers. 2021;13:5543. https://doi.org/10.3390/cancers13215543.

Deininger MW, Shah NP, Altman JK, Berman E, Bhatia R, Bhatnagar B, DeAngelo DJ, Gotlib J, Hobbs G, Maness L, Mead M, Metheny L, Mohan S, Moore JO, Naqvi K, Oehler V, Pallera AM, Patnaik M, Pratz K, Pusic I, Rose MG, Smith BD, Snyder DS, Sweet KL, Talpaz M, Thompson J, Yang DT, Gregory KM, Sundar H. Chronic myeloid leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Nat Comprehensive Cancer Network. 2020;18(10):1385–1415. doi: https://doi.org/10.6004/jnccn.2020.0047.

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