With high survival rates for chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs), emerging consequences, such as arterial ischemic events, require consideration when evaluating treatment options. Cardiovascular ischemic event incidence in clinical trials was evaluated in 2712 dasatinib-treated patients with Philadelphia chromosome-positive (Ph+) leukemias from 11 first- and second-line trials (pooled), newly diagnosed CML patients treated with dasatinib or imatinib (DASISION), and prostate cancer patients treated with dasatinib or placebo plus docetaxel/prednisone (READY). Overall, 2-4% of dasatinib-treated patients had cardiovascular ischemic events. Most dasatinib-treated patients with an event had a history of and/or risk factor for atherosclerosis (pooled 77 with history/risk and event/96 with events; DASISION 8/10; READY 15/18). Most cardiovascular ischemic events occurred within 1 year of initiating dasatinib (pooled 69/96; DASISION 7/10; READY 16/18). Comparison of observed and expected event rates through standardized incidence ratios indicates that dasatinib does not increase risk for cardiovascular ischemic events compared with external reference populations.

Bristol Myers Squibb Princeton NJ USA

Calvary Mater Newcastle Hospital University of Newcastle Waratah NSW Australia

Charité Campus Virchow Klinikum Universitätsmedizin Berlin Berlin Germany

Clinical and Biological Sciences of the University of Turin San Luigi Hospital 10043 Orbassano Torino Italy

Department of Internal Medicine Hematology and Oncology Masaryk University Hospital Brno Brno Czech Republic

Laboratoire d'Hématologie et Service des Maladies du Sang Bordeaux et Institut Bergonié Centre Hospitalier Universitaire de Bordeaux Bordeaux France

The University of Texas MD Anderson Cancer Center Houston TX USA

UCSF School of Medicine San Francisco CA USA

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Baccarani M, Efficace F, Rosti G. Moving towards patient-centered decision-making in chronic myeloid leukemia: assessment of quality of life and symptom burden. Haematologica. 2014;99:205–208. doi: 10.3324/haematol.2013.094045. PubMed DOI PMC

Gleevec (imatinib) [package insert] (2015) Novartis Pharmaceuticals Corporation, East Hanover, NJ

Iclusig (ponatinib) [package insert] (2014) ARIAD Pharmaceuticals, Inc., Cambridge, MA

Sprycel (dasatinib) [package insert] (2015) Bristol-Myers Squibb Company, Princeton, NJ

Tasigna (nilotinib) [package insert] (2015) Novartis Pharmaceuticals Corporation, East Hanover, NJ

FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales [news release]; November 5 (2013) United States Food and Drug Administration website. http://www.fda.gov/drugs/drugsafety/ucm373040.htm. Accessed 3 Mar 2016

Valent P, Hadzijusufovic E, Schernthaner GH, Wolf D, Rea D, le Coutre P. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125:901–906. doi: 10.1182/blood-2014-09-594432. PubMed DOI

Cortes J, Mauro M, Steegmann JL, Saglio G, Malhotra R, Ukropec JA, Wallis NT. Cardiovascular and pulmonary adverse events in patients treated with BCR-ABL inhibitors: data from the FDA Adverse Event Reporting System. Am J Hematol. 2015;90:E66–E72. doi: 10.1002/ajh.23938. PubMed DOI PMC

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;30:1044–1054. doi: 10.1038/leu.2016.5. PubMed DOI PMC

Chai-Adisaksopha C, Lam W, Hillis C. Major arterial events in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a meta-analysis. Leuk Lymphoma. 2016;57:1300–1310. doi: 10.3109/10428194.2015.1091929. PubMed DOI

Douxfils J, Haguet H, Mullier F, Chatelain C, Graux C, Dogné JM (2016) Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: a systematic review and meta-analysis. JAMA Oncol. doi:10.1001/jamaoncol.2015.5932 PubMed

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-Naїve Chronic Myeloid Leukemia Patients trial. J Clin Oncol. 2016;34:2333–2340. doi: 10.1200/JCO.2015.64.8899. PubMed DOI PMC

Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F, Boqué C, Chuah C, Bleickardt E, Bradley-Garelik MB, Zhu C, Szatrowski T, Shapiro D, Baccarani M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–2270. doi: 10.1056/NEJMoa1002315. PubMed DOI

Araujo JC, Trudel GC, Saad F, Armstrong AJ, Yu EY, Bellmunt J, Wilding G, McCaffrey J, Serrano SV, Matveev VB, Efstathiou E, Oudard S, Morris MJ, Sizer B, Goebell PJ, Heidenreich A, de Bono JS, Begbie S, Hong JH, Richardet E, Gallardo E, Paliwal P, Durham S, Cheng S, Logothetis CJ. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 2013;14:1307–1316. doi: 10.1016/S1470-2045(13)70479-0. PubMed DOI PMC

Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S, Hochhaus A, Guilhot F, Saglio G, Apperley J, Ottmann O, Shah N, Erben P, Branford S, Agarwal P, Gollerkeri A, Baccarani M. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109:3207–3213. doi: 10.1182/blood-2006-09-046888. PubMed DOI

Cortes J, Sawyers CL, Kantarjian H, Shah NP, Paquette R, Bleickardt E, Paliwal P, Talpaz M. Dasatinib is associated with durable treatment responses in chronic phase chronic myeloid leukemia: long-term follow-up from the phase I trial. Haematologica. 2008;93(suppl 1):47.

Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ, Amadori S, de Souza CA, Lipton JH, Hochhaus A, Heim D, Larson RA, Branford S, Muller MC, Agarwal P, Gollerkeri A, Talpaz M. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007;109:4143–4150. doi: 10.1182/blood-2006-09-046839. PubMed DOI

Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, Facon T, Goldberg SL, Cervantes F, Niederwieser D, Silver RT, Stone RM, Hughes TP, Muller MC, Ezzeddine R, Countouriotis AM, Shah NP. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303–2309. doi: 10.1182/blood-2006-09-047266. PubMed DOI

Huang XJ, Hu JD, Li JY, Jin J, Meng FY, Shen ZX, Liu T, Wu DP, Wang JM, Wang JX. Study on efficiency and safety of dasatinib in Chinese patients with chronic myelogenous leukemia who are resistant or intolerant to imatinib [in Chinese] Zhonghua Xue Ye Xue Za Zhi. 2012;33:889–895. PubMed

Kantarjian H, Cortes J, Kim DW, Dorlhiac-Llacer P, Pasquini R, DiPersio J, Müller MC, Radich JP, Khoury HJ, Khoroshko N, Bradley-Garelik MB, Zhu C, Tallman MS. 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;113:6322–6329. doi: 10.1182/blood-2008-11-186817. PubMed DOI PMC

Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, Robak T, Khoroshko N, Masszi T, Skotnicki A, Hellmann A, Zaritsky A, Golenkov A, Radich J, Hughes T, Countouriotis A, Shah N. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109:5143–5150. doi: 10.1182/blood-2006-11-056028. PubMed DOI

Shah NP, Kantarjian HM, Kim DW, Réa D, Dorlhiac-Llacer PE, Milone JH, Vela-Ojeda J, Silver RT, Khoury HJ, Charbonnier A, Khoroshko N, Paquette RL, Deininger M, Collins RH, Otero I, Hughes T, Bleickardt E, Strauss L, Francis S, Hochhaus A. 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;26:3204–3212. doi: 10.1200/JCO.2007.14.9260. PubMed DOI

Trudel GC, Paliwal P, Lainas I (2012) Dasatinib plus SMO antagonist versus dasatinib alone for treating patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP): design of CA180-363, a phase II open-label randomized trial. J Clin Oncol 30(suppl) (abstract TPS6634)

MedDRA Maintenance and Support Services Organization . Introductory guide to MedDRA version 15.0. Chantilly: International Federation of Pharmaceutical Manufacturers and Associations; 2012.

le Coutre PD, Hughes TP, Mahon FX, Kim DW, Steegmann JL, Shah NP, Gooden K, Wallis N, Cortes JE. Low incidence of peripheral arterial disease in patients receiving dasatinib in clinical trials. Leukemia. 2016;30:1593–1596. doi: 10.1038/leu.2015.352. PubMed DOI PMC

Abruzzese E, Breccia M, Latagliata R. Second-generation tyrosine kinase inhibitors in first-line treatment of chronic myeloid leukaemia (CML) BioDrugs. 2014;28:17–26. doi: 10.1007/s40259-013-0056-z. PubMed DOI

Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM, ENESTnd Investigators Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–2259. doi: 10.1056/NEJMoa0912614. PubMed DOI

Rea D, Mirault T, Raffoux E, Miclea J-M, Rousselot P, Dombret H, Messas E. Identification of patients (pts) with chronic myeloid leukemia (CML) at high risk of artery occlusive events (AOE) during treatment with the 2nd generation tyrosine kinase inhibitor (TKI) nilotinib, using risk stratification for cardiovascular diseases (CVD) Blood. 2013;122:2726.

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 (2013) A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369:1783–1796 PubMed PMC

Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio JF, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Muller MC, Gambarcorti-Passerini C, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Shah NP, Kantarjian H. Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial. Blood. 2014;124:3135. PubMed PMC

Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB, American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–e322. doi: 10.1161/CIR.0000000000000152. PubMed DOI

Paquette R, Mauro M, Simonsson B, Abruzzese E, Andorksy D, Hansen R, Subar M, Turner M, Zyczynski T, Mohamed H, Goldberg SL. Cardiovascular (CV)-related hospitialization in patients with chronic-phase chronic myeloid leukemia (CP-CML) in SIMPLICITY, a prospective observational study. Haematologica. 2015;100(suppl 1):437.

Conteduca V, Di Lorenzo G, Tartarone A, Aieta M. The cardiovascular risk of gonadotropin releasing hormone agonists in men with prostate cancer: an unresolved controversy. Crit Rev Oncol Hematol. 2013;86:42–51. doi: 10.1016/j.critrevonc.2012.09.008. PubMed DOI