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Annals of Hematology

, Volume 96, Issue 4, pp 549–558 | Cite as

Identification, prevention and management of cardiovascular risk in chronic myeloid leukaemia patients candidate to ponatinib: an expert opinion

  • Massimo BrecciaEmail author
  • Patrizia Pregno
  • Paolo Spallarossa
  • Eleonora Arboscello
  • Fabio Ciceri
  • Mauro Giorgi
  • Alberto Grossi
  • Mario Mallardo
  • Savina Nodari
  • Stefano Ottolini
  • Carla Sala
  • Giovanni Tortorella
  • Gianantonio Rosti
  • Fabrizio Pane
  • Giorgio Minotti
  • Michele Baccarani
Review Article

Abstract

Ponatinib (Iclusig, ARIAD Pharmaceuticals-Incyte Co.) is a third-generation structure-guided tyrosine kinase inhibitor that is approved for treatment of Philadelphia chromosome-positive leukaemias resistant or intolerant to other inhibitors. The clinical use of ponatinib is complicated by the possible development of cardiovascular events, primarily hypertension and arterial or venous thrombotic events. The US Food and Drug Administration and the European Medicine Agency recommend that the cardiovascular profile of patients candidate for ponatinib should be carefully evaluated. For patients deemed to carry a high risk of cardiovascular events, other life-saving therapeutic options should be considered. When alternative options are not available, treatment with ponatinib is indicated but requires that haematologists and cardiologists collaborate and identify modalities of surveillance and risk mitigation in the best interest of the patient. This article reports on the expert opinion provided by a panel of Italian haematologists, cardiologists and clinical pharmacologists. It summarises suggestions that may help to improve the therapeutic index of ponatinib, primarily in the settings of chronic-phase chronic myeloid leukaemia.

Keywords

Chronic myeloid leukaemia Ponatinib Cardiovascular risk Assessment Management 

Abbreviations

TKI

Tyrosine kinase inhibitor

VEGF

Vascular endothelial growth factor

CML

Chronic myeloid leukaemia

AP

Acute phase

CP

Chronic phase

BC

Blastic crisis

Ph+

Philadelphia chromosome positive

MCyR

Major cytogenetic response

CCyR

Complete cytogenetic response

MMR

Major molecular response

MR4.5

Deep molecular response

PFS

Progression-free survival

OS

Overall survival

(S)AE

(Serious) adverse event

ALL

Acute lymphoblastic leukaemia

GCP

Good clinical practice

ESC

European Society of Cardiology

ESH

European Society of Hypertension

LVEF

Left ventricle ejection fraction

ABI

Ankle brachial index

SCORE

Systematic coronary risk evaluation

CHA2DS2VASc score

Congestive heart failure, hypertension, age ≥75 years (doubled), diabetes mellitus, stroke (doubled), vascular disease, age 65–74 years, sex category

HAS-BLED score

Hypertension, abnormal renal and liver function, stroke, bleeding, labile INRs, elderly and drugs or alcohol

INR

International normalised ratio

NOA

New oral anticoagulants

LMWH

Low molecular weight heparin

(N)STEMI

(Non)ST elevation myocardial infarction

ARB

Angiotensin II receptor blocker

DASH

Dietary approaches to stop hypertension

Notes

Compliance with ethical standards

Conflict of interests

The authors declare that they have no conflict of interest.

References

  1. 1.
    Hoy SM (2014) Ponatinib: a review of its use in adults with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Drugs 74:793–806CrossRefPubMedGoogle Scholar
  2. 2.
    Zhou T, Commodore L, Huang WS et al (2011) Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem Biol Drug Des 77:1–11CrossRefPubMedGoogle Scholar
  3. 3.
    O’Hare T, Shakespeare WC, Zhu X et al (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16:401–412CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Cortes JE, Kantarjian H, Shah NP et al (2012) Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 367:2075–2088CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Talpaz M, Cortes JE, Kantarjian H et al (2014) Long-term follow-up of a phase 1 study of ponatinib in patients with chronic phase chronic myeloid leukemia. Blood 124:4558AGoogle Scholar
  6. 6.
    Cortes JE, Kim DW, Pinilla-Ibarz J et al (2013) A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369:1783–1796CrossRefPubMedGoogle Scholar
  7. 7.
    Hochhaus A, Cortes JE, Kim D-W et al (2015) Efficacy and safety of ponatinib in CP-CML patients by number of prior tyrosine kinase inhibitors: 4-year follow-up of the phase 2 PACE trial. Blood 126:4025AGoogle Scholar
  8. 8.
    Gainor JF, Chabner BA (2015) Ponatinib: accelerated disapproval. Oncologist 20:847–848CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lipton J, Chuah C, Guerci-Bresler A et al (2014) EPIC: a phase 3 trial of ponatinib compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CP-CML). Blood 124:519ACrossRefGoogle Scholar
  10. 10.
    Kantarjian HM, Kim D-W, Pinilla-Ibarz J et al (2014) Ponatinib in patients (pts) with Philadelphia chromosome-positive (Ph+) leukemias resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation: longer-term follow up of the PACE trial. J Clin Oncol 32(5S):7081AGoogle Scholar
  11. 11.
    Cortes JE, Kim D-W, Pinilla-Ibarz J et al (2014) Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial. Blood 124:3135AGoogle Scholar
  12. 12.
    Mauro MJ, Talpaz M, Cortes JE, et al. (2015) Four-year minimum follow-up for patients with chronic-phase chronic myeloid leukemia continuing to receive ponatinib in a phase 1 trial. European School of Haematology, 17th Annual John Goldman Conference on Chronic Myeloid Leukemia: Biology and Therapy (abstract)Google Scholar
  13. 13.
    Huang WS, Metcalf CA, Sundaramoorthi R et al (2010) Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl) phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem 53:4701–4719CrossRefPubMedGoogle Scholar
  14. 14.
    Perk J, De Backer G, Gohlke H et al (2012) European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 33:1635–1701CrossRefPubMedGoogle Scholar
  15. 15.
    Mancia G, Fagard R, Narkiewicz K et al (2013) 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 34:2159–2219CrossRefPubMedGoogle Scholar
  16. 16.
    Leng GC, Fowkes FG (1992) The Edinburgh Claudication Questionnaire: an improved version of the WHO/Rose Questionnaire for use in epidemiological surveys. Clin Epidemiol 45:1101–1109CrossRefGoogle Scholar
  17. 17.
    Heiblig M, Sobh M, Nicolini FE (2014) Subcutaneous omocetaxine mepesuccinate in patients with chronic myeloid leukemia in tyrosine kinase inhibitor-resistant patients: review and perspectives. Leuk Res 38:1145–1153CrossRefPubMedGoogle Scholar
  18. 18.
    European Stroke Organisation, Tendera M, Aboyans V (2011) ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 32:2851–2906CrossRefGoogle Scholar
  19. 19.
    Conroy RM, Pyörälä K, Fitzgerald AP et al (2003) Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 24:987–1003CrossRefPubMedGoogle Scholar
  20. 20.
    Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ (2010) Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest 137:263–272CrossRefPubMedGoogle Scholar
  21. 21.
    European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U et al (2010) Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 31:2369–2429CrossRefGoogle Scholar
  22. 22.
    Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY (2010) A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 138:1093–1100CrossRefPubMedGoogle Scholar
  23. 23.
    Heidbuchel H, Verhamme P, Alings M et al (2015) Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 17:1467–1507CrossRefPubMedGoogle Scholar
  24. 24.
    Committee for Medicinal Products for Human Use (2014) Annex 1, summary of product characteristics., pp 1–60Google Scholar
  25. 25.
    Task Force Members, Windecker S, Kolh P et al (2014) 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 35:2541–2619CrossRefGoogle Scholar
  26. 26.
    Lip GY (2008) Don’t add aspirin for associated stable vascular disease in a patient with atrial fibrillation receiving anticoagulation. BMJ 336:614–615CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Konstantinides SV, Torbicki A, Agnelli G et al (2014) 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 35:3033–3069CrossRefPubMedGoogle Scholar
  28. 28.
    Loren CP, Aslan JE, Rigg RA et al (2015) The BCR-ABL inhibitor ponatinib inhibits platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling, platelet activation and aggregate formation under shear. Thromb Res 135:155–160CrossRefPubMedGoogle Scholar
  29. 29.
    Neelakantan P, Marin D, Laffan M et al (2012) Platelet dysfunction associated with ponatinib, a new pan BCR-ABL inhibitor with efficacy for chronic myeloid leukemia resistant to multiple tyrosine kinase inhibitor therapy. Haematologica 97:1444CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Nazha A, Romo CG, Kantarjian H, Cortes J (2013) The clinical impact of ponatinib on the risk of bleeding in patients with chronic myeloid leukemia. Haematologica 98:e131CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    American Diabetes Association (2012) Diagnosis and classification of diabetes mellitus. Diabetes Care 35:S64–S71CrossRefGoogle Scholar
  32. 32.
    Authors/Task Force Members, Rydén L, Grant PJ et al (2013) ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 34:3035–3087CrossRefGoogle Scholar
  33. 33.
    Nicolini FE, Cortes JE, Kim D-W, et al. (2014) Dose intensity on response to ponatinib in patients with Philadelphia chromosome-positive leukemias. 19th Congress of the European Hematology Association, 894AGoogle Scholar
  34. 34.
    Knickerbocker R, Dorer D, Haluska F et al (2014) Impact of dose intensity of ponatinib on selected adverse events: multivariate analysis from a pooled population of clinical trial patients. Blood 124:4546AGoogle Scholar
  35. 35.
    Steegmann JL, Baccarani M, Breccia M et al (2016) European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. doi: 10.1038/leu.2016.104 Google Scholar
  36. 36.
    Valent P, Hadzijusufovic E, Schernthaner G-H et al (2015) Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood 125:901–906CrossRefPubMedGoogle Scholar
  37. 37.
    Moslehi JJ, Deininger M (2015) Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol 33:4210–4218CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Gozgit JM, Song Y, Baker T, et al. (2015) Comparative analysis of BCR-ABL and VEGFR2 inhibitory activities of ponatinib, PF-114, and axitinib. 25th Meeting of the European School of Hematology, 1075AGoogle Scholar
  39. 39.
    Rivera VM, Pritchard JR, Gonzalvez F et al (2014) Comparative TKI profiling analyses to explore potential mechanisms of ponatinib-associated arterial adverse events. Blood 124:1784AGoogle Scholar
  40. 40.
    Saneei P, Salehi-Abargouei A, Esmaillzadeh A, Azadbakht L (2014) Influence of dietary approaches to stop hypertension (DASH) diet on blood pressure: a systematic review and meta-analysis on randomized controlled trials. Nutr Metab Cardiovasc Dis 24:1253–1261CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Massimo Breccia
    • 1
    Email author
  • Patrizia Pregno
    • 2
  • Paolo Spallarossa
    • 3
  • Eleonora Arboscello
    • 4
  • Fabio Ciceri
    • 5
  • Mauro Giorgi
    • 6
  • Alberto Grossi
    • 7
  • Mario Mallardo
    • 8
  • Savina Nodari
    • 9
  • Stefano Ottolini
    • 10
  • Carla Sala
    • 11
  • Giovanni Tortorella
    • 12
  • Gianantonio Rosti
    • 13
  • Fabrizio Pane
    • 14
  • Giorgio Minotti
    • 15
  • Michele Baccarani
    • 13
  1. 1.Department of Cellular Biotechnologies and HematologySapienza University-Azienda Policlinico Umberto 1RomeItaly
  2. 2.S.C. Ematologia, Dip. di Oncologia ed EmatologiaA.O.U.Città della Salute e della Scienza di TorinoRomeItaly
  3. 3.Clinica Malattie dell’Apparato CardiovascolareIRCCS AOU San MartinoGenoaItaly
  4. 4.Dipartimento di Medicina InternaUniversità degli Studi di GenovaGenoaItaly
  5. 5.Servizio Immunoematologia TrasfusionaleIRCCS San RaffaeleMilanoItaly
  6. 6.S.C. Cardiologia U., Dip. Cardiovascolare e ToracicoA.O.U.Città della Salute e della Scienza di TorinoTurinItaly
  7. 7.Ematologia Istituto Leonardo Da VinciFlorenceItaly
  8. 8.U.O.C. di Cardiologia e Riabilitazione CardiologicaOsp. San GennaroNapoliItaly
  9. 9.Dipartimento di Cardiologia e Chirurgia CardiotoracicaSpedali CiviliBresciaItaly
  10. 10.Centro Medico EcograficoPaviaItaly
  11. 11.UOC Malattie Cardiovascolari-IRCCS PoliclinicoUniversità di MilanoMilanItaly
  12. 12.CardiologiaArcispedale S. Maria NuovaReggio EmiliaItaly
  13. 13.Dipartimento di Ematologia e Oncologia “L. e A. Seràgnoli”Università di BolognaBolognaItaly
  14. 14.UO Ematologia e Trapianti di MidolloPoliclinico di NapoliItaly
  15. 15.Dip. MedicinaUniversità Campus Bio-MedicoRomeItaly

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