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Adverse Events Associated with ATP-Competitive BCR-ABL1 Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

Part of the book series: Hematologic Malignancies ((HEMATOLOGIC))

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Abstract

Long-term survival without transformation to blast phase CML has become a reality in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 oncoprotein. However, the majority of patients need to be treated during their entire lifespan; thus outcome does not solely depend on treatment efficacy but also on how well therapy is tolerated. Although TKIs have shown an overall favorable efficacy versus toxicity balance, many patients may encounter drug-related adverse events. These usually occur early after treatment initiation, are mild to moderate in intensity and resolve spontaneously, or are easily controlled with adequate supportive care, TKI dose reduction, or switch to an alternative TKI. However, evidence has emerged that second- and third- generation TKIs may sometimes threaten vital organs such as the cardiovascular system, the lung, and the liver, especially when comorbidities are present. Thus the decision regarding which TKI should be used and at what dose must take into account CML-related, TKI-related, and patient-related variables. The purpose of this chapter is to provide an up-to-date review of common adverse events associated with TKIs and how these events may be managed.

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References

  1. Sasaki K, Strom SS, O’Brien S, Jabbour E, Ravandi F, Konopleva M, Borthakur G, Pemmaraju N, Daver N, Jain P, Pierce S, Kantarjian H, Cortes JE. Relative survival in patients with chronic-phase chronic myeloid leukemia in the tyrosine kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015;2:e189–93.

    Article  Google Scholar 

  2. Bower H, Björkholm M, Dickman PW, Höglund 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.

    Article  CAS  PubMed  Google Scholar 

  3. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O'Brien SG, Druker BJ, IRIS Investigators. 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 

  4. Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, Hanfstein B, Proetel U, Fabarius A, Krause SW, Rinaldetti S, Dengler J, Falge C, Oppliger-Leibundgut E, Burchert A, Neubauer A, Kanz L, Stegelmann F, Pfreundschuh M, Spiekermann K, Scheid C, Pfirrmann M, Hochhaus A, Hasford J, Hehlmann R. 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 

  5. Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, Neubauer A, Hossfeld DK, Nerl C, Gratwohl A, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Müller MC, Jeromin S, Proetel U, Kohlbrenner K, Voskanyan A, Rinaldetti S, Seifarth W, Spieß B, Balleisen L, Goebeler MC, Hänel M, Ho A, Dengler J, Falge C, Kanz L, Kremers S, Burchert A, Kneba M, Stegelmann F, Köhne CA, Lindemann HW, Waller CF, Pfreundschuh M, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Pezzutto A, Schenk M, Brossart P, Geer T, Bildat S, Schäfer E, Hochhaus A, Hasford J. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017;31:2398–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rea D, Cayuela JM. Treatment-free remission in patients with chronic myeloid leukemia. Int J Hematol. 2018;108:355–64.

    Article  PubMed  Google Scholar 

  8. 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;26:3204–12.

    Article  CAS  PubMed  Google Scholar 

  9. 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;362:2260–70.

    Article  CAS  PubMed  Google Scholar 

  10. 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 Oncol. 2016;34:2333–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, Hochhaus A, Radich JP, Saglio G, Hughes TP, Martinelli G, Kim DW, Shou Y, Gallagher NJ, Blakesley R, Baccarani M, Cortes J, le Coutre PD. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117:1141–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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;362:2251–9.

    Article  CAS  PubMed  Google Scholar 

  13. 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;30:1044–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hughes TP, Saglio G, Larson RA, Kantarjian HM, Kim D-W, Issaragrisil S, Le Coutre P, Etienne G, Boquimpani C, Clark RE, Dubruille V, Flinn IW, Kyrcz-Krzemien S, Medras E, Zanichelli M, Bendit I, Sondhi M, Titorenko K, Nourry-Boulot C, Aimone P, Hochhaus A. Long-term outcomes in patients with chronic myeloid leukemia in chronic phase receiving frontline nilotinib versus imatinib: Enestnd 10-year analysis. Blood. 2019;134(Supplement_1):2924.

    Article  Google Scholar 

  15. Gambacorti-Passerini C, Cortes JE, Lipton JH, Kantarjian HM, Kim DW, Schafhausen P, Crescenzo R, Bardy-Bouxin N, Shapiro M, Noonan K, Leip E, DeAnnuntis L, Brümmendorf TH, Khoury HJ. 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 

  16. Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Dyagil I, Glushko N, Milojkovic D, le Coutre P, Garcia-Gutierrez V, Reilly L, Jeynes-Ellis A, Leip E, Bardy-Bouxin N, Hochhaus A, Brümmendorf TH. 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 

  17. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, Di Persio 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. N Engl J Med. 2013;369:1783–96.

    Article  CAS  PubMed  Google Scholar 

  18. 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;132:393–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, Mathieson T, Perrin J, Raida M, Rau C, Reader V, Sweetman G, Bauer A, Bouwmeester T, Hopf C, Kruse U, Neubauer G, Ramsden N, Rick J, Kuster B, Drewes G. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 2007;25:1035–44.

    Article  CAS  PubMed  Google Scholar 

  20. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Müller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009;23:477–85.

    Article  CAS  PubMed  Google Scholar 

  21. Huang WS, Metcalf CA, Sundaramoorthi R, Wang Y, Zou D, Thomas RM, Zhu X, Cai L, Wen D, Liu S, Romero J, Qi J, Chen I, Banda G, Lentini SP, Das S, Xu Q, Keats J, Wang F, Wardwell S, Ning Y, Snodgrass JT, Broudy MI, Russian K, Zhou T, Commodore L, Narasimhan NI, Mohemmad QK, Iuliucci J, Rivera VM, Dalgarno DC, Sawyer TK, Clackson T, Shakespeare WC. 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. 2010;53:4701–19.

    Article  CAS  PubMed  Google Scholar 

  22. Steegmann JL, Baccarani M, Breccia M, Casado LF, García-Gutiérrez V, Hochhaus A, Kim DW, Kim TD, Khoury HJ, Le Coutre P, Mayer J, Milojkovic D, Porkka K, Rea D, Rosti G, Saussele S, Hehlmann R, Clark RE. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30:1648–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rabian F, Lengline E, Rea D. Towards a personalized treatment of chronic myeloid leukemia. Curr Hematol Malig Rep. 2019;14:492–500.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Mustjoki S, Richter J, Barbany G, Ehrencrona H, Fioretos T, Gedde-Dahl T, Gjertsen BT, Hovland R, Hernesniemi S, Josefsen D, Koskenvesa P, Dybedal I, Markevärn B, Olofsson T, Olsson-Strömberg U, Rapakko K, Thunberg S, Stenke L, Simonsson B, Porkka K, Hjorth-Hansen H, Nordic CML Study Group (NCMLSG). Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients. Leukemia. 2013;27:1520–6.

    Article  CAS  PubMed  Google Scholar 

  25. Bumm T, Müller C, Al-Ali HK, Krohn K, Shepherd P, Schmidt E, Leiblein S, Franke C, Hennig E, Friedrich T, Krahl R, Niederwieser D, Deininger MW. Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood. 2003;101:1941–9.

    Article  CAS  PubMed  Google Scholar 

  26. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ. IRIS investigators. 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 

  27. Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA, IRIS Investigators. 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 

  28. Sneed TB, Kantarjian HM, Talpaz M, O'Brien S, Rios MB, Bekele BN, Zhou X, Resta D, Wierda W, Faderl S, Giles F, Cortes JE. The significance of myelosuppression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase. Cancer. 2004;100:116–21.

    Article  CAS  PubMed  Google Scholar 

  29. Quintas-Cardama A, Kantarjian H, O'Brien S, Garcia-Manero G, Rios MB, Talpaz M, Cortes J. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer. 2004;100:2592–7.

    Article  CAS  PubMed  Google Scholar 

  30. Cortes J, O'Brien S, Quintas A, Giles F, Shan J, Rios MB, Talpaz M, Kantarjian H. Erythropoietin is effective in improving the anemia induced by imatinib mesylate therapy in patients with chronic myeloid leukemia in chronic phase. Cancer. 2004;100:2396–402.

    Article  CAS  PubMed  Google Scholar 

  31. Shoukier M, Borthakur G, Jabbour E, Ravandi F, Garcia-Manero G, Kadia T, Matthews J, Masarova L, Naqvi K, Sasaki K, Verstovsek S, Cortes J. The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis. https://doi.org/10.3324/haematol.2020.260125

  32. Amitay-Maish I, Stemmer SM, Lacouture ME. Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib and dasatinib. Dermatol Ther. 2011;24:386–95.

    Article  Google Scholar 

  33. Brazzelli V, Grasso V, Borroni G. Imatinib, dasatinib and nilotinib: a review of adverse cutaneous reactions with emphasis on our clinical experience. J Eur Acad Dermatol Venereol. 2013;27:1471–80.

    Article  CAS  PubMed  Google Scholar 

  34. Patel AB, Solomon AR, Mauro MJ, Ehst BD. Unique cutaneous reaction to second- and third-generation tyrosine kinase inhibitors for chronic myeloid leukemia. Dermatology. 2016;232:122–5.

    Article  CAS  PubMed  Google Scholar 

  35. Tanaka C, Yin OQ, Sethuraman V, Smith T, Wang X, Grouss K, Kantarjian H, Giles F, Ottmann OG, Galitz L, Schran H. Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib. Clin Pharmacol Ther. 2010;87:197–203.

    Article  CAS  PubMed  Google Scholar 

  36. Quintás-Cardama A, Kantarjian H, Ravandi F, O'Brien S, Thomas D, Vidal-Senmache G, Wierda W, Kornblau S, Cortes J. Bleeding diathesis in patients with chronic myelogenous leukemia receiving dasatinib therapy. Cancer. 2009;115:2482–90.

    Article  PubMed  CAS  Google Scholar 

  37. Patodi N, Sagar N, Rudzki Z, Langman G, Sharma N. Haemorrhagic colitis caused by dasatinib. Case Rep Hematol. 2012;2012:417106.

    PubMed  PubMed Central  Google Scholar 

  38. Quintás-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009;114:261–3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Ong J, Yeung D, Filshie R, Hughes TP, Nandurkar H. Imatinib-induced gastric antral vascular ectasia in three patients with chronic myeloid leukaemia. Int J Hematol. 2015;102:639–42.

    Article  CAS  PubMed  Google Scholar 

  40. Deininger MW, O'Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol. 2003;21:1637–47.

    Article  CAS  PubMed  Google Scholar 

  41. Singer JB, Shou Y, Giles F, Kantarjian HM, Hsu Y, Robeva AS, Rae P, Weitzman A, Meyer JM, Dugan M, Ottmann OG. UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia. Leukemia. 2007;21:2311–5.

    Article  CAS  PubMed  Google Scholar 

  42. Rosti G, Castagnetti F, Gugliotta G, Palandri F, Baccarani M. Physician's guide to the clinical management of adverse events on nilotinib therapy for the treatment of CML. Cancer Treat Rev. 2012;38:241–8.

    Article  PubMed  Google Scholar 

  43. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O'Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hohenegger M. Drug induced rhabdomyolysis. Curr Opin Pharmacol. 2012;12:335–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Breccia M, D'Elia GM, D'Andrea M, Latagliata R, Alimena G. Pleural-pericardic effusion as uncommon complication in CML patients treated with Imatinib. Eur J Haematol. 2005;74:89–90.

    Article  PubMed  Google Scholar 

  46. Esmaeli B, Prieto VG, Butler CE, Kim SK, Ahmadi MA, Kantarjian HM, Talpaz M. Severe periorbital edema secondary to STI571 (Gleevec). Cancer. 2002;95:881–7.

    Article  PubMed  Google Scholar 

  47. Moore JC, Dennehey CF, Anavim A, Kong KM, Tiong OS. Multiple joint effusions associated with high-dose imatinib therapy in a patient with chronic myelogenous leukaemia. Eur J Haematol. 2006;76:444–6.

    Article  PubMed  Google Scholar 

  48. Hughes TP, Laneuville P, Rousselot P, Snyder DS, Rea D, Shah NP, Paar D, Abruzzese E, Hochhaus A, Lipton JH, Cortes JE. Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia. Haematologica. 2019;104:93–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brümmendorf TH, Porkka K, Martinelli G, Durrant S, Leip E, Kelly V, Turnbull K, Besson N, Gambacorti-Passerini C. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014;123:1309–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, Zaritskey A, Countouriotis A, Besson N, Leip E, Kelly V, Brümmendorf TH. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119:3403–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bergeron A, Réa D, Levy V, Picard C, Meignin V, Tamburini J, Bruzzoni-Giovanelli H, Calvo F, Tazi A, Rousselot P. Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. Am J Respir Crit Care Med. 2007;176:814–8.

    Article  CAS  PubMed  Google Scholar 

  52. Goldblatt M, Huggins JT, Doelken P, Gurung P, Sahn SA. Dasatinib-induced pleural effusions: a lymphatic network disorder? Am J Med Sci. 2009;338:414–7.

    Article  PubMed  Google Scholar 

  53. Montani D, Bergot E, Günther S, Savale L, Bergeron A, Bourdin A, Bouvaist H, Canuet M, Pison C, Macro M, Poubeau P, Girerd B, Natali D, Guignabert C, Perros F, O'Callaghan DS, Jaïs X, Tubert-Bitter P, Zalcman G, Sitbon O, Simonneau G, Humbert M. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125:2128–37.

    Article  CAS  PubMed  Google Scholar 

  54. Montani D, Seferian A, Savale L, Simonneau G, Humbert M. Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev. 2013;22:244–50.

    Article  PubMed  Google Scholar 

  55. Riou M, Seferian A, Savale L, Chaumais MC, Guignabert C, Canuet M, Magro P, Rea D, Sitbon O, Jaïs X, Humbert M, Montani D. Deterioration of pulmonary hypertension and pleural effusion with bosutinib following dasatinib lung toxicity. Eur Respir J. 2016;48:1517–9.

    Article  PubMed  Google Scholar 

  56. Shah NP, Wallis N, Farber HW, Mauro MJ, Wolf RA, Mattei D, Guha M, Rea D, Peacock A. Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. Am J Hematol. 2015;90:1060–4.

    Article  CAS  PubMed  Google Scholar 

  57. des Guetz G, Uzzan B, Chouahnia K, Morère JF. Cardiovascular toxicity of anti-angiogenic drugs. Target Oncol. 2011;6:197–202.

    Article  PubMed  Google Scholar 

  58. Saussele S, Haverkamp W, Lang F, Koschmieder S, Kiani A, Jentsch-Ullrich K, Stegelmann F, Pfeifer H, La Rosée P, Goekbuget N, Rieger C, Waller CF, Franke GN, le Coutre P, Kirchmair R, Junghanss C. Ponatinib in the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute leukemia: recommendations of a German expert consensus panel with focus on cardiovascular management. Acta Haematol. 2020;143:217–31.

    Article  CAS  PubMed  Google Scholar 

  59. Kerkelä R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, Van Etten RA, Alroy J, Durand JB, Force T. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908–16.

    Article  PubMed  CAS  Google Scholar 

  60. Breccia M, Cannella L, Frustaci A, Stefanizzi C, Levi A, Alimena G. Cardiac events in imatinib mesylate-treated chronic myeloid leukemia patients: a single institution experience. Leuk Res. 2008;32:835–6.

    Article  CAS  PubMed  Google Scholar 

  61. Atallah E, Durand JB, 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 

  62. Dorer DJ, Knickerbocker RK, Baccarani M, Cortes JE, Hochhaus A, Talpaz M, Haluska FG. 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 

  63. Hochhaus A, Breccia M, Saglio G, García-Gutiérrez V, Réa D, Janssen J, Apperley J. Expert opinion-management of chronic myeloid leukemia after resistance to second-generation tyrosine kinase inhibitors. Leukemia. 2020;34:1495–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Aichberger KJ, Herndlhofer S, Schernthaner GH, Schillinger M, Mitterbauer-Hohendanner G, Sillaber C, Valent P. 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 

  65. Le Coutre P, Rea D, Abruzzese E, Dombret H, Trawinska MM, Herndlhofer S, Dörken B, Valent P. Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst. 2011;103:1347–8.

    Article  PubMed  CAS  Google Scholar 

  66. Rea D, Mirault T, Raffoux E, Boissel N, Andreoli AL, Rousselot P, Dombret H, Messas E. Usefulness of the 2012 European CVD risk assessment model to identify patients at high risk of cardiovascular events during nilotinib therapy in chronic myeloid leukemia. Leukemia. 2015;29:1206–9.

    Article  CAS  PubMed  Google Scholar 

  67. Rea D, Ame S, Charbonnier A, Coiteux V, Cony-Makhoul P, Escoffre-Barbe M, Etienne G, Gardembas M, Guerci-Bresler A, Legros L, Nicolini F, Tulliez M, Hermet E, Huguet F, Johnson-Ansah H, Lapusan S, Quittet P, Rousselot P, Mahon FX, Messas E. Management of the cardiovascular disease risk during nilotinib treatment in chronic myeloid leukemia: 2015 recommendations from the France Intergroupe des Leucémies Myéloïdes Chroniques. Bull Cancer. 2016;103:180–9.

    Article  PubMed  Google Scholar 

  68. Berman E, Nicolaides M, Maki RG, Fleisher M, Chanel S, Scheu K, Wilson BA, Heller G, Sauter NP. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med. 2006;354:2006–13.

    Article  CAS  PubMed  Google Scholar 

  69. O'Sullivan S, Horne A, Wattie D, Porteous F, Callon K, Gamble G, Ebeling P, Browett P, Grey A. Decreased bone turnover despite persistent secondary hyperparathyroidism during prolonged treatment with imatinib. J Clin Endocrinol Metab. 2009;94:1131–6.

    Article  CAS  PubMed  Google Scholar 

  70. Alemán JO, Farooki A, Girotra M. Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies. Endocr Relat Cancer. 2014;21:R247–59.

    Article  PubMed  CAS  Google Scholar 

  71. Narayanan KR, Bansal D, Walia R, Sachdeva N, Bhansali A, Varma N, Marwaha RK. Growth failure in children with chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF-1 axis. Pediatr Blood Cancer. 2013;60:1148–53.

    Article  CAS  PubMed  Google Scholar 

  72. Hijiya N, Suttorp M. How I treat chronic myeloid leukemia in children and adolescents. Blood. 2019;133:2374–84.

    Article  CAS  PubMed  Google Scholar 

  73. Racil Z, Koritakova E, Sacha T, Klamova H, Belohlavkova P, Faber E, Rea D, Malaskova L, Prochazkova J, Zackova D, Voglova J, Wącław J, Cetkovsky P, Zak P, Mayer J. Insulin resistance is an underlying mechanism of impaired glucose metabolism during nilotinib therapy. Am J Hematol. 2018;93:E342–5.

    Article  PubMed  Google Scholar 

  74. Rea D, Mirault T, Cluzeau T, Gautier JF, Guilhot F, Dombret H, Messas E. Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia. Haematologica. 2014;99:1197–203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Veneri D, Franchini M, Bonora E. Imatinib and regression of type 2 diabetes. N Engl J Med. 2005;352:1049–50.

    Article  CAS  PubMed  Google Scholar 

  76. Gottardi M, Manzato E, Gherlinzoni F. Imatinib and hyperlipidemia. N Engl J Med. 2005;353:2722–3.

    Article  CAS  PubMed  Google Scholar 

  77. Kim TD, Schwarz M, Nogai H, Grille P, Westermann J, Plöckinger U, Braun D, Schweizer U, Arnold R, Dörken B, le Coutre P. Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia. Thyroid. 2010;20:1209–14.

    Article  CAS  PubMed  Google Scholar 

  78. Samis J, Lee P, Zimmerman D, Arceci RJ, Suttorp M, Hijiya N. Recognizing Endocrinopathies associated with tyrosine kinase inhibitor therapy in children with chronic myelogenous leukemia. Pediatr Blood Cancer. 2016;63:1332–8.

    Article  PubMed  Google Scholar 

  79. de Groot JW, Zonnenberg BA, Plukker JT, van Der Graaf WT, Links TP. Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther. 2005;78:433–8.

    Article  PubMed  CAS  Google Scholar 

  80. Miranda MB, Lauseker M, Kraus M-P, Proetel U, Hanfstein B, Fabarius A, Baerlocher GM, Heim D, Hossfeld DK, Kolb H-J, Krause SW, Nerl C, Brümmendorf TH, Verbeek W, Fauser AA, Prümmer O, Neben K, Hess U, Mahlberg R, Plöger C, Flasshove M, Rendenbach B, Hofmann W-K, Müller MC, Pfirrmann M, Hochhaus A, Hasford J, Hehlmann R, Saußele S. Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML study IV. Leukemia. 2016;30:1255–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, Wang J, Ipiña JJ, Kim DW, Ogura M, Pavlovsky C, Junghanss C, Milone JH, Nicolini FE, Robak T, Van Droogenbroeck J, Vellenga E, Bradley-Garelik MB, Zhu C, Hochhaus A. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119:1123–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ando T, Kojima K, Isoda H, Eguchi Y, Honda T, Ishigami M, Kimura S. Reactivation of resolved infection with the hepatitis B virus immune escape mutant G145R during dasatinib treatment for chronic myeloid leukemia. Int J Hematol. 2015;102:379–82.

    Article  CAS  PubMed  Google Scholar 

  83. Ikeda K, Shiga Y, Takahashi A, Kai T, Kimura H, Takeyama K, Noji H, Ogawa K, Nakamura A, Ohira H, Sato Y, Maruyama Y. Fatal hepatitis B virus reactivation in a chronic myeloid leukemia patient during imatinib mesylate treatment. Leuk Lymphoma. 2006;47:155–7.

    Article  CAS  PubMed  Google Scholar 

  84. Lai G-M, Yan S-L, Chang C-S, Tsai C-Y. Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor. World J Gastroenterol. 2013;19:1318–21.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Bernal-Bello D, Jaenes-Barrios B, Morales-Ortega A, Ruiz-Giardin JM, García-Bermúdez V, Frutos-Pérez B, Farfán-Sedano AI, de Ancos-Aracil C, Bermejo F, García-Gil M, Zapatero-Gaviria A, San Martín-López JV. Imatinib might constitute a treatment option for lung involvement in COVID-19. Autoimmun Rev. 2020;19:102565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Marcolino MS, Boersma E, Clementino NC, Macedo AV, Marx-Neto AD, Silva MH, van Gelder T, Akkerhuis KM, Ribeiro AL. Imatinib treatment duration is related to decreased estimated glomerular filtration rate in chronic myeloid leukemia patients. Ann Oncol. 2011;22:2073–9.

    Article  CAS  PubMed  Google Scholar 

  87. Vidal-Petiot E, Rea D, Serrano F, Stehlé T, Gardin C, Rousselot P, Peraldi M-N, Flamant M. Imatinib increases serum creatinine by inhibiting its tubular secretion in a reversible fashion in chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2016;16:169–74.

    Article  PubMed  Google Scholar 

  88. Cortes JE, Gambacorti-Passerini C, Kim DW, Kantarjian HM, Lipton JH, Lahoti A, Talpaz M, Matczak E, Barry E, Leip E, Brümmendorf TH, Khoury HJ. Effects of Bosutinib Treatment on Renal Function in Patients with Philadelphia Chromosome-Positive Leukemias. Clin Lymphoma Myeloma Leuk. 2017;17:684–95.

    Article  PubMed  Google Scholar 

  89. Cortes JE, Apperley JF, DeAngelo DJ, Deininger MW, Kota VK, Rousselot P, Gambacorti-Passerini C. Management of adverse events associated with bosutinib treatment of chronic-phase chronic myeloid leukemia: expert panel review. J Hematol Oncol. 2018;11:143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Service d’Hématologie Adulte, Hôpital Saint-Louis, AP-HP, Paris, France

    Delphine Rea

  2. France Intergroupe des Leucémies Myéloïdes chroniques, Fi-LMC, Lyon, France

    Delphine Rea

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    Rüdiger Hehlmann

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Rea, D. (2021). Adverse Events Associated with ATP-Competitive BCR-ABL1 Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia. In: Hehlmann, R. (eds) Chronic Myeloid Leukemia. Hematologic Malignancies. Springer, Cham. https://doi.org/10.1007/978-3-030-71913-5_6

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