Advertisement

Long-Term Side Effects of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Abstract

Most patients with chronic myeloid leukemia have deep and durable responses when treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs). Imatinib (the first approved TKI), nilotinib, and dasatinib are used in newly diagnosed, relapsed or intolerant patients, while bosutinib and ponatinib are used only in relapsed or intolerant patients. Previously the drug of choice was related to the likelihood of response and, to a small extent, patient comorbidities. The long-term toxicities, particularly cardiopulmonary side effects, are now impacting treatment choice, making patient comorbidities of significant concern. About 10 % of patients do not tolerate their initial BCR-ABL1 TKI and an increasing number are developing long-term side effects, particularly with the second generation drugs. Side effects of the five drugs reviewed here highlight the differences between cardiovascular, pulmonary, gastrointestinal, and endocrine toxicities, as well as possible second malignancies. There is increasing evidence that patients whose disease is controlled by TKI’s will have greater impact on their quality of life from comorbidities or drug adverse events than from the disease itself. Research into management of long-term toxicities is needed.

This is a preview of subscription content, log in to check access.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011;103:553–61.

  2. 2.

    The WJYJ, Capable ABL. What is its biological function? Mol Cell Biol. 2014;34:1188–97.

  3. 3.

    Hantschel O. Structure, regulation, signaling, and targeting of Abl kinases in cancer. Genes Cancer. 2012;3:436–46.

  4. 4.

    Bartram CR, de Klein A, Hagemeijer A, et al. Translocation of c-abl1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1983;306:277–80.

  5. 5.

    Groffen J, Stephenson JR, Heisterkamp N, et al. Philadelphia chromosomal breakpoints are clustered within a limited region, BCR, on chromosome 22. Cell. 1984;36:93–9.

  6. 6.

    Deininger MW, Manley P. What do kinase inhibition profiles tell us about tyrosine kinase inhibitors used for the treatment of CML? Leuk Res. 2012;36:253–61.

  7. 7.•

    Rea D. Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia. Ann Hematol. 2015;94 Suppl 2:S149–58. Most recent discussion of clinical management of TKI side effects.

  8. 8.

    Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up for patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.

  9. 9.•

    Brummendorf TH, Cortes JE, de Souza AC, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2014;168:69–81. Randomized trial comparing the outcome and side effects of imatinib to bosutinib.

  10. 10.•

    Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014;123:494–500. Randomized trial comparing the outcome and side effects of imatinib to dasatinib.

  11. 11.•

    Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs. imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26:2197–203. Randomized trial comparing the outcome of imatinib to nilotinib.

  12. 12.

    Uitdehaag JC, de Roos JA, van Doornmalen AM, et al. Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use. PLoS ONE. 2014;9:e921–46.

  13. 13.

    Cheng H, Force T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ Res. 2010;106:21–34.

  14. 14.

    Hochhaus A, O’Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054–61.

  15. 15.

    O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.

  16. 16.

    Efficace F, Baccarani M, Breccia M, et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood. 2011;118:4554–60.

  17. 17.

    Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–70.

  18. 18.

    Hughes TP, Lipton JH, Spector N, et al. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014;124:729–36.

  19. 19.

    Kantarjian HM, Giles FJ, Bhalla KN, et al. 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.

  20. 20.

    Cortes JE, Kim DW, Kantarjian HM, 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.

  21. 21.

    Lipton JH, Chuah C, Guerci-Bresler A, et al. EPIC: A phase 3 trial of ponatinib compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CP-CML). Blood. Abstract 2014;124:519.

  22. 22.•

    Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783–96. First report on the efficacy and side effects of ponatinib.

  23. 23.

    Shah NP, Guilhot F, Cortes JE, et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood. 2014;123:2317–24.

  24. 24.

    Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013;27:107–12.

  25. 25.

    Kantarjian HM, Cortes JE, Kim DW, et al. 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.

  26. 26.

    Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783.

  27. 27.

    Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–7.

  28. 28.

    Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature. 2006;12:908–16.

  29. 29.

    Atallah E, Durand JB, Kantarjian H, et al. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood. 2007; 110.

  30. 30.

    Orphanos GS, Ioannidis GN, Ardavanis AG. Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncol. 2009;48:964–70.

  31. 31.

    Groarke JD, Cheng S, Moslehi J. Cancer-drug discovery and cardiovascular surveillance. N Engl J Med. 2013;369:1779–81.

  32. 32.

    Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nature. 2007;7:332–44.

  33. 33.

    Bronte G, Bronte E, Novo G, et al. Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy. Expert Opin Drug Saf. 2015;14:253–67.

  34. 34.•

    Kalmanti L, Saussele S, Lauseker M, et al. 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. Long-term study showing the side effects of imatinib and nilotinib.

  35. 35.

    Castagnetti F, Gugliotta G, Breccia M. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia. 2015;29:1823–31.

  36. 36.

    Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2006.

  37. 37.

    Iclusig (ponatinib) [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.;2012.

  38. 38.•

    Cortes JE, Saglio G, Baccarani M, et al. Final study results of the phase 3 dasatinib vs. imatinib in newly diagnosed chronic myeloid leukemia (CML-CP) trial (DASISION). Blood. Abstract. 2014;124(21):152. Long-term toxicities of imatinib and dasatinib show differences.

  39. 39.•

    Larson RA, Kim DW, Issaragrilsil S, et al. Efficacy and safety of nilotinib (NIL) vs imatinib (IM) in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): long-term follow-up of ENESTnd. Blood. Abstract. 2014;124:4541. Long-term side effects comparing imatinib and nilotinib show differences.

  40. 40.

    Tasigna (nilotinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. 2007.

  41. 41.

    Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542–51.

  42. 42.

    Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib, a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive CML-CP following imatinib resistance and intolerance. Blood. 2007;110(10):3540–6.

  43. 43.

    Dahlen T, Edgren G, Hoglund M, et al. Increased risk of cardiovascular events associated with TKI treatment in chronic phase chronic myeloid leukemia: data from Swedish population-based registries. Blood. Abstract 2014;124:3134

  44. 44.

    Breccia M, Loglisci G, Salaroli A, et al. Nilotinib-mediated increase in fasting glucose level is reversible, does not convert to type 2 diabetes, and is likely correlated with increase body mass index. Leuk Res. 2012; e66-e67.

  45. 45.

    Rea D, Mirault T, Cluzeau T, et al. Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia. Haematolgica. 2014;99:1197–203.

  46. 46.

    Giles FJ, Mauro MJ, Hong F, 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. 2013;27:1310–15.

  47. 47.

    Aichberger KJ, Herndhofer S, Schernthaner GH, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol. 2011;86:533–9.

  48. 48.

    Le Coutre P, Rea D, Abruzzese E, et al. Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst. 2011;103:1347–8.

  49. 49.

    Quintas-Cardama A, Kantarjian H, Cortes J, et al. Nilotinib-associated vascular events. Clin Lymphoma Myeloma Leuk. 2012;12:337–40.

  50. 50.

    Levato L, Cantaffa R, Kroop MD, et al. 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.

  51. 51.

    Gugliotta G, Castagnetti F, Breccia M, et al. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia. Haematologica. 2015;100:1146–50.

  52. 52.

    Kim TD, Rea D, Schwarz M, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia. 2013;27:1316–21.

  53. 53.

    Breccia M, Molica M, Zacheo I, et al. Application of systematic coronary risk evaluation chart to identify chronic myeloid leukemia patients at risk of cardiovascular diseases during nilotinib treatment. Ann Hematol. 2015;94:393–7.

  54. 54.

    Tefferi A. Nilotinib treatment-associated accelerated atherosclerosis: when is the risk justified? Leukemia. 2013;27:1939–40.

  55. 55.

    Jain P, Kantarjian H, Jabbour E, et al. Ponatinib as first-line treatment for patients with chronic myeloid leukemia in chronic phase: a phase 2 study. Lancet. 2015;2:e376–83.

  56. 56.

    Hochhaus A. Optimizing tolerability of TKI therapy in CML. Blood. 2014;123:1284.

  57. 57.••

    Valent P, Hadzijusufovic E, Schernthaner GH, et al. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125:901–6. Review of cardiovascular toxicities of TKIs with discussion of how these toxicities were initially overlooked.

  58. 58.••

    Moslehi JJ, Deininger M. Tyrosine Kinase Inhibitor-Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia. J Clin Oncol. 2015;33. Important review of the published data on cardiovascular toxicities.

  59. 59.••

    Saussele S, Krauss MP, Hehlmann R, et al. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML Study IV. Blood. 2015;126:42–9. Co-morbidities in responsive patients appear to have major impact upon survival in CML.

  60. 60.

    Ohnishi K, Sakai F, Kudoh S, et al. Twenty-seven cases of drug-induced interstitial lung disease associated with imatinib mesylate. Leukemia. 2006;20:1162–4.

  61. 61.

    Peerzada MM, Spiro TP, Daw HA. Pulmonary toxicities of tyrosine kinase inhibitors. Clin Adv Hematol Oncol. 2011;9:824–36.

  62. 62.

    Go SI, Lee WS, Kang JH, et al. Nilotinib-induced interstitial lung disease. Int J Hematol. 2013;98:361–5.

  63. 63.

    Shah NP, Wallis N, Farber HW, et al. Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. Am J Hematol. 2015;90:1060–4.

  64. 64.

    Tatarczuch M, Burbury K, Creati L, et al. Dasatinib therapy can result in significant pulmonary toxicity. Am J Hematol. 2015; Accepted Article.

  65. 65.

    Quintas-Cardama A, Kantarjian H, Ravendi F, et al. Bleeding diathesis in patients with chronic myelogenous leukemia receiving dasatinib therapy. Cancer. 2009;115:2482–90.

  66. 66.

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

  67. 67.

    Patodi N, Sagar N, Rudzki Z, et al. Haematologic colitis caused By dasatinib. Case Rep Hematol. 2012;2012:ID 417106.

  68. 68.

    Apperley JF. Chronic myeloid leukaemia. Lancet. 2015;385:1447–59.

  69. 69.

    Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013;36:491–503.

  70. 70.

    Bosulif (bosutinib) [package insert]. New York, NY: Pfizer Laboratories Div. Pfizer Inc.; 2012.

  71. 71.

    Gleevec (imatinib mesylate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2001.

  72. 72.

    Marcolino MS, Boersma E, Clementino NCD, et al. Imatinib treatment duration is related to decreased estimated glomerular filtration rate in chronic myeloid leukemia patients. Ann Oncol. 2011;22:2073–9.

  73. 73.

    Yilmaz M, Lahoti A, O’Brien S, et al. Estimated glomerular filtration rate changes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Cancer. 2015;121:3894–904.

  74. 74.

    Salie R, Silver RT. Uncommon or delayed adverse events associated with imatinib treatment for chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2010;10:331–5.

  75. 75.

    Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med. 2006;354:2006–13.

  76. 76.

    Aleman 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.

  77. 77.

    Farmer S, Horvath-Puho E, Vestergaard H, et al. Chronic myeloproliferative neoplasms and risk of osteoporotic fractures; a nationwide population-based cohort study. Brit J Haematol. 2013;163:603–10.

  78. 78.

    Millot F, Guilhot J, Baruchel A, et al. Growth deceleration in children treated with imatinib for chronic myeloid leukemia. Eur J Cancer. 2014;50:3206–11.

  79. 79.

    Narayanan KR, Bansal D, Walia R, et al. 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.

  80. 80.

    Giona F, Mariani S, Gnessi L, et al. Bone mineral metabolism, growth rate and pubertal development in children with chronic myeloid leukemia treated with imatinib during puberty. Haematolgica. 2013;98:e25–7.

  81. 81.

    Gambacorti-Passerini C, Tornaghi L, Cavagnini F, et al. Gynaecomastia in men with chronic myeloid leukemia after imatinib. Lancet. 2003;361:1954–6.

  82. 82.

    Pilot PR, Sablinska K, Owen S, et al. Epidemiologic analysis of second primary malignancies in more than 9,500 patients treated with imatinib. Leukemia. 2006;20:148.

  83. 83.

    Verma D, Kantarjian H, Strom S, et al. Malignancies occurring during therapy with tyrosine kinase inhibitors for chronic myeloid leukemia and other hematologic malignancies. Blood. 2011;118:4353–8.

  84. 84.

    Togasaki-Yoshimoto E, Shono K, Onoda M, et al. The occurrence of second neoplasms after treatment with tyrosine kinase inhibitors for chronic myeloid leukemia. Leuk Lymphoma. 2014;55:453–6.

  85. 85.•

    Gunnarsson N, Stenke L, Hoglund M, et al. Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era. Br J Haematol. 2015;169:683–8. Long-term concern is reopened regarding second malignancies from this retrospective population-based study.

  86. 86.

    Helbig G, Bober G, Seweryn M, et al. Occurrence of secondary malignancies in chronic myeloid leukemia during therapy with imatinib mesylate-single institution experience. Mediterr J Hematol Infect Dis. 2015;7:e2015003.

  87. 87.

    Duman BB, Paydas S, Disel U, et al. Secondary malignancy after imatinib therapy: eight cases and review of the literature. Leuk Lymphoma. 2012;53:1706–8.

Download references

Author information

Correspondence to Luke Akard.

Ethics declarations

Conflict of Interest

Lauren Caldemeyer, Michael Dugan, and John Edwards report no potential conflicts of interest.

Luke Akard: Speakers Bureau: Ariad, BMS, Novartis, Teva. Research funding: Ariad, BMS, Novartis, Pfizer, Teva.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Chronic Myeloid Leukemias

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Caldemeyer, L., Dugan, M., Edwards, J. et al. Long-Term Side Effects of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia. Curr Hematol Malig Rep 11, 71–79 (2016). https://doi.org/10.1007/s11899-016-0309-2

Download citation

Keywords

  • CML
  • BCR-ABL1
  • TKI
  • Imatinib
  • Dasatinib
  • Nilotinib