Second Generation Tyrosine Kinase Inhibitors and Their Toxicity in Treatment of Patients in Chronic Phase of Chronic Myeloid Leukemia

Background & Aims. Certain experience in the use of new tyrosine kinase inhibitors (TKIs) in treatment of patients with chronic myeloid leukemia has been obtained over the last years. The article summarizes literature data on toxicity obtained in international clinical trials. The aim of the study is to evaluate adverse effects of second generation TKIs in the routine clinical practice and to assess their effect on patient future life.

Methods. We analyzed our own data obtained during routine clinical practice. 76 patients (36 men and 40 women) over 18 years of age (median age was 49 years, range 26–75) with chronic myeloid leukemia were enrolled in the retrospective trial. 48 patients were treated with nilotinib, 28 patients received dazatinib during the chronic phase of the disease as a second line therapy after withdrawal of imatinib mesylate. The toxicity degree was determined according to CTCAE 4.0 criteria.

Results. III–IV degree hematologic toxicity was registered in 36.8 % of patients. No significant difference in the incidence of complications between nilotinib and dazatinib groups was observed: 39.6 % and 32.1 %, respectively. II–IV degree non-hematologic toxicity was found in 35.4 % patients on nilotinib and in 25 % of patients on dazatinib. The incidence of individual types of toxicity did not exceed 15 %. A combination of different types of non-hematologic toxicity was observed in 9.2 % of patients. No TKI2 toxicity-related lethal outcomes were registered.

Conclusion. Hematologic and/or non-hematologic toxicity related to TKI2 was registered in more than 50 % of patients. In most cases, the complications were transient and eliminated after discontinuation of TKI2 or after dose reduction. TKI2-associated complications did not affect the possibility to achieve a complete cytogenetic response and its stability.

• N.S. Lazorko Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russia, 197341 ; ФГБУ «Северо-западный федеральный медицинский исследовательский центр», ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
• Elza Galaktionovna Lomaia Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russia, 197341 ; ФГБУ «Северо-западный федеральный медицинский исследовательский центр», ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
• E.G. Romanova Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russia, 197341 ; ФГБУ «Северо-западный федеральный медицинский исследовательский центр», ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
• E.I. Sbityakova Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russia, 197341 ; ФГБУ «Северо-западный федеральный медицинский исследовательский центр», ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
• E.R. Machyulaitene Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russia, 197022 ; ГОУВПО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова», ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022
• P.A. Butylin Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russia, 197341; Saint Petersburg State University of Information Technologies, Mechanics and Optics, Institute of Translational Medicine, 49 Kronverkskii pr-t, Saint Petersburg, Russia, 197101 ; ФГБУ «Северо-западный федеральный медицинский исследовательский центр», ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341; Университет ИТМО, Институт трансляционной медицины, Кронверкский пр., д. 49, Санкт-Петербург, Российская Федерация, 197101
• A.Yu. Zaritskii Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russia, 197341; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russia, 197022 ; ФГБУ «Северо-западный федеральный медицинский исследовательский центр», ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341; ГОУВПО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова», ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022

1. Kantarjian H, Pasquini R, Hamerschlak N, et al. 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(12):5143–50. doi: 10.1182/blood-2006-11-056028. DOI: https://doi.org/10.1182/blood-2006-11-056028
2. Kantarjian H, Giles F, Bhalla K, 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(4):1141–5. doi: 10.1182/blood-2010-03-277152. DOI: https://doi.org/10.1182/blood-2010-03-277152
3. Лазорко Н.С., Ломаиа Е.Г., Сбитякова Е.И., Зарицкий А.Ю. Нилотиниб и дазатиниб в первой линии терапии больных хроническим миелолейкозом в хронической фазе. Современная онкология. 2011;13(1):38–40.
4. [Lazorko NS, Lomaia EG, Sbityakova EI, Zaritskii AYu. Nilotinib and dazatinib as first line therapy of patients in chronic phase of chronic myeloid leukemia. Sovremennaya onkologiya. 2011;13(1):38–40. (In Russ)]
5. Ломаиа Е.Г., Романова Е.Г., Сбитякова Е.И., Зарицкий А.Ю. Эффективность и безопасность ингибиторов тирозинкиназ 2-го поколения (дазатиниб, нилотиниб) в терапии хронической фазы хронического миелолейкоза. Онкогематология. 2013;2:22–33.
6. [Lomaia EG, Romanova EG, Sbityakova EI, Zaritskii AYu. Efficacy and safety of 2nd generation tyrosine kinase inhibitors (dasatinib, nilotinib) in teatment of chronic phase of chronic myeloid leukemia. Onkogematologiya. 2013;2:22–33. (In Russ)]
7. Туркина А.Г., Хорошко Н.Д., Гусарова Г.А. и др. Российский опыт применения нилотиниба во второй линии терапии больных хроническим миелолейкозом с резистентностью или непереносимостью иматиниба: оценка безопасности и эффективности в исследовании ENACT (расширенный доступ к нилотинибу в клинических исследованиях). Вестник гематологии. 2010;1(2):92–3.
8. [Turkina AG, Khoroshko ND, Gusarova GA, et al. Russian experience in use of nilotinib in second line therapy of patients with chronic myeloid leukemia and imatinib resistance or intolerance: evaluation of safety and efficacy in ENACT trial (Expanding Nilotinib Access in Clinical Trials). Vestnik gematologii. 2010;1(2):92–3. (In Russ)]
9. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
10. Kantarjian H, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540–6. doi: 10.1182/blood-2007-03-080689. DOI: https://doi.org/10.1182/blood-2007-03-080689
11. Saglio G, Kim D, Issaragrisil S, et al. Nilotinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–9. doi: 10.1517/14656566.2011.534780. DOI: https://doi.org/10.1056/NEJMoa0912614
12. Hochhaus A, Kantarjian H, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303–9. doi: 10.1182/blood-2006-09-047266. DOI: https://doi.org/10.1182/blood-2006-09-047266
13. Kantarjian H, Shah N, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–70. doi: 10.1056/nejmoa1002315. DOI: https://doi.org/10.1056/NEJMoa1002315
14. Shah R. Drug-induced hepatotoxicity: pharmacokinetic perspectives and strategies for risk reduction. Adv Drug React Toxicol Rev. 1999;18:181–233.
15. Russmann S, Kullak-Ublick G, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 2009;16(23):3041–53. DOI: https://doi.org/10.2174/092986709788803097
16. Teo YL, Ho HK, Chan A. Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: A meta-analysis. Cancer Treat Rev. 2013;39(2):199–206. doi: 10.1016/j.ctrv.2012.09.004. DOI: https://doi.org/10.1016/j.ctrv.2012.09.004
17. Saglio G, Pinilla-Ibarz J, Cortes J, et al. Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia. Blood. 2011;117(4):688−697. doi: 10.1002/cncr.25648. DOI: https://doi.org/10.1002/cncr.25648
18. Rosti G, Castagnetti F, Gugliotta G, et al. Dasatinib and nilotinib in imatinib resistant Philadelphia-positive chronic myelogenous leukemia: a ‘head-to-head’ comparison. Leuk Lymphoma 2010;51(4):583–91. doi: 10.3109/10428191003637282. DOI: https://doi.org/10.3109/10428191003637282
19. Shah R, Morganroth J, Shah D. Hepatotoxicity of Tyrosine Kinase Inhibitors: Clinical and Regulatory Perspectives. Drug Saf. 2013;36(7):491–503. doi: 10.1007/s40264-013-0048-4. DOI: https://doi.org/10.1007/s40264-013-0048-4
20. Lammie A, Drobnjak M, Gerald W, et al. Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem. 1994;42(11):1417–25. doi: 10.1177/42.11.7523489. DOI: https://doi.org/10.1177/42.11.7523489
21. Grichnik J, Burch J, Burchette J, Shea C. The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J Invest Dermatol. 1998;111(2):233–8. DOI: https://doi.org/10.1046/j.1523-1747.1998.00272.x
22. Kantarjian H, Pasquini R, Levy V, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer. 2009;115(18):4136–47. doi: 10.1002/cncr.24504. DOI: https://doi.org/10.1002/cncr.24504
23. Irvine E, Williams C. Treatment-, Patient-, and Disease-Related Factors and the Emergence of Adverse Events with Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia. Pharmacotherapy. 2013;33(8):868–81. doi: 10.1002/phar.1266. DOI: https://doi.org/10.1002/phar.1266
24. Van Etten RA. Cycling, stressed-out and nervous: cellular functions of cAbl. Trends Cell Biol. 1999;9(5):179–86. doi: 10.1016/s0962-8924(99)01549-4. DOI: https://doi.org/10.1016/S0962-8924(99)01549-4
25. Wasle B, Edwardson J. The regulation of exocytosis in the pancreatic acinar cell. Cell Signal. 2002;14(3):191–7. doi: 10.1016/s0898-6568(01)00257-1. DOI: https://doi.org/10.1016/S0898-6568(01)00257-1
26. Mooren F, Hlouschek V, Finkes T, et al. Early changes in pancreatic acinar cell calcium signalling after pancreatic duct obstruction. J Biol Chem. 2003;278(11):9361–9. doi: 10.1074/jbc.m207454200. DOI: https://doi.org/10.1074/jbc.M207454200
27. Fitter S, Vandyke K, Gronthos S, Zannettino AC. Suppression of PDGF-induced PI3 kinase activity by imatinib promotes adipogsis and adiponectin secretion. J Mol Endocrinol. 2012;48(3):229–40. doi: 10.1530/jme-12-0003. DOI: https://doi.org/10.1530/JME-12-0003
28. Racil Z, Razga F, Drapalova J, et al. Mechanism of impaired glucose metabolism during nilotinib therapy in patients with chronic myelogenous leukemia. Haematologica. 2013;98(10):e124–6. doi: 10.3324/haematol.2013.086355. DOI: https://doi.org/10.3324/haematol.2013.086355
29. le Coutre P, Giles F, Hochhaus A, et al. Analysis of glucose profiles in imatinib resistant or intolerant chronic myelogenous leukemia (CML) patients treated with nilotinib: lack of correlation between glucose levels and nilotinib efficacy. Blood. 2007;110: Abstract 4588. DOI: https://doi.org/10.1182/blood.V110.11.4588.4588
30. Breccia M, Alimena G. Pleural/pericardic effusions during dasatinib treatment: incidence, management and risk factors associated to their development. Exp Opin Drug Saf. 2010;9(5):713–21. doi: 10.1517/14740331003742935. DOI: https://doi.org/10.1517/14740331003742935
31. de Lavallade H, Punnialingam S, Milojkovic D, et al. Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune-mediated pathogenesis. Br J Haematol. 2008;141(5):745–7. doi: 10.1111/j.1365-2141.2008.07108.x. DOI: https://doi.org/10.1111/j.1365-2141.2008.07108.x
32. Porkka K, Khoury H, Paquette R, et al. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer. 2010;116(2):377–86. doi: 10.1002/cncr.24734. DOI: https://doi.org/10.1002/cncr.24734
33. Shah N, Kantarjian H, Kim D, et al. Six-year (yr) follow-up of patients (pts) with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. J Clin Oncol. 2012;30:6506. DOI: https://doi.org/10.1200/jco.2012.30.15_suppl.6506
34. Hasinoff BB. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity. Toxicol Appl Pharmacol. 2010;244(2):190–5. doi: 10.1016/j.taap.2009.12.032. DOI: https://doi.org/10.1016/j.taap.2009.12.032
35. Albini A, Pennesi G, Donatelli F, et al. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst. 2010;102(1):14–25. doi: 10.1093/jnci/djp440. DOI: https://doi.org/10.1093/jnci/djp440
36. Strevel E, Ing D, Siu L. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol. 2007;25(22):3362–71. doi: 10.1200/jco.2006.09.6925. DOI: https://doi.org/10.1200/JCO.2006.09.6925
37. Haverkamp W, Breithardt G, Camm A, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J. 2000;21(15):1216–31. doi: 10.1053/euhj.2000.2249. DOI: https://doi.org/10.1053/euhj.2000.2249
38. Priori S, Schwartz P, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866–74. doi: 10.1056/nejmoa022147. DOI: https://doi.org/10.1056/NEJMoa022147
39. Sauer A, Moss A, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol. 2007;49(3):329–37. doi: 10.1016/j.jacc.2006.08.057. DOI: https://doi.org/10.1016/j.jacc.2006.08.057
40. Center for Drug Evaluation and Research: Nilotinib Pharmacology/Toxicology Review and Evaluation; 2007.
41. Le Coutre P, Ottmann O, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008;111(4):1834–9. doi: 10.1182/blood-2007-04-083196. DOI: https://doi.org/10.1182/blood-2007-04-083196
42. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542–51. doi: 10.1056/nejmoa055104. DOI: https://doi.org/10.1056/NEJMoa055104
43. Kim T, 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(6):1316–21. doi: 10.1038/leu.2013.70. DOI: https://doi.org/10.1038/leu.2013.70
44. Larson R, Hochhaus A, Hughes T, 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(10):2197–203. doi: 10.1038/leu.2012.134. DOI: https://doi.org/10.1038/leu.2012.134
45. Aichberger K, Herndlhofer S, Schernthaner G, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol. 2011;86(7):533–9. doi: 10.1002/ajh.22037. DOI: https://doi.org/10.1002/ajh.22037
46. Verma D, Verstovsek S, Kantarjian H, et al. Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. Blood. 2011;118(16):4353–8. doi: 10.1182/blood-2011-06-362889. DOI: https://doi.org/10.1182/blood-2011-06-362889
47. Hoffmann V, Baccarani M, Hasford J. The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries. Leukemia. 2015;29(6):1336–43. doi: 10.1038/leu.2015.73 [Epub 2015 Mar 18] DOI: https://doi.org/10.1038/leu.2015.73