Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia

Robert S Negrin, MD
Charles A Schiffer, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD


Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome t(9;22)(q34;q11) resulting in the BCR-ABL1 fusion gene. This genetic abnormality results in the formation of a unique gene product (BCR-ABL1), a constitutively active tyrosine kinase that produces a continued proliferative signal resulting in the clinical manifestations of CML.

Once this mechanism was understood, efforts were aimed at developing compounds that could selectively inhibit the aberrant tyrosine kinase resulting from this molecular rearrangement. Imatinib mesylate was the first of these to be used in the treatment of CML. Since then, several other tyrosine kinase inhibitors (TKIs) have been developed and tested in patients with CML, most notably dasatinib, nilotinib, bosutinib, and ponatinib. TKIs have become the initial treatment of choice for most patients with CML.

This topic will review the clinical use of TKIs for the treatment of CML. The mechanisms of action and resistance will be discussed along with practical information about dosing, drug interactions, and management of side effects. The treatment options for chronic myeloid leukemia at various phases of disease and monitoring of disease are discussed separately. (See "Overview of the treatment of chronic myeloid leukemia" and "Initial treatment of chronic myeloid leukemia in chronic phase" and "Treatment of chronic myeloid leukemia in accelerated phase" and "Treatment of chronic myeloid leukemia in blast crisis".)

Imatinib also inhibits KIT and platelet-derived growth factor receptor (PDGFR), and has been successfully employed in other malignancies in which these kinases are mutated. This is discussed separately. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors" and "Hypereosinophilic syndromes: Treatment" and "Dermatofibrosarcoma protuberans: Treatment", section on 'Treatment of locally advanced, recurrent, and metastatic disease'.)


Tyrosine kinase inhibitors (TKIs) block the initiation of the BCR-ABL1 pathway [1-6]. As described below, many of the TKIs also affect other signaling pathways. These differences in targeted pathways may be responsible for their varied clinical effects in tumors with different mechanisms of resistance to imatinib.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Mar 29, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305:399.
  2. Verstovsek S, Golemovic M, Kantarjian H, et al. AMN107, a novel aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells. Cancer 2005; 104:1230.
  3. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7:129.
  4. Weisberg E, Manley P, Mestan J, et al. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer 2006; 94:1765.
  5. Kantarjian HM, Giles F, Quintás-Cardama A, Cortes J. Important therapeutic targets in chronic myelogenous leukemia. Clin Cancer Res 2007; 13:1089.
  6. Weisberg E, Manley PW, Cowan-Jacob SW, et al. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 2007; 7:345.
  7. Mauro MJ, Druker BJ. STI571: targeting BCR-ABL as therapy for CML. Oncologist 2001; 6:233.
  8. Savage DG, Antman KH. Imatinib mesylate--a new oral targeted therapy. N Engl J Med 2002; 346:683.
  9. Tsao AS, Kantarijian H, Talpaz M. STI-571 in chronic myelogenous leukaemia. Br J Haematol 2002; 119:15.
  10. Holtz MS, Slovak ML, Zhang F, et al. Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 2002; 99:3792.
  11. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2:561.
  12. Jabbour E, Cortes JE, Giles FJ, et al. Current and emerging treatment options in chronic myeloid leukemia. Cancer 2007; 109:2171.
  13. Shah NP. Medical management of CML. Hematology Am Soc Hematol Educ Program 2007; :371.
  14. O'Dwyer ME, Mauro MJ, Blasdel C, et al. Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood 2004; 103:451.
  15. Kantarjian HM, Talpaz M, O'Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003; 101:473.
  16. Kantarjian H, Talpaz M, O'Brien S, et al. Prediction of initial cytogenetic response for subsequent major and complete cytogenetic response to imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Cancer 2003; 97:2225.
  17. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol 2005; 23:4100.
  18. Mizutani T, Kondo T, Darmanin S, et al. A novel FRET-based biosensor for the measurement of BCR-ABL activity and its response to drugs in living cells. Clin Cancer Res 2010; 16:3964.
  19. Zhang WW, Cortes JE, Yao H, et al. Predictors of primary imatinib resistance in chronic myelogenous leukemia are distinct from those in secondary imatinib resistance. J Clin Oncol 2009; 27:3642.
  20. Lucas CM, Harris RJ, Holcroft AK, et al. Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients. Leukemia 2015.
  21. Lucas CM, Harris RJ, Giannoudis A, et al. Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression. Blood 2011; 117:6660.
  22. Milojkovic D, Apperley J. Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia. Clin Cancer Res 2009; 15:7519.
  23. Marin D, Goldman JM, Olavarria E, Apperley JF. Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses. Blood 2003; 102:2702.
  24. McWeeney SK, Pemberton LC, Loriaux MM, et al. A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib. Blood 2010; 115:315.
  25. Oehler VG, Yeung KY, Choi YE, et al. The derivation of diagnostic markers of chronic myeloid leukemia progression from microarray data. Blood 2009; 114:3292.
  26. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293:876.
  27. Kantarjian HM, Talpaz M, Giles F, et al. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med 2006; 145:913.
  28. O'Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007; 110:2242.
  29. White DL, Dang P, Engler J, et al. Functional activity of the OCT-1 protein is predictive of long-term outcome in patients with chronic-phase chronic myeloid leukemia treated with imatinib. J Clin Oncol 2010; 28:2761.
  30. Soverini S, Colarossi S, Gnani A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006; 12:7374.
  31. Jones D, Thomas D, Yin CC, et al. Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors. Cancer 2008; 113:985.
  32. Skaggs BJ, Gorre ME, Ryvkin A, et al. Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants. Proc Natl Acad Sci U S A 2006; 103:19466.
  33. O'Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005; 65:4500.
  34. Jiang X, Saw KM, Eaves A, Eaves C. Instability of BCR-ABL gene in primary and cultured chronic myeloid leukemia stem cells. J Natl Cancer Inst 2007; 99:680.
  35. Willis SG, Lange T, Demehri S, et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood 2005; 106:2128.
  36. Koptyra M, Falinski R, Nowicki MO, et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 2006; 108:319.
  37. Nowak D, Ogawa S, Müschen M, et al. SNP array analysis of tyrosine kinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary genomic alterations. Blood 2010; 115:1049.
  38. Druker BJ. Circumventing resistance to kinase-inhibitor therapy. N Engl J Med 2006; 354:2594.
  39. von Bubnoff N, Manley PW, Mestan J, et al. Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood 2006; 108:1328.
  40. Soverini S, Martinelli G, Colarossi S, et al. Presence or the emergence of a F317L BCR-ABL mutation may be associated with resistance to dasatinib in Philadelphia chromosome-positive leukemia. J Clin Oncol 2006; 24:e51.
  41. Lee TS, Potts SJ, Kantarjian H, et al. Molecular basis explanation for imatinib resistance of BCR-ABL due to T315I and P-loop mutations from molecular dynamics simulations. Cancer 2008; 112:1744.
  42. Saglio G, Fava C. BCR-ABL1 mutation ≠ ponatinib resistance. Blood 2016; 127:666.
  43. Deininger MW, Hodgson JG, Shah NP, et al. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients. Blood 2016; 127:703.
  44. Haouala A, Widmer N, Duchosal MA, et al. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood 2011; 117:e75.
  45. van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014; 15:e315.
  46. Smith PF, Bullock JM, Booker BM, et al. Induction of imatinib metabolism by hypericum perforatum. Blood 2004; 104:1229.
  47. Smith P, Bullock JM, Booker BM, et al. The influence of St. John's wort on the pharmacokinetics and protein binding of imatinib mesylate. Pharmacotherapy 2004; 24:1508.
  48. Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 2004; 22:935.
  49. 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.
  50. Ramanathan RK, Egorin MJ, Takimoto CH, et al. Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 2008; 26:563.
  51. Gibbons J, Egorin MJ, Ramanathan RK, et al. Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 2008; 26:570.
  52. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=211ef2da-2868-4a77-8055-1cb2cd78e24b#section-8.6 (Accessed on June 21, 2013).
  53. Dasatinib (Sprycel) for CML and Ph + ALL. Med Lett Drugs Ther 2007; 49:6.
  54. Brave M, Goodman V, Kaminskas E, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res 2008; 14:352.
  55. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4764f37b-c9e6-4ede-bcc2-8a03b7c521df (Accessed on June 21, 2013).
  56. Shah NP, Kantarjian HM, Kim DW, et al. 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.
  57. Yin OQ, Giles FJ, Baccarani M, et al. Concurrent use of proton pump inhibitors or H2 blockers did not adversely affect nilotinib efficacy in patients with chronic myeloid leukemia. Cancer Chemother Pharmacol 2012; 70:345.
  58. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=6093952a-5248-45cb-ad17-33716a411146 (Accessed on June 21, 2013).
  59. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm182234.htm (Accessed on July 15, 2013).
  60. Yin OQ, Gallagher N, Fischer D, et al. Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib. J Clin Pharmacol 2010; 50:960.
  61. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf (Accessed on June 19, 2013).
  62. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203469s007s008lbl.pdf (Accessed on January 22, 2014).
  63. Steegmann JL, Baccarani M, Breccia M, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia 2016; 30:1648.
  64. Pinilla-Ibarz J, Cortes J, Mauro MJ. Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: Definitions and clinical implications. Cancer 2011; 117:688.
  65. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010; 28:2381.
  66. Brouard M, Saurat JH. Cutaneous reactions to STI571. N Engl J Med 2001; 345:618.
  67. Hsiao LT, Chung HM, Lin JT, et al. Stevens-Johnson syndrome after treatment with STI571: a case report. Br J Haematol 2002; 117:620.
  68. Rule SA, O'Brien SG, Crossman LC. Managing cutaneous reactions to imatinib therapy. Blood 2002; 100:3434.
  69. Valeyrie L, Bastuji-Garin S, Revuz J, et al. Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective study of 54 patients. J Am Acad Dermatol 2003; 48:201.
  70. 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.
  71. Williams LA, Garcia Gonzalez AG, Ault P, et al. Measuring the symptom burden associated with the treatment of chronic myeloid leukemia. Blood 2013; 122:641.
  72. 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.
  73. Goldman JM. How I treat chronic myeloid leukemia in the imatinib era. Blood 2007; 110:2828.
  74. Cortes J, O'Brien S, Quintas A, et al. 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.
  75. Santos FP, Alvarado Y, Kantarjian H, et al. Long-term prognostic impact of the use of erythropoietic-stimulating agents in patients with chronic myeloid leukemia in chronic phase treated with imatinib. Cancer 2011; 117:982.
  76. Khoury HJ, Guilhot F, Hughes TP, et al. Dasatinib treatment for Philadelphia chromosome-positive leukemias: practical considerations. Cancer 2009; 115:1381.
  77. Quintas-Cardama A, Kantarjian H, O'Brien S, et al. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer 2004; 100:2592.
  78. Quintás-Cardama A, De Souza Santos FP, Kantarjian H, et al. Dynamics and management of cytopenias associated with dasatinib therapy in patients with chronic myeloid leukemia in chronic phase after imatinib failure. Cancer 2009; 115:3935.
  79. Quintás-Cardama A, Kantarjian H, Ravandi F, et al. Bleeding diathesis in patients with chronic myelogenous leukemia receiving dasatinib therapy. Cancer 2009; 115:2482.
  80. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006; 354:2531.
  81. Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007; 109:3207.
  82. Gratacap MP, Martin V, Valéra MC, et al. The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo. Blood 2009; 114:1884.
  83. 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.
  84. Roux C, Nicolini FE, Rea D, et al. Reversible lymph node follicular hyperplasia associated with dasatinib treatment of chronic myeloid leukemia in chronic phase. Blood 2013; 122:3082.
  85. Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist 2004; 9:271.
  86. Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12:908.
  87. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf?et_cid=30657199&et_rid=463648356&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2012%2f203469lbl.pdf (Accessed on May 29, 2013).
  88. Mann DL. Targeted cancer therapeutics: the heartbreak of success. Nat Med 2006; 12:881.
  89. Hatfield A, Owen S, Pilot PR. In reply to 'Cardiotoxicity of the cancer therapeutic agent imatinib mesylate'. Nat Med 2007; 13:13; author reply 15.
  90. Atallah E, Durand JB, Kantarjian H, Cortes J. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 2007; 110:1233.
  91. Verweij J, Casali PG, Kotasek D, et al. Imatinib does not induce cardiac left ventricular failure in gastrointestinal stromal tumours patients: analysis of EORTC-ISG-AGITG study 62005. Eur J Cancer 2007; 43:974.
  92. Hazarika M, Jiang X, Liu Q, et al. Tasigna for chronic and accelerated phase Philadelphia chromosome--positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res 2008; 14:5325.
  93. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM217737.pdf (Accessed on August 20, 2010).
  94. Brave M, et al. Briefing document for Oncology Drug Advisory Committee. Available at: <www.fda.gov/ohrms/dockets/AC/06/briefing/2006-4220-B1-02FDA-Background.pdf>. Accessed on December 15, 2006.
  95. Dahlén T, Edgren G, Lambe M, et al. Cardiovascular Events Associated With Use of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Population-Based Cohort Study. Ann Intern Med 2016; 165:161.
  96. Quintás-Cardama A, Kantarjian H, Cortes J. Nilotinib-associated vascular events. Clin Lymphoma Myeloma Leuk 2012; 12:337.
  97. Tefferi A, Letendre L. Nilotinib treatment-associated peripheral artery disease and sudden death: yet another reason to stick to imatinib as front-line therapy for chronic myelogenous leukemia. Am J Hematol 2011; 86:610.
  98. Gambacorti-Passerini C, Piazza R. Choosing the right TKI for chronic myeloid leukemia: when the truth lies in "long-term" safety and efficacy. Am J Hematol 2011; 86:531.
  99. Aichberger KJ, Herndlhofer 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.
  100. 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.
  101. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf (Accessed on June 11, 2013).
  102. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm370971.htm (Accessed on October 15, 2013).
  103. http://www.fda.gov/Drugs/DrugSafety/ucm379554.htm (Accessed on January 14, 2014).
  104. Hochhaus A, Saglio G, Hughes TP, et al. 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.
  105. Valent P, Hadzijusufovic E, Schernthaner GH, et al. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood 2015; 125:901.
  106. 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.
  107. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J Hematol 2014; 89:947.
  108. 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.
  109. Porkka K, Khoury HJ, Paquette RL, 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; 116:377.
  110. Goldblatt M, Huggins JT, Doelken P, et al. Dasatinib-induced pleural effusions: a lymphatic network disorder? Am J Med Sci 2009; 338:414.
  111. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm275176.htm (Accessed on October 11, 2011).
  112. Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012; 125:2128.
  113. 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.
  114. Osorio S, Noblejas AG, Durán A, Steegmann JL. Imatinib mesylate induces hypophosphatemia in patients with chronic myeloid leukemia in late chronic phase, and this effect is associated with response. Am J Hematol 2007; 82:394.
  115. Owen S, Hatfield A, Letvak L. Imatinib and altered bone and mineral metabolism. N Engl J Med 2006; 355:627; author reply 628.
  116. Fitter S, Dewar AL, Kostakis P, et al. Long-term imatinib therapy promotes bone formation in CML patients. Blood 2008; 111:2538.
  117. Gambacorti-Passerini C, Tornaghi L, Cavagnini F, et al. Gynaecomastia in men with chronic myeloid leukaemia after imatinib. Lancet 2003; 361:1954.
  118. Verma D, Kantarjian H, Strom SS, et al. Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. Blood 2011; 118:4353.
  119. Apperley J. Issues of imatinib and pregnancy outcome. J Natl Compr Canc Netw 2009; 7:1050.
  120. Hensley ML, Ford JM. Imatinib treatment: specific issues related to safety, fertility, and pregnancy. Semin Hematol 2003; 40:21.
  121. Russell MA, Carpenter MW, Akhtar MS, et al. Imatinib mesylate and metabolite concentrations in maternal blood, umbilical cord blood, placenta and breast milk. J Perinatol 2007; 27:241.
  122. Berveiller P, Andreoli A, Mir O, et al. A dramatic fetal outcome following transplacental transfer of dasatinib. Anticancer Drugs 2012; 23:754.
  123. Palani R, Milojkovic D, Apperley JF. Managing pregnancy in chronic myeloid leukaemia. Ann Hematol 2015; 94 Suppl 2:S167.
  124. Kobayashi K, Takebayashi C, Miyata S, et al. Successful delivery after planned discontinuation of imatinib in a patient with chronic myeloid leukemia. Intern Med 2009; 48:369.
  125. Ali R, Ozkalemkas F, Ozcelik T, et al. Imatinib and pregnancy. J Clin Oncol 2006; 24:3812.
  126. Milojkovic D, Apperley JF. How I treat leukemia during pregnancy. Blood 2014; 123:974.
  127. Ault P, Kantarjian H, O'Brien S, et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol 2006; 24:1204.
  128. Heartin E, Walkinshaw S, Clark RE. Successful outcome of pregnancy in chronic myeloid leukaemia treated with imatinib. Leuk Lymphoma 2004; 45:1307.
  129. Prabhash K, Sastry PS, Biswas G, et al. Pregnancy outcome of two patients treated with imatinib. Ann Oncol 2005; 16:1983.
  130. AlKindi S, Dennison D, Pathare A. Imatinib in pregnancy. Eur J Haematol 2005; 74:535.
  131. Ali R, Ozkalemkaş F, Ozçelik T, et al. Pregnancy under treatment of imatinib and successful labor in a patient with chronic myelogenous leukemia (CML). Outcome of discontinuation of imatinib therapy after achieving a molecular remission. Leuk Res 2005; 29:971.
  132. Choudhary DR, Mishra P, Kumar R, et al. Pregnancy on imatinib: fatal outcome with meningocele. Ann Oncol 2006; 17:178.
  133. Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Blood 2008; 111:5505.
  134. Gambacorti-Passerini CB, Tornaghi L, Marangon E, et al. Imatinib concentrations in human milk. Blood 2007; 109:1790.
  135. Kuwabara A, Babb A, Ibrahim A, et al. Poor outcome after reintroduction of imatinib in patients with chronic myeloid leukemia who interrupt therapy on account of pregnancy without having achieved an optimal response. Blood 2010; 116:1014.
  136. Ramasamy K, Hayden J, Lim Z, et al. Successful pregnancies involving men with chronic myeloid leukaemia on imatinib therapy. Br J Haematol 2007; 137:374.