Skip to main content

Advertisement

SpringerLink
Log in

Management Options for Refractory Chronic Myeloid Leukemia: Considerations for the Elderly

  • Therapy in Practice
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Despite the excellent results obtained with standard-dose imatinib as first-line therapy for chronic myeloid leukemia in the chronic phase, one third of patients do not achieve an optimal response and require alternative therapies due to the emergence of drug resistance. Studies of resistance mechanisms, first tested in vitro and then in vivo, have driven the development of second-generation tyrosine kinase inhibitors (TKIs), dasatinib and nilotinib. These agents have been proven effective in a large number of patients resistant to imatinib and are also effective in older patients. The use of second-generation TKIs in first-line treatment has increased the rate of cytogenetic and molecular responses and reduced the number of patients experiencing disease progression. In this review, we detail the various mechanisms of resistance and management options for refractory patients, in particular in older patients. No differences in terms of efficacy were reported in this subset of patients when treated with nilotinib or dasatinib after imatinib resistance. Results of trials that tested second-generation TKIs as first-line treatment showed similar results in older and younger patients.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451–64.

    Article  PubMed  CAS  Google Scholar 

  2. Hantschel O, Superti-Furga G. Regulation of the c-Abl and Bcr–Abl tyrosine kinases. Nat Rev Mol Cell Biol. 2004;5:33–44.

    Article  PubMed  CAS  Google Scholar 

  3. Faderl S, Talpaz M, Estrov Z, Kantarjian H. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131:207–19.

    Article  PubMed  CAS  Google Scholar 

  4. Melo JV, Deininger MW. Biology of chronic myelogenous leukemia-signaling pathways of initiation and transformation. Hematol Oncol Clin N Am. 2004;18:545–68.

    Article  Google Scholar 

  5. Sattler M, Griffin JD. Molecular mechanisms of transformation by the BCR–ABL oncogene. Semin Hematol. 2003;40:4–10.

    Article  PubMed  CAS  Google Scholar 

  6. Yeung DT, Hughes TP. Therapeutic targeting of BCR–ABL: prognostic markers of response and resistance mechanism in chronic myeloid leukemia. Crit Rev Oncog. 2012;17:17–30.

    Article  PubMed  Google Scholar 

  7. Garcia-Manero G, Faderl S, O’Brien S, Cortes J, Talpaz M, Kantarjian HM. Chronic myelogenous leukaemia: a review and update of therapeutic strategies. Cancer. 2003;98:437–57.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  9. Johnson JR, Bross P, Cohen M, et al. Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukaemia in chronic phase. Clin Cancer Res. 2003;9:1972–9.

    PubMed  CAS  Google Scholar 

  10. Deininger MW, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukaemia. Blood. 2005;105:2640–53.

    Article  PubMed  CAS  Google Scholar 

  11. O’Brien SG, Guilhot F, Goldman JM, et al. International randomized study of interferon versus STI571 (IRIS) 7-year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CMLCP) treated with imatinib (IM). Blood. 2008;112:abstr 186.

  12. Deininger MW, O’Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow-up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood. 2009;114:abstr 1126.

  13. Baccarani M, Saglio G, Goldman J, European LeukemiaNet, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809–20.

    Article  PubMed  CAS  Google Scholar 

  14. Baccarani M, Cortes J, Pane F, European LeukemiaNet, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041–51.

    Article  PubMed  CAS  Google Scholar 

  15. Simonsson B, Kloke O, Stahel RA, ESMO Guidelines Task Force. ESMO minimum clinical recommendations for the diagnosis, treatment and follow-up of chronic myelogenous leukemia (CML). Ann Oncol. 2005;16(Suppl 1):i52–3.

    Article  PubMed  Google Scholar 

  16. O’Brien SM, Kantarjian H, Radich J. Update: chronic myelogenous leukemia clinical practice guidelines. J Natl Compr Cancer Netw. 2003;1(Suppl 1):S29–40.

    Google Scholar 

  17. Cortes J, Talpaz M, O’Brien S, et al. Effects of age on prognosis with imatinib mesylate therapy for patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Cancer. 2003;98:1105–13.

    Article  PubMed  CAS  Google Scholar 

  18. Rosti G, Iacobucci I, Bassi S, et al. Impact of age on the outcome off patients with chronic myeloid leukemia in late chronic phase: results off a phase II study off the GIMEMA CML Working Party. Haematologica. 2007;92:101–5.

    Article  PubMed  Google Scholar 

  19. Latagliata R, Breccia M, Carmosino I, et al. “Real-life” results of front-line treatment with imatinib in older patients (>65 years) with newly diagnosed chronic myelogenous leukemia. Leuk Res. 2010;34:1472–5.

    Article  PubMed  CAS  Google Scholar 

  20. Pletsch N, Lauseker M, Saussele S, et al. Therapy with imatinib in elderly CML patients (>65 years) is well tolerated but cytogenetic and molecular remissions seem to be achieved later compared to younger patients. Haematologica. 2009;94:253 abstr 0625.

    Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. La Roseè P, Deininger MW. Resistance to imatinib: mutations and beyond. Semin Hematol. 2010;47:335–43.

    Article  PubMed  Google Scholar 

  23. Roychowdhury S, Talpaz M. Managing resistance in chronic myeloid leukemia. Blood Rev. 2011;25:279–90.

    Article  PubMed  Google Scholar 

  24. Vaidya S, Ghosh K, Vundinti BR. Recent developments in drug resistance mechanism in chronic myeloid leukemia: a review. Eur J Haematol. 2011;87:381–93.

    Article  PubMed  CAS  Google Scholar 

  25. Von Bubnoff N, Peschel C, Duyster J. Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back. Leukemia. 2003;17:829–38.

    Article  Google Scholar 

  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;293:876–80.

    Article  PubMed  CAS  Google Scholar 

  27. von Bubnoff N, Barwisch S, Speicher MR, et al. A cell-based screening strategy that predicts mutations in oncogenic tyrosine kinases: implications for clinical resistance in targeted cancer treatment. Cell Cycle. 2005;4:400–6.

    Article  Google Scholar 

  28. Branford S, Rudzki Z, Walsh S, et al. Detection of BCR–ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (p-loop) are associated with a poor prognosis. Blood. 2003;102:276–83.

    Article  PubMed  CAS  Google Scholar 

  29. 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;12:7374–9.

    Article  PubMed  CAS  Google Scholar 

  30. 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;23:4100–9.

    Article  PubMed  CAS  Google Scholar 

  31. Parker WT, Lawrence RM, Ho M, et al. Sensitive detection of BCR–ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy. J Clin Oncol. 2011;29:4250–9.

    Article  PubMed  CAS  Google Scholar 

  32. le Coutre P, Tassi E, Varella-Garcia M, et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood. 2000;95:1758–66.

    PubMed  Google Scholar 

  33. Mahon FX, Deininger MW, Schultheis B, et al. Selection and characterization of BCR–ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000;96:1070–9.

    PubMed  CAS  Google Scholar 

  34. Hochhaus A, Kreil S, Corbin AS. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190–6.

    Article  PubMed  CAS  Google Scholar 

  35. Piazza RG, Magistroni V, Andreoni F, et al. Imatinib dose increase up to 1200 mg daily can induce new durable complete cytogenetic remissions in relapsed Ph+ chronic myeloid leukemia patients. Leukemia. 2005;19:1985–7.

    Article  PubMed  CAS  Google Scholar 

  36. Thomas J, Wang L, Clark RE, et al. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004;104:3739–45.

    Article  PubMed  CAS  Google Scholar 

  37. Wang J, Giannoudis A, Lane S, et al. Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther. 2008;83:258–64.

    Article  PubMed  CAS  Google Scholar 

  38. White DL, Saunders VA, Dang P, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood. 2007;110:4064–72.

    Article  PubMed  CAS  Google Scholar 

  39. 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;28:2761–7.

    Article  PubMed  CAS  Google Scholar 

  40. Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101:2368–73.

    Article  PubMed  CAS  Google Scholar 

  41. Dulucq S, Bouchet S, Turcq B, et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2008;112:2024–7.

    Article  PubMed  CAS  Google Scholar 

  42. Larson RA, Druker BJ, Guilhot F, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111:4022–8.

    Article  PubMed  CAS  Google Scholar 

  43. Noens L, van Lierde MA, De Bock R, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood. 2009;113:5401–11.

    Article  PubMed  CAS  Google Scholar 

  44. 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;28:2381–8.

    Article  PubMed  CAS  Google Scholar 

  45. Green H, Skoglund K, Rommel F, et al. CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity. Eur J Clin Pharmacol. 2010;66:383–6.

    Article  PubMed  CAS  Google Scholar 

  46. Gambacorti-Passerini C, Barni R, le Coutre P, et al. Role of alpha 1 acid glycoprotein in the vivo resistance of human BCR–ABL(+) leukemic cells to the abl inhibitor STI571. J Natl Cancer Inst. 2000;92:1641–50.

    Article  PubMed  CAS  Google Scholar 

  47. Debaldo C, Chatelut E, Re M, et al. Pharmacokinetic–pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clin Cancer Res. 2006;12:6073–8.

    Article  Google Scholar 

  48. Gambacorti-Passerini C, Zucchetti M, Russo D, et al. Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res. 2003;9:625–32.

    PubMed  CAS  Google Scholar 

  49. Holyoake T, Jiang X, Eaves C, et al. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood. 1999;94:2056–64.

    PubMed  CAS  Google Scholar 

  50. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351:657–67.

    Article  PubMed  CAS  Google Scholar 

  51. Abrahamsson AE, Geron J, Gotlib J, et al. Glycogen synthase kinase 3B missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci. 2009;106:3925–9.

    Article  PubMed  CAS  Google Scholar 

  52. Naka K, Hoshii T, Muraguchi T, et al. TGF–bgr–FOXO signalling maintains leukemia-initiating cells in chronic myeloid leukemia. Nature. 2010;463:676–80.

    Article  PubMed  CAS  Google Scholar 

  53. Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukemia. Nature. 2009;458:776–9.

    Article  PubMed  CAS  Google Scholar 

  54. Warsch W, Kollmann K, Eckelhart E, et al. High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia. Blood. 2011;117:3409–20.

    Article  PubMed  CAS  Google Scholar 

  55. Quintas-Cardama A, Cortes J. Molecular biology of bcr–abl1-positive chronic myeloid leukemia. Blood. 2009;113:1619–30.

    Article  PubMed  CAS  Google Scholar 

  56. Hu Y, Liu Y, Pelletier S, et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR–ABL1 induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet. 2004;36:453–61.

    Article  PubMed  CAS  Google Scholar 

  57. Gross S, Puissant A, Dufies M, et al. Gene expression profiling of imatinib and PD166326-resistant CML cell lines identifies Fyn as a gene associated with resistance to BCR–ABL inhibitors. Mol Cancer Ther. 2009;8:1924–33.

    Article  Google Scholar 

  58. Wu J, Meng F, Kong LY, et al. Association between imatinib-resistant BCR–ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst. 2008;100:926–39.

    Article  PubMed  CAS  Google Scholar 

  59. 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;101:473–5.

    Article  PubMed  CAS  Google Scholar 

  60. Marin D, Goldman JM, Olavarria E, et al. Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses. Blood. 2003;102:2702–3.

    Article  PubMed  CAS  Google Scholar 

  61. Zonder JA, Pemberton P, Brandt H, et al. The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment. Clin Cancer Res. 2003;9:2092–7.

    PubMed  CAS  Google Scholar 

  62. Kantarjian HM, Larson RA, Guilhot F, et al. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer. 2009;115:551–60.

    Article  PubMed  CAS  Google Scholar 

  63. Jabbour E, Kantarjian HM, Jones D, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard dose imatinib therapy. Blood. 2009;113:2154–60.

    Article  PubMed  CAS  Google Scholar 

  64. Rea D, Etienne G, Corm S, et al. Imatinib dose escalation for chronic phase-chronic myelogenous leukemia patients in primary suboptimal response to imatinib 400 mg daily standard therapy. Leukemia. 2009;23:1193–6.

    Article  PubMed  CAS  Google Scholar 

  65. Breccia M, Stagno F, Vigneri P, et al. Imatinib dose escalation in 74 failure or suboptimal response chronic myeloid leukemia patients at 3-year follow up. Am J Hematol. 2010;85:375–7.

    PubMed  CAS  Google Scholar 

  66. Shah NP, Kim DW, Kantarjian H, et al. Potent, transient inhibition of BCR–ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica. 2010;95:232–40.

    Article  PubMed  CAS  Google Scholar 

  67. Rea D, Vellenga E, JunghanB C, et al. Six-year follow-up of patients with imatinib-resistant or imatinib-intolerant chronic-phase chronic myeloid leukemia (CP-CML) receiving dasatinib. Haematologica. 2012;97(Suppl 1):199.

    Google Scholar 

  68. Muller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to pre-existing BCR–ABL mutations. Blood. 2009;114:4944–53.

    Article  PubMed  Google Scholar 

  69. 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.

    Article  PubMed  CAS  Google Scholar 

  70. Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR–ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27:4204–10.

    Article  PubMed  CAS  Google Scholar 

  71. Lipton JH, le Coutre PD, Wang J, et al. Nilotinib in elderly chronic myeloid leukemia patients in chronic phase (CML-CP) with imatinib resistance or intolerance: efficacy and safety analysis. Blood. 2008;112:3233.

    Google Scholar 

  72. le Coutre PD, Turkina A, Kim DW, et al. Efficacy and safety of nilotinib in elderly patients with imatinib-resistant or intolerant chronic myeloid leukemia (VML) in chronic phase: a subanalysis of the ENACT (Expanding nilotinib access in clinical trials) study. Blood. 2009;114:3286.

    Google Scholar 

  73. Latagliata R, Breccia M, Castagnetti F, et al. Dasatinib is safe and effective in unselected chronic myeloid leukemia elderly patients resistant/intolerant to imatinib. Leuk Res. 2011;35:1164–9.

    Article  PubMed  CAS  Google Scholar 

  74. Gambacorti-Passerini C, Brummendorf T, Cortes J, et al. Efficacy and safety of bosutinib for Philadelphia chromosome-positive leukemia in older versus younger patients. Haematologica. 2012;97(Suppl 1):757.

    Google Scholar 

  75. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075–88.

    Article  PubMed  CAS  Google Scholar 

  76. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A pivotal phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR–ABL mutation: 12-month follow-up of the PACE trial. Blood. 2012;120:163.

    Google Scholar 

  77. Nanda N, Cortes J, Lipton J, et al. Treatment of chronic phase (CP) chronic myeloid leukemia (CML) patients who harbor the BCR–ABL T315I mutation with subcutaneous omacetaxine results in improved survival compared to historical data. Haematologica. 2011;96:422–3.

    Google Scholar 

  78. Cortes J, Raghunadharao D, Parikh P, et al. Safety and efficacy of subcutaneous-administered omacetaxine mepesuccinate in chronic myeloid leukemia (CML) patients who are resistant or intolerant to two or more tyrosine kinase inhibitors-results of a multicenter phase 2/3 study. Blood. 2009;114:861.

    Google Scholar 

  79. Cortes J, Lipton JH, Rea D, et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012;120:2573–80.

    Article  PubMed  CAS  Google Scholar 

  80. Warlick E, Ahn KW, Pedersen TL, et al. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era. Blood. 2012;119:4083–90.

    Article  PubMed  CAS  Google Scholar 

  81. Khoury HJ, Cortes JE, Kantarjian HM, et al. Safety and efficacy of dasatinib (DAS) vs imatinib (IM) by baseline comorbidity in patients with chronic myeloid leukemia in chronic phase (CML-CP): analysis of the DASISION trial. Blood. 2010;116:3421.

    Google Scholar 

  82. Kantarjian HM, Shah NP, Cortes JP, et al. 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  PubMed  CAS  Google Scholar 

  83. Larson RA, Bunworasate U, Turkina AG, et al. Nilotinib shows safety and efficacy in older patients (<65 years) with newly diagnosed chronic myeloid leukemia in chronic phase comparable with that in younger patients with chronic myeloid leukemia in chronic phase: results from ENESTnd. Blood. 2011;114:3768.

    Google Scholar 

  84. Kantarjian H, Kim DW, Issagrisil S, et al. ENESTnd 4-year update: continued superiority of nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP). Blood. 2012;120:1676.

    Google Scholar 

  85. 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.

    Article  PubMed  CAS  Google Scholar 

  86. Breccia M, Efficace F, Alimena G. Progressive arterial occlusive disease (PAOD) and pulmonary arterial hypertension (PAH) as new adverse events of second generation TKIs in CML treatment: who’s afraid of the big bad wolf? Leuk Res. 2012;36:813–4.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  88. Schwarz M, Kim TD, Mirault T, et al. Elevated risk of peripheral artery occlusive disease (PAOD) in nilotinib treated chronic phase chronic myeloid leukemia (CML) patients assessed by ankle-brachial index (ABI) and duplex ultrasonography. Blood. 2012;120:914.

    Article  Google Scholar 

  89. 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.

    Article  PubMed  CAS  Google Scholar 

  90. Gambacorti-Passerini C, Brummendorf TH, Kim DW, et al. Efficacy and tolerability of bosutinib and imatinib in older versus younger patients with newly diagnosed chronic phase chronic myeloid leukemia-BELA trial. Blood. 2012;120:4442.

    Google Scholar 

Download references

Acknowledgments

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Cellular Biotechnologies and Hematology, Sapienza University, Via Benevento 6, 00161, Rome, Italy

    Massimo Breccia & Giuliana Alimena

Authors
  1. Massimo Breccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giuliana Alimena
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massimo Breccia.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Breccia, M., Alimena, G. Management Options for Refractory Chronic Myeloid Leukemia: Considerations for the Elderly. Drugs Aging 30, 467–477 (2013). https://doi.org/10.1007/s40266-013-0085-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-013-0085-9

Keywords

Search

Navigation