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Chronic Myeloid Leukemia: Overview of New Agents and Comparative Analysis

  • Leukemia (JP Dutcher, Section Editor)
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Opinion statement

Discovery of targeted BCR-ABL protein tyrosine kinase inhibitors (TKI) in the therapy of patients with chronic myeloid leukemia (CML) is perhaps the most popular success story in oncology. Imatinib is the most common TKI modality used as a frontline therapy in CML across the world. Lately, randomized control trials have shown that second-generation TKI, such as dasatinib and nilotinib, are superior to imatinib in terms of tolerability and efficacy. Therefore, second-generation TKI have been used increasingly as a first choice for patients with CML in chronic phase (CML-CP). Recently, ponatinib has shown significant efficacy against the most resistant cases (including those with T315I mutations) with CML. Omacetaxine is a non-TKI agent with a different mechanism of action and has shown benefit in resistant CML. Analysis of other novel agents and newer mechanisms affecting CML stem cells are under exploration. With these developments, the life expectancy of the majority of patients (>90 %) with CML-CP has become comparable to a healthy age-matched individual. The focus has now shifted to achieving faster and deeper responses, considering these parameters as a surrogate for long-term outcome and possibly cures in patients with CML. Adherence to therapy with TKI, proper monitoring by standardized techniques, and adequate use of the available therapies are established rules of managing patients with CML. However, even with these advances, problems of drug resistance, loss of response, kinase domain mutations, transformations in CML (accelerated and blast phase), and patient noncompliance prevail in the community practice. Early identification of resistant cases, feasibility for allogeneic stem cell transplantation (allo-SCT), and enrollment in clinical trials with newer drugs is warranted. This article compares the efficacy and safety results of various TKI and non-TKI modalities and other novel pharmacological agents in the therapy of CML.

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References and Recommended Reading

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

  1. van Etten RA, Mauro M, Radich JP, et al. Advances in the biology and therapy of chronic myeloid leukemia: proceedings from the 6th Post-ASH International Chronic Myeloid Leukemia and Myeloproliferative Neoplasms Workshop. Leuk Lymphoma. 2012. doi:10.3109/10428194.2012.745524.

  2. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341:164–72.

    Article  PubMed  CAS  Google Scholar 

  3. SEER cancer statistics review (1975–2007) [database on the Internet]: 2013. Accessed January 21st 2013.

  4. Chen Y, Wang H, Kantarjian H, Cortes J. Trends in chronic myeloid leukemia incidence and survival in the United States from 1975 to 2009. Leuk Lymphoma. 2012. doi:10.3109/10428194.2012.745525.

  5. Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290–3.

    Article  PubMed  CAS  Google Scholar 

  6. Heisterkamp N, Stam K, Groffen J, de Klein A, Grosveld G. Structural organization of the bcr gene and its role in the Ph' translocation. Nature. 1985;315(6022):758–61.

    Article  PubMed  CAS  Google Scholar 

  7. Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984;36:93–9.

    Article  PubMed  CAS  Google Scholar 

  8. Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990;247:1079–82.

    Article  PubMed  CAS  Google Scholar 

  9. Soverini S, Martinelli G, Rosti G, Iacobucci I, Baccarani M. Advances in treatment of chronic myeloid leukemia with tyrosine kinase inhibitors: the evolving role of Bcr-Abl mutations and mutational analysis. Pharmacogenomics. 2012;13:1271–84.

    Article  PubMed  CAS  Google Scholar 

  10. Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood. 2012;120:1390–7. This article provides a clinically practical approach to manage patients with CML.

    Article  PubMed  CAS  Google Scholar 

  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;2:561–6.

    Article  PubMed  CAS  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399–401.

    Article  PubMed  CAS  Google Scholar 

  14. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–41.

    Article  PubMed  CAS  Google Scholar 

  15. 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.

    Article  PubMed  CAS  Google Scholar 

  16. 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 

  17. Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120:3898–905.

    Article  PubMed  CAS  Google Scholar 

  18. Kantarjian HM, Shah NP, Cortes JE, 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 

  19. Cortes JE, Jones D, O'Brien S, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010;28:392–7.

    Article  PubMed  CAS  Google Scholar 

  20. Cortes JE, Jones D, O'Brien S, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010;28:398–404.

    Article  PubMed  CAS  Google Scholar 

  21. 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. This trial has shown efficacy of Bosutinib in the frontline setting.

    Article  PubMed  CAS  Google Scholar 

  22. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075–88. This landmark study has shown the efficacy of ponatinib in T315I mutant CML patients. Ponatinib was approved by FDA in the relapsed refractory patients with CML.

    Article  PubMed  CAS  Google Scholar 

  23. O'Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401–12.

    Article  PubMed  Google Scholar 

  24. 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 

  25. Jorge E. Cortes D-WK, Javier Pinilla-Ibarz, Philipp D. Le Coutre, et al. Initial Findings From the PACE Trial: A Pivotal Phase 2 Study of Ponatinib in Patients with CML and Ph + ALL Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I Mutation. [Abstract 163]. Presented at ASH meeting 2012 in Atlanta December 9–13,2012.

  26. Gora-Tybor J. Emerging therapies in chronic myeloid leukemia. Curr Cancer Drug Targets. 2012;12:458–70.

    Article  PubMed  CAS  Google Scholar 

  27. O'Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012;12:513–26.

    Article  PubMed  Google Scholar 

  28. Cortes J. CML: the good, the better, and the difficult choices. Blood. 2012;120:3866–7.

    Article  PubMed  CAS  Google Scholar 

  29. Goldman JM. Marin D: Is imatinib still an acceptable first-line treatment for CML in chronic phase? Oncology (Williston Park). 2012;26:901–7.

    Google Scholar 

  30. 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. Omacetaxine was approved by FDA for relapsed refractory patients with CML who have failed therapy with TKI.

    Article  PubMed  CAS  Google Scholar 

  31. Shami PJ. How to choose frontline therapy for chronic myelogenous leukemia: so many drugs, not so many patients. J Natl Compr Canc Netw. 2012;10:112–8.

    PubMed  CAS  Google Scholar 

  32. Marin D. Initial choice of therapy among plenty for newly diagnosed chronic myeloid leukemia. Hematol Am Soc Hematol Educ Program. 2012;1:115–121.

  33. 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;115:4136–47.

    Article  PubMed  CAS  Google Scholar 

  34. 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 

  35. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303–9.

    Article  PubMed  CAS  Google Scholar 

  36. 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;109:3207–13.

    Article  PubMed  CAS  Google Scholar 

  37. 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.

    Article  PubMed  Google Scholar 

  38. Deininger M, 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. [Abstract 1126]. Presented at ASH meeting 2009 in New Orleans December 5–8,2009,

  39. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26:3358–63.

    Article  PubMed  Google Scholar 

  40. Lucas CM, Wang L, Austin GM, et al. A population study of imatinib in chronic myeloid leukaemia demonstrates lower efficacy than in clinical trials. Leukemia. 2008;22:1963–6.

    Article  PubMed  CAS  Google Scholar 

  41. Hehlmann R, Lauseker M, Jung-Munkwitz S, et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol. 2011;29:1634–42.

    Article  PubMed  CAS  Google Scholar 

  42. Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010;363:2511–21.

    Article  PubMed  CAS  Google Scholar 

  43. Cortes J, Quintas-Cardama A, Jones D, et al. Immune modulation of minimal residual disease in early chronic phase chronic myelogenous leukemia: a randomized trial of frontline high-dose imatinib mesylate with or without pegylated interferon alpha-2b and granulocyte-macrophage colony-stimulating factor. Cancer. 2011;117:572–80.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  45. Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol. 2010;28:424–30. This study has shown achievement of earlier molecular responses with high dose imatinib over standard dose imatinib.

    Article  PubMed  CAS  Google Scholar 

  46. Baccarani M, Rosti G, Castagnetti F, et al. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. Blood. 2009;113:4497–504.

    Article  PubMed  CAS  Google Scholar 

  47. Alattar ML, Kantarjian HM, Jabbour E, et al. Clinical Significance of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR) Achieved with Different Treatment Modalities Used As Frontline Therapy In Chronic Myeloid Leukemia (CML) Chronic Phase (CP). [Abstract 745]. Presented at ASH meeting 2011 in San Diego December 10–13,2011.

  48. Haouala A, Widmer N, Duchosal MA, et al. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011;117:e75–87.

    Article  PubMed  CAS  Google Scholar 

  49. Jabbour E, Jones D, Kantarjian HM, et al. Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations. Blood. 2009;114:2037–43.

    Article  PubMed  CAS  Google Scholar 

  50. Quintas-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  CAS  Google Scholar 

  51. Shah N.P., Kantarjian H., Kim DW, et al. Six-year (yr) follow-up of patients (pts) with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. [Abstract 6506]. Presented at ASCO meeting 2012 in Chicago June 3–7,2012.

  52. 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 

  53. 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. DASISION trial was a landmark phase III trial comparing dasatinib and imatinib in the frontline setting. Dasatinib showed higher and deeper rate of responses. Dasatinib was approved by FDA in the frontline setting.

    Article  PubMed  CAS  Google Scholar 

  54. Marin D, Hedgley C, Clark RE, et al. Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib. Blood. 2012;120:291–4.

    Article  PubMed  CAS  Google Scholar 

  55. Brixey AG, Light RW. Pleural effusions due to dasatinib. Curr Opin Pulm Med. 2010;16:351–6.

    Article  PubMed  Google Scholar 

  56. Kreutzman A, Juvonen V, Kairisto V, et al. Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood. 2010;116:772–82.

    Article  PubMed  CAS  Google Scholar 

  57. Montani D, Bergot E, Gunther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125:2128–37.

    Article  PubMed  CAS  Google Scholar 

  58. Giles FJ, O'Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia. 2009;23:1698–707.

    Article  PubMed  CAS  Google Scholar 

  59. Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118:1208–15.

    Article  PubMed  CAS  Google Scholar 

  60. Khorashad JS, Kelley TW, Szankasi P, et al. BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood. 2013;121:489–98.

    Article  PubMed  CAS  Google Scholar 

  61. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12:841–51.

    Article  PubMed  CAS  Google Scholar 

  62. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–9. Nilotinib was compared with imatinib in the frontline setting in two dose levels in a phase III randomized control trial. This trial has shown the superior efficacy of nilotinib over imatinib. ENESTnd trial. Nilotinib was approved by FDA in the frontline setting.

    Article  PubMed  CAS  Google Scholar 

  63. Hochhaus A, Hughes TP, Saglio G, et al. Outcome of Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Based On Early Molecular Response and Factors Associated with Early Response: 4-Year Follow-up Data From Enestnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients). [Abstract 167]. Presented at ASH meeting 2012 in Atlanta December 9–13,2012.

  64. Nicolini FE, Etienne G, Dubruille V, et al. Pegylated Interferon-{alpha} 2a in Combination to Nilotinib As First Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia Provides High Rates of MR4.5. Preliminary Results of a Phase II Study. [Abstract 166]. Presented at ASH meeting 2012 in Atlanta December 9–13,2012.

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

    Article  PubMed  CAS  Google Scholar 

  66. Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118:4567–76. This study has shown efficacy of Bosutinib in imatinib resistant or intolerant patients. Bosutinib was later approved by FDA.

    Article  PubMed  CAS  Google Scholar 

  67. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119:3403–12. Bosutinib was studied in patients who have failed two lines of TKI in this study.

    Article  PubMed  CAS  Google Scholar 

  68. Wetzler M, Segal D. Omacetaxine as an anticancer therapeutic: what is old is new again. Curr Pharm Des. 2011;17:59–64.

    Article  PubMed  CAS  Google Scholar 

  69. Nicolini F.E., Lipton JH, Hagop Kantarjian, et al. Subcutaneous omacetaxine mepesuccinate in patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) resistant/intolerant to two or three approved tyrosine-kinase inhibitors (TKIs). [Abstract 6513]. Presented at ASCO meeting 2012 in Chicago June 3–7,2012.

  70. Cortes J, Digumarti R, Parikh PM, et al. The Omacetaxine 203 Study G: Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. American Journal of Hematology 2013. doi:10.1002/ajh.23408.

  71. Chan WW, Wise SC, Kaufman MD, et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell. 2011;19:556–68.

    Article  PubMed  CAS  Google Scholar 

  72. Cortes JE, Talpaz, Moshe, Kantarjian, Hagop M, et al. A Phase 1 Study of DCC-2036, a Novel Oral Inhibitor of BCR-ABL Kinase, in Patients with Philadelphia Chromosome Positive (Ph+) Leukemias Including Patients with T315I Mutation. [Abstract 601]. Presented at ASH meeting 2011 in San Diego December 9–13,2011.

  73. Harrington EA, Bebbington D, Moore J, et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med. 2004;10:262–7.

    Article  PubMed  CAS  Google Scholar 

  74. Gontarewicz A, Balabanov S, Keller G, et al. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I. Blood. 2008;111:4355–64.

    Article  PubMed  CAS  Google Scholar 

  75. Shiotsu Y, Kiyoi H, Ishikawa Y, et al. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009;114:1607–17.

    Article  PubMed  CAS  Google Scholar 

  76. Giles FJ, Swords RT, Nagler A, et al. MK-0457, an Aurora kinase and BCR-ABL inhibitor, is active in patients with BCR-ABL T315I leukemia. Leukemia. 2013;27:113–7.

    Article  PubMed  CAS  Google Scholar 

  77. Cortes-Franco J, Dombret, Herve, et al. Danusertib Hydrochloride (PHA-739358), a Multi-Kinase Aurora Inhibitor, Elicits Clinical Benefit in Advanced Chronic Myeloid Leukemia and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia [Abstract 864]. Presented at ASH meeting 2009 in New Orleans December 4–8,2009.

  78. Gorre ME, Ellwood-Yen K, Chiosis G, Rosen N, Sawyers CL. BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood. 2002;100:3041–4.

    Article  PubMed  CAS  Google Scholar 

  79. Wang Y, Trepel JB, Neckers LM, Giaccone G. STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs. 2010;11:1466–76.

    PubMed  CAS  Google Scholar 

  80. Zhang J, Adrian FJ, Jahnke W, et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010;463:501–6.

    Article  PubMed  CAS  Google Scholar 

  81. Helgason GV, Karvela M, Holyoake TL. Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML. Blood. 2011;118:2035–43.

    Article  PubMed  CAS  Google Scholar 

  82. Goussetis DJ, Gounaris E, Wu EJ, et al. Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide. Blood. 2012;120:3555–62.

    Article  PubMed  CAS  Google Scholar 

  83. Ito K, Bernardi R, Morotti A, et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature. 2008;453:1072–8.

    Article  PubMed  CAS  Google Scholar 

  84. Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411:349–54.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  86. Neviani P, Santhanam R, Trotta R, et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell. 2005;8:355–68.

    Article  PubMed  CAS  Google Scholar 

  87. Neviani P, Santhanam R, Oaks JJ, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest. 2007;117:2408–21.

    Article  PubMed  CAS  Google Scholar 

  88. Zhang B, Strauss AC, Chu S, et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell. 2010;17:427–42.

    Article  PubMed  Google Scholar 

  89. Chen Y, Li D, Li S. The Alox5 gene is a novel therapeutic target in cancer stem cells of chronic myeloid leukemia. Cell Cycle. 2009;8(21):3488–92.

    Article  PubMed  CAS  Google Scholar 

  90. Zhang B, Li M, McDonald T, et al. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-Cadherin and Wnt-beta-catenin signaling. Blood. 2013;121:1824–38.

    Google Scholar 

  91. Reddiconto G, Toto C, Palama I, et al. Targeting of GSK3beta promotes imatinib-mediated apoptosis in quiescent CD34+ chronic myeloid leukemia progenitors, preserving normal stem cells. Blood. 2012;119:2335–45.

    Article  PubMed  CAS  Google Scholar 

  92. 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 

  93. Shah NP, Skaggs BJ, Branford S, et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clin Invest. 2007;117:2562–9.

    Article  PubMed  CAS  Google Scholar 

  94. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029–35. This study was a major attempt to study the outcomes of those patients who have stopped taking imatinib on achieveing long term cytogenetic and/or molecular response and about a third of patients have relapsed.

    Article  PubMed  CAS  Google Scholar 

  95. Crews LA, Jamieson CH. Selective elimination of leukemia stem cells: Hitting a moving target. Cancer Lett. 2012. doi:10.1016/j.canlet.2012.08.006.

  96. Wang D, Zhang L, Li Y, et al. Construction and expression of humanized chimeric T cell receptor specific for chronic myeloid leukemia cells. Biotechnol Lett. 2012;34:1193–201.

    Article  PubMed  CAS  Google Scholar 

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Conflict of Interest

Preetesh Jain declares that he has no conflict of interest.

Hagop Kantarjian received research support from Ariad, Pfizer, Chemgenex, BMS and Novartis.

Jorge Cortes is a consultant to Ariad, Teva, and Pfizer.

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  1. Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX, 77030, USA

    Preetesh Jain MD, PhD, Hagop Kantarjian MD & Jorge Cortes MD

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  1. Preetesh Jain MD, PhD
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Correspondence to Jorge Cortes MD.

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Jain, P., Kantarjian, H. & Cortes, J. Chronic Myeloid Leukemia: Overview of New Agents and Comparative Analysis. Curr. Treat. Options in Oncol. 14, 127–143 (2013). https://doi.org/10.1007/s11864-013-0234-8

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