Current Hematologic Malignancy Reports

, Volume 6, Issue 2, pp 96–103 | Cite as

New Drugs for Chronic Myelogenous Leukemia

Article

Abstract

The introduction of tyrosine kinase inhibitors (TKIs) has changed the landscape of therapy for chronic myelogenous leukemia (CML). Once considered an incurable malignancy, CML now has become a manageable chronic condition. Despite the great advances that imatinib has brought to the treatment of CML, some patients still develop resistance to imatinib and other TKIs, such as dasatinib and nilotinib. Furthermore, none of the clinically available TKIs is capable of eradicating leukemia stem cells and therefore curing CML. Several new compounds have been developed in recent years in an attempt to manage TKI-resistant CML. These include third-generation TKIs (ponatinib, danusertib) and even old compounds such as omacetaxine, which were developed before imatinib and now find a possible niche in the treatment of imatinib-resistant CML. We review the current preclinical and clinical data on the most promising new compounds for the treatment of CML.

Keywords

Chronic myeloid leukemia Ponatinib Aurora kinase inhibitors Homoharringtonine Tyrosine kinase inhibitors 

References

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

  1. 1.
    Quintas-Cardama A, Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood. 2009;113(8):1619–30.PubMedCrossRefGoogle Scholar
  2. 2.
    Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041–51.PubMedCrossRefGoogle Scholar
  3. 3.
    Deininger M, O'Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes TP, 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]. Blood. 2009;114 (22), Abstract 1126Google Scholar
  4. 4.
    Part AJF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(11):1018–29.CrossRefGoogle Scholar
  5. 5.
    Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22(6):1200–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Garg RJ, Kantarjian H, O'Brien S, Quintas-Cardama A, Faderl S, Estrov Z, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood. 2009;114(20):4361–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood. 2006;107(11):4532–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99(1):319–25.PubMedCrossRefGoogle Scholar
  12. 12.
    Jorgensen HG, Allan EK, Jordanides NE, Mountford JC, Holyoake TL. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood. 2007;109(9):4016–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL, et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood. 2003;101(12):4701–7.PubMedCrossRefGoogle Scholar
  14. 14.
    O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, 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(5):401–12.PubMedCrossRefGoogle Scholar
  15. 15.
    •• Cortes J, Talpaz M, Bixby D, Deininger M, Shah N, Flinn IW, et al. A phase 1 trial of oral ponatinib (AP24534) in patients with refractory chronic myelogenous leukemia (cml) and other hematologic malignancies: emerging safety and clinical response findings [abstract]. Blood. 2010;116 (21), Abstract 210. This abstract reports the results of a phase I clinical trial of ponatinib in patients with imatinib-refractory CML; ponatinib was found to have activity in T315I mutated disease. Google Scholar
  16. 16.
    Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol. 2003;4(11):842–54.PubMedCrossRefGoogle Scholar
  17. 17.
    Ye D, Garcia-Manero G, Kantarjian HM, Xiao L, Vadhan-Raj S, Fernandez MH, et al. Analysis of Aurora kinase A expression in CD34(+) blast cells isolated from patients with myelodysplastic syndromes to acute myeloid leukemia. J Hematop. 2009;2(1):2–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Gontarewicz A, Balabanov S, Keller G, Colombo R, Graziano A, Pesenti E, 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(8):4355–64.PubMedCrossRefGoogle Scholar
  19. 19.
    Carter TA, Wodicka LM, Shah NP, Velasco AM, Fabian MA, Treiber DK, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci USA. 2005;102(31):11011–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Hoover RR, Harding MW. Synergistic activity of the aurora kinase inhibitor MK-0457 (VX-680) with idarubicin, ara-C, and inhibitors of BCR-ABL [abstract]. Blood. 2006;108 (11), Abstract 1384Google Scholar
  21. 21.
    Young MA, Shah NP, Chao LH, Seeliger M, Milanov ZV, Biggs 3rd WH, et al. Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the aurora kinase inhibitor VX-680. Cancer Res. 2006;66(2):1007–14.PubMedCrossRefGoogle Scholar
  22. 22.
    Giles F, Cortes J, Bergstrom DA, Xiao A, Bristow P, Jones D, et al. MK-0457, a novel aurora kinase and BCR-ABL inhibitor, is active against BCR-ABL T315I mutant chronic myelogenous leukemia (CML) [abstract]. Blood. 2006;108 (11), Abstract 163Google Scholar
  23. 23.
    Cortes J, Dombret H, Schafhausen P, Brummendorf TH, Boissel N, Latini F, 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]. Blood. 2009;114 (22), Abstract 864Google Scholar
  24. 24.
    Brummendorf TH, Gontarewicz A, Keller G, Moll J, Braig M, Rohe I, et al. Resistance to danusertib (formerly PHA-739358) in BCR-ABL-positive cells is mediated by up regulation of the drug transporter Abcg2 and can be suppressed in vitro by combination treatment with imatinib [abstract]. Blood. 2009;114 (22), Abstract 1724Google Scholar
  25. 25.
    Shah NP, Kasap C, Paquette R, Cortes J, Pinilla J, Talpaz M, et al. Targeting drug-resistant CML and Ph+-ALL with the spectrum selective protein kinase inhibitor XL228 [abstract]. Blood. 2007;110 (11), Abstract 47Google Scholar
  26. 26.
    Cortes J, Paquette R, Talpaz M, Pinilla J, Asatiani E, Wetzler M, et al. Preliminary clinical activity in a phase I trial of the BCR-ABL/IGF- 1R/aurora kinase inhibitor XL228 in patients with Ph++ leukemias with either failure to multiple TKI therapies or with T315I mutation [abstract]. Blood. 2008;112(11):3232.Google Scholar
  27. 27.
    Howard S, Berdini V, Boulstridge JA, Carr MG, Cross DM, Curry J, et al. Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem. 2009;52(2):379–88.PubMedCrossRefGoogle Scholar
  28. 28.
    Tanaka R, Squires MS, Kimura S, Yokota A, Nagao R, Yamauchi T, et al. Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells. Blood. 2010;116(12):2089–95.PubMedCrossRefGoogle Scholar
  29. 29.
    Foran JM, Ravandi F, O'Brien SM, Borthakur G, Rios MB, Boone P, et al. Phase I and pharmacodynamic trial of AT9283, an aurora kinase inhibitor, in patients with refractory leukemia [abstract]. J Clin Oncol. 2008;26 (15S), Abstract 2518Google Scholar
  30. 30.
    Van Etten RA, Chan WW, Zaleskas VM, Evangelista P, Lazarides K, Peng C, et al. DCC-2036: a novel switch pocket inhibitor of ABL tyrosine kinase with therapeutic efficacy against BCR-ABL T315I in vitro and in a CML mouse model [abstract]. Blood. 2007;110 (11), Abstract 463Google Scholar
  31. 31.
    Cortes J, Quintas-Cardama A, Garcia-Manero G, O'Brien S, Jones D, Faderl S, et al. Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure. Cancer. 2007;110(9):2000–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Copland M, Pellicano F, Richmond L, Allan EK, Hamilton A, Lee FY, et al. BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood. 2008;111(5):2843–53.PubMedCrossRefGoogle Scholar
  33. 33.
    Cortes J, Faderl S, Estey E, Kurzrock R, Thomas D, Beran M, et al. Phase I study of BMS-214662, a farnesyl transferase inhibitor in patients with acute leukemias and high-risk myelodysplastic syndromes. J Clin Oncol. 2005;23(12):2805–12.PubMedCrossRefGoogle Scholar
  34. 34.
    Thomas EK, Cancelas JA, Chae HD, Cox AD, Keller PJ, Perrotti D, et al. Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease. Cancer Cell. 2007;12(5):467–78.PubMedCrossRefGoogle Scholar
  35. 35.
    Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S, 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(5):355–68.PubMedCrossRefGoogle Scholar
  36. 36.
    • Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, Blaser BW, 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 (9), 2408–21. This article explains a preclinical rationale for studying PP2A activators in CML. PubMedCrossRefGoogle Scholar
  37. 37.
    Nimmanapalli R, O'Bryan E, Bhalla K. Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. Cancer Res. 2001;61(5):1799–804.PubMedGoogle Scholar
  38. 38.
    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(8):3041–4.PubMedCrossRefGoogle Scholar
  39. 39.
    Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA, et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci USA. 1998;95(6):3003–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood. 2003;101(8):3236–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Fiskus W, Pranpat M, Bali P, Balasis M, Kumaraswamy S, Boyapalle S, et al. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Blood. 2006;108(2):645–52.PubMedCrossRefGoogle Scholar
  42. 42.
    Fiskus W, Pranpat M, Balasis M, Bali P, Estrella V, Kumaraswamy S, et al. Cotreatment with vorinostat (suberoylanilide hydroxamic acid) enhances activity of dasatinib (BMS-354825) against imatinib mesylate-sensitive or imatinib mesylate-resistant chronic myelogenous leukemia cells. Clin Cancer Res. 2006;12(19):5869–78.PubMedCrossRefGoogle Scholar
  43. 43.
    Nimmanapalli R, Fuino L, Bali P, Gasparetto M, Glozak M, Tao J, et al. Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res. 2003;63(16):5126–35.PubMedGoogle Scholar
  44. 44.
    George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood. 2005;105(4):1768–76.PubMedCrossRefGoogle Scholar
  45. 45.
    •• Zhang B, Strauss AC, Chu S, Li M, Ho Y, Shiang KD, et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell. 2010;17 (5), 427–42. This article demonstrates that HDACI can target quiescent leukemic stem cells in CML. PubMedCrossRefGoogle Scholar
  46. 46.
    Guilhot F, Dubruille V, Skotnicki AB, Hellmann A, Shamsazar J, Bourquelot PM, et al. A phase II study of oral panobinostat (LBH589) in accelerated phase (AP) or blast crisis (BC) chronic myeloid leukemia (CML) patients resistant to >=2 BCR-ABL tyrosine kinase inhibitors [abstract]. Blood. 2008;112 (11), Abstract 4263Google Scholar
  47. 47.
    Quintas-Cardama A, Kantarjian H, Cortes J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer. 2009;115(23):5382–93.PubMedCrossRefGoogle Scholar
  48. 48.
    Tang R, Faussat AM, Majdak P, Marzac C, Dubrulle S, Marjanovic Z, et al. Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells. Mol Cancer Ther. 2006;5(3):723–31.PubMedCrossRefGoogle Scholar
  49. 49.
    • Cortes J, Khoury HJ, Nicolini FE, Corm S, Lipton JH, Jones D, et al. Safety and efficacy of subcutaneous-administered omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia (CML) patients who harbor the Bcr- Abl T315I mutation—results of an ongoing multicenter phase 2/3 study [abstract]. Blood. 2009;114 (22), Abstract 644. This abstract reports results of a phase 2 study of omacetaxine in patients with T315I-mutated CML. Google Scholar
  50. 50.
    Cortes J, Raghunadharao D, Parikh P, Wetzler M, Lipton JH, Jones D, 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 [abstract]. Blood. 2009;114 (22), Abstract 861.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Fabio P. S. Santos
    • 2
  • Alfonso Quintás-Cardama
    • 1
  1. 1.Department of Leukemia, Unit 428M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Hematology DepartmentHospital Israelita Albert EinsteinSão PauloBrazil

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