New Agents in the Treatment of Chronic Myelogenous Leukemia

Authors:
Javier Pinilla-Ibarz From the Division of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, and Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

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 MD, PhD
and
Alfonso Quintás-Cardama From the Division of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, and Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

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 MD
Volume/Issue:
Volume 7: Issue 9
Online Publication Date:
Oct 2009
DOI:
https://doi.org/10.6004/jnccn.2009.0066
Full access

The discovery of molecularly targeted agents that selectively inhibit bcr-abl tyrosine kinase activity, such as imatinib, has revolutionized the treatment and natural history of chronic myelogenous leukemia (CML). Treatment of chronic-phase CML with imatinib showed complete cytogenetic response rates of more than 40% in patients after failure of interferon-α, and more than 80% in patients with newly diagnosed CML. Patients with CML can now expect excellent long-term survival, often without major side effects. In most patients, however, residual leukemic burden remains detectable using a sensitive reverse transcription-polymerase chain reaction method. In addition, many patients undergoing imatinib therapy will either not respond or lose their response over time because of resistance or intolerance. The introduction of second-generation tyrosine kinase inhibitors (TKIs) re-establishes response in approximately half of these patients. Several agents are being developed for treating patients who experience suboptimal response to second-generation TKIs and for those who develop resistance caused by the emergence of highly resistant BCR-ABL1 mutations. This article provides an overview of novel targeted agents available for CML.

Correspondence: Javier Pinilla-Ibarz, MD, PhD, Malignant Hematology Division, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, MRC-3056H, Tampa, FL 33612. E-mail: Javier.Pinilla@moffitt.org
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  • 1

    Buchdunger E, Cioffi CL, Law N et al.. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 2000;295:139–145.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Druker BJ, Guilhot F, O’Brien SG et al.. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408–2417.

  • 3

    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;2:561–566.

  • 4

    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.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    [Package Insert]I. Imatinib Novartis Pharmaceuticals Corporation. 2006.

  • 6

    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;26:3358–3363.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    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;22:1963–1966.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Steegmann JL, Michallet M, Morra E et al.. Imatinib use in chronic phase CML in clinical practice: the UNIC study [abstract]. J Clin Oncol 2008;26(Suppl 1):Abstract 7077.

  • 9

    Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 2004;18:1321–1331.

  • 10

    Litzow MR. Imatinib resistance: obstacles and opportunities. Arch Pathol Lab Med 2006;130:669–679.

  • 11

    Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004;104:3739–3745.

  • 12

    Zong Y, Zhou S, Sorrentino BP. Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia. Leukemia 2005;19:1590–1596.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    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;293:876–880.

  • 14

    Hochhaus A, Kreil S, Corbin AS et al.. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002;16:2190–2196.

  • 15

    Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005;353:172–187.

  • 16

    Lahaye T, Riehm B, Berger U et al.. Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up. Cancer 2005;103:1659–1669.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Hughes T, Deininger M, Hochhaus A et al.. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28–37.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005;105:2640–2653.

  • 19

    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;102:276–283.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Jabbour E, Kantarjian HM, Jones D et al.. Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. Blood 2008;112:4839–4842.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    La Rosee P, Corbin AS, Stoffregen EP et al.. Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res 2002;62:7149–7153.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Azam M, Latek RR, Daley GQ. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 2003;112:831–843.

  • 23

    Ban K, Gao Y, Amin HM et al.. BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia. Blood 2008;111:2904–2908.

  • 24

    Donato NJ, Wu JY, Stapley J et al.. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003;101:690–698.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Donato NJ, Wu JY, Stapley J et al.. Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Cancer Res 2004;64:672–677.

  • 26

    Lionberger JM, Wilson MB, Smithgall TE. Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck. J Biol Chem 2000;275:18581–18585.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Alvarado Y, Kantarjian H, O’Brien S et al.. Significance of suboptimal response to imatinib, as defined by the European LeukemiaNet, in the long-term outcome of patients with early chronic myeloid leukemia in chronic phase. Cancer 2009;115:3709–3718.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Kantarjian H, O’Brien S, Shan J et al.. Cytogenetic and molecular responses and outcome in chronic myelogenous leukemia: need for new response definitions? Cancer 2008;112:837–845.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Quintas-Cardama A, Kantarjian H, Jones D et al.. Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. Blood 2009;113:6315–6321.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Baccarani M, Saglio G, Goldman J et al.. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:1809–1820.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Cortes J, Baccarani M, Guilhot F et al.. A phase III, randomized, open-label study of 400 mg versus 800 mg of imatinib mesylate (IM) in patients (pts) with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) Using molecular endpoints: 1-year results of TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) study [abstract]. Blood 2008;112:Abstract 335.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Golemovic M, Verstovsek S, Giles F et al.. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res 2005;11:4941–4947.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    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;104:1230–1236.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Weisberg E, Manley PW, Mestan J. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer 2006;94:1765–1769.

  • 35

    Weisberg E, Manley PW, Breitenstein W et al.. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005;7:129–141.

  • 36

    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;65:4500–4505.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Hochhaus A, Kim DW, Martinelli G et al.. Nilotinib efficacy according to baseline BCR-ABL mutations in patients with imatinib-resistant chronic myeloid leukemia in chronic phase (CML-CP) [abstract]. Blood 2008;112:Abstract 3216.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Kantarjian HM, Giles F, Bhalla KN et al.. Nilotinib in chronic myeloid leukemia patients in chronic phase (CMLCP) with Imatinib resistance or intolerance: 2-year follow-up results of a phase 2 study [abstract]. Blood 2008;112:Abstract 3238.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    le Coutre P, Ottmann OG, Giles F et al.. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 2008;111:1834–1839.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    le Coutre PD, Giles F, Hochhaus A et al.. Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib resistance or intolerance: 2-year follow-up results of a phase 2 study [abstract]. Blood 2008;112:Abstract 3229.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Cortes J, O’Brien S, Jones D et al.. Efficacy of nilotinib (formerly AMN107) in patients (pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP) [abstract]. Blood 2008;112:Abstract 446.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Lee FY, Wen ML, Bhide R et al.. Dasatinib (BMS-354825) overcomes multiple mechanisms of imatinib resistance in chronic myeloid leukemia (CML) [abstract]. Blood 2005;106:Abstract 1994.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Lombardo LJ, Lee FY, Chen P et al.. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004;47:6658–6661.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    PI. Dasatinib Bristol Myers Squibb Company. Sprycel. 2006

  • 45

    Schittenhelm MM, Shiraga S, Schroeder A et al.. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res 2006;66:473–481.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Talpaz M, Shah NP, Kantarjian H et al.. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531–2541.

  • 47

    Tokarski JS, Newitt JA, Chang CY et al.. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 2006;66:5790–5797.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Hochhaus A, Baccarani M, Deininger M et al.. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 2008;22:1200–1206.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Mauro MJ, Baccarani M, Cervantes F et al.. Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous leukemia (CML-CP) with resistance or intolerance to imatinib (START-C) [abstract]. J Clin Oncol 2008;26(Suppl 1):Abstract 7009.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Stone RM, Kantarjian HM, Baccarani M et al.. Efficacy of dasatinib in patients with chronic-phase chronic myelogenous leukemia with resistance or intolerance to imatinib: 2-year follow-up data from START-C (CA180-013) [abstract]. Blood 2007;110:Abstract 734.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    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;115:4136–4147.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Apperley JF, Cortes JE, Kim DW et al.. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START A Trial. J Clin Oncol 2009;27:3472–3479.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Guilhot F, Apperley JF, Kim DW et al.. Efficacy of Dasatinib in patients with accelerated-phase chronic myelogenous leukemia with resistance or intolerance to imatinib: 2-year follow-up data from START-A (CA180-005) [abstract]. Blood 2007;110:Abstract 470.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Gambacorti C, Cortes J, Kim DW et al.. Efficacy and safety of dasatinib in patients with chronic myeloid leukemia in blast phase whose disease is resistant or intolerant to imatinib: 2-year follow-up data from the START program [abstract]. Blood 2007;110:Abstract 472.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Stone RM, Kim DW, Kantarjian HM et al.. Dasatinib dose-optimization study in chronic phase chronic myeloid leukemia (CML-CP): three-year follow-up with dasatinib 100 mg once daily and landmark analysis of cytogenetic response and progression-free survival (PFS) [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 7007.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Cortes J, O’Brien S, Borthakur G et al.. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP) [abstract]. Blood 2008;112:Abstract 182.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    Cortes J, Kantarjian HM, Kim DW et al.. Efficacy and safety of bosutinib (SKI-606) in patients with chronic phase (CP) Ph+ chronic myelogenous leukemia (CML) with resistance or intolerance to imatinib [abstract]. Blood 2008;112:Abstract 1098.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Passerini CG, Pogliani EM, Baccarani M et al.. Bosutinib (SKI-606) demonstrates clinical activity and is well tolerated in patients with AP and BP CML and Ph+ ALL [abstract]. Blood 2008;112:Abstract 1101.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Naito H, Kimura S, Nakaya Y et al.. In vivo antiproliferative effect of NS-187, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor, on leukemic cells harbouring Abl kinase domain mutations. Leuk Res 2006;30:1443–1446.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60

    Yokota A, Kimura S, Masuda S et al.. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. Blood 2007;109:306–314.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61

    Kantarjian HM, Cortes J, le Coutre P et al.. A phase I study of INNO-406 in patients with advanced Philadelphia (Ph+) chromosome-positive leukemias who are resistant or intolerant to imatinib and second generation tyrosine kinase inhibitors [abstract]. Blood 2007;110:Abstract 469.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    Pinilla-Ibarz J, Kantarjian HM, Cortes JE et al.. A phase I study of INNO-406 in patients with advanced Philadelphia chromosome-positive (Ph+) leukemias who are resistant or intolerant to imatinib and may have also failed second-generation tyrosine kinase inhibitors [abstract]. J Clin Oncol 2008;26(Suppl 1):Abstract 7018.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2001;2:21–32.

  • 64

    Giles FJ, Cortes J, Jones D et al.. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 2007;109:500–502.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65

    Shah NP, Kasap C, Paquette R et al.. Targeting drug-resistant CML and Ph+-ALL with the spectrum selective protein kinase inhibitor XL228 [abstract]. Blood 2007;110:Abstract 474.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66

    Cortes J, Paquette R, Talpaz 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:Abstract 3232.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    Paquette RL, Shah NP, Sawyers CL et al.. PHA-739358, an Aurora kinase inhibitor, induces clinical responses in chronic myeloid leukemia harboring T315I mutations of BCR-ABL [abstract]. Blood 2007;110:Abstract 1030.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 68

    Van Etten RA, Chan WW, Zaleskas VM et al.. Switch pocket inhibitors of the ABL tyrosine kinase: distinct kinome inhibition profiles and in vivo efficacy in mouse models of CML and B-lymphoblastic leukemia induced by BCR-ABL T315I [abstract]. Blood 2008;112:Abstract 576.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69

    Cortes J, Khoury HJ, Corm S et al.. Subcutaneous omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia (CML) patients (Pts) with the T315I mutation: Data from an ongoing phase II/III trial [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 7008.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70

    Nimmanapalli R, Fuino L, Stobaugh C et al.. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood 2003;101:3236–3239.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71

    Bali P, Pranpat M, Bradner J et al.. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 2005;280:26729–26734.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72

    Fiskus W, Pranpat M, Bali P et al.. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Blood 2006;108:645–652.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73

    Fiskus W, Pranpat M, Balasis M 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;12:5869–5878.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74

    Ly C, Arechiga AF, Melo JV et al.. Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res 2003;63:5716–5722.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75

    Dengler J, von Bubnoff N, Decker T et al.. Combination of imatinib with rapamycin or RAD001 acts synergistically only in Bcr-Abl-positive cells with moderate resistance to imatinib. Leukemia 2005;19:1835–1838.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76

    Mayerhofer M, Aichberger KJ, Florian S et al.. Identification of mTOR as a novel bifunctional target in chronic myeloid leukemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells. Faseb J 2005;19:960–962.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 77

    Mohi MG, Boulton C, Gu TL et al.. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci U S A 2004;101:3130–3135.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 78

    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;8:355–368.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 79

    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;117:2408–2421.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 80

    Dierks C, Beigi R, Guo GR et al.. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 2008;14:238–249.

  • 81

    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;114:2037–2043.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 82

    Mauro MJ. Appropriate sequencing of tyrosine kinase inhibitors in chronic myelogenous leukemia: when to change? A perspective in 2009. Curr Opin Hematol 2009;16:135–139.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 83

    Jabbour E, Soverini S. Understanding the role of mutations in therapeutic decision making for chronic myeloid leukemia. Semin Hematol 2009;46:S22–26.

  • 84

    Gambacorti-Passerini C, Pogliani E, Baccarani M et al.. Bosutinib (SKI-606) demonstrates clinical activity and is well tolerated in patients with AP and BP CML and Ph+ ALL [abstract]. Blood 2008;112:Abstract 1101.

    • PubMed
    • Search Google Scholar
    • Export Citation
Copyright:
Copyright © 2009 by the National Comprehensive Cancer Network 2009
Page Numbers:
10
Article Category:
Research Article
Received:
11 Jul 2009
Accepted:
27 Aug 2009
Print Publication Date:
01 Oct 2009
Online Publication Date:
Oct 2009
Keywords:
Chronic myeloid leukemia; imatinib resistance; imatinib intolerant; second generation tyrosine kinase inhibitors
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