New Agents in the Treatment of Chronic Myelogenous Leukemia

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  • a 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.

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.

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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
  • 1

    Buchdunger E, Cioffi CL, Law N. 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;295:139145.

    • Search Google Scholar
    • Export Citation
  • 2

    Druker BJ, Guilhot F, O’Brien SG. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:24082417.

    • Search Google Scholar
    • Export Citation
  • 3

    Druker BJ, Tamura S, Buchdunger E. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996;2:561566.

    • Search Google Scholar
    • Export Citation
  • 4

    O’Brien SG, Guilhot F, Larson RA. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:9941004.

    • Search Google Scholar
    • Export Citation
  • 5

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

  • 6

    de Lavallade H, Apperley JF, Khorashad JS. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008;26:33583363.

    • Search Google Scholar
    • Export Citation
  • 7

    Lucas CM, Wang L, Austin GM. A population study of imatinib in chronic myeloid leukaemia demonstrates lower efficacy than in clinical trials. Leukemia 2008;22:19631966.

    • Search Google Scholar
    • Export Citation
  • 8

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

    • Search Google Scholar
    • Export Citation
  • 9

    Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 2004;18:13211331.

    • Search Google Scholar
    • Export Citation
  • 10

    Litzow MR. Imatinib resistance: obstacles and opportunities. Arch Pathol Lab Med 2006;130:669679.

  • 11

    Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004;104:37393745.

    • Search Google Scholar
    • Export Citation
  • 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;19:15901596.

    • Search Google Scholar
    • Export Citation
  • 13

    Gorre ME, Mohammed M, Ellwood K. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876880.

    • Search Google Scholar
    • Export Citation
  • 14

    Hochhaus A, Kreil S, Corbin AS. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002;16:21902196.

  • 15

    Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005;353:172187.

  • 16

    Lahaye T, Riehm B, Berger U. 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;103:16591669.

    • Search Google Scholar
    • Export Citation
  • 17

    Hughes T, Deininger M, Hochhaus A. 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;108:2837.

    • 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;105:26402653.

    • Search Google Scholar
    • Export Citation
  • 19

    Branford S, Rudzki Z, Walsh S. 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;102:276283.

    • Search Google Scholar
    • Export Citation
  • 20

    Jabbour E, Kantarjian HM, Jones D. Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. Blood 2008;112:48394842.

    • Search Google Scholar
    • Export Citation
  • 21

    La Rosee P, Corbin AS, Stoffregen EP. 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;62:71497153.

    • 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;112:831843.

    • Search Google Scholar
    • Export Citation
  • 23

    Ban K, Gao Y, Amin HM. BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia. Blood 2008;111:29042908.

  • 24

    Donato NJ, Wu JY, Stapley J. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003;101:690698.

    • Search Google Scholar
    • Export Citation
  • 25

    Donato NJ, Wu JY, Stapley J. Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Cancer Res 2004;64:672677.

    • Search Google Scholar
    • Export Citation
  • 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;275:1858118585.

    • Search Google Scholar
    • Export Citation
  • 27

    Alvarado Y, Kantarjian H, O’Brien S. 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;115:37093718.

    • Search Google Scholar
    • Export Citation
  • 28

    Kantarjian H, O’Brien S, Shan J. Cytogenetic and molecular responses and outcome in chronic myelogenous leukemia: need for new response definitions? Cancer 2008;112:837845.

    • Search Google Scholar
    • Export Citation
  • 29

    Quintas-Cardama A, Kantarjian H, Jones D. 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;113:63156321.

    • Search Google Scholar
    • Export Citation
  • 30

    Baccarani M, Saglio G, Goldman J. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:18091820.

    • Search Google Scholar
    • Export Citation
  • 31

    Cortes J, Baccarani M, Guilhot F. 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.

    • Search Google Scholar
    • Export Citation
  • 32

    Golemovic M, Verstovsek S, Giles F. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res 2005;11:49414947.

    • Search Google Scholar
    • Export Citation
  • 33

    Verstovsek S, Golemovic M, Kantarjian H. AMN107, a novel aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells. Cancer 2005;104:12301236.

    • 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;94:17651769.

  • 35

    Weisberg E, Manley PW, Breitenstein W. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005;7:129141.

    • Search Google Scholar
    • Export Citation
  • 36

    O’Hare T, Walters DK, Stoffregen EP. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005;65:45004505.

    • Search Google Scholar
    • Export Citation
  • 37

    Hochhaus A, Kim DW, Martinelli G. 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.

    • Search Google Scholar
    • Export Citation
  • 38

    Kantarjian HM, Giles F, Bhalla KN. 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.

    • Search Google Scholar
    • Export Citation
  • 39

    le Coutre P, Ottmann OG, Giles F. 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;111:18341839.

    • Search Google Scholar
    • Export Citation
  • 40

    le Coutre PD, Giles F, Hochhaus A. 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.

    • Search Google Scholar
    • Export Citation
  • 41

    Cortes J, O’Brien S, Jones D. 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.

    • Search Google Scholar
    • Export Citation
  • 42

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

    • Search Google Scholar
    • Export Citation
  • 43

    Lombardo LJ, Lee FY, Chen P. 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;47:66586661.

    • Search Google Scholar
    • Export Citation
  • 44

    PI. Dasatinib Bristol Myers Squibb Company. Sprycel. 2006

  • 45

    Schittenhelm MM, Shiraga S, Schroeder A. 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;66:473481.

    • Search Google Scholar
    • Export Citation
  • 46

    Talpaz M, Shah NP, Kantarjian H. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:25312541.

    • Search Google Scholar
    • Export Citation
  • 47

    Tokarski JS, Newitt JA, Chang CY. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 2006;66:57905797.

    • Search Google Scholar
    • Export Citation
  • 48

    Hochhaus A, Baccarani M, Deininger M. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 2008;22:12001206.

    • Search Google Scholar
    • Export Citation
  • 49

    Mauro MJ, Baccarani M, Cervantes F. 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.

    • Search Google Scholar
    • Export Citation
  • 50

    Stone RM, Kantarjian HM, Baccarani M. 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.

    • Search Google Scholar
    • Export Citation
  • 51

    Kantarjian H, Pasquini R, Levy V. 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;115:41364147.

    • Search Google Scholar
    • Export Citation
  • 52

    Apperley JF, Cortes JE, Kim DW. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START A Trial. J Clin Oncol 2009;27:34723479.

    • Search Google Scholar
    • Export Citation
  • 53

    Guilhot F, Apperley JF, Kim DW. 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.

    • Search Google Scholar
    • Export Citation
  • 54

    Gambacorti C, Cortes J, Kim DW. 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.

    • Search Google Scholar
    • Export Citation
  • 55

    Stone RM, Kim DW, Kantarjian HM. 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.

    • Search Google Scholar
    • Export Citation
  • 56

    Cortes J, O’Brien S, Borthakur G. 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.

    • Search Google Scholar
    • Export Citation
  • 57

    Cortes J, Kantarjian HM, Kim DW. 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.

    • Search Google Scholar
    • Export Citation
  • 58

    Passerini CG, Pogliani EM, Baccarani M. 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.

    • Search Google Scholar
    • Export Citation
  • 59

    Naito H, Kimura S, Nakaya Y. 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;30:14431446.

    • Search Google Scholar
    • Export Citation
  • 60

    Yokota A, Kimura S, Masuda S. 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;109:306314.

    • Search Google Scholar
    • Export Citation
  • 61

    Kantarjian HM, Cortes J, le Coutre P. 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.

    • Search Google Scholar
    • Export Citation
  • 62

    Pinilla-Ibarz J, Kantarjian HM, Cortes JE. 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.

    • Search Google Scholar
    • Export Citation
  • 63

    Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2001;2:2132.

  • 64

    Giles FJ, Cortes J, Jones D. 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;109:500502.

    • Search Google Scholar
    • Export Citation
  • 65

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

    • Search Google Scholar
    • Export Citation
  • 66

    Cortes J, Paquette R, Talpaz M. 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.

    • Search Google Scholar
    • Export Citation
  • 67

    Paquette RL, Shah NP, Sawyers CL. 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.

    • Search Google Scholar
    • Export Citation
  • 68

    Van Etten RA, Chan WW, Zaleskas VM. 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.

    • Search Google Scholar
    • Export Citation
  • 69

    Cortes J, Khoury HJ, Corm S. 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.

    • Search Google Scholar
    • Export Citation
  • 70

    Nimmanapalli R, Fuino L, Stobaugh C. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood 2003;101:32363239.

    • Search Google Scholar
    • Export Citation
  • 71

    Bali P, Pranpat M, Bradner J. 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;280:2672926734.

    • Search Google Scholar
    • Export Citation
  • 72

    Fiskus W, Pranpat M, Bali P. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Blood 2006;108:645652.

    • Search Google Scholar
    • Export Citation
  • 73

    Fiskus W, Pranpat M, Balasis M. 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;12:58695878.

    • Search Google Scholar
    • Export Citation
  • 74

    Ly C, Arechiga AF, Melo JV. 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;63:57165722.

    • Search Google Scholar
    • Export Citation
  • 75

    Dengler J, von Bubnoff N, Decker T. Combination of imatinib with rapamycin or RAD001 acts synergistically only in Bcr-Abl-positive cells with moderate resistance to imatinib. Leukemia 2005;19:18351838.

    • Search Google Scholar
    • Export Citation
  • 76

    Mayerhofer M, Aichberger KJ, Florian S. 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;19:960962.

    • Search Google Scholar
    • Export Citation
  • 77

    Mohi MG, Boulton C, Gu TL. 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;101:31303135.

    • Search Google Scholar
    • Export Citation
  • 78

    Neviani P, Santhanam R, Trotta R. 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;8:355368.

    • Search Google Scholar
    • Export Citation
  • 79

    Neviani P, Santhanam R, Oaks JJ. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest 2007;117:24082421.

    • Search Google Scholar
    • Export Citation
  • 80

    Dierks C, Beigi R, Guo GR. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 2008;14:238249.

    • Search Google Scholar
    • Export Citation
  • 81

    Jabbour E, Jones D, Kantarjian HM. 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;114:20372043.

    • 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;16:135139.

    • 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:S2226.

    • Search Google Scholar
    • Export Citation
  • 84

    Gambacorti-Passerini C, Pogliani E, Baccarani M. 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.

    • Search Google Scholar
    • Export Citation
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