Chronic Myelogenous Leukemia

Restricted access
  • 1

    Jemal A, Siegel R, Xu J, Ward E. Cancer Statistics, 2010. CA Cancer J Clin 2010:277-300.

  • 2

    Faderl S, Talpaz M, Estrov Z. The biology of chronic myeloid leukemia. N Engl J Med 1999;341:164-172.

  • 3

    Radich JP, Dai H, Mao M. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 2006;103:2794-2799.

    • Search Google Scholar
    • Export Citation
  • 4

    Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340:1330-1340.

  • 5

    Jamieson CHM, Ailles LE, Dylla SJ. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004;351:657-667.

    • Search Google Scholar
    • Export Citation
  • 6

    Sokal J, Cox E, Baccarani M. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 1984;63:789-799.

  • 7

    Hasford J, Pfirrmann M, Hehlmann R. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998;90:850-858.

    • Search Google Scholar
    • Export Citation
  • 8

    Jabbour E, Cortes JE, Giles FJ. Current and emerging treatment options in chronic myeloid leukemia. Cancer 2007;109:2171-2181.

  • 9

    Stone RM. Optimizing treatment of chronic myeloid leukemia: a rational approach. Oncologist 2004;9:259-270.

  • 10

    Kantarjian H, Sawyers C, Hochhaus A. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645-652.

    • Search Google Scholar
    • Export Citation
  • 11

    Hochhaus A, Druker B, Sawyers C. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood 2008;111:1039-1043.

    • Search Google Scholar
    • Export Citation
  • 12

    O'Brien SG, Guilhot F, Larson RA. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronicphase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.

    • Search Google Scholar
    • Export Citation
  • 13

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

    • Search Google Scholar
    • Export Citation
  • 14

    Deininger M, O'Brien SG, Guilhot F. 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:Abstract 1126.

    • Search Google Scholar
    • Export Citation
  • 15

    Kantarjian HM, Talpaz M, O'Brien S. Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 2006;108:1835-1840.

    • Search Google Scholar
    • Export Citation
  • 16

    Roy L, Guilhot J, Krahnke T. Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood 2006;108:1478-1484.

    • Search Google Scholar
    • Export Citation
  • 17

    Guilhot F, Druker B, Larson RA. High rates of durable response are achieved with imatinib after treatment with interferon alpha plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial. Haematologica 2009;94:1669-1675.

    • Search Google Scholar
    • Export Citation
  • 18

    Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med 2007;357:258-265.

  • 19

    Berman E, Nicolaides M, Maki RG. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006;354:2006-2013.

  • 20

    Quintas-Cardama A, Kantarjian H, O'Brien S. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer 2004;100:2592-2597.

    • Search Google Scholar
    • Export Citation
  • 21

    Cortes J, O'Brien S, Quintas A. Erythropoietin is effective in improving the anemia induced by imatinib mesylate therapy in patients with chronic myeloid leukemia in chronic phase. Cancer 2004;100:2396-2402.

    • Search Google Scholar
    • Export Citation
  • 22

    Santos FP, Alvarado Y, Kantarjian H. Long-term prognostic impact of the use of erythropoietic-stimulating agents in patients with chronic myeloid leukemia in chronic phase treated with imatinib. Cancer 2011;117:982-991.

    • Search Google Scholar
    • Export Citation
  • 23

    Kerkela R, Grazette L, Yacobi R. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:908-916.

  • 24

    Atallah E, Durand JB, Kantarjian H, Cortes J. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 2007;110:1233-1237.

    • Search Google Scholar
    • Export Citation
  • 25

    Hughes TP, Branford S, White DL. Impact of early dose intensity on cytogenetic and molecular responses in chronic-phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 2008;112:3965-3973.

    • Search Google Scholar
    • Export Citation
  • 26

    Kantarjian H, Talpaz M, O'Brien S. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 2004;103:2873-2878.

    • Search Google Scholar
    • Export Citation
  • 27

    Cortes JE, Kantarjian HM, Goldberg SL. High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol 2009;27:4754-4759.

    • Search Google Scholar
    • Export Citation
  • 28

    Castagnetti F, Palandri F, Amabile M. Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party. Blood 2009;113:3428-3434.

    • Search Google Scholar
    • Export Citation
  • 29

    Baccarani M, Rosti G, Castagnetti F. 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;113:4497-4504.

    • Search Google Scholar
    • Export Citation
  • 30

    Cortes JE, Baccarani M, Guilhot F. 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;28:424-430.

    • Search Google Scholar
    • Export Citation
  • 31

    Hehlmann R, Lauseker M, Jung-Munkwitz S. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 2011;29:1634-1642.

    • Search Google Scholar
    • Export Citation
  • 32

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

  • 33

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

  • 34

    Hochhaus A, Kantarjian HM, Baccarani M. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007;109:2303-2309.

    • Search Google Scholar
    • Export Citation
  • 35

    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:Abstract 7009.

    • Search Google Scholar
    • Export Citation
  • 36

    Baccarani M, Rosti G, Saglio G. Dasatinib time to and durability of major and complete cytogenetic response (MCyR and CCyR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) [abstract]. Blood 2008;112:Abstract 450.

    • Search Google Scholar
    • Export Citation
  • 37

    Guilhot F, Apperley J, Kim DW. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007;109:4143-4150.

    • Search Google Scholar
    • Export Citation
  • 38

    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;27:3472-3479.

    • Search Google Scholar
    • Export Citation
  • 39

    Cortes J, Rousselot P, Kim DW. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007;109:3207-3213.

    • Search Google Scholar
    • Export Citation
  • 40

    Cortes J, Kim DW, Raffoux E. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia 2008;22:2176-2183.

    • Search Google Scholar
    • Export Citation
  • 41

    Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 2009;114:261-263.

    • Search Google Scholar
    • Export Citation
  • 42

    Quintas-Cardama A, Kantarjian H, O'Brien S. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol 2007;25:3908-3914.

    • Search Google Scholar
    • Export Citation
  • 43

    Mustjoki S, Ekblom M, Arstila TP. Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia 2009;23:1398-1405.

    • Search Google Scholar
    • Export Citation
  • 44

    Porkka K, Khoury HJ, Paquette RL. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer 2010;116:377-386.

    • Search Google Scholar
    • Export Citation
  • 45

    Schiffer CA, Cortes JE, Saglio G. Association of lymphocytosis following treatment with dasatinib with response and outcome [abstract]. J Clin Oncol 2010;28:Abstract 6553.

    • Search Google Scholar
    • Export Citation
  • 46

    Schiffer CA, Cortes JE, Saglio G. Lymphocytosis following first-line treatment for CML in chronic phase with dasatinib is associated with improved responses: a comparison with imatinib [abstract]. Blood 2010;116:Abstract 358.

    • Search Google Scholar
    • Export Citation
  • 47

    Shah NP, Kantarjian HM, Kim DW. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008;26:3204-3212.

    • Search Google Scholar
    • Export Citation
  • 48

    Shah NP, Kim DW, Kantarjian H. 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;95:232-240.

    • Search Google Scholar
    • Export Citation
  • 49

    Shah NP, Cortes JE, Schiffer CA. Five-year follow-up of patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib [abstract]. J Clin Oncol 2011;29 (Suppl 15):Abstract 6512.

    • Search Google Scholar
    • Export Citation
  • 50

    Kantarjian H, Cortes J, Kim DW. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood 2009;113:6322-6329.

    • Search Google Scholar
    • Export Citation
  • 51

    Saglio G, Hochhaus A, Goh YT. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 2010;116:3852-3861.

    • Search Google Scholar
    • Export Citation
  • 52

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

    • Search Google Scholar
    • Export Citation
  • 53

    Kantarjian H, Shah NP, Hochhaus A. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010;362:2260-2270.

    • Search Google Scholar
    • Export Citation
  • 54

    Kantarjian H, Shah NP, Cortes JE. Dasatinib or imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): two-year follow-up from DASISION [abstract]. J Clin Oncol 2011;29 (Suppl 15):Abstract 6510.

    • Search Google Scholar
    • Export Citation
  • 55

    Radich JP, Kopecky KJ, Kamel-Reid S. A randomized phase II trial of dasatinib 100 mg vs imatinib 400 mg in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): the S0325 Intergroup trial [abstract]. Blood 2010;116:Abstract LBA-6.

    • Search Google Scholar
    • Export Citation
  • 56

    Kantarjian H, Giles F, Wunderle L. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542-2551.

    • Search Google Scholar
    • Export Citation
  • 57

    Kantarjian HM, Giles F, Gattermann N. 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;110:3540-3546.

    • Search Google Scholar
    • Export Citation
  • 58

    Kantarjian HM, Giles FJ, Bhalla KN. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 2011;117:1141-1145.

    • Search Google Scholar
    • Export Citation
  • 59

    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;111:1834-1839.

    • Search Google Scholar
    • Export Citation
  • 60

    le Coutre PD, Giles F, Hochhaus A. Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib (IM) resistance or intolerance: longer follow-up results of a phase II study [abstract]. J Clin Oncol 2009;27 (Suppl 15):Abstract 7057.

    • Search Google Scholar
    • Export Citation
  • 61

    Giles FJ, Kantarjian H, le Coutre PD. Use of nilotinib to induce responses with 24-month (mo) minimum follow-up in patients (pts) with chronic myeloid leukemia in blast crisis (CML-BC) resistant to or intolerant of imatinib [abstract]. J Clin Oncol 2010;28 (Suppl 15):Abstract 6510.

    • Search Google Scholar
    • Export Citation
  • 62

    Cortes JE, Jones D, O'Brien S. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol 2010;28:392-397.

    • Search Google Scholar
    • Export Citation
  • 63

    Rosti G, Palandri F, Castagnetti F. Nilotinib for the frontline treatment of Ph+ chronic myeloid leukemia. Blood 2009;114:4933-4938.

  • 64

    Saglio G, Kim DW, Issaragrisil S. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010;362:2251-2259.

  • 65

    Larson RA, Kim D, Rosti G. Comparison of nilotinib and imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 24-month follow-up [abstract]. J Clin Oncol 2011;29 (Suppl 15):Abstract 6511.

    • Search Google Scholar
    • Export Citation
  • 66

    Ali R, Ozkalemkas F, Kimya Y. Imatinib use during pregnancy and breast feeding: a case report and review of the literature. Arch Gynecol Obstet 2009;280:169-175.

    • Search Google Scholar
    • Export Citation
  • 67

    AlKindi S, Dennison D, Pathare A. Imatinib in pregnancy. Eur J Haematol 2005;74:535-537.

  • 68

    Ault P, Kantarjian H, O'Brien S. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol 2006;24:1204-1208.

  • 69

    Choudhary DR, Mishra P, Kumar R. Pregnancy on imatinib: fatal outcome with meningocele. Ann Oncol 2006;17:178-179.

  • 70

    Heartin E, Walkinshaw S, Clark RE. Successful outcome of pregnancy in chronic myeloid leukaemia treated with imatinib. Leuk Lymphoma 2004;45:1307-1308.

    • Search Google Scholar
    • Export Citation
  • 71

    Prabhash K, Sastry PS, Biswas G. Pregnancy outcome of two patients treated with imatinib. Ann Oncol 2005;16:1983-1984.

  • 72

    Pye SM, Cortes J, Ault P. The effects of imatinib on pregnancy outcome. Blood 2008;111:5505-5508.

  • 73

    Ramasamy K, Hayden J, Lim Z. Successful pregnancies involving men with chronic myeloid leukaemia on imatinib therapy. Br J Haematol 2007;137:374-375.

    • Search Google Scholar
    • Export Citation
  • 74

    Seymour JF, Grigg A, Reynolds J. Two year data from a prospective safety study analyzing the consequences of imatinib mesylate inhibition of sensitive kinases other than bcr-abl in patients with previously untreated chronic phase CML [abstract]. Blood 2006;108:Abstract 2147.

    • Search Google Scholar
    • Export Citation
  • 75

    Cortes J, O'Brien S, Ault P. Pregnancy outcomes among patients with chronic myeloid leukemia treated with dasatinib [abstract]. Blood 2008;112:Abstract 3230.

    • Search Google Scholar
    • Export Citation
  • 76

    Conchon M, Sanabani SS, Serpa M. Successful pregnancy and delivery in a patient with chronic myeloid leukemia while on dasatinib therapy. Adv Hematol 2010;2010:136252.

    • Search Google Scholar
    • Export Citation
  • 77

    Oweini H, Otrock ZK, Mahfouz RAR, Bazarbachi A. Successful pregnancy involving a man with chronic myeloid leukemia on dasatinib [published online ahead of print May 15, 2010]. Arch Gynecol Obstet 2011;283:133-134.

    • Search Google Scholar
    • Export Citation
  • 78

    Conchon M, Sanabani SS, Bendit I. Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study. J Hematol Oncol 2009;2:42.

    • Search Google Scholar
    • Export Citation
  • 79

    Deininger MW, O'Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol 2003;21:1637-1647.

    • Search Google Scholar
    • Export Citation
  • 80

    Guo JQ, Wang JYJ, Arlinghaus RB. Detection of BCR-ABL proteins in blood cells of benign phase chronic myelogenous leukemia patients. Cancer Research 1991;51:3048-3051.

    • Search Google Scholar
    • Export Citation
  • 81

    Cortes JE, Talpaz M, Beran M. Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer 1995;75:464-470.

    • Search Google Scholar
    • Export Citation
  • 82

    O'Brien S, Berman E, Moore JO. NCCN Task Force report: tyrosine kinase inhibitor therapy selection in the management of patients with chronic myelogenous leukemia. J Natl Compr Canc Netw 2011;9 (Suppl 2):S1-S25.

    • Search Google Scholar
    • Export Citation
  • 83

    Lipton JH, Khoroshko N, Golenkov A. Phase II, randomized, multicenter, comparative study of peginterferon-alpha-2a (40 kD) (Pegasys) versus interferon alpha-2a (Roferon-A) in patients with treatment-naive, chronic-phase chronic myelogenous leukemia. Leuk Lymphoma 2007;48:497-505.

    • Search Google Scholar
    • Export Citation
  • 84

    Michallet M, Maloisel F, Delain M. Pegylated recombinant interferon alpha-2b vs recombinant interferon alpha-2b for the initial treatment of chronic-phase chronic myelogenous leukemia: a phase III study. Leukemia 2004;18:309-315.

    • Search Google Scholar
    • Export Citation
  • 85

    Gambacorti-Passerini C, Zucchetti M, Russo D. Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 2003;9:625-632.

    • Search Google Scholar
    • Export Citation
  • 86

    Larson RA, Druker BJ, Guilhot F. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008;111:4022-4028.

    • Search Google Scholar
    • Export Citation
  • 87

    Picard S, Titier K, Etienne G. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:3496-3499.

    • Search Google Scholar
    • Export Citation
  • 88

    Ault P, Kantarjian HM, Bryan J. Clinical use of imatinib plasma levels in patients with chronic myeloid leukemia (CML) [abstract]. Blood 2008;112:Abstract 4255.

    • Search Google Scholar
    • Export Citation
  • 89

    Forrest DL, Trainor S, Brinkman RR. Cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia are correlated with Sokal risk scores and duration of therapy but not trough imatinib plasma levels. Leuk Res 2009;33:271-275.

    • Search Google Scholar
    • Export Citation
  • 90

    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.

    • Search Google Scholar
    • Export Citation
  • 91

    Wang L, Giannoudis A, Lane S. Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther 2008;83:258-264.

    • Search Google Scholar
    • Export Citation
  • 92

    White DL, Saunders VA, Dang P. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 2007;110:4064-4072.

    • Search Google Scholar
    • Export Citation
  • 93

    White DL, Dang P, Engler J. Functional activity of the OCT-1 protein is predictive of long-term outcome in patients with chronic-phase chronic myeloid leukemia treated with imatinib. J Clin Oncol 2010;28:2761-2767.

    • Search Google Scholar
    • Export Citation
  • 94

    Giannoudis A, Davies A, Lucas CM. Effective dasatinib uptake may occur without human organic cation transporter 1 (hOCT1): implications for the treatment of imatinib-resistant chronic myeloid leukemia. Blood 2008;112:3348-3354.

    • Search Google Scholar
    • Export Citation
  • 95

    Hiwase DK, Saunders V, Hewett D. Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res 2008;14:3881-3888.

    • Search Google Scholar
    • Export Citation
  • 96

    Davies A, Jordanides NE, Giannoudis A. Nilotinib concentration in cell lines and primary CD34(+) chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters. Leukemia 2009;23:1999-2006.

    • Search Google Scholar
    • Export Citation
  • 97

    White DL, Saunders VA, Dang P. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 2006;108:697-704.

    • Search Google Scholar
    • Export Citation
  • 98

    Gorre ME, Mohammed M, Ellwood K. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876-880.

    • Search Google Scholar
    • Export Citation
  • 99

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

  • 100

    le Coutre P, Tassi E, Varella-Garcia M. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 2000;95:1758-1766.

    • Search Google Scholar
    • Export Citation
  • 101

    Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007;8:1018-1029.

  • 102

    Khorashad JS, de Lavallade H, Apperley JF. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol 2008;26:4806-4813.

    • Search Google Scholar
    • Export Citation
  • 103

    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;102:276-283.

    • Search Google Scholar
    • Export Citation
  • 104

    Nicolini FE, Corm S, Le QH. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia 2006;20:1061-1066.

    • Search Google Scholar
    • Export Citation
  • 105

    Soverini S, Colarossi S, Gnani A. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006;12:7374-7379.

    • Search Google Scholar
    • Export Citation
  • 106

    Soverini S, Martinelli G, Rosti G. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol 2005;23:4100-4109.

    • Search Google Scholar
    • Export Citation
  • 107

    Jabbour E, Kantarjian H, Jones D. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 2006;20:1767-1773.

    • Search Google Scholar
    • Export Citation
  • 108

    Jabbour E, Kantarjian H, Jones D. Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood 2008;112:53-55.

    • Search Google Scholar
    • Export Citation
  • 109

    Nicolini FE, Hayette S, Corm S. Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation. Haematologica 2007;92:1238-1241.

    • Search Google Scholar
    • Export Citation
  • 110

    O'Dwyer ME, Mauro MJ, Kurilik G. The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 2002;100:1628-1633.

    • Search Google Scholar
    • Export Citation
  • 111

    O'Dwyer ME, Mauro MJ, Blasdel C. Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood 2004;103:451-455.

    • Search Google Scholar
    • Export Citation
  • 112

    Majlis A, Smith TL, Talpaz M. Significance of cytogenetic clonal evolution in chronic myelogenous leukemia. J Clin Oncol 1996;14:196-203.

  • 113

    Cortes JE, Talpaz M, Giles F. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood 2003;101:3794-3800.

    • Search Google Scholar
    • Export Citation
  • 114

    Verma D, Kantarjian H, Shan J. Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. Cancer 2010;116:2673-2681.

    • Search Google Scholar
    • Export Citation
  • 115

    Kantarjian HM, Talpaz M, O'Brien S. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003;101:473-475.

    • Search Google Scholar
    • Export Citation
  • 116

    Marin D, Goldman JM, Olavarria E, Apperley JF. Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses. Blood 2003;102:2702-2704.

    • Search Google Scholar
    • Export Citation
  • 117

    Zonder JA, Pemberton P, Brandt H. The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment. Clin Cancer Res 2003;9:2092-2097.

    • Search Google Scholar
    • Export Citation
  • 118

    Jabbour E, Kantarjian HM, Jones D. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standarddose imatinib therapy. Blood 2009;113:2154-2160.

    • Search Google Scholar
    • Export Citation
  • 119

    Kantarjian HM, Larson RA, Guilhot F. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 2009;115:551-560.

    • Search Google Scholar
    • Export Citation
  • 120

    Kantarjian H, Pasquini R, Hamerschlak N. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 2007;109:5143-5150.

    • Search Google Scholar
    • Export Citation
  • 121

    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;115:4136-4147.

    • Search Google Scholar
    • Export Citation
  • 122

    Quintas-Cardama A, Cortes J. Therapeutic options against BCR-ABL1 T315I-positive chronic myelogenous leukemia. Clin Cancer Res 2008;14:4392-4399.

    • Search Google Scholar
    • Export Citation
  • 123

    Marin D, Kaeda JS, Andreasson C. Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer 2005;103:1850-1855.

    • Search Google Scholar
    • Export Citation
  • 124

    Quintas-Cardama A, Kantarjian H, Garcia-Manero G. Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer 2007;109:248-255.

    • Search Google Scholar
    • Export Citation
  • 125

    Cortes JE, 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 15):Abstract 7008.

    • Search Google Scholar
    • Export Citation
  • 126

    Wetzler M, Hellmann A, Lipton J. Subcutaneous omacetaxine mepesuccinate in chronic myeloid leukemia (CML) patients resistant or intolerant to two or more tyrosine kinase inhibitors (TKIs): data from an ongoing phase II trial [abstract]. J Clin Oncol 2009;27(Suppl 15):Abstract 7027.

    • Search Google Scholar
    • Export Citation
  • 127

    Kantarjian H, Schiffer C, Jones D, Cortes J. Monitoring the response and course of chronic myeloid leukemia in the modern era of BCR-ABL tyrosine kinase inhibitors: practical advice on the use and interpretation of monitoring methods. Blood 2008;111:1774-1780.

    • Search Google Scholar
    • Export Citation
  • 128

    Hughes TP, Branford S. Monitoring disease response to tyrosine kinase inhibitor therapy in CML. Hematology Am Soc Hematol Educ Program 2009:477-487.

    • Search Google Scholar
    • Export Citation
  • 129

    Radich JP. How I monitor residual disease in chronic myeloid leukemia. Blood 2009;114:3376-3381.

  • 130

    Landstrom AP, Ketterling RP, Knudson RA, Tefferi A. Utility of peripheral blood dual color, double fusion fluorescent in situ hybridization for BCR/ABL fusion to assess cytogenetic remission status in chronic myeloid leukemia. Leuk Lymphoma 2006;47:2055-2061.

    • Search Google Scholar
    • Export Citation
  • 131

    Muhlmann J, Thaler J, Hilbe W. Fluorescence in situ hybridization (FISH) on peripheral blood smears for monitoring Philadelphia chromosome-positive chronic myeloid leukemia (CML) during interferon treatment: a new strategy for remission assessment. Genes Chromosomes Cancer 1998;21:90-100.

    • Search Google Scholar
    • Export Citation
  • 132

    Douet-Guilbert N, Morel F, Le Charpentier T. Interphase FISH for follow-up of Philadelphia chromosome-positive chronic myeloid leukemia treatment. Anticancer Res 2004;24:2535-2539.

    • Search Google Scholar
    • Export Citation
  • 133

    Seong DC, Kantarjian HM, Ro JY. Hypermetaphase fluorescence in situ hybridization for quantitative monitoring of Philadelphia chromosome-positive cells in patients with chronic myelogenous leukemia during treatment. Blood 1995;86:2343-2349.

    • Search Google Scholar
    • Export Citation
  • 134

    Dewald GW, Wyatt WA, Juneau AL. Highly sensitive fluorescence in situ hybridization method to detect double BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia. Blood 1998;91:3357-3365.

    • Search Google Scholar
    • Export Citation
  • 135

    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;26:3358-3363.

    • Search Google Scholar
    • Export Citation
  • 136

    Quintas-Cardama A, Cortes JE, O'Brien S. Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia. Cancer 2009;115:2912-2921.

    • Search Google Scholar
    • Export Citation
  • 137

    Jabbour E, Kantarjian HM, Shan J. The achievement of an early complete cytogenetic response (CCyR) is a major determinant for outcome in patients (pts) with early chronic phase (CP) chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) [abstract]. Blood 2010;116:Abstract 3429.

    • Search Google Scholar
    • Export Citation
  • 138

    Bumm T, Muller C, Al-Ali HK. Emergence of clonal cytogenetic abnormalities in Ph-cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003;101:1941-1949.

    • Search Google Scholar
    • Export Citation
  • 139

    Feldman E, Najfeld V, Schuster M. The emergence of Ph-, trisomy -8+ cells in patients with chronic myeloid leukemia treated with imatinib mesylate. Exp Hematol 2003;31:702-707.

    • Search Google Scholar
    • Export Citation
  • 140

    Medina J, Kantarjian H, Talpaz M. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Cancer 2003;98:1905-1911.

    • Search Google Scholar
    • Export Citation
  • 141

    Terre C, Eclache V, Rousselot P. Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia. Leukemia 2004;18:1340-1346.

    • Search Google Scholar
    • Export Citation
  • 142

    Deininger MW, Cortes J, Paquette R. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in philadelphia chromosome-negative cells. Cancer 2007;110:1509-1519.

    • Search Google Scholar
    • Export Citation
  • 143

    Jabbour E, Kantarjian HM, Abruzzo LV. Chromosomal abnormalities in Philadelphia chromosome negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2007;110:2991-2995.

    • Search Google Scholar
    • Export Citation
  • 144

    Kantarjian HM, Talpaz M, Cortes J. Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; gleevec) in chronic-phase chronic myelogenous leukemia. Clin Cancer Res 2003;9:160-166.

    • Search Google Scholar
    • Export Citation
  • 145

    Baccarani M, Cortes J, Pane F. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009;27:6041-6051.

    • Search Google Scholar
    • Export Citation
  • 146

    Cross NC. Standardisation of molecular monitoring for chronic myeloid leukaemia. Best Pract Res Clin Haematol 2009;22:355-365.

  • 147

    Branford S, Cross NCP, Hochhaus A. Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia. Leukemia 2006;20:1925-1930.

    • Search Google Scholar
    • Export Citation
  • 148

    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;108:28-37.

    • Search Google Scholar
    • Export Citation
  • 149

    Hughes TP, Kaeda J, Branford S. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003;349:1423-1432.

    • Search Google Scholar
    • Export Citation
  • 150

    Press RD, Love Z, Tronnes AA. BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib mesylate-treated patients with CML. Blood 2006;107:4250-4256.

    • Search Google Scholar
    • Export Citation
  • 151

    Press RD, Galderisi C, Yang R. A half-log increase in BCR-ABL RNA predicts a higher risk of relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic response. Clin Cancer Res 2007;13:6136-6143.

    • Search Google Scholar
    • Export Citation
  • 152

    Hughes TP, Hochhaus A, Branford S. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 2010;116:3758-3765.

    • Search Google Scholar
    • Export Citation
  • 153

    Cortes J, Talpaz M, O'Brien S. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res 2005;11:3425-3432.

    • Search Google Scholar
    • Export Citation
  • 154

    Iacobucci I, Saglio G, Rosti G. Achieving a major molecular response at the time of a complete cytogenetic response (CCgR) predicts a better duration of CCgR in imatinib-treated chronic myeloid leukemia patients. Clin Cancer Res 2006;12:3037-3042.

    • Search Google Scholar
    • Export Citation
  • 155

    Palandri F, Iacobucci I, Soverini S. Treatment of Philadelphia-positive chronic myeloid leukemia with imatinib: importance of a stable molecular response. Clin Cancer Res 2009;15:1059-1063.

    • Search Google Scholar
    • Export Citation
  • 156

    Marin D, Milojkovic D, Olavarria E. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 2008;112:4437-4444.

    • Search Google Scholar
    • Export Citation
  • 157

    Cervantes F, López-Garrido P, Montero MI. Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group. Haematologica 2010;95:1317-1324.

    • Search Google Scholar
    • Export Citation
  • 158

    Kantarjian H, Cortes J. Considerations in the management of patients with Philadelphia chromosome-positive chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy. J Clin Oncol 2011;29:1512-1516.

    • Search Google Scholar
    • Export Citation
  • 159

    Branford S, Rudzki Z, Parkinson I. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood 2004;104:2926-2932.

    • Search Google Scholar
    • Export Citation
  • 160

    Wang L, Knight K, Lucas C, Clark R. The role of serial BCR-ABL transcript monitoring in predicting the emergence of BCR-ABL kinase mutations in imatinib-treated patients with chronic myeloid leukemia. Haematologica 2006;91:235-239.

    • Search Google Scholar
    • Export Citation
  • 161

    Kantarjian HM, Shan J, Jones D. Significance of rising levels of minimal residual disease in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in complete cytogenetic response (CGCR) [abstract]. Blood 2008;112:Abstract 445.

    • Search Google Scholar
    • Export Citation
  • 162

    Press RD, Willis SG, Laudadio J. Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib. Blood 2009;114:2598-2605.

    • Search Google Scholar
    • Export Citation
  • 163

    Kantarjian HM, Shan J, Jones D. Significance of increasing levels of minimal residual disease in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in complete cytogenetic response. J Clin Oncol 2009;27:3659-3663.

    • Search Google Scholar
    • Export Citation
  • 164

    Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood 2009;114:5426-5435.

    • Search Google Scholar
    • Export Citation
  • 165

    Jabbour E, Branford S, Saglio G. Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia. Cancer 2011;117:1800-1811.

    • Search Google Scholar
    • Export Citation
  • 166

    Muller MC, Cortes JE, Kim DW. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 2009;114:4944-4953.

    • Search Google Scholar
    • Export Citation
  • 167

    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;112:4839-4842.

    • Search Google Scholar
    • Export Citation
  • 168

    Soverini S, Colarossi S, Gnani A. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica 2007;92:401-404.

    • Search Google Scholar
    • Export Citation
  • 169

    Hughes T, Saglio G, Branford S. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 2009;27:4204-4210.

    • Search Google Scholar
    • Export Citation
  • 170

    Soverini S, Gnani A, Colarossi S. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors. Blood 2009;114:2168-2171.

    • Search Google Scholar
    • Export Citation
  • 171

    Testoni N, Marzocchi G, Luatti S. Chronic myeloid leukemia: a prospective comparison of interphase fluorescence in situ hybridization and chromosome banding analysis for the definition of complete cytogenetic response: a study of the GIMEMA CML WP. Blood 2009;114:4939-4943.

    • Search Google Scholar
    • Export Citation
  • 172

    Lima L, Bernal-Mizrachi L, Saxe D. Peripheral blood monitoring of chronic myeloid leukemia during treatment with imatinib, second-line agents, and beyond. Cancer 2011;117:1245-1252.

    • Search Google Scholar
    • Export Citation
  • 173

    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;115:3709-3718.

    • Search Google Scholar
    • Export Citation
  • 174

    Breccia M, Stagno F, Vigneri P. Imatinib dose escalation in 74 failure or suboptimal response chronic myeloid leukaemia patients at 3-year follow-up. Am J Hematol 2010;85:375-377.

    • Search Google Scholar
    • Export Citation
  • 175

    Koh Y, Kim I, Yoon SS. Phase IV study evaluating efficacy of escalated dose of imatinib in chronic myeloid leukemia patients showing suboptimal response to standard dose imatinib. Ann Hematol 2010;89:725-731.

    • Search Google Scholar
    • Export Citation
  • 176

    Yeung DT, Osborn M, White DL. Selective escalation of imatinib therapy and early switching to nilotinib in de novo chronic phase CML patients: interim results from the TIDEL-II trial [abstract]. Blood 2010;116:Abstract 209.

    • Search Google Scholar
    • Export Citation
  • 177

    Hochhaus A, Muller MC, Radich J. Dasatinib-associated major molecular responses are rapidly achieved in patients with chronic myeloid leukemia in chronic phase (CML-CP) following resistance, suboptimal response, or intolerance on imatinib [abstract]. Blood 2008;112:Abstract 1095.

    • Search Google Scholar
    • Export Citation
  • 178

    Nicolini FE, Kim DW, Ceglarek B. Impact of prior therapy and suboptimal response to imatinib on the efficacy and safety of nilotinib among 1,422 patients with imatinib-resistant or --intolerant chronic myeloid leukemia (CML) in chronic phase (CP): sub-analyses of the ENACT (Expanding Nilotinib Access In Clinical Trials) study [abstract]. Blood 2009;114:Abstract 2201.

    • Search Google Scholar
    • Export Citation
  • 179

    Yang AS, Jillella A, Miller CB. Nilotinib-associated molecular responses achieved in chronic myeloid leukemia in chronic phase (CML-CP) patients with a suboptimal molecular response to imatinib [abstract]. Blood 2009;114:Abstract 2206.

    • Search Google Scholar
    • Export Citation
  • 180

    Tam CS, Kantarjian H, Garcia-Manero G. Failure to achieve a major cytogenetic response by 12 months defines inadequate response in patients receiving nilotinib or dasatinib as second or subsequent line therapy for chronic myeloid leukemia. Blood 2008;112:516-518.

    • Search Google Scholar
    • Export Citation
  • 181

    Milojkovic D, Nicholson E, Apperley JF. Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Haematologica 2010;95:224-231.

    • Search Google Scholar
    • Export Citation
  • 182

    Shah NP, Cortes JE, Schiffer CA. Four-year follow-up of patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving 100 mg of dasatinib once daily [abstract]. J Clin Oncol 2010;28 (Suppl 15):Abstract 6512.

    • Search Google Scholar
    • Export Citation
  • 183

    Branford S, Lawrence R, Fletcher L. The initial molecular response of chronic phase cml patients treated with second generation ABL inhibitor therapy after imatinib failure can predict inadequate response and provide indications for rational mutation screening [abstract]. Blood 2008;112:Abstract 331.

    • Search Google Scholar
    • Export Citation
  • 184

    Branford S, Kim DW, Soverini S. Molecular response at 3 months on nilotinib therapy predicts response and long-term outcomes in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase (CML-CP) [abstract]. Blood 2009;114:Abstract 3292.

    • Search Google Scholar
    • Export Citation
  • 185

    Jabbour E, Kantarjian H, O'Brien S. Predictive factors for outcome and response in patients treated with second-generation tyrosine kinase inhibitors for chronic myeloid leukemia in chronic phase after imatinib failure. Blood 2011;117:1822-1827.

    • Search Google Scholar
    • Export Citation
  • 186

    Garg RJ, Kantarjian H, O'Brien S. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood 2009;114:4361-4368.

    • Search Google Scholar
    • Export Citation
  • 187

    Hochhaus A. Advances in the treatment of haematological malignancies: optimal sequence of CML treatment. Ann Oncol 2007;18 (Suppl 9):ix58-63.

    • Search Google Scholar
    • Export Citation
  • 188

    Cortes J, O'Brien S, Kantarjian H. Discontinuation of imatinib therapy after achieving a molecular response. Blood 2004;104:2204-2205.

  • 189

    Rousselot P, Huguet F, Rea D. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007;109:58-60.

    • Search Google Scholar
    • Export Citation
  • 190

    Ross DM, Grigg A, Schwarer A. The majority of chronic myeloid leukaemia patients who cease imatinib after achieving a sustained complete molecular response (CMR) remain in cmr, and any relapses occur early [abstract]. Blood 2008;112:Abstract 1102.

    • Search Google Scholar
    • Export Citation
  • 191

    Mahon FX, Rea D, Guilhot J. 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 2010:1029-1035.

    • Search Google Scholar
    • Export Citation
  • 192

    Darkow T, Henk HJ, Thomas SK. Treatment interruptions and non-adherence with imatinib and associated healthcare costs: a retrospective analysis among managed care patients with chronic myelogenous leukaemia. Pharmacoeconomics 2007;25:481-496.

    • Search Google Scholar
    • Export Citation
  • 193

    Marin D, Bazeos A, Mahon FX. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010;28:2381-2388.

    • Search Google Scholar
    • Export Citation
  • 194

    Noens L, van Lierde MA, De Bock R. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood 2009;113:5401-5411.

    • Search Google Scholar
    • Export Citation
  • 195

    Ibrahim AR, Eliasson L, Apperley JF. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 2011;117:3733-3736.

    • Search Google Scholar
    • Export Citation
  • 196

    Partridge AH, Avorn J, Wang PS, Winer EP. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst 2002;94:652-661.

  • 197

    Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487-497.

  • 198

    Quintas-Cardama A, Cortes JE, Kantarjian H. Practical management of toxicities associated with tyrosine kinase inhibitors in chronic myeloid leukemia. Clin Lymphoma Myeloma 2008;8 (Suppl 3):S82-S88.

    • Search Google Scholar
    • Export Citation
  • 199

    Kantarjian HM, Deisseroth A, Kurzrock R. Chronic myelogenous leukemia: a concise update. Blood 1993;82:691-703.

  • 200

    Savage DG, Szydlo RM, Chase A. Bone marrow transplantation for chronic myeloid leukaemia: the effects of differing criteria for defining chronic phase on probabilities of survival and relapse. Br J Haematol 1997;99:30-35.

    • Search Google Scholar
    • Export Citation
  • 201

    Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 1988;25:49-61.

  • 202

    Swerdlow SH, Campo E, Harris NL. WHO classification of tumours of haematopoietic and lymphoid tissues (ed 4). Lyon, France:IARC;2008.

  • 203

    Cortes JE, Talpaz M, O'Brien S. Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer 2006;106:1306-1315.

    • Search Google Scholar
    • Export Citation
  • 204

    Druker BJ. Chronic Myelogenous Leukemia In: DeVita VT, Lawrence TS, Rosenburg SA, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. Vol. 2(ed 8): Lippincott, Williams and Wilkins; 2007:2267-2304.

    • Search Google Scholar
    • Export Citation
  • 205

    Shah NP. Advanced CML: therapeutic options for patients in accelerated and blast phases. J Natl Compr Canc Netw 2008;6 (Suppl 2):S31-S36.

    • Search Google Scholar
    • Export Citation
  • 206

    Talpaz M, Silver RT, Druker BJ. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002;99:1928-1937.

    • Search Google Scholar
    • Export Citation
  • 207

    Palandri F, Castagnetti F, Alimena G. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica 2009;94:205-212.

    • Search Google Scholar
    • Export Citation
  • 208

    Kantarjian HM, Cortes J, O'Brien S. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 2002;99:3547-3553.

    • Search Google Scholar
    • Export Citation
  • 209

    Sawyers CL, Hochhaus A, Feldman E. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002;99:3530-3539.

    • Search Google Scholar
    • Export Citation
  • 210

    Palandri F, Castagnetti F, Testoni N. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up. Haematologica 2008;93:1792-1796.

    • Search Google Scholar
    • Export Citation
  • 211

    Fava C, Kantarjian HM, Jabbour E. Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase. Blood 2009;113:5058-5063.

    • Search Google Scholar
    • Export Citation
  • 212

    de Labarthe A, Rousselot P, Huguet-Rigal F. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood 2007;109:1408-1413.

    • Search Google Scholar
    • Export Citation
  • 213

    Yanada M, Naoe T. Imatinib combined chemotherapy for Philadelphia chromosome-positive acute lymphoblastic leukemia: major challenges in current practice. Leuk Lymphoma 2006;47:1747-1753.

    • Search Google Scholar
    • Export Citation
  • 214

    Thomas DA, Faderl S, Cortes J. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 2004;103:4396-4407.

    • Search Google Scholar
    • Export Citation
  • 215

    Thomas DA, O'Brien SM, Faderl S. Long-term outcome after hyper-CVAD and imatinib (IM) for de novo or minimally treated Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) [abstract]. J Clin Oncol 2010;28 (Suppl 15):Abstract 6506.

    • Search Google Scholar
    • Export Citation
  • 216

    Ravandi F, O'Brien S, Thomas D. First report of phase II study of dasatinib with hyperCVAD for the frontline treatment of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Blood 2010:2070-2077.

    • Search Google Scholar
    • Export Citation
  • 217

    Radich J. Stem cell transplant for chronic myeloid leukemia in the imatinib era. Semin Hematol 2010;47:354-361.

  • 218

    Pavlu J, Szydlo RM, Goldman JM, Apperley JF. Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood 2011;117:755-763.

    • Search Google Scholar
    • Export Citation
  • 219

    Davies SM, DeFor TE, McGlave PB. Equivalent outcomes in patients with chronic myelogenous leukemia after early transplantation of phenotypically matched bone marrow from related or unrelated donors. Am J Med 2001;110:339-346.

    • Search Google Scholar
    • Export Citation
  • 220

    Hansen JA, Gooley TA, Martin PJ. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 1998;338:962-968.

    • Search Google Scholar
    • Export Citation
  • 221

    Horowitz MM, Rowlings PA, Passweg JR. Allogeneic bone marrow transplantation for CML: a report from the International Bone Marrow Transplant Registry. Bone Marrow Transplant 1996;17 (Suppl 3):S5-S6.

    • Search Google Scholar
    • Export Citation
  • 222

    Gratwohl A, Brand R, Apperley J. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 2006;91:513-521.

    • Search Google Scholar
    • Export Citation
  • 223

    Saussele S, Lauseker M, Gratwohl A. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 2010;115:1880-1885.

    • Search Google Scholar
    • Export Citation
  • 224

    Goldman JM, Majhail NS, Klein JP. Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J Clin Oncol 2010;28:1888-1895.

    • Search Google Scholar
    • Export Citation
  • 225

    Velev N, Cortes J, Champlin R. Stem cell transplantation for patients with chronic myeloid leukemia resistant to tyrosine kinase inhibitors with BCR-ABL kinase domain mutation T315I. Cancer 2010;116:3631-3637.

    • Search Google Scholar
    • Export Citation
  • 226

    Jabbour E, Cortes J, Santos FP. Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations. Blood 2011;117:3641-3647.

    • Search Google Scholar
    • Export Citation
  • 227

    Crawley C, Szydlo R, Lalancette M. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 2005;106:2969-2976.

    • Search Google Scholar
    • Export Citation
  • 228

    Giralt S, Estey E, Albitar M. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997;89:4531-4536.

    • Search Google Scholar
    • Export Citation
  • 229

    Giralt S, Thall PF, Khouri I. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001;97:631-637.

    • Search Google Scholar
    • Export Citation
  • 230

    McSweeney PA, Niederwieser D, Shizuru JA. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001;97:3390-3400.

    • Search Google Scholar
    • Export Citation
  • 231

    Or R, Shapira MY, Resnick I. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood 2003;101:441-445.

    • Search Google Scholar
    • Export Citation
  • 232

    Champlin R, Lima Md, Kebriaei P. Nonmyeloablative allogeneic stem cell transplantation for chronic myelogenous leukemia in the imatinib era. Clin Lymphoma Myeloma 2009;9 (Suppl 3):S261-S265.

    • Search Google Scholar
    • Export Citation
  • 233

    Beelen DW, Graeven U, Elmaagacli AH. Prolonged administration of interferon-alpha in patients with chronicphase Philadelphia chromosome-positive chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome. Blood 1995;85:2981-2990.

    • Search Google Scholar
    • Export Citation
  • 234

    Goldman JM, Szydlo R, Horowitz MM. Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood 1993;82:2235-2238.

    • Search Google Scholar
    • Export Citation
  • 235

    Morton AJ, Gooley T, Hansen JA. Association between pretransplant interferon-alpha and outcome after unrelated donor marrow transplantation for chronic myelogenous leukemia in chronic phase. Blood 1998;92:394-401.

    • Search Google Scholar
    • Export Citation
  • 236

    Deininger M, Schleuning M, Greinix H. The effect of prior exposure to imatinib on transplant-related mortality. Haematologica 2006;91:452-459.

  • 237

    Lee SJ, Kukreja M, Wang T. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood 2008;112:3500-3507.

    • Search Google Scholar
    • Export Citation
  • 238

    Oehler VG, Gooley T, Snyder DS. The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood 2007;109:1782-1789.

    • Search Google Scholar
    • Export Citation
  • 239

    Jabbour E, Cortes J, Kantarjian H. Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: no evidence for increased transplant-related toxicity. Cancer 2007;110:340-344.

    • Search Google Scholar
    • Export Citation
  • 240

    le Coutre PD, Hemmati P, Neuburger S. Allogeneic stem cell transplantation (SCT) in advanced chronic myeloid leukemia (CML) patients after tyrosine kinase inhibitor (TKI) therapy [abstract]. Blood 2008;112:Abstract 4419.

    • Search Google Scholar
    • Export Citation
  • 241

    Shimoni A, Leiba M, Schleuning M. Prior treatment with the tyrosine kinase inhibitors dasatinib and nilotinib allows stem cell transplantation (SCT) in a less advanced disease phase and does not increase SCT toxicity in patients with chronic myelogenous leukemia and philadelphia positive acute lymphoblastic leukemia. Leukemia 2009;23:190-194.

    • Search Google Scholar
    • Export Citation
  • 242

    Breccia M, Palandri F, Iori AP. Second-generation tyrosine kinase inhibitors before allogeneic stem cell transplantation in patients with chronic myeloid leukemia resistant to imatinib. Leuk Res 2010;34:143-147.

    • Search Google Scholar
    • Export Citation
  • 243

    Nicolini F, Modolo L, Raus N. Allogeneic stem cell transplantation for blast crisis (BC) chronic myelogenous leukemia (CML) in the tyrosine kinase inhibitors (TKIs) era. Analysis of pre-transplant variables on transplant outcome. On behalf of the Societe Francaise De Greffe De Moelle Et De Therapie Cellulaire and the French Group of CML [abstract]. Blood 2010;116:Abstract 2266.

    • Search Google Scholar
    • Export Citation
  • 244

    Hehlmann R, Berger U, Pfirrmann M. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 2007;109:4686-4692.

    • Search Google Scholar
    • Export Citation
  • 245

    Roth M, Antin J, Ash R. Prognostic significance of Philadelphia chromosome-positive cells detected by the polymerase chain reaction after allogeneic bone marrow transplant for chronic myelogenous leukemia. Blood 1992;79:276-282.

    • Search Google Scholar
    • Export Citation
  • 246

    Delage R, Soiffer R, Dear K, Ritz J. Clinical significance of bcr-abl gene rearrangement detected by polymerase chain reaction after allogeneic bone marrow transplantation in chronic myelogenous leukemia. Blood 1991;78:2759-2767.

    • Search Google Scholar
    • Export Citation
  • 247

    Radich JP, Gehly G, Gooley T. Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood 1995;85:2632-2638.

    • Search Google Scholar
    • Export Citation
  • 248

    Mackinnon S, Barnett L, Heller G. Polymerase chain reaction is highly predictive of relapse in patients following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukemia. Bone Marrow Transplant 1996;17:643-647.

    • Search Google Scholar
    • Export Citation
  • 249

    Olavarria E, Kanfer E, Szydlo R. Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2001;97:1560-1565.

    • Search Google Scholar
    • Export Citation
  • 250

    Radich JP, Gooley T, Bryant E. The significance of bcr-abl molecular detection in chronic myeloid leukemia patients «late,» 18 months or more after transplantation. Blood 2001;98:1701-1707.

    • Search Google Scholar
    • Export Citation
  • 251

    Costello RT, Kirk J, Gabert J. Value of PCR analysis for long term survivors after allogeneic bone marrow transplant for chronic myelogenous leukemia: a comparative study. Leuk Lymphoma 1996;20:239-243.

    • Search Google Scholar
    • Export Citation
  • 252

    van Rhee F, Lin F, Cross NC. Detection of residual leukaemia more than 10 years after allogeneic bone marrow transplantation for chronic myelogenous leukaemia. Bone Marrow Transplant 1994;14:609-612.

    • Search Google Scholar
    • Export Citation
  • 253

    Kolb HJ, Schattenberg A, Goldman JM. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995;86:2041-2050.

    • Search Google Scholar
    • Export Citation
  • 254

    Luznik L, Fuchs EJ. Donor lymphocyte infusions to treat hematologic malignancies in relapse after allogeneic blood or marrow transplantation. Cancer Control 2002;9:123-137.

    • Search Google Scholar
    • Export Citation
  • 255

    Gilleece MH, Dazzi F. Donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukaemia. Leuk Lymphoma 2003;44:23-28.

    • Search Google Scholar
    • Export Citation
  • 256

    Simula MP, Marktel S, Fozza C. Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. Leukemia 2007;21:943-948.

    • Search Google Scholar
    • Export Citation
  • 257

    Kantarjian HM, O'Brien S, Cortes JE. Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 2002;100:1590-1595.

    • Search Google Scholar
    • Export Citation
  • 258

    Anderlini P, Sheth Sl, Hicks K. Re: Imatinib mesylate administration in the first 100 days after stem cell transplantation. Biol Blood Marrow Transplant 2004;10:883-884.

    • Search Google Scholar
    • Export Citation
  • 259

    DeAngelo DJ, Hochberg EP, Alyea EP. Extended follow-up of patients treated with imatinib mesylate (gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease. Clin Cancer Res 2004;10:5065-5071.

    • Search Google Scholar
    • Export Citation
  • 260

    Hess G, Bunjes D, Siegert W. Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study. J Clin Oncol 2005;23:7583-7593.

    • Search Google Scholar
    • Export Citation
  • 261

    Carpenter PA, Snyder DS, Flowers MED. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood 2007;109:2791-2793.

    • Search Google Scholar
    • Export Citation
  • 262

    Weisser M, Tischer J, Schnittger S. A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation. Haematologica 2006;91:663-666.

    • Search Google Scholar
    • Export Citation
  • 263

    Porkka K, Koskenvesa P, Lundan T. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 2008;112:1005-1012.

    • Search Google Scholar
    • Export Citation