Identifying the time to change BCR-ABL inhibitor therapy in patients with chronic myeloid leukemia

Acta Haematologica

Volumn 130, Issue 4, 2013, Pages 268-278

  Savona, Michael R ^a   Saglio, Giuseppe ^b  

^a SARAH CANNON RESEARCH INSTITUTE   (United States)

^b UNIVERSITY OF TURIN   (Italy)

Author keywords

BCR ABL inhibitor; Chronic myeloid leukemia; Dasatinib; Imatinib; Nilotinib

Indexed keywords

ANTILEUKEMIC AGENT; BCR ABL PROTEIN INHIBITOR; BOSUTINIB; DANUSERTIB; DASATINIB; IMATINIB; NILOTINIB; PONATINIB; PROTEIN TYROSINE KINASE INHIBITOR; SGX 393; UNCLASSIFIED DRUG;

CANCER CHEMOTHERAPY; CANCER RESISTANCE; CANCER SURVIVAL; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL (TOPIC); DRUG SUBSTITUTION; DRUG TREATMENT FAILURE; DRUG WITHDRAWAL; HUMAN; MULTICENTER STUDY (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHASE 4 CLINICAL TRIAL (TOPIC); PRACTICE GUIDELINE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TREATMENT OUTCOME; TREATMENT RESPONSE;

EID: 84888264472     PISSN: 00015792     EISSN: 14219662     Source Type: Journal    
DOI: 10.1159/000353163     Document Type: Review

References (69)

1. Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML, Gathmann I, Bolton AE, van Hoomissen IC, Goldman JM, Radich JP, International Randomised Study of Interferon versus STI571 (IRIS) Study Group: Frequency of major molecular responses to imatinib or interferon alfa plus cy-tarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003; 349:1423-1432.
2. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ, IRIS Investigators: Imatinib compared with interfer-on and low dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994-1004.
3. Deininger M, O'Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes TP, Radich J P, Hatfield AK, Mone M, Filian J, Reynolds J, Gathmann I, Larson RA, Druker BJ: International Randomized Study of Interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (abstract 1126). Blood 2009;114(suppl).
4. Druker BJ, Guilhot F, O'Brien S, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA, IRIS Investigators: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355:2408-2417.
5. Chronic Myeloid Leukemia Trialists' Collaborative Group: Interferon-alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials. J Natl Cancer Inst 1997; 89:1616-1620.
6. de Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, Bua M, Szydlo R, Ola-varria E, Kaeda J, Goldman JM, Marin D: 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.
7. Lucas CM, Wang L, Austin GM, Knight K, Watmough SJ, Shwe KH, Dasgupta R, Butt NM, Galvani D, Hoyle CF, Seale JR, Clark RE: A population study of imatinib in chronic myeloid leukaemia demonstrates lower efficacy than in clinical trials. Leukemia 2008;22: 1963-1966.
8. Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM, Müller MC, Radich JP, Rudoltz M, Mone M, Gath-mann I, Hughes TP, Larson RA, IRIS Investigators: Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009; 23:1054-1061.
9. Boschelli DH, Ye F, Wang YD, Dutia M, Johnson SL, Wu B, Miller K, Powell DW, Yac-zko D, Young M, Tischler M, Arndt K, Disca-fani C, Etienne C, Gibbons J, Grod J, Lucas J, Weber JM, Boschelli F: Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem 2001; 44:3965-3977.
10. Lombardo LJ, Lee FY, Chen P, Norris D, Bar-rish JC, Behnia K, Castaneda S, Cornelius LA, Das J, Doweyko AM, Fairchild C, Hunt JT, Inigo I, Johnston K, Kamath A, Kan D, Klei H, Marathe P, Pang S, Peterson R, Pitt S, Schieven GL, Schmidt RJ, Tokarski J, Wen ML, Wityak J, Borzilleri RM: Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylami-no)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent an-titumor activity in preclinical assays. J Med Chem 2004; 47:6658-6661.
11. O'Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Lee FY, Heinrich MC, Deininger MW, Druker BJ: In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005; 65:4500-4505.
12. Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A, Ahmed S, Re-daelli S, Piazza R, Magistroni V, Andreoni F, Scapozza L, Formelli F, Gambacorti-Passerini C: In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-re-sistant Bcr-Abl+ neoplastic cells. Cancer Res 2006; 66:11314-11322.
13. Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, Gambacorti-Passerini C, Boschelli F: Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol 2009; 27: 469-471.
14. Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, Lee FY, Bokemeyer C, Deininger MW, Druker BJ, Heinrich MC: Da-satinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res 2006; 66:473-481.
15. Weisberg E, Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E, Kung AL, Mestan J, Daley GQ, Callahan L, Catley L, Cavazza C, Azam M, Neuberg D, Wright RD, Gilliland DG, Griffin JD: Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7:129-141.
16. Brave M, Goodman V, Kaminskas E, Farrell A, Timmer W, Pope S, Harapanhalli R, Saber H, Morse D, Bullock J, Men A, Noory C, Ram-chandani R, Kenna L, Booth B, Gobburu J, Jiang X, Sridhara R, Justice R, Pazdur R: Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res 2008; 14: 352-359.
17. SPRYCEL (prescribing information). Princeton Bristol-Myers Squibb 2012.
18. Hazarika M, Jiang X, Liu Q, Lee SL, Ramchan-dani R, Garnett C, Orr MS, Sridhara R, Booth B, Leighton JK, Timmer W, Harapanhalli R, Dagher R, Justice R, Pazdur R: Tasigna for chronic and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia resistant to or intolerant of ima-tinib. Clin Cancer Res 2008; 14:5325-5331.
19. Khoury HJ, Cortes JE, Kantarjian HM, Gam-bacorti-Passerini C, Baccarani M, Kim DW, Zaritskey A, Countouriotis A, Besson N, Leip E, Kelly V, Brümmendorf TH: Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012; 119:3403-3412.
20. Tasigna (prescribing information). East Hanover, Novartis Pharmaceuticals Corporation 2012.
21. Bosulif (prescribing information). New York, Pfizer, 2012.
22. Iclusig (prescribing information). Cambridge ARIAD Pharmaceuticals 2012.
23. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F, Bo-qué C, Chuah C, Bleickardt E, Bradley-Gare-lik MB, Zhu C, Szatrowski T, Shapiro D, Bac-carani M: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362: 2260-2270.
24. Saglio G, Kim D-W, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM, ENESTnd Investigators: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362:2251-2259.
25. Kantarjian HM, Shah NP, Cortes JE, Bacca-rani M, Agarwal MB, Undurraga MS, Wang J, Ipiña JJ, Kim DW, Ogura M, Pavlovsky C, Junghanss C, Milone JH, Nicolini FE, Robak T, Van Droogenbroeck J, Vellenga E, Brad-ley-Garelik MB, Zhu C, Hochhaus A: Dasat-inib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119:1123-1129.
26. Hochhaus A, Shah N, Cortes J, Baccarani M, Bradley-Garelik MB, Dejardin D, Kantarjian H: Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): DASISION 3-year follow-up (abstract 6504). J Clin Oncol 2012; 15(suppl 1).
27. Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ, Hoenekopp A, Blakesley RE, Larson RA, Hughes TP: Nilo-tinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011; 12:841-851.
28. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology TM. Chronic myelogenous leukemia v.3.2013. http://www.nccn.org/professionals/physician-gls/f-guidelines.asp#site.
29. Baccarani M, Pileri S, Steegmann JL, Muller M, Soverini S, Dreyling M, on behalf of the ESMO Guidelines Working Group: Chronic myeloid leukemia: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol 2012; 23(suppl 7):vii72-vii73.
30. Baccarani M, Deininger MW, Rosti G, Hoch-haus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Han-sen H, Hughes TP, Kantarjian HM, Kim D-W, Larson RA, Lipton JH, Mahon F-X, Martinelli G, Mayer J, Müller MC, Niederwi-eser D, Pane F, Radich JP, Rousselot P, Saglio G, Saußele S, Schiffer C, Silver R, Simonsson B, Steegmann J-L, Goldman JM, Rüdiger H: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; ePub ahead of print, DOI: 10.1182/blood-2013-05-501569.
31. Kantarjian HM, Flinn IW, Goldberg S, Bun-worasate U, Zanichelli MA, Nakamae H, Hughes TP, Hochhaus A, Saglio G, Woodman RC, Blakesley RE, Kemp CN, Kalaycio ME, Larson RA: Nilotinib versus imatinib in patients with newly diagnosed chronic my-eloid leukemia in chronic phase (CML-CP): ENESTnd 3-year follow-up (abstract 6509). J Clin Oncol 2012; 30(suppl).
32. Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, Flinn IW, Kurokawa M, Moiraghi B, Yu R, Blakesley RE, Gallagher NJ, Saglio G, Kantarjian HM: Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 2012; 26:2197-2203.
33. Calabretta B, Perrotti D: The biology of CML blast crisis. Blood 2004; 103:4010-4022.
34. Cortes J, O'Dwyer ME: Clonal evolution in chronic myelogenous leukemia. Hematol Oncol Clin North Am 2004; 18:671-684.
35. Goldman JM, Melo JV: Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344:1084-1086.
36. Hehlmann R, Saussele S: Treatment of chronic myeloid leukemia in blast crisis. Haemato-logica 2008; 93:1765-1769.
37. Soverini S, Martinelli G, Rosti G, Bassi S, Am-abile M, Poerio A, Giannini B, Trabacchi E, Castagnetti F, Testoni N, Luatti S, de Vivo A, Cilloni D, Izzo B, Fava M, Abruzzese E, Alber-ti D, Pane F, Saglio G, Baccarani M: 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.
38. Khorashad JS, de Lavallade H, Apperley JF, Milojkovic D, Reid AG, Bua M, Szydlo R, Olavarria E, Kaeda J, Goldman JM, Marin D: 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.
39. Baccarani M, Giles F, Ottmann O, Reynolds J, Woodman R, le Coutre P, Kantarjian H: Long-term outcome (progression-free survival) in patients receiving nilotinib for ima-tinib failure who meet suboptimal response criteria according to European LeukemiaNet 2009 CML recommendations (abstract 0132). Haematologica 2010; 95(suppl 2):53.
40. Cortes JE, Shah NP, Schiffer CA, LeCoutre PD, Saglio G, Quintás-Cardama A, Kantarji-an H, Jabbour E, Bahceci E, Chen A, Lambert A, Guilhot F: Significance of ELN provisional response definitions in predicting long-term outcomes of patients with CP-CML treated with dasatinib after imatinib failure (abstract 3439). Blood 2010;116(suppl).
41. Hanfstein B, Müller MC, Erben P, Schnittger S, Saussele S, Leitner A, Proetel U, Ehninger G, Hossfeld DK, Kolb H-J, Krause SW, Nerl C, Pralle H, Heim D, Baerlocher GM, Heim-pel H, Hehlmann R, Hochhaus A, The German CML-Study Group: Molecular response after 3 months of 1st-line imatinib therapy is predictive for treatment failure and disease progression in patients with chronic phase chronic myeloid leukemia-a follow-up analysis of the German CML study IV (abstract 360). Blood 2010; 116(suppl).
42. Hanfstein B, Müller MC, Hehlmann R, Er-ben P, Lauseker M, Fabarius A, Schnittger S, Haferlach C, Göhring G, Proetel U, Kolb HJ, Krause SW, Hofmann WK, Schubert J, Einsele H, Dengler J, Hänel M, Falge C, Kanz L, Neubauer A, Kneba M, Stegel-mann F, Pfreundschuh M, Waller CF, Bran-ford S, Hughes TP, Spiekermann K, Baerlo-cher GM, Pfirrmann M, Hasford J, Saussele S, Hochhaus A, SAKK, German CML Study Group: Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic my-eloid leukemia (CML). Leukemia 2012; 26: 2096-2102.
43. Hochhaus A, Saglio G, Larson RA, Kim D-W, Flinn IW, Goh Y-T, Dorlhiac-Llacer PE, Porkka K, Kurokawa M, DeSouza C, Shou Y, Gallagher NJ, Haque A, Kantarjian H, Hughes TP: Nilotinib lowers the incidence of BCR-ABL mutations and improves the molecular response kinetics compared with imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia (CML) (abstract 3431). Blood 2010; 116(suppl).
44. Hochhaus A, Boqué C, Bradley Garelik MB, Manos G, Steegmann JL: Molecular response kinetics and BCR-ABL reductions in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) receiving da-satinib versus imatinib: DASISION 3-year follow-up (abstract 0192). Haematologica 2012; 97(suppl 1).
45. Marin D, Hedgley C, Clark RE, Apperley J, Foroni L, Milojkovic D, Pocock C, Goldman JM, O'Brien S: Predictive value of early molecular response in patients with chronic my-eloid leukemia treated with first-line dasat-inib. Blood 2012;120:291-294.
46. Marin D, Ibrahim AR, Lucas C, Gerrard G, Wang L, Szydlo RM, Clark RE, Apperley JF, Milojkovic D, Bua M, Pavlu J, Paliompeis C, Reid A, Rezvani K, Goldman JM, Foroni L: Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine ki-nase inhibitors. J Clin Oncol 2012; 30: 232-238.
47. Saglio G, Kantarjian HM, Shah N, Jabbour EJ, Quintas-Cardama A, Steegmann JL, Boqué C, Chuah C, Pavlovsky C, Mayer J, Ukropec J, Wildgust M, Hochhaus A: Early response (molecular and cytogenetic) and long-term outcomes in newly diagnosed chronic my-eloid leukemia in chronic phase (CML-CP): exploratory analysis of DASISION 3-year data (abstract 1675). Blood 2012; 120(suppl).
48. Quintas-Cardama A, Kantarjian H, Jones D, Shan J, Borthakur G, Thomas D, Kornblau S, O'Brien S, Cortes J: Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. Blood 2009; 113:6315-6321.
49. Marin D, Milojkovic D, Olavarria E, Khora-shad JS, de Lavallade H, Reid AG, Foroni L, Rezvani K, Bua M, Dazzi F, Pavlu J, Klammer M, Kaeda JS, Goldman JM, Apperley JF: 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.
50. Alvarado Y, Kantarjian H, O'Brien S, Faderl S, Borthakur G, Burger J, Wierda W, Garcia-Manero G, Shan J, Cortes J: 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 reference. Cancer 2009; 115:3709-3718.
51. Breccia M, Orlandi SM, Latagliata R, Gram-matico S, Diverio D, Mancini M, Loglisci G, Salaroli A, Federico V, Santopietro M, Alime-na G: Suboptimal response to imatinib according to 2006-2009 European Leukaemi-aNet criteria: a 'grey zone' at 3, 6 and 12 months identifies chronic myeloid leukaemia patients who need early intervention. Br J Haematol 2011; 152:119-121.
52. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, Guilhot F, Hoch-haus A, Horowitz M, Hughes T, Kantarjian H, Larson R, Radich J, Simonsson B, Silver RT, Goldman J, Hehlmann R, European Leuke-miaNet: Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009;27:6041-6051.
53. O'Brien S, Berman E, Moore JO, Pinilla-Ibarz J, Radich JP, Shami PJ, Smith BD, Snyder DS, Sundar HM, Talpaz M, Wetzler M: 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.
54. Yeung T, Osborn P, White L, Branford S, Ko-rnhauser M, Slader A, Hiwase K, Hertzberg S, Schwarer P, Filshie J, Arthur K, Kwan L, Forsyth J, Ross D, Mills A, Grigg P, Hughes P: CML patients failing to achieve MMR by 12 months may benefit from dose escalation or switching to nilotinib: a 24 month update of results from the TIDEL-II trial (abstract 0137). Haematologica 2011; 96(suppl 2):55.
55. Kantarjian H, O'Brien S, Talpaz M, Borthakur G, Ravandi F, Faderl S, Verstovsek S, Rios MB, Shan J, Giles F, Cortes J: Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure. Cancer 2007; 109: 1556-1560.
56. Quintas-Cardama A, Cortes JE, O'Brien S, Ravandi F, Borthakur G, Liu D, Bleickardt E, Chen TT, Kantarjian HM: Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia. Cancer 2009; 115: 2912-2921.
57. Morra E, Michallet M, Marin D, Hellmann A, Niederwieser D, Schlöegl E, Björeman M, Fo-ryciarz K, Ho A, Kuliczkowski K, Ossenkop-pele G, Gozzini A, Gora-Tybor J, Guerra L, Verhoef G: Delaying the initiation of dasat-inib after imatinib failure has a negative impact on CP-CML patients outcome: results from a European observational study (FORTE; CA180-211) (abstract 0701). Hae-matologica 2011; 96(suppl 2).
58. Pinilla-Ibarz J, Cortes J, Mauro MJ: Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: definitions and clinical implication. Cancer 2011; 117:688-697.
59. Rudzki J, Wolf D: Dose escalation of imatinib in chronic-phase chronic myeloid leukemia patients: is it still reasonable? Expert Rev He-matol 2011; 4:153-159.
60. Bristol-Myers Squibb: ClinicalTrials.gov. NLM identifier: NCT01593254. Bethesda, National Library of Medicine (US), 2000-present.
61. Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, Apperley JF, Sz ydlo R, Desai R, Kozlowski K, Paliompeis C, Latham V, Foroni L, Molimard M, Reid A, Rezvani K, de Lavallade H, Guallar C, Goldman J, Khorashad JS: 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.
62. Baranska M, Lewandowski K, Gniot M, Iwoła M, Lewandowska M, Komarnicki M: Dasat-inib treatment can overcome imatinib and ni-lotinib resistance in CML patient carrying F359I mutation of BCR-ABL oncogene. J Appl Genet 2008; 49:201-203.
63. Kim D, Kim DW, Cho BS, Goh HG, Kim SH, Kim WS, Lee J, Kweon IY, Park SH, Yoon JH, Kim ND, Chun H: Structural modeling of V299L and E459K Bcr-Abl mutation, and sequential therapy of tyrosine kinase inhibitors for the compound mutations. Leuk Res 2009; 33:1260-1265.
64. Giles FJ, Abruzzese E, Rosti G, Kim DW, Bha-tia R, Bosly A, Goldberg S, Kam GL, Jagasia M, Mendrek W, Fischer T, Facon T, Dünz-inger U, Marin D, Mueller MC, Shou Y, Gallagher NJ, Larson RA, Mahon FX, Baccarani M, Cortes J, Kantarjian HM: Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of ima-tinib and dasatinib therapy. Leukemia 2010; 24:1299-1301.
65. Cortes JE, Kim DW, Pinilla-Ibarz J, Paquette R, le Coutre PD, Chuah C, Nicolini FE, Ap-perley J, Khoury HJ, Talpaz M, DePersio JF, DeAngelo DJ, Rea D, Abruzzese E, Müller MC, Baccarani M, Gambacorti-Passerini C, Turner CD, Haluska FG, Kantarjian H: PACE: a pivotal phase II trial of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation (abstract 6503). J Clin Oncol 2012;30(suppl).
66. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009; 16: 401-412.
67. Gontarewicz A, Balabanov S, Keller G, Colombo R, Graziano A, Pesenti E, Benten D, Boke-meyer C, Fiedler W, Moll J, Brümmendorf TH: Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-re-sistant BCR-ABL mutations including T315I. Blood 2008; 111:4355-4364.
68. O'Hare T, Eide CA, Tyner JW, Corbin AS, Wong MJ, Buchanan S, Holme K, Jessen KA, Tang C, Lewis HA, Romero RD, Burley SK, Deininger MW: SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib. Proc Natl Acad Sci USA 2008; 105: 5507-5512.
69. Cortes JE: Not only response but early response to tyrosine kinase inhibitors in chronic myeloid leukemia. J Clin Oncol 2012; 30: 223-224.