Treatment options for patients with chronic myeloid leukemia who are resistant to or unable to tolerate imatinib

Clinical Therapeutics

Volumn 32, Issue 5, 2010, Pages 804-820

  Stein, Brady ^a   Douglas Smith, B ^b  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

Chronic myelogenous leukemia; Chronic myeloid leukemia; CML; Dasatinib; Imatinib; Nilotinib; Tyrosine kinase inhibitors

Indexed keywords

AMIODARONE; ATAZANAVIR; BEPRIDIL; CARBAMAZEPINE; CHLOROQUINE; CLARITHROMYCIN; DASATINIB; DEXAMETHASONE; DISOPYRAMIDE; HALOFANTRINE; HALOPERIDOL; IMATINIB; INDINAVIR; ITRACONAZOLE; KETOCONAZOLE; METHADONE; NEFAZODONE; NELFINAVIR; NILOTINIB; PARACETAMOL; PHENOBARBITAL; PHENYTOIN; RIFABUTIN; RIFAMPICIN; RITONAVIR; SAQUINAVIR; TELITHROMYCIN; UNINDEXED DRUG; VORICONAZOLE; WARFARIN;

ANEMIA; CANCER CHEMOTHERAPY; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG HYPERSENSITIVITY; DRUG MECHANISM; DRUG MEGADOSE; DRUG RESPONSE; DRUG TOLERABILITY; GENE MUTATION; HUMAN; NEUTROPENIA; REVIEW; THROMBOCYTOPENIA;

ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; DRUG RESISTANCE, NEOPLASM; FUSION PROTEINS, BCR-ABL; HUMANS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; MUTATION; PIPERAZINES; PROTEIN KINASE INHIBITORS; PYRIMIDINES; THIAZOLES;

EID: 77954794865     PISSN: 01492918     EISSN: 1879114X     Source Type: Journal    
DOI: 10.1016/j.clinthera.2010.05.003     Document Type: Review

References (102)

1. Sawyers CL Chronic myeloid leukemia. N Engl J Med. 1999, 340:1330-1340.
2. Nowell PC, Hungerford DA A minute chromosome in human chronic granulocytic leukemia. Science 1960, 132:1497.
3. Rowley JD Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973, 243:290-293.
4. Bartram CR, de Klein A, Hagemeijer A, et al. Translocation of c-ab1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1983, 306:277-280.
5. Groffen J, Stephenson JR, Heisterkamp N, et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984, 36:93-99.
6. Lugo TG, Pendergast AM, Muller AJ, Witte ON Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990, 247:1079-1082.
7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Chronic myelogenous leukemia V.2 2010 Accessed December 30, 2009. http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf.
8. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996, 2:561-566.
9. Gleevec (imatinib mesylate) [prescribing information] 2009, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
10. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003, 348:994-1004. IRIS Investigators.
11. Deininger M, O'Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: Sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood (ASH Annual Meeting Abstracts) 2009, 114:1126.
12. O'Brien SG, Guilhot F, Goldman JM, et al. International randomized study of interferon versus STI571 (IRIS) 7-year follow-up: Sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CMLCP) treated with imatinib (IM). Blood (ASH Annual Meeting Abstracts) 2008, 112:186.
13. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006, 355:2408-2417. IRIS Investigators.
14. Hochhaus A, O'Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009, 23:1054-1061. IRIS Investigators.
15. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006, 108:1809-1820. European LeukemiaNet.
16. Sprycel (dasatinib) [prescribing information] 2009, Bristol-Myers Squibb Company, Princeton, NJ.
17. Tasigna (nilotinib) [prescribing information] 2007, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
18. Guilhot F, Druker B, Larson RA, et al. 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.
19. Palandri F, Castagnetti F, Alimena G, et al. 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.
20. Kantarjian HM, Talpaz M, Giles F, et al. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med. 2006, 145:913-923.
21. Weisberg E, Manley PW, Cowan-Jacob SW, et al. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 2007, 7:345-356.
22. Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003, 102:276-283.
23. Jabbour E, Cortes J, Giles F, et al. Preliminary activity of nilotinib (AMN107), a novel selective potent oral bcr-abl tyrosine kinase inhibitor, in newly diagnosed Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukemia (CML-CP). Blood (ASH Annual Meeting Abstracts) 2006, 108:2172.
24. Hochhaus A, Erben P, Ernst T, Mueller MC Resistance to targeted therapy in chronic myelogenous leukemia. Semin Hematol 2007, 44(Suppl 1):S15-S24.
25. Soverini S, Martinelli G, Rosti G, et al. 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.
26. Nicolini FE, Corm S, Lê QH, et al. 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.
27. La Rosée P, Corbin AS, Stoffregen EP, et al. Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res. 2002, 62:7149-7153.
28. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004, 305:399-401.
29. O'Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005, 65:4500-4505.
30. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl [published correction appears in Cancer Cell. 2005;7:399]. Cancer Cell 2005, 7:129-141.
31. Tokarski JS, Newitt JA, Chang CY, et al. The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res. 2006, 66:5790-5797.
32. Mauro M. Imatinib resistance: Current concepts in detection and management. Hematol Oncol. In press.
33. Hochhaus A, Druker BJ, Larson RA, et al. IRIS 6-year follow-up: Sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood (ASH Annual Meeting Abstracts) 2007, 110:25.
34. 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.
35. Cortes JE, Kantarjian HM, Goldberg SL, et al. 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. Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) Trial Study Group.
36. Baccarani M, Rosti G, Castagnetti F, et al. 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.
37. Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, openlabel 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.
38. Hehlmann R, Jung-Munkwitz S, Lauseker M, et al. Randomized comparison of imatinib 800 mg vs. imatinib 400 mg +/- IFN in newly diagnosed BCR/ABL positive chronic phase CML: Analysis of molecular remission at 12 months; The German CML-Study IV. Blood (ASH Annual Meeting Abstracts) 2009, 114:339. German CML Study Group.
39. Jain N, Kantarjian HM, Fava C, et al. Imatinib dose can be safely reduced after complete cytogenetic response (CCyR) in patients (pts) with chronic myeloid leukemia (CML) in early chronic phase (CP) treated with high-dose imatinib. Blood (ASH Annual Meeting Abstracts) 2007, 110:1043.
40. Corbin AS, La Rosée P, Stoffregen EP, et al. Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood 2003, 101:4611-4614.
41. Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib- resistant BCR/ABL mutants. J Clin Oncol 2009, 27:469-471.
42. Roumiantsev S, Shah NP, Gorre ME, et al. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc Natl Acad Sci USA 2002, 99:10700-10705.
43. Azam M, Latek RR, Daley GQ Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 2003, 112:831-843.
44. Kantarjian HM, Talpaz M, O'Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003, 101:473-475.
45. Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or highdose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: A randomized phase 2 trial. Blood 2007, 109:5143-5150.
46. 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, 102:2702-2703. Letter.
47. Zonder JA, Pemberton P, Brandt H, et al. 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.
48. Jabbour E, Kantarjian H, Atallah E, et al. Impact of imatinib mesylate dose escalation on resistance and sub-optimal responses to standarddose therapy in patients (pts) with chronic myeloid leukemia (CML). Blood (ASH Annual Meeting Abstracts) 2007, 110:1035.
49. Breccia M, Stagno F, Latagliata R, et al. Results of imatinib dose escalation after 36 months of follow-up in chronic myeloid leukemia patients with failure or sub-optimal response according to 2006 European LeukemiaNet (ELN) criteria. Blood (ASH Annual Meeting Abstracts) 2009, 114:3302.
50. Cortes J, Kantarjian H Response: Dose escalation of imatinib may improve responses in patients with CML who fail standard-dose imatinib. Blood 2003, 102:2703.
51. Jabbour E, Kantarjian HM, Jones D, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 2009, 113:2154-2160.
52. Kantarjian HM, Larson RA, Guilhot F, et al. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 2009, 115:551-560. International Randomized Study of Interferon and STI571 (IRIS) Investigators.
53. Kim DY, Kim HJ, Jeong JS, et al. Efficacy of imatinib mesylate doseescalation in CML patients showing suboptimal response to standard dose. Blood 2007, 110:871a. Abstract 2967.
54. Rea D, Etienne G, Corm S, et al. Imatinib dose escalation for chronic phase-chronic myelogenous leukaemia patients in primary suboptimal response to imatinib 400 mg daily standard therapy. Leukemia 2009, 23:1193-1196.
55. Kantarjian H, Pasquini R, Lévy V, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: Two-year follow-up of a randomized phase 2 study (START-R). Cancer 2009, 115:4136-4147.
56. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001, 293:876-880.
57. Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002, 16:2190-2196.
58. White DL, Saunders VA, Dang P, et al. 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.
59. Giannoudis A, Davies A, Lucas CM, et al. Unlike imatinib, dasatinib uptake into chronic myeloid leukaemia cells is independent of hOCT1 expression. Blood (ASH Annual Meeting Abstracts) 2007, 110:3458.
60. Hiwase DK, White DL, Saunders VA, et al. In contrast to imatinib, OCT-1 mediated influx has minimal impact on cellular uptake of dasatinib in CML patients at diagnosis. Blood (ASH Annual Meeting Abstracts) 2007, 110:1937.
61. Bradeen HA, Eide CA, O'Hare T, et al. Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based muta-genesis screen: High efficacy of drug combinations. Blood 2006, 108:2332-2338.
62. Cortes J, Rousselot P, Kim DW, et al. 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.
63. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy [published correction appears in Blood. 2007;110:1438]. Blood 2007, 109:2303-2309.
64. Baccarani M, Rosti G, Saglio G, et al. 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). Blood (ASH Annual Meeting Abstracts) 2008, 112:450.
65. Khoury HJ, Mauro MJ, Matloub Y, et al. Dasatinib is well-tolerated and efficacious in imatinib-intolerant patients with chronic-phase chronic myeloid leukemia (CP-CML). Blood (ASH Annual Meeting Abstracts) 2009, 114:1128.
66. Apperley JF, Cortes JE, Kim DW, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: The START a trial. J Clin Oncol. 2009, 27:3472-3479.
67. Cortes J, Kim DW, Raffoux E, et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia 2008, 22:2176-2183.
68. Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinibresistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007, 109:4143-4150.
69. Rousselot P, Bergeron A, Réa D, et al. Pleural and pulmonary events in patients treated with dasatinib for chronic myeloid leukemia in chronic phase. Haematologica 2007, 92(Suppl 2):203. Abstract 0546.
70. Stone RM, Kantarjian HM, Baccarani M, et al. Efficacy of dasatinib in patients with chronic-phase chronic myelogenous leukemia with resistance or intolerance to imatinib: 2-Year follow-up data from START-C (CA180-013). Blood (ASH Annual Meeting Abstracts) 2007, 110:734.
71. Guilhot F, Apperley JF, Kim DW, et al. Efficacy of dasatinib in patients with accelerated-phase chronic myelogenous leukemia with resistance or intolerance to imatinib: 2-Year follow-up data from START-A (CA180-005). Blood (ASH Annual Meeting Abstracts) 2007, 110:470.
72. Müller MC, Cortes JE, Kim D, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: Analysis of responses according to preexisting BCR-ABL mutations. Blood 2009, 114:4944-4953.
73. Mueller MC, Erben P, Ernst T, et al. Molecular response according to type of preexisting BCR-ABL mutations after second line dasatinib therapy in chronic phase CML patients. Blood (ASH Annual Meeting Abstracts) 2007, 110:319.
74. Müller MC, Erben P, Schenk T, et al. Response to dasatinib after imatinib failure according to type of preexisting BCR-ABL mutations. Blood (ASH Annual Meeting Abstracts) 2006, 108:748.
75. Shah NP, Kim DW, Kantarjian HM, et al. Dasatinib dose-optimization in chronic phase chronic myeloid leukemia (CML-CP): Two-year data from CA180-034 show equivalent long-term efficacy and improved safety with 100 mg once daily dose. Blood (ASH Annual Meeting Abstracts) 2008, 112:3225.
76. Kantarjian HM, Kim DW, Dorlhiac-Llacer P, et al. Dasatinib 140 mg once daily (QD) demonstrates equivalent efficacy and improved safety compared with 70 mg twice daily (BID) in patients with accelerated phase chronic myeloid leukemia (CML-AP): 2-Year follow-up data from CA180-035. Blood (ASH Annual Meeting Abstracts) 2008, 112:3224.
77. Larson RA, Ottmann OG, Shah NP, et al. Dasatinib 140 mg once daily (QD) has equivalent efficacy and improved safety compared with 70 mg twice daily (BID) in patients with imatinib-resistant or -intolerant Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL): 2-Year data from CA180-035. Blood (ASH Annual Meeting Abstracts) 2008, 112:2926.
78. Saglio G, Kantarjian HM, Hochhaus A, et al. Dasatinib 140 mg once daily (QD) demonstrates equivalent effi- cacy and improved safety compared with 70 mg twice daily (BID) in patients with chronic myeloid leukemia in blast phase (CML-BP): 2-Year data from CA180-035. Blood (ASH Annual Meeting Abstracts) 2008, 112:3226.
79. Kantarjian H, Cortes J, Kim DW, et al. 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.
80. Cortes J, Borthakur G, O'Brien S, et al. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). Blood (ASH Annual Meeting Abstracts) 2009, 114:338.
81. A phase III study of dasatinib vs. imatinib in patients with newly diagnosed chronic phase CML (DASI-SION). ClinicalTrials.gov Identifier NCT00481247 Accessed April 5, 2010. http://www.clinicaltrials.gov/ct2/show/NCT00481247?term=NCT00481247&rank=1.
82. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN 107), 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.
83. Kantarjian HM, Giles F, Bhalla KN, et al. Nilotinib in chronic myeloid leukemia patients in chronic phase (CMLCP) with imatinib resistance or intolerance: 2-Year follow-up results of a phase 2 study. Blood (ASH Annual Meeting Abstracts) 2008, 112:3238.
84. Kantarjian HM, Giles FJ, Bhalla KN, et al. Update on imatinib-resistant chronic myeloid leukemia patients in chronic phase (CML-CP) on nilotinib therapy at 24 months: Clinical May 2010 819 Clinical Therapeutics response, safety, and long-term outcomes. Blood (ASH Annual Meeting Abstracts) 2009, 114:1129.
85. Powell BL, Khoury HJ, Lipton JH, et al. Nilotinib responses and tolerability confirmed in North American patients with chronic myeloid leukemia (CML) from ENACT (expanding nilotinib access in clinical trials). Blood (ASH Annual Meeting Abstracts) 2009, 114:3295.
86. le Coutre PD, Giles F, Hochhaus A, et al. Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib resistance or intolerance: 2-Year follow-up results of a phase 2 study. Blood (ASH Annual Meeting Abstracts) 2008, 112:3229.
87. Giles FJ, le Coutre P, Bhalla KN, et al. Nilotinib therapy after dasatinib failure in patients with imatinib-resistant or -intolerant chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast crisis (BC). Blood (ASH Annual Meeting Abstracts) 2007, 110:1029.
88. Jabbour E, Kantarjian HM, Baccarani M, et al. Minimal cross-intolerance between nilotinib and imatinib in patients with imatinib-intolerant chronic myeloid leukemia in chronic phase (CML-CP) or accelerated phase (CML-AP). Blood (ASH Annual Meeting Abstracts) 2008, 112:3215.
89. Branford S, Shou Y, Lawrence R, et al. The P-Loop mutations Y253H and E255K/V may develop more frequently than T315I during nilotinib therapy after imatinib failure and are associated with progression in patients with Ph-positive leukemia. Haematologica 2007, 92(Suppl 2):337. Abstract 0904.
90. Hughes T, Saglio G, Branford S, et al. 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.
91. Saglio G, Kim DW, Hochhaus A, et al. Correlation of clinical response to nilotinib with BCR-ABL mutation status in advanced phase chronic myelogenous leukemia (CML-AP) patients with imatinib-resistance or intolerance. Blood (ASH Annual Meeting Abstracts) 2007, 110:1940.
92. Hochhaus A, Kim D, Martinelli G, et al. Nilotinib efficacy according to baseline BCR-ABL mutations in patients with imatinib-resistant chronic myeloid leukemia in chronic phase (CML-CP). Blood (ASH Annual Meeting Abstracts) 2008, 112:3216.
93. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib demonstrates superior efficacy compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase: Results from the International Randomized Phase III ENES-Tnd trial. Blood (ASH Annual Meeting Abstracts) 2009, 114:1.
94. Cortes J, O'Brien S, Jones D, et al. Efficacy of nilotinib in patients (pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP). Blood (ASH Annual Meeting Abstracts) 2009, 114:341.
95. Cortes J, O'Brien S, Jones D, et al. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). Blood (ASH Annual Meeting Abstracts) 2007, 110:30.
96. Rosti G, Palandri F, Castagnetti F, et al. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood 2009, 114:4933-4938. GIMEMA CML Working Party.
97. Giles F, le Coutre PD, Bhalla KN, et al. Efficacy and tolerability of nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP) who failed prior imatinib and dasatinib therapy: Updated results of a phase 2 study. Blood (ASH Annual Meeting Abstracts) 2008, 112:3234.
98. Garg RJ, Kantarjian H, O'Brien S, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: Long-term follow-up. Blood 2009, 114:4361-4368.
99. Kantarjian HM, Druker BJ, Guilhot F, et al. Imatinib dose escalation is effective in patients with chronic myeloid leukemia in chronic phase (CML-CP). Blood (ASH Annual Meeting Abstracts) 2007, 110:1047.
100. Hughes T, Saglio G, Martinelli G, et al. Responses and disease progression in CML-CP patients treated with nilotinib after imatinib failure appear to be affected by the BCR-ABL mutation status and types. Blood (ASH Annual Meeting Abstracts) 2007, 110:320.
101. Jabbour E, Kantarjian H, O'Brien S, et al. Predictive factors for response and outcome in patients (pts) treated with second generation tyrosine kinase inhibitors (2-TKI) for chronic myeloid leukemia in chronic phase (CML-CP) post imatinib failure. Blood (ASH Annual Meeting Abstracts) 2009, 114:509.
102. Vertex Pharmaceuticals. Vertex's collaborator Merck suspends patient enrollment in clinical trials of MK-0457 (VX-680) pending full analysis of clinical data Accessed October 6, 2009. http://files.shareholder.com/downloads/VRTX/0x0x145756/5991297b-3934-487f-8a4a-c1aef639f13f/VRTX_News_2007_11_20_General.pdf.