Selection of Therapy: Rational Decisions Based on Molecular Events

Hematology/Oncology Clinics of North America

Volumn 25, Issue 5, 2011, Pages 1009-1023

  Khorashad, Jamshid S ^a   Deininger, Michael W N ^a  

^a UNIVERSITY OF UTAH   (United States)

Author keywords

BCR ABL; Chronic myeloid leukemia; HOCT1; Imatinib; Mutation; Resistance

Indexed keywords

ALPHA INTERFERON; BCR ABL PROTEIN; DASATINIB; HYDROXYUREA; IMATINIB; NILOTINIB;

ALLOGENEIC STEM CELL TRANSPLANTATION; CANCER CHEMOTHERAPY; CANCER RESISTANCE; CHEMOSENSITIVITY; CHRONIC MYELOID LEUKEMIA; COMPARATIVE GENOMIC HYBRIDIZATION; DISEASE SEVERITY; GENE MUTATION; GENETIC ASSOCIATION; HUMAN; NEUTROPENIA; OVERALL SURVIVAL; PRIORITY JOURNAL; PROGNOSIS; REVIEW; RISK ASSESSMENT; RISK FACTOR; SCORING SYSTEM; TREATMENT FAILURE; TREATMENT RESPONSE;

GENES, ABL; HUMANS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; MUTATION; PROGNOSIS; PROTEIN STRUCTURE, TERTIARY; TUMOR MARKERS, BIOLOGICAL;

EID: 80755125625     PISSN: 08898588     EISSN: 15581977     Source Type: Journal    
DOI: 10.1016/j.hoc.2011.09.006     Document Type: Review

References (106)

1. Goldman J.M., Melo J.V. Chronic myeloid leukemia-advances in biology and new approaches to treatment. N Engl J Med 2003, 349:1451-1464.
2. Giles F.J., Rosti G., Beris P., et al. Nilotinib is superior to imatinib as first-line therapy of chronic myeloid leukemia: the ENESTnd study. Expert Rev Hematol 2010, 3:665-673.
3. Deininger M., Buchdunger E., Druker B.J. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005, 105:2640-2653.
4. Hughes T.P., Hochhaus A., Branford S., et al. 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.
5. Scerni A.C., Alvares L.A., Beltrao A.C., et al. Influence of late treatment on how chronic myeloid leukemia responds to imatinib. Clinics (Sao Paulo) 2009, 64:731-734.
6. Palandri F., Iacobucci I., Martinelli G., et al. Long-term outcome of complete cytogenetic responders after imatinib 400 mg in late chronic phase, Philadelphia-positive chronic myeloid leukemia: the GIMEMA Working Party on CML. J Clin Oncol 2008, 26:106-111.
7. Druker B., Guilhot F., O'Brien S., et al. Five-year follow-up of imatinib therapy for newly diagnosed chronic myelogenous leukemia in chronic-phase shows sustained responses and high overall survival. N Engl J Med 2006, 355:2408-2417.
8. Cortes J., Kantarjian H. Advanced-phase chronic myeloid leukemia. Semin Hematol 2003, 40:79-86.
9. Goldman J.M., Marin D., Olavarria E., et al. Clinical decisions for chronic myeloid leukemia in the imatinib era. Semin Hematol 2003, 40:98-103.
10. Talpaz M., Silver R.T., Druker B.J., et al. 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.
11. Sawyers C.L., Hochhaus A., Feldman E., et al. 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.
12. Kantarjian H.M., Cortes J., O'Brien S., et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 2002, 99:3547-3553.
13. Kantarjian H., Shah N.P., Hochhaus A., et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010, 362:2260-2270.
14. Saglio G., Kim D.W., Issaragrisil S., et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010, 362:2251-2259.
15. Giles F.J., Abruzzese E., Rosti G., et al. Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy. Leukemia 2010, 24:1299-1301.
16. Apperley J.F., Cortes J.E., Kim D.W., 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.
17. Saglio G., Hochhaus A., Goh Y.T., et al. 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.
18. Kantarjian H.M., Giles F., Gattermann N., et al. 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.
19. Cortes J., Rousselot P., Kim D.W., 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.
20. Sokal J.E., Cox E.B., Baccarani M., et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 1984, 63:789-799.
21. de Lavallade H., Apperley J.F., Khorashad J.S., et al. Imatinib for newly diagnosed patients with chronic myeloid leukaemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008, 26:3358-3363.
22. Hehlmann R., Ansari H., Hasford J., et al. Comparative analysis of the impact of risk profile and of drug therapy on survival in CML using Sokal's index and a new score. German chronic myeloid leukaemia (CML)-Study Group. Br J Haematol 1997, 97:76-85.
23. Hasford J., Pfirrmann M., Hehlmann R., et al. 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.
24. Hasford J., Baccarani M., Hoffmann V., et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011, 118(3):686-692.
25. Milojkovic D., Nicholson E., Apperley J.F., et al. 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.
26. Breccia M., Stagno F., Gozzini A., et al. Hammersmith score application identifies chronic myeloid leukemia patients with poor prognosis before treatment with second-generation tyrosine kinase inhibitors. Am J Hematol 2011, 86:523-525.
27. Jabbour E., Kantarjian H., O'Brien S., et al. 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.
28. Tam C.S., Kantarjian H., Garcia-Manero G., et al. Failure to achieve a major cytogenetic response by twelve 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.
29. Kantarjian H.M., Smith T.L., McCredie K.B., et al. Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival. Blood 1985, 66:1326-1335.
30. Sokal J.E., Gomez G.A., Baccarani M., et al. Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive chronic granulocytic leukemia. Blood 1988, 72:294-298.
31. Kantarjian H.M., Dixon D., Keating M.J., et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer 1988, 61:1441-1446.
32. Sessarego M., Panarello C., Coviello D.A., et al. Karyotype evolution in CML: high frequency of translocations other than the Ph. Cancer Genet Cytogenet 1987, 25:73-80.
33. Majlis A., Smith T.L., Talpaz M., et al. Significance of cytogenetic clonal evolution in chronic myelogenous leukemia. J Clin Oncol 1996, 14:196-203.
34. Kantarjian H., Sawyers C., Hochhaus A., et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002, 346:645-652.
35. Cortes J.E., Talpaz M., Giles F., et al. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood 2003, 101:3794-3800.
36. O'Dwyer M.E., Mauro M.J., Blasdel C., et al. 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.
37. Willis S.G., Lange T., Demehri S., et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood 2005, 106:2128-2137.
38. Marktel S., Marin D., Foot N., et al. Chronic myeloid leukemia in chronic phase responding to imatinib: the occurrence of additional cytogenetic abnormalities predicts disease progression. Haematologica 2003, 88:260-267.
39. Deininger M.W. Cytogenetic studies in patients on imatinib. Semin Hematol 2003, 40:50-55.
40. Baccarani M., Cortes J., Pane F., et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009, 27:6041-6051.
41. Verma D., Kantarjian H., Shan J., et al. Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. Cancer 2010, 116:2673-2681.
42. Yong A.S., Szydlo R.M., Goldman J.M., et al. Molecular profiling of CD34+ cells identifies low expression of CD7, along with high expression of proteinase 3 or elastase, as predictors of longer survival in patients with CML. Blood 2006, 107:205-212.
43. Radich J.P., Dai H., Mao M., et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 2006, 103:2794-2799.
44. McWeeney S.K., Pemberton L.C., Loriaux M.M., et al. A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib. Blood 2010, 115:315-325.
45. Zhang W.W., Cortes J.E., Yao H., et al. Predictors of primary imatinib resistance in chronic myelogenous leukemia are distinct from those in secondary imatinib resistance. J Clin Oncol 2009, 27:3642-3649.
46. Zheng C., Li L., Haak M., et al. Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis. Leukemia 2006, 20:1028-1034.
47. Oehler V.G., Yeung K.Y., Choi Y.E., et al. The derivation of diagnostic markers of chronic myeloid leukemia progression from microarray data. Blood 2009, 114:3292-3298.
48. Khorashad J.S., De Melo V.A., Fiegler H., et al. Multiple sub-microscopic genomic lesions are a universal feature of chronic myeloid leukaemia at diagnosis. Leukemia 2008, 22:1806-1807.
49. Hosoya N., Sanada M., Nannya Y., et al. Genomewide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high-resolution array-based comparative genomic hybridization. Genes Chromosomes Cancer 2006, 45:482-494.
50. Boultwood J., Perry J., Zaman R., et al. High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression. Leukemia 2010, 24:1139-1145.
51. Joha S., Dauphin V., Lepretre F., et al. Genomic characterization of Imatinib resistance in CD34+ cell populations from chronic myeloid leukaemia patients. Leuk Res 2011, 35:448-458.
52. Nadarajan V.S., Phan C.L., Ang C.H., et al. Identification of copy number alterations by array comparative genomic hybridization in patients with late chronic or accelerated phase chronic myeloid leukemia treated with imatinib mesylate. Int J Hematol 2011, 93:465-473.
53. Deluche L., Joha S., Corm S., et al. Cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion in a case of progressive chronic myeloid leukemia: a complex chromosomal rearrangement of underestimated frequency in disease progression?. Genes Chromosomes Cancer 2008, 47:1110-1117.
54. Nowak D., Ogawa S., Muschen M., et al. SNP array analysis of tyrosine kinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary genomic alterations. Blood 2010, 115:1049-1053.
55. Schultheis B., Szydlo R., Mahon F.X., et al. Analysis of total phosphotyrosine levels in CD34+ cells from CML patients to predict the response to imatinib mesylate treatment. Blood 2005, 105:4893-4894.
56. Hamilton A., Elrick L., Myssina S., et al. BCR-ABL activity and its response to drugs can be determined in CD34+ CML stem cells by CrkL phosphorylation status using flow cytometry. Leukemia 2006, 20:1035-1039.
57. Hamilton A., Alhashimi F., Myssina S., et al. Optimization of methods for the detection of BCR-ABL activity in Philadelphia-positive cells. Exp Hematol 2009, 37:395-401.
58. Copland M., Hamilton A., Elrick L.J., et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006, 107:4532-4539.
59. Khorashad J.S., Wagner S., Greener L., et al. The level of BCR-ABL1 kinase activity before treatment does not identify chronic myeloid leukemia patients who fail to achieve a complete cytogenetic response on imatinib. Haematologica 2009, 94(6):861-864.
60. White D., Saunders V., Grigg A., et al. Measurement of in vivo BCR-ABL kinase inhibition to monitor imatinib-induced target blockade and predict response in chronic myeloid leukemia. J Clin Oncol 2007, 25:4445-4451.
61. Cilloni D., Messa F., Gottardi E., et al. Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation. Cancer 2004, 101:979-988.
62. Jordanides N.E., Jorgensen H.G., Holyoake T.L., et al. Functional ABCG2 is overexpressed on primary CML CD34+ cells and is inhibited by imatinib mesylate. Blood 2006, 108:1370-1373.
63. Engler J.R., Frede A., Saunders V.A., et al. Chronic myeloid leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 activity. Leukemia 2010, 24:765-770.
64. Hatziieremia S., Jordanides N.E., Holyoake T.L., et al. Inhibition of MDR1 does not sensitize primitive chronic myeloid leukemia CD34+ cells to imatinib. Exp Hematol 2009, 37:692-700.
65. Dohse M., Scharenberg C., Shukla S., et al. Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab Dispos 2010, 38:1371-1380.
66. Thomas J., Wang L., Clark R.E., et al. Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004, 104:3739-3745.
67. Wang L., Giannoudis A., Lane S., et al. 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.
68. White D.L., Saunders V.A., Dang P., et al. 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.
69. White D.L., Dang P., Engler J., et al. 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.
70. Bazeos A., Marin D., Reid A.G., et al. hOCT1 transcript levels and single nucleotide polymorphisms as predictive factors for response to imatinib in chronic myeloid leukemia. Leukemia 2010, 24:1243-1245.
71. Hu S., Franke R.M., Filipski K.K., et al. Interaction of imatinib with human organic ion carriers. Clin Cancer Res 2008, 14:3141-3148.
72. Marin D., Bazeos A., Mahon F.X., et al. 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.
73. Crossman L.C., Druker B.J., Deininger M.W., et al. hOCT 1 and resistance to imatinib. Blood 2005, 106:1133-1134.
74. Davies A., Jordanides N.E., Giannoudis A., et al. 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.
75. Giannoudis A., Davies A., Lucas C.M., et al. 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.
76. Fava C., Saglio G. Can we and should we improve on frontline imatinib therapy for chronic myeloid leukemia?. Semin Hematol 2010, 47:319-326.
77. Cortes J., Hochhaus A., Hughes T., et al. Front-line and salvage therapies with tyrosine kinase inhibitors and other treatments in chronic myeloid leukemia. J Clin Oncol 2011, 29:524-531.
78. Lucas C.M., Wang L., Austin G.M., et al. A population study of imatinib in chronic myeloid leukaemia demonstrates lower efficacy than in clinical trials. Leukemia 2008, 22:1963-1966.
79. Hochhaus A., O'Brien S.G., 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.
80. 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.
81. O'Hare T., Walters D.K., Stoffregen E.P., 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.
82. Azam M., Latek R.R., Daley G.Q. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 2003, 112:831-843.
83. Shah N., Nicoll J., Nagar B., et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002, 2:117-223.
84. von Bubnoff N., Schneller F., Peschel C., et al. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet 2002, 359:487-491.
85. Gorre M.E., 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.
86. Bradeen H.A., Eide C.A., O'Hare T., et al. Comparison of imatinib, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood 2006, 108(7):2332-2338.
87. Ernst T., Erben P., Muller M.C., et al. Dynamics of BCR-ABL mutated clones prior to hematologic or cytogenetic resistance to imatinib. Haematologica 2008, 93:186-192.
88. Khorashad J.S., Milojkovic D., Mehta P., et al. In vivo kinetics of kinase domain mutations in CML patients treated with dasatinib after failing imatinib. Blood 2008, 111:2378-2381.
89. Soverini S., Colarossi S., Gnani A., et al. 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.
90. Pfeifer H., Wassmann B., Pavlova A., et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 2007, 110:727-734.
91. 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.
92. Griswold I.J., Macpartlin M., Bumm T., et al. Kinase domain mutants of Bcr-Abl exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib. Mol Cell Biol 2006, 26:6082-6093.
93. Khorashad J., de Lavallade H., Apperley J., et al. The finding of kinase domain mutations in chronic phase CML patients responding to imatinib may identify those at high risk of disease progression. J Clin Oncol 2008, 26:4806-4813.
94. Chu S., Xu H., Shah N.P., et al. Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 2005, 105:2093-2098.
95. Soverini S., Gnani A., Colarossi S., et al. 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.
96. Skaggs B.J., Gorre M.E., Ryvkin A., et al. Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants. Proc Natl Acad Sci U S A 2006, 103:19466-19471.
97. Branford S., Melo J.V., Hughes T.P. 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(27):5426-5435.
98. Laneuville P., Dilea C., Yin O.Q., et al. Comparative In vitro cellular data alone are insufficient to predict clinical responses and guide the choice of BCR-ABL inhibitor for treating imatinib-resistant chronic myeloid leukemia. J Clin Oncol 2010, 28:e169-e171.
99. Nicolini F.E., Mauro M.J., Martinelli G., et al. Epidemiologic study on survival of chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia patients with BCR-ABL T315I mutation. Blood 2009, 114:5271-5278.
100. Azam M., Seeliger M.A., Gray N.S., et al. Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat Struct Mol Biol 2008, 15:1109-1118.
101. Hanfstein B., Muller M.C., Kreil S., et al. Dynamics of mutant BCR-ABL-positive clones after cessation of tyrosine kinase inhibitor therapy. Haematologica 2011, 96:360-366.
102. de Lavallade H., Khorashad J.S., Davis H.P., et al. Interferon-{alpha} or homoharringtonine as salvage treatment for chronic myeloid leukemia patients who acquire the T315I BCR-ABL mutation. Blood 2007, 110:2779-2780.
103. O'Hare T., Shakespeare W.C., Zhu X., et al. 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.
104. Cortes J, Talpaz M, Bixby D, et al. A phase 1 trial of oral ponatinib (AP24534) in patients with refractory chronic myelogenous leukemia (CML) and other hematologic malignancies: emerging safety and clinical response findings. ASH Annual Meeting Abstracts. Orlando (FL), December 4-7, 2010;116: p. 210.
105. Daghistani M., Marin D., Khorashad J.S., et al. EVI-1 oncogene expression predicts survival in chronic-phase CML patients resistant to imatinib treated with second-generation tyrosine kinase inhibitors. Blood 2010, 116:6014-6017.
106. Mahon F.X., Rea D., Guilhot J., et al. 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, 11:1029-1035.