Skip to main content Accessibility help
×
×
Home
  • Print publication year: 2010
  • Online publication date: January 2011

4 - Chronic myeloid leukemia

Summary

Introduction

Chronic myeloid leukemia (CML) is a relatively rare disease but is one of the most extensively studied and best understood neoplasms, and one for which a direct gene link has been found. CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome (Ph). The molecular consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein. Bcr-Abl displays transforming activity owing to its constitutive kinase activity, which results in multiple signal transduction pathways leading to uncontrolled cell proliferation and reduced apoptosis and resulting in the malignant expansion of pluripotent stem cells in bone marrow. CML is usually diagnosed in the chronic phase (CP) and, if not treated, progresses through an accelerated phase (AP) to a terminal blastic phase (BP).

Incidence, epidemiology, and etiology

CML accounts for 15% to 20% of cases of leukemia in the United States. There is a slight male preponderance. Its annual incidence is about 1 to 2 cases per 100,000 individuals. About 5000 to 6000 cases of CML are diagnosed annually. This incidence has not changed over the past few decades, and increases with age. The median age at CML diagnosis is 55 to 60 years; it is uncommon in children and adolescents. Before imatinib therapy, the prevalence of CML was about 25,000 cases in the United States.

Recommend this book

Email your librarian or administrator to recommend adding this book to your organisation's collection.

Management of Hematologic Malignancies
  • Online ISBN: 9780511781926
  • Book DOI: https://doi.org/10.1017/CBO9780511781926
Please enter your name
Please enter a valid email address
Who would you like to send this to *
×
References
Barnes, DJ, Melo, JV. Cytogenetic and molecular genetic aspects of chronic myeloid leukaemia. Acta Haematol 2002;108:180–202.
Faderl, S, Talpaz, M, Estrov, Z, et al. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med 1999;131:207–19.
Litzow, MR. Imatinib resistance: obstacles and opportunities. Arch Pathol Lab Med 2006;130:669–79.
Rowley, JD.Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290–3.
Koptyra, M, Falinski, R, Nowicki, MO, et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 2006;108:319–27.
Hu, Y, Liu, Y, Pelletier, S, et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 2004;36:453–61.
Bhatia, R, Holtz, M, Niu, N, et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003;101:4701–7.
Ries, LAG, Eisner, MP, Kosary, CL, et al. SEER Cancer Statistics Review, 1975–2000. Bethesda, MD, National Cancer Institute, 2003.
Brown, WM, Doll, R. Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis. BMJ 1965;5474:1327–32.
Boice, JD, Day, NE, Andersen, A, et al. Second cancers following radiation treatment for cervical cancer: an international collaboration among cancer registries. J Natl Cancer Inst 1985;74:955–75.
Kato, H, Schull, WJ. Studies of the mortality of A-bomb survivors: 7. Mortality, 1950–1978: Part I. Cancer mortality. Radiat Res 1982;90:395–432.
Nowell, PC, Hungerford, DA. A minute chromosome in human chronic granulocytic leukemia. Science 1960;132:1497.
Rowley, JD. A new consistent abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290–3.
Lugo, TG, Pendergast, AM, Muller, AJ, et al. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990;247:1079–82.
Pendergast, AM, Quilliam, , Cripe, LD, et al. BCRABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell 1993;75:175–85.
Puil, L, Liu, J, Gish, G, et al. Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J 1994;13:764–73.
Marais, R, Light, Y, Paterson, HF, et al. Ras remits Raf-I to the plasma membrane for activation by tyrosine phosphorylation. EMBO J 1995;14:3136–45.
Skorski, T, Kanakaraj, P, Nieborowska-Skorska, M, et al. Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood 1995;86:726–36.
Skorski, T, Bellacosa, A, Nieborowska-Skorska, M, et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J 1997;16:6151–61.
Franke, TF, Kaplan, DR, Cantley, LC. PI3K: downstream AKTion blocks apoptosis. Cell 1997;88:435–7.
Shuai, K, Halpern, J, ten Hoeve, J, et al. Constitutive activation of STAT5 by the Bcr-Abl oncogene in chronic myelogenous leukemia. Oncogene 1996;13:247–54.
Haria, RL, Etten, RA. P2IO and PI90(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem 1996;271:31 704–10.
Klejman, A, Schreiner, SJ, Nieborowska-Skorska, M, et al. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J 2002;21:5766–74.
Menssen, A, Hermeking, H. Characterization of the c-MYC-regulated transcriptome by SAGE: identification and analysis of c-MYC target genes. Proc Natl Acad Sci U S A 2002;99:6274–9.
Sawyers, CL, Callahan, W, Witte, ON. Dominant negative MYC blocks transformation by ABL oncogenes. Cell 1992;70:901–10.
Alar, , Goga, A, McLaughlin, J, et al. Differential complementation of Bcr-Abl point mutants with c-Myc. Science 1994;264:424–6.
Skorski, T, Nieborowska-Skorska, M, Wlodarski, P, et al. Blastic transformation of p53-deficient bone marrow cells by p2lObcr/abl tyrosine kinase. Proc Natl Acad Sci U S A 1996;93:13 137–42.
Serrano, M, Lee, H, Chin, L, et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 1996;85:27–37.
Beck, Z, Kiss, A, Tóth, FD, et al. Alterations of P53 and RB genes and the evolution of the accelerated phase of chronic myeloid leukemia. Leuk Lymphoma 2000;38:587–97.
Sherr, C, McCormick, F. The RB and p53 pathways in cancer. Cancer Cell 2002;2:103–12.
Schoch, C, Schnittger, S, Bursch, S, et al. Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases. Leukemia 2002;16:53–9.
Wang, YL, Bagg, A, Pear, W, et al. Chronic myelogenous leukemia: laboratory diagnosis and monitoring. Genes Chromosomes Cancer 2001;32:97–111.
Faderl, S, Talpaz, M, Estrov, Z, et al. The biology of chronic myeloid leukemia. N Engl J Med 1999;341:164–72.
Guilhot, F, Chastang, C, Michallet, M, et al. Interferon Alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med 1997;337:223–9.
Kantarjian, HM, O'Brien, S, Smith, TL, et al. Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine. J Clin Oncol 1999;17:284–92.
Deininger, M, Buchdunger, E, Druker, BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005;105:2640–53.
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;355:2408–17.
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). ASH Annual Meeting Abstracts 2008;112:186.
Kantarjian, H, Talpaz, M, O'Brien, S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 2004;103:2873–8.
Cortes, J, Baccarani, M, Guilhot, F, et al. A phase III, randomized, open-label study of 400 mg versus 800 mg of imatinib mesylate (IM) in patients (pts) with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) using molecular endpoints: 1-year results of TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) Study. ASH Annual Meeting Abstracts 2008;112:335.
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;113:4497–504.
2009. NccnNCpgioCMLV.
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;108:1809–20.
Hughes, T, Branford, S. Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev 2006;20:29–41.
Kantarjian, H, O'Brien, S, Shan, J, et al. Cytogenetic and molecular responses and outcome in chronic myelogenous leukemia: need for new response definitions?Cancer 2008;112:837–45.
Quintas-Cardama, A, Kantarjian, H, Jones, D, et al. 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;113:6315–21.
Apperley, JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007;8:1018–29.
Soverini, S, Colarossi, S, Gnani, A, et al. 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;12:7374–9.
Donato, NJ, Wu, JY, Stapley, J, et al. Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Cancer Res 2004;64:672–7.
Penserga, ET, Skorski, T. Fusion tyrosine kinases: a result and cause of genomic instability. Oncogene 2007;26:11–20.
Kantarjian, HM, Larson, RA, Guilhot, F, et al. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 2009;115:551–60.
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;113:2154–60.
Lombardo, LJ, Lee, FY, Chen, P, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004;47:6658–61.
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 mutagenesis screen: high efficacy of drug combinations. Blood 2006;108:2332–8.
Guilhot, F, Apperley, J, Kim, DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007;109:4143–50.
Hochhaus, A, Baccarani, M, Deininger, M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 2008;22:1200–6.
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;109:3207–13.
Shah, NP, Kim, D-W, 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. ASH Annual Meeting Abstracts 2008;112:3225.
Porkka, K, Khoury, HJ, Paquette, R, et al. Dasatinib 100 mg once daily (QD) maintains long-term efficacy and minimizes the occurrence of pleural effusion: an analysis of 24-month data in patients with resistance, suboptimal response, or intolerance to imatinib (CA180–034). ASH Annual Meeting Abstracts 2008;112:3242.
Mauro, MJ, Baccarani, M, Cervantes, F, et al. Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous leukemia (CP-CML) with resistance or intolerance to imatinib (START-C). J Clin Oncol (2008 ASCO Annual Meeting Proceedings) 2008;26:Abstract 7009.
Hochhaus, A, Mueller, M, Cortes, JE, et al. Dasatinib efficacy by dosing schedule across individual baseline BCR-ABL mutations in chronic phase chronic myelogenous leukemia (CP-CML) after imatinib failure. J Clin Oncol (2008 ASCO Annual Meeting Proceedings) 2008;26: Abstract 7014.
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;92:401–4.
Shah, NP, Skaggs, BJ, Branford, S, et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clin Invest 2007;117:2562–9.
Khorashad, JS, Milojkovic, D, Mehta, P, et al. In vivo kinetics of kinase domain mutations in CML patients treated with dasatinib after failing imatinib. Blood 2008;111:2378–81.
Jabbour, E, Kantarjian, HM, Jones, D, et al. Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. Blood 2008;112:4839–42.
Kantarjian, H, Pasquini, R, Hamerschlak, N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 2007;109:5143–50.
Kantarjian, H, Pasquinin, R, Levy, 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;115:4136–47.
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(21):3472–9.
Martinelli, G, Hochhaus, A, Coutre, S, et al. Dasatinib (SPRYCEL) efficacy and safety in patients (pts) with chronic myelogenous leukemia in lymphoid (CML-LB) or myeloid blast (CML-MB) phase who are imatinib-resistant (im-r) or -intolerant (im-i). Blood 2006;108:Abstract 745.
Ottmann, O, Dombret, H, Baccarani, M, et al. Dasatinib induces rapid hematologic and cytogenetic responses in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase II study. Blood 2007;110:2309–15.
Weisberg, E, Manley, PW, Breitenstein, W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005;7:129–41.
Kantarjian, HM, 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;110:3540–6.
Coutre, P, Ottmann, OG, Giles, F, et al. 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;111:1834–9.
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. ASH Annual Meeting Abstracts 2008;112:3238.
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. ASH Annual Meeting Abstracts 2008;112:3229.
Giles, FJ, Larson, RA, Kantarjian, HM, et al. Nilotinib in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis (CML-BC) who are resistant or intolerant to imatinib. J Clin Oncol (2008 ASCO Annual Meeting Proceedings) 2008;26: Abstract 7017.
Hochhaus, A, Kim, D-W, Martinelli, G, et al. Nilotinib efficacy according to baseline BCR-ABL mutations in patients with imatinib-resistant chronic myeloid leukemia in chronic phase (CP-CML). ASH Annual Meeting Abstracts 2008;112:3216.
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;27:469–71.
Cortes, J, Kantarjian, HM, Kim, D-W, et al. Efficacy and safety of bosutinib (SKI-606) in patients with chronic phase (CP) Ph+ chronic myelogenous leukemia (CML) with resistance or intolerance to imatinib. ASH Annual Meeting Abstracts 2008;112:1098.
Cortes, J, Paquette, R, Talpaz, M, et al. Preliminary clinical activity in a phase I trial of the BCR-ABL/IGF-1R/aurora kinase inhibitor XL228 in patients with Ph+ leukemias with either failure to multiple TKI therapies or with T315I mutation. ASH Annual Meeting Abstracts 2008;112:3232.
Gontarewicz, A, Balabanov, S, Keller, G, et al. Simultaneous targeting of aurora kinases and Bcr-Abl by the small molecule inhibitor PHA-739358 is effective in imatinib-resistant mutations including T315I. ASH Annual Meeting Abstracts 2007;110:1042.
Gontarewicz, A, Balabanov, S, Keller, G, et al. PHA-680626 exhibits anti-proliferative and pro-apoptotic activity on imatinib-resistant chronic myeloid leukemia cell lines and primary CD34+ cells by inhibition of both Bcr-Abl tyrosine kinase and aurora kinases. ASH Annual Meeting Abstracts 2007;110:4568.
Paquette, RL, Shah, NP, Sawyers, CL, et al. PHA-739358, an aurora kinase inhibitor, induces clinical responses in chronic myeloid leukemia harboring T315I mutations of BCR-ABL. ASH Annual Meeting Abstracts 2007;110:1030.
Giles, FJ, Cortes, J, Jones, D, et al. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 2007;109:500–2.
Cortes, J, Talpaz, T, Deininger, M, et al. A phase 1 trial of oral AP24534 in patients with refractory chronic myeloid leukemia and other hematologic malignancies: first results of safety and clinical activity against T315I and resistant mutations. Blood 2009;114:643.
Etten, RA, Chan, WW, Zaleskas, VM, et al. Switch pocket inhibitors of the ABL tyrosine kinase: distinct kinome inhibition profiles and in vivo efficacy in mouse models of CML and B-lymphoblastic leukemia induced by BCR-ABL T315I. Blood 2008;112:576.
Kantarjian, HM, Talpaz, M, Santini, V, et al. Homoharringtonine: history, current research, and future direction. Cancer 2001;92:1591–605.
O'Brien, S, Kantarjian, H, Keating, M, et al. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood 1995;86:3322–6.
Cortes, J, Khoury, HJ, Corm, S, et al. Safety and efficacy of subcutaneous (SC) omacetaxine mepesuccinate in imatinib (IM)-resistant chronic myeloid leukemia (CML) patients (pts) with the T315I mutation – results of an ongoing multicenter phase II study. ASH Annual Meeting Abstracts 2008;112:3239.
Shah, NP, Nicoll, JM, Branford, S, et al. Molecular analysis of dasatinib resistance mechanisms in CML patients identifies novel BCR-ABL mutations predicted to retain sensitivity to imatinib: rationale for combination tyrosine kinase inhibitor therapy. Blood 2005;106:1093.
Weisberg, E, Catley, L, Wright, RD, et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood 2007;109:2112–20.
Fiskus, W, Pranpat, M, Bali, P, et al. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Blood 2006;108:645–52.
O'Hare, T, Eide, CA, Tyner, JW, et al. SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib. Proc Natl Acad Sci U S A 2008;105:5507–12.
Baccarani, M, Martinelli, G, Rosti, G, et al. Imatinib and pegylated human recombinant interferon alpha2b in early chronic-phase chronic myeloid leukemia. Blood 2004;104:4245–51.
Guilhot, F, Mahon, F, Guilhot, J, et al. Randomized comparison of imatinib versus imatinib combination therapies in newly diagnosed chronic myeloid leukaemia (CML) patients in chronic phase (CP): first results of the phase III (SPIRIT) trial from the French CML Group (FI LMC)Blood 2008;112:183.
Quintas-Cardama, A, Kantarjian, HM, Ravandi, F, et al. Immune modulation of minimal residual disease (MRD) in patients (pts) with chronic myelogenous leukemia (CML) in early chronic phase (CP): a randomized trial of frontline high-dose (HD) imatinib mesylate (IM) with or without pegylated-interferon (PEG-IFN) and GM-CSF. Blood 2006;108:2207.
Mahon, F, Huguet, F, Guilhot, F, et al. Is it possible to stop imatinib in patients with chronic myeloid leukemia? An update from a French pilot study and first results from the multicentre “Stop Imatinib” (STIM) study. Blood 2008;112:187.
Rosti, G, Castagnetti, F, Poerio, A, et al. High and early rates of cytogenetic and molecular response with nilotinib 800 mg daily as first line treatment of Ph-positive chronic myeloid leukemia in chronic phase: results of a phase 2 trial of the GIMEMA CML Working Party. ASH Annual Meeting Abstracts 2008;112:181.
Cortes, J, O'Brien, S, Jones, D, et al. Efficacy of nilotinib (formerly AMN107) in patients (pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CP-CML). ASH Annual Meeting Abstracts 2008;112:446.
Cortes, J, O'Brien, S, Borthakur, G, et al. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). ASH Annual Meeting Abstracts 2008;112:182.
Marin, D, Milojkovic, D, Olavarria, E, et al. 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;112:4437–44.
Alvarado, Y, Kantarjian, H, O'Brien, S, et al. 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;115:3709–18.
Tam, CS, Kantarjian, H, Garcia-Manero, G, et al. 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;112:516–18.
Jabbour, E, Kantarjian, H, Jones, D, et al. Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations. Blood 2009;114:2037–43.