Book contents
- Frontmatter
- Dedication
- Contents
- List of Contributors
- Preface
- Part 1.1 Analytical techniques: analysis of DNA
- Part 1.2 Analytical techniques: analysis of RNA
- Part 2.1 Molecular pathways underlying carcinogenesis: signal transduction
- Part 2.2 Molecular pathways underlying carcinogenesis: apoptosis
- Part 2.3 Molecular pathways underlying carcinogenesis: nuclear receptors
- Part 2.4 Molecular pathways underlying carcinogenesis: DNA repair
- Part 2.5 Molecular pathways underlying carcinogenesis: cell cycle
- Part 2.6 Molecular pathways underlying carcinogenesis: other pathways
- Part 3.1 Molecular pathology: carcinomas
- Part 3.2 Molecular pathology: cancers of the nervous system
- Part 3.3 Molecular pathology: cancers of the skin
- Part 3.4 Molecular pathology: endocrine cancers
- Part 3.5 Molecular pathology: adult sarcomas
- Part 3.6 Molecular pathology: lymphoma and leukemia
- 68 Molecular pathology of lymphoma
- 69 The molecular basis of acute myeloid leukemia
- 70 Molecular oncology of acute promyelocytic leukemia (APL)
- 71 Acute lymphoblastic leukemia (ALL)
- 72 B-cell chronic lymphocytic leukemia
- 73 Chronic myeloid leukemia: imatinib and next-generation ABL inhibitors
- 74 Multiple myeloma
- 75 EMS: the 8p11 myeloproliferative syndrome
- 76 JAK2 and myeloproliferative neoplasms
- Part 3.7 Molecular pathology: pediatric solid tumors
- Part 4 Pharmacologic targeting of oncogenic pathways
- Index
- References
73 - Chronic myeloid leukemia: imatinib and next-generation ABL inhibitors
from Part 3.6 - Molecular pathology: lymphoma and leukemia
Published online by Cambridge University Press: 05 February 2015
Book contents
- Frontmatter
- Dedication
- Contents
- List of Contributors
- Preface
- Part 1.1 Analytical techniques: analysis of DNA
- Part 1.2 Analytical techniques: analysis of RNA
- Part 2.1 Molecular pathways underlying carcinogenesis: signal transduction
- Part 2.2 Molecular pathways underlying carcinogenesis: apoptosis
- Part 2.3 Molecular pathways underlying carcinogenesis: nuclear receptors
- Part 2.4 Molecular pathways underlying carcinogenesis: DNA repair
- Part 2.5 Molecular pathways underlying carcinogenesis: cell cycle
- Part 2.6 Molecular pathways underlying carcinogenesis: other pathways
- Part 3.1 Molecular pathology: carcinomas
- Part 3.2 Molecular pathology: cancers of the nervous system
- Part 3.3 Molecular pathology: cancers of the skin
- Part 3.4 Molecular pathology: endocrine cancers
- Part 3.5 Molecular pathology: adult sarcomas
- Part 3.6 Molecular pathology: lymphoma and leukemia
- 68 Molecular pathology of lymphoma
- 69 The molecular basis of acute myeloid leukemia
- 70 Molecular oncology of acute promyelocytic leukemia (APL)
- 71 Acute lymphoblastic leukemia (ALL)
- 72 B-cell chronic lymphocytic leukemia
- 73 Chronic myeloid leukemia: imatinib and next-generation ABL inhibitors
- 74 Multiple myeloma
- 75 EMS: the 8p11 myeloproliferative syndrome
- 76 JAK2 and myeloproliferative neoplasms
- Part 3.7 Molecular pathology: pediatric solid tumors
- Part 4 Pharmacologic targeting of oncogenic pathways
- Index
- References
Summary
Events surrounding the development of the ABL kinase inhibitor imatinib (Gleevec) for the treatment of chronic myeloid leukemia (CML) have been extensively chronicled in numerous reviews (1–4). Rather than retell that history here, this chapter reviews recent and emerging issues in the biology and treatment of CML and speculates on future directions. To set the stage, ABL kinase inhibitors have been the mainstay of CML therapy for more than 10 years. This has resulted in a profound shift in the lifespan of CML patients, from a median survival of 5–6 years to an estimated 10–20 years. This success is largely attributable to: (i) a profound reduction in disease burden by 3–4 orders of magnitude with single-agent ABL kinase inhibitor therapy, (ii) durable responses if treatment is initiated early in the course of disease, and (iii) the availability of second-generation ABL inhibitors such as dasatinib, nilotinib, and bosutinib that are effective in many patients who develop resistance to imatinib. While this is an enviable track record of success in cancer, many patients fail to respond optimally or develop multi-drug resistance after sequential treatment with different ABL kinase inhibitors. In addition, this treatment approach commits patients to decades of chronic therapy, with unknown risks of possible late relapse and long-term side effects. An emerging question is whether CML might be cured with the right combination of these or other targeted therapies.
- Type
- Chapter
- Information
- Molecular OncologyCauses of Cancer and Targets for Treatment, pp. 793 - 798Publisher: Cambridge University PressPrint publication year: 2013
References
. Shifting paradigms: the seeds of oncogene addiction. Nature Medicine 2009;15:1158–61.CrossRefGoogle ScholarPubMed
. Perspectives on the development of imatinib and the future of Cancer Research. Nature Medicine 2009;15:1149–52 (2009).CrossRefGoogle ScholarPubMed
, , , 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;99:3530–9.CrossRefGoogle ScholarPubMed
, , , et al. Activity of a specific inhibitor of the BCR–ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. New England Journal of Medicine 2001;344:1038–42.CrossRefGoogle ScholarPubMed
, , , et al. Dynamics of chronic myeloid leukaemia. Nature 2005;435:1267–70.CrossRefGoogle ScholarPubMed
, , , et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876–80.CrossRefGoogle ScholarPubMed
, , , et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000;289:1938–42.CrossRefGoogle ScholarPubMed
, , , et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Medicine 2005;2:e73.Google ScholarPubMed
, , , et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. New England Journal of Medicine 2010;363:1734–9.CrossRefGoogle ScholarPubMed
, , , et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clinical Cancer Research 2005;11:4182–90.CrossRefGoogle ScholarPubMed
, , , et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 2004:127:294–9.CrossRefGoogle Scholar
. Ponatinib: targeting the T315I mutation in chronic myelogenous leukemia. Clinical Advances in Hematology and Oncology 2011;9:925–6.Google ScholarPubMed
, , , 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;2:117–25.CrossRefGoogle ScholarPubMed
, , , et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399–401.CrossRefGoogle ScholarPubMed
, , , et al. The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Research 2006;66:5790–7.CrossRefGoogle ScholarPubMed
, , , , . Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proceedings of the National Academy of Sciences USA 2005;102:3395–400.CrossRefGoogle ScholarPubMed
, , . Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 2003;112:831–43.CrossRefGoogle ScholarPubMed
, , , et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New England Journal of Medicine 2006;354:2531–41.CrossRefGoogle ScholarPubMed
, , , et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. New England Journal of Medicine 2006;354:2542–51.CrossRefGoogle ScholarPubMed
, , , et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012;119:3403–12.CrossRefGoogle ScholarPubMed
, , , et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. New England Journal of Medicine 2010;362:2260–70.CrossRefGoogle ScholarPubMed
, , , et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. New England Journal of Medicine 2010;362:2251–9.CrossRefGoogle ScholarPubMed
. Even better kinase inhibitors for chronic myeloid leukemia. New England Journal of Medicine 2010;362:2314–15.CrossRefGoogle ScholarPubMed
, , . et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA Trial. Journal of Clinical Oncology 2012;30:3486–92.CrossRefGoogle ScholarPubMed
, , , et al. 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 kinase inhibitors. Journal of Clinical Oncology 2012;30:232–8.CrossRefGoogle ScholarPubMed
, , , et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. Journal of Clinical Investigation 2007;117:2562–9.CrossRefGoogle ScholarPubMed
, , , et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. New England Journal of Medicine 2006;355:2408–17.CrossRefGoogle ScholarPubMed
, , , et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009;23:1054–61.CrossRefGoogle ScholarPubMed
, . Can we and should we improve on frontline imatinib therapy for chronic myeloid leukemia? Seminars on Hematology 2010;47:319–26.CrossRefGoogle ScholarPubMed
, , , 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 Oncology 2010;11:1029–35.CrossRefGoogle ScholarPubMed
, , , et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002;99:319–25.CrossRefGoogle ScholarPubMed
, , , et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006;107:4532–9.CrossRefGoogle Scholar
, , , et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009;458:776–9.CrossRefGoogle ScholarPubMed
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