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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Stein, Brady Smith, B. Douglas
Description	Country affiliation: United States Author Affiliation: Stein B ( Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.)
Abstract	BACKGROUND: Imatinib has been found to substantially improve outcomes in patients with chronic myeloid leukemia (CML) compared with previously available therapies. However, its use is complicated by development of resistance or drug intolerance, prompting dose escalation or a trial of dasatinib or nilotinib, the second-generation tyrosine kinase inhibitors (TKIs). OBJECTIVES: This article reviews the mechanisms of TKI resistance; discusses the tolerability and efficacy of high-dose imatinib, dasatinib, and nilotinib; and provides background for the rational use of second-line treatment options. METHODS: MEDLINE (1966-December 2009) and EMBASE (1993-December 2009) were searched for pertinent English-language publications using search terms that included, but were not limited to, chronic myeloid leukemia, imatinib, dasatinib, nilotinib, and clinical trial. Abstracts from American Society of Hematology annual meetings (2005-2009) were also reviewed. There were no prespecified inclusion or exclusion criteria. RESULTS: Major and complete cytogenetic responses (MCyR and CCyR, respectively) to second-line treatment with high-dose (600-800 mg/d PO) imatinib were restricted to CML patients who had achieved a CyR to standard-dose imatinib: >90% of patients without a previous CyR failed to respond. The expected durability of the response to this approach remains unclear. Grade 3/4 thrombocytopenia, neutropenia, and anemia occurred in 14%, 39%, and 8%, respectively, of patients receiving high-dose imatinib. In patients who failed first-line treatment with imatinib, dasatinib (70 mg BID PO) was associated with higher rates of CCyR at 2 years compared with imatinib (44% vs 18%, respectively; P = 0.003), as well as higher estimated rates of progression-free survival at 2 years (86% vs 65%; P = 0.001). Dasatinib use was complicated by grade 3/4 thrombocytopenia and neutropenia in 57% and 63% of patients, respectively, and pleural effusion in 5%. Nilotinib treatment was effective in patients who were resistant to or unable to tolerate imatinib, with 46% and 58% achieving a CCyR and MCyR, respectively, at 2 years. Nilotinib use was complicated by grade 3/4 thrombocytopenia and neutropenia in 28% and 40% of patients, respectively, and QTc-interval prolongation in 1% to 10% of patients. Neither agent was clinically effective in patients with the common T315I mutation. CONCLUSION: Dasatinib and nilotinib were effective and generally well tolerated as second-line treatments for CML patients with a suboptimal response to standard doses of imatinib or imatinib intolerance.
File Format	HTM / HTML
ISSN	01492918
e-ISSN	1879114X
DOI	10.1016/j.clinthera.2010.05.003
Journal	Clinical Therapeutics
Issue Number	5
Volume Number	32
Language	English
Publisher	Elsevier
Publisher Date	2010-05-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Pharmacology Antineoplastic Agents Therapeutic Use Leukemia, Myelogenous, Chronic, Bcr-abl Positive Drug Therapy Piperazines Protein Kinase Inhibitors Pyrimidines Benzamides Clinical Trials As Topic Dasatinib Drug Resistance, Neoplasm Fusion Proteins, Bcr-abl Genetics Imatinib Mesylate Mutation Thiazoles Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical)

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