Authors' recommendations: Chronic myelogenous leukemia (CML) is a malignancy of the hematopoietic stem cells that comprises 15% of all adult leukemias. CML may occur at any age, but is more common in individuals age 65 and older. In 2010, an estimated 4870 cases of CML were diagnosed in the United States. CML is characterized by a particular chromosomal abnormality known as the Philadelphia chromosome (Ph+) that contains a fusion of two genes—the breakpoint cluster region (BCR) gene and the c-abl oncogene 1, nonreceptor tyrosine kinase (ABL1) gene; this fusion gene is called BCR-ABL1. BCR-ABL1 encodes a tyrosine kinase, BCR-ABL1, which causes CML as well as some other leukemias. CML may be divided into two to three phases, distinguished from one another by the development of additional abnormalities in affected cells. The earliest disease phase is chronic phase (CP) CML, followed in cases that progress by advanced phase (AP) CML, and ultimately, blast crisis (BC) phase, which is fatal. Some patients progress directly from CP-CML to BC-CML without going through AP-CML. Experts note that these disease definitions may change as new CML treatments have different effects upon natural disease course. CML treatment focuses on inhibition of BCR-ABL1 kinase activity. The previous standard of care had limited success and introduction of tyrosine kinase inhibitors (TKIs) has changed the landscape of CML, greatly improving prospects for patients. The first TKI to be approved by the Food and Drug Administration (FDA), in 2001, was imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp.). Newly diagnosed CP-CML patients treated with imatinib achieve high rates of response, and few progress to AP- or BC-CML. Side effects of imatinib treatment are relatively minor and it is generally well tolerated by patients. Other, more recently introduced TKIs include nilotinib hydrochloride monohydrate (Tasigna; Novartis Pharmaceuticals Corp.) and dasatinib (Sprycel; Bristol-Myers Squibb Co.). Other TKIs are currently in development. Imatinib induces rapid response in the majority of CP-CML patients. Some patients, however, fail to respond to imatinib therapy, or respond initially and then develop resistance over time. The most common mechanism of imatinib resistance is genetic variants in the ABL1 kinase domain (KD) of the BCR-ABL1 fusion oncogene. More than 100 different BCR-ABL1 variants have been reported in TKI-resistant CML patients. Most of these variants are rare, and a few make up the majority of all detected. In vitro studies indicate that cells carrying different BCR-ABL1 variants have different sensitivities to different TKIs; some variants may confer resistance to nilotinib, for example, while others may confer resistance to dasatinib. Testing for BCR-ABL1 variants may therefore provide information of clinical relevance for directing therapy following the development of imatinib resistance, although results of in vitro studies do not always correlate with responses seen in vivo.

Project Status: Completed

Year Published: 2012

URL for published report: The report may be purchased from:http://www.hayesinc.com/hayes/crd/?crd=14558

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: United States

Organisation Name: HAYES, Inc.

Contact Address: 157 S. Broad Street, Suite 200, Lansdale, PA 19446, USA. Tel: 215 855 0615; Fax: 215 855 5218

Contact Name: saleinfo@hayesinc.com

Contact Email: saleinfo@hayesinc.com

Copyright: 2012 Winifred S. Hayes, Inc