Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib
Open Access
- 1 March 2009
- journal article
- Published by Informa UK Limited in Drug Design, Development and Therapy
- Vol. 3, 89-101
- https://doi.org/10.2147/DDDT.S3069
Abstract
Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib Ronan Swords, Devalingam Mahalingam, Swaminathan Padmanabhan, Jennifer Carew, Francis GilesInstitute for Drug Development, Cancer Therapy and Research Centre, University of Texas Health Science Centre at San Antonio, USA Chronic myeloid leukemia (CML) is the consequence of a single balanced translocation that produces the BCR-ABL fusion oncogene which is detectable in over 90% of patients at presentation. The BCR-ABL inhibitor imatinib mesylate (IM) has improved survival in all phases of CML and is the standard of care for newly diagnosed patients in chronic phase. Despite the very significant therapeutic benefits of IM, a small minority of patients with early stage disease do not benefit optimally while IM therapy in patients with advanced disease is of modest benefit in many. Diverse mechanisms may be responsible for IM failures, with point mutations within the Bcr-Abl kinase domain being amongst the most common resistance mechanisms described in patients with advanced CML. The development of novel agents designed to overcome IM resistance, while still primarily targeted on BCR-ABL, led to the creation of the high affinity aminopyrimidine inhibitor, nilotinib. Nilotinib is much more potent as a BCR-ABL inhibitor than IM and inhibits both wild type and IM-resistant BCR-ABL with significant clinical activity across the entire spectrum of BCR-ABL mutants with the exception of T315I. The selection of a second generation tyrosine kinase inhibitor to rescue patients with imatinib failure will be based on several factors including age, co-morbid medical problems and ABL kinase mutational profile. It should be noted that while the use of targeted BCR-ABL kinase inhibitors in CML represents a paradigm shift in CML management these agents are not likely to have activity against the quiescent CML stem cell pool. The purpose of this review is to summarize the pre-clinical and clinical data on nilotinib in patients with CML who have failed prior therapy with IM or dasatinib.Keywords: nilotinib, chronic myeloid leukemia, imatinibKeywords
This publication has 32 references indexed in Scilit:
- Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phaseLeukemia, 2008
- Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemiaBlood, 2008
- 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 intoleranceBlood, 2007
- Novel Abl Kinase Inhibitors in Chronic Myeloid Leukemia in Blastic Phase and Philadelphia Chromosome–Positive Acute Lymphoblastic LeukemiaClinical Lymphoma Myeloma and Leukemia, 2007
- ImatinibDrugs, 2007
- Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid LeukemiaNew England Journal of Medicine, 2006
- Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kitLeukemia Research, 2006
- Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)–based mutagenesis screen: high efficacy of drug combinationsBlood, 2006
- Kinase Domain Mutants of Bcr-Abl Exhibit Altered Transformation Potency, Kinase Activity, and Substrate Utilization, Irrespective of Sensitivity to ImatinibMolecular and Cellular Biology, 2006
- Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistanceProceedings of the National Academy of Sciences of the United States of America, 2006