The role of dasatinib in the management of chronic myeloid leukemia

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The role of dasatinib in the management of chronic myeloid leukemia

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Author(s): Runzhe Chen , Baoan Chen

Publication date (Electronic): 09 February 2015

Journal: Drug Design, Development and Therapy

Publisher: Dove Medical Press

Keywords: imatinib, tyrosine kinase inhibitor, clinical trials

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Abstract

Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) for chronic, blastic, or accelerated phase chronic myeloid leukemia (CML) patients who are resistant or intolerant to previous treatment. It potently inhibits BCR/ABL and SRC-family kinases (SRC, LCK, HCK, YES, FYN, FGR, BLK, LYN, FRK), as well as c-KIT, PDGFR-a and -b, and ephrin receptor kinase. Various clinical trials have provided evidence that it has more durable complete hematologic and cytogenetic responses, as well as more potency in imatinib-resistant or -intolerant CML, and it has also shown its advantages in newly diagnosed CML compared to imatinib. In this review, we mainly focus on the structure, mechanisms, pharmacokinetics, and pharmacogenetics of dasatinib. We also summarize clinical trials with dasatinib on CML and provide our recommendations for dasatinib in the treatment of CML.

Most cited references 61

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Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.

Hagop Kantarjian, Neil P. Shah, Andreas Hochhaus … (2010)

Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML. In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons. After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P=0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P=0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar. Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.) 2010 Massachusetts Medical Society

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Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets.

Melanie Planyavsky, Peter Valent, Ines Kaupe … (2007)

The BCR-ABL tyrosine kinase inhibitor imatinib represents the current frontline therapy in chronic myeloid leukemia. Because many patients develop imatinib resistance, 2 second-generation drugs, nilotinib and dasatinib, displaying increased potency against BCR-ABL were developed. To predict potential side effects and novel medical uses, we generated comprehensive drug-protein interaction profiles by chemical proteomics for all 3 drugs. Our studies yielded 4 major findings: (1) The interaction profiles of the 3 drugs displayed strong differences and only a small overlap covering the ABL kinases. (2) Dasatinib bound in excess of 30 Tyr and Ser/Thr kinases, including major regulators of the immune system, suggesting that dasatinib might have a particular impact on immune function. (3) Despite the high specificity of nilotinib, the receptor tyrosine kinase DDR1 was identified and validated as an additional major target. (4) The oxidoreductase NQO2 was bound and inhibited by imatinib and nilotinib at physiologically relevant drug concentrations, representing the first nonkinase target of these drugs.

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Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction.

Joanne Mountford, Robin W. Baird, Tracey Hamilton … (2006)

Dasatinib (BMS-354825), a novel dual SRC/BCR-ABL kinase inhibitor, exhibits greater potency than imatinib mesylate (IM) and inhibits the majority of kinase mutations in IM-resistant chronic myeloid leukemia (CML). We have previously demonstrated that IM reversibly blocks proliferation but does not induce apoptosis of primitive CML cells. Here, we have attempted to overcome this resistance with dasatinib. Primitive IM-resistant CML cells showed only single-copy BCR-ABL but expressed significantly higher BCR-ABL transcript levels and BCR-ABL protein compared with more mature CML cells (P = .031). In addition, CrKL phosphorylation was higher in the primitive CD34(+)CD38(-) than in the total CD34(+) population (P = .002). In total CD34(+) CML cells, IM inhibited phosphorylation of CrKL at 16 but not 72 hours, consistent with enrichment of an IM-resistant primitive population. CD34(+)CD38(-) CML cells proved resistant to IM-induced inhibition of CrKL phosphorylation and apoptosis, whereas dasatinib led to significant inhibition of CrKL phosphorylation. Kinase domain mutations were not detectable in either IM or dasatinib-resistant primitive CML cells. These data confirm that dasatinib is more effective than IM within the CML stem cell compartment; however, the most primitive quiescent CML cells appear to be inherently resistant to both drugs.

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Author and article information

Journal

Journal ID (nlm-ta): Drug Des Devel Ther

Journal ID (iso-abbrev): Drug Des Devel Ther

Journal ID (publisher-id): Drug Design, Development and Therapy

Title: Drug Design, Development and Therapy

Publisher: Dove Medical Press

ISSN (Electronic): 1177-8881

Publication date Collection: 2015

Publication date (Electronic): 09 February 2015

Volume: 9

Pages: 773-779

Affiliations

Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of China

Author notes

Correspondence: Baoan Chen, Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing, Jiangsu Province, People’s Republic of China, Tel +86 25 8327 2006, Fax +86 25 8327 2011, Email cba8888@ 123456hotmail.com

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Publisher ID: dddt-9-773

DOI: 10.2147/DDDT.S80207

PMC ID: 4330036

PubMed ID: 25709401

SO-VID: 5e592ca2-6263-46e7-85ee-f4f1303310d1

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The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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The role of dasatinib in the management of chronic myeloid leukemia

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Abstract

Most cited references 61

Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.

Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets.

Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction.

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