HPR61 Impact of an Imatinib Volume-Based Purchase Policy (VBP) on the Use of Tyrosine Kinase Inhibitors (TKI) for Chronic Myeloid Leukemia (CML) in Chinese Tertiary Care Hospitals: A Retrospective Analysis
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First-line treatment for chronic myelogenous leukemia (CML) is imatinib, but some patients do not respond or develop resistance to the drug, leading to suboptimal responses. Dasatinib and nilotinib are approved second-line compounds for patients experiencing imatinib failure. In a prospective comparison of dasatinib with high-dose imatinib in patients who did not respond to first-line imatinib, dasatinib was more effective and well tolerated. Nilotinib also is effective, but cross-intolerance does occur in a substantial number of patients. This article explores the importance of suboptimal response to imatinib and the appropriate second-line therapy as well as nursing implications for caring for patients with CML.
Chronic myelogenous leukemia
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Treatment with the tyrosine kinase inhibitor imatinib is the standard of care for newly diagnosed patients with chronic myeloid leukemia. In recent years, several second-generation inhibitors - such as dasatinib and nilotinib - have become available: these promise to overcome some of the mutations associated with acquired resistance to imatinib. Despite eliciting similar clinical responses, the molecular effects of these agents on different subpopulations of leukemic cells remain incompletely understood. Furthermore, the consequences of using high-dose imatinib therapy have not been investigated in detail. Here we utilized clinical data from patients treated with dasatinib, nilotinib, or high-dose imatinib, together with a statistical data analysis and mathematical modeling approach, to investigate the molecular treatment response of leukemic cells to these agents. We found that these drugs elicit very similar responses if administered front-line. However, patients display significantly different kinetics when treated second-line, both in terms of differences between front-line and second-line treatment for the same drug, and among agents when used as second-line. We then utilized a mathematical framework describing the behavior of four differentiation levels of leukemic cells during therapy to predict the treatment response kinetics for the different cohorts of patients. The dynamics of BCR-ABL1 clearance observed in our study suggest that the use of standard or high-dose imatinib or a second-generation tyrosine kinase inhibitor such as nilotinib or dasatinib elicits similar responses when administered as front-line therapy for patients with chronic myeloid leukemia in chronic phase.
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The Bcr-Abl kinase inhibitor imatinib is the standard treatment for chronic myeloid leukaemia (CML). Some subjects with CML do not respond to, or are intolerant of, imatinib. Nilotinib and dasatinib were initially developed to treat these subjects, and were shown to be effective. They are now being trialled as initial 'inib' treatment for CML. The objective was to evaluate the recent Phase III clinical trials comparing nilotinib or dasatinib with imatinib in newly diagnosed CML. Nilotinib and dasatinib were shown to give a higher rate of complete cytogenic and major molecular responses than imatinib over 1 year. They should be considered as first choice in the treatment of subjects who develop CML. However, there are still major limitations to the populations with which these 'inib' drugs can be used, and how they can be used.
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There have been few reports of a response to dasatinib or nilotinib after failure of two prior sequential tyrosine kinase inhibitors. We report the outcome of 82 chronic phase patients who received nilotinib or dasatinib as third-line alternative tyrosine kinase inhibitor therapy. Thirty-four patients failed to respond to nilotinib and were started on dasatinib as third-line tyrosine kinase inhibitor therapy while 48 patients were switched to nilotinib after dasatinib failure. Overall, we obtained a cytogenetic response in 32 of 82 patients and major molecular response in 13 patients; disease progression occurred in 12 patients. At last follow up, 70 patients (85.4%) were alive with a median overall survival of 46 months. Our results show that third-line tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients after failure of two prior sequential tyrosine kinase inhibitors may induce a response that, in some instances, could prolong overall survival and affect event-free survival.
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Imatinib was the first treatment for chronic myeloid leukemia (CML) that specifically targeted the causative BCR-ABL oncoprotein, and represented a major therapeutic advance in this disease; however, some patients develop resistance or intolerance. Resistance can be classified as BCR-ABL-dependent (e.g., mutation in the BCR-ABL gene) or BCR-ABL-independent (alternative pathways of disease progression, e.g., SRC-family tyrosine kinases). The investigation of therapeutic options post-imatinib failure resulted in the development and regulatory approval of dasatinib, a BCR-ABL and SRC-family kinase inhibitor. Dasatinib is active across all phases of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, and demonstrates activity in almost all imatinib-resistant mutations. Other therapeutic options are also under investigation, with nilotinib being the most clinically advanced. Nilotinib is an analog of imatinib with similar multiple kinase targets, but without inhibition of SRC, and reduced in vitro activity against BCR-ABL P-loop mutations compared with dasatinib. Similar to dasatinib, nilotinib has no activity against T315I mutations. The availability of dasatinib and development of other tyrosine kinase inhibitors provide positive prospects for patients with imatinib-resistant or -intolerant CML. Here, we discuss several of these new strategies for treating patients after imatinib failure.
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Chronic myeloid leukaemia
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Imatinib Mesylate
Chronic myelogenous leukemia
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All available data from ongoing studies of second-generation tyrosine kinase inhibitors (TKIs) for treatment of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) were reviewed. In two nilotinib phase 2 trials, the speed and depth of molecular and cytogenetic responses were greater than responses to imatinib. Furthermore, only one patient in each study progressed to accelerated or blastic phase. In the phase 3 ENESTnd study, molecular and cytogenetic responses to nilotinib were superior to imatinib, and more patients achieved undetectable levels of disease with nilotinib. Nilotinib also demonstrated significantly lower progression than did imatinib. In the ongoing phase 2 study of dasatinib, the speed and depth of molecular and cytogenetic responses were higher compared with expected responses to imatinib; no patient to date has progressed. In the phase 3 DASISION study, molecular and cytogenetic responses to dasatinib were superior to those of imatinib and fewer patients progressed. The results suggest that second-generation TKIs have the potential to replace imatinib as the standard of care for patients with early CML-CP. Future CML therapy might include earlier use of these agents to help more patients achieve complete molecular response and may be a path to a CML cure.
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Clinical effect of imatinib,nero imatinib and dasatinib on chronic myeloid leukemia in chronic phase
Objective To compare the clinical efficacy and safety of imatinib,nilotinib and dasatinib on chronic myelogenous leukemia( CML)in chronic phase patients and explore the best first-line treatment for chronic phase CML. Methods A total of 123 patients with chronic phase CML treated by tyrosine kinase inhibitors were divided into three groups: imatinib group A( n = 64); nilotinib group B( n = 31) and dasatinib group C( n = 28). Based on the clinical data and follow-up records,the CCyR、CHR and MMR at 18 months were analyzed in three groups. Results MMR,CHR and CCyR showed a rising trend in imatinib group after 3,6,12,18 months treatment. CCyR in group B and C had been significantly improved( P 0. 05); CHR in group B and C had significant improvement( P 0. 01) compared with group A. There was no difference in CHR between three groups at any time. The safety results showed that there was no difference in three groups during the follow-up period. Conclusion Nilotinib and dasatinib treatment can obtain faster complete cytogenetic remission and major molecular remission than imatinib,and the response to treatment is usually dramatic in these groups.
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Chronic myelogenous leukemia
Imatinib Mesylate
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