Tyrosine kinase inhibitors as a first‐line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed‐treatment comparison
Belal FirwanaMohamad Bassam SonbolMaria DiabShahzad RazaRim HasanIbrahim M. YousefAhmad ZarzourArchana GaripalliDonald C. DollM. Hassan MuradAref Al‐Kali
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Abstract:
Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP-CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP-CML and enrolling 2,456 patients were included. Follow-up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%(IS)) achievement with second-generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed-treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR(4.5) ≤ 0.0032%(IS)) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new-generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow-up period. It is important to note out that MTC is not a substitute for well-conducted RCTs investigating direct comparisons.Keywords:
Chronic myelogenous leukemia
Introduction: Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder distinctly characterized by the presence of the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. The resulting translocation leads to the development of the BCR-ABL1 oncogene, a constitutively active fusion protein, which leads to uncontrolled cell proliferation and reduced apoptosis and has a clear association with driving the malignant activity of CML cells.Areas covered: Given that the BCR-ABL1 oncogene is a known key cause of CML, it has led to the development of numerous small molecule tyrosine-kinase inhibitors (TKIs), which target the specific oncogene mutation in CML. Presently, there are three FDA-approved TKI agents, imatinib, dasatinib and nilotinib, for the treatment of frontline CML. Herein, we review the frontline options for the management of patients with CML and how to best choose these agents.Expert opinion: Imatinib, dasatinib and nilotinib are all effective at yielding hematological, molecular and cytogenetic responses in patients with newly diagnosed CML. Frontline therapy may depend on physician experience, patient age and ability to tolerate therapy, and with the lack of data comparing all three agents alongside each other, imatinib, dasatinib, or nilotinib may all be suitable frontline choices.
Chronic myelogenous leukemia
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Imatinib Mesylate
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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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Treatment with imatinib has demonstrated high response rates and improved prognosis in chronic myelogenous leukemia. However, while the short-term response to imatinib is high, there are some concerns that the long-term response is substantially lower. Durable response with imatinib is difficult to achieve in patients with resistant disease. The use of higher doses has also been associated with increased toxicity and intolerance. Dasatinib is a new SRC–ABL-kinase inhibitor that has been developed for treating chronic myelogenous leukemia patients, across all phases of disease, who are resistant or intolerant to imatinib. This article details the existing evidence on the clinical efficacy, safety and value for money of dasatinib in the treatment of imatinib-resistant and -intolerant patients with chronic myelogenous leukemia. Dasatinib is associated with higher levels of response compared with high-dose imatinib. In addition, higher levels of response are associated with improved health outcomes in terms of both quality- and quantity-of-life years.
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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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