Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy
Masayuki ShisekiChikashi YoshidaNaoki TakezakoAkira OhwadaTakashi KumagaiKaichi NishiwakiAkira HorikoshiTetsuya FukudaHina TakanoYasuji KouzaiJunji TanakaSatoshi MoritaJunichi SakamotoHisashi SakamakiKoiti Inokuchi
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Abstract:
With the introduction of imatinib, a first-generation tyrosine kinase inhibitor (TKI) to inhibit BCR-ABL1 kinase, the outcome of chronic-phase chronic myeloid leukemia (CP-CML) has improved dramatically. However, only a small proportion of CP-CML patients subsequently achieve a deep molecular response (DMR) with imatinib. Dasatinib, a second-generation TKI, is more potent than imatinib in the inhibition of BCR-ABL1 tyrosine kinase in vitro and more effective in CP-CML patients who do not achieve an optimal response with imatinib treatment.In the present study, we attempted to investigate whether switching the treatment from imatinib to dasatinib can induce DMR in 16 CP-CML patients treated with imatinib for at least two years who achieved a major molecular response (MMR) with detectable levels of BCR-ABL1 transcripts.The rates of achievement of DMR at 1, 3, 6 and 12 months after switching to dasatinib treatment in the 16 patients were 44% (7/16), 56% (9/16), 63% (10/16) and 75% (12/16), respectively. The cumulative rate of achieving DMR at 12 months from initiation of dasatinib therapy was 93.8% (15/16). The proportion of natural killer cells and cytotoxic T cells in peripheral lymphocytes increased after switching to dasatinib. In contrast, the proportion of regulatory T cells decreased during treatment. The safety profile of dasatinib was consistent with previous studies.Switching to dasatinib would be a therapeutic option for CP-CML patients who achieved MMR but not DMR by imatinib, especially for patients who wish to discontinue TKI therapy.Keywords:
Imatinib Mesylate
Dasatinib is a second-generation tyrosine kinase inhibitor that is approved for the treatment of imatinib-resistant or imatinib-intolerant chronic myeloid leukemia. It has a 325 times stronger in vitro activity against to native BCR-ABL when comparing with imatinib. Little is known about the effects of dasatinib on renal function. A literature review revealed only one case with imatinib-resistant chronic myeloid leukemia that developed renal failure after being placed on dasatinib therapy. Here we report a patient with imatinib-resistant chronic myeloid leukemia who developed gastroenteritis and acute renal failure after a short time from the initiation of dasatinib therapy. After dasatinib interruption, these side effects resolved completely in days. In summary, dasatinib is a potent drug in the treatment of chronic myeloid leukemia, but close clinical monitoring and the timely interruption of the therapy in patients who developed acute renal failure are warranted.
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For patients with chronic myeloid leukemia (CML) failing imatinib therapy, second-generation tyrosine kinase inhibitors (TKIs) are recommended. Here, we describe two patients with advanced CML who failed imatinib therapy and did not tolerate the recommended dose of dasatinib, but then achieved a major molecular response with the combination of imatinib and dasatinib with no significant extramedullary toxicity. Our observations suggest that combination of TKIs may provide an additive/synergistic antileukemic effect.
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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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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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Dasatinib is a multitargeted tyrosine kinase inhibitor (TKI), recommended for chronic myeloid leukemia (CML) in chronic, accelerated and blastic phases that are resistant or intolerant to imatinib. The recognition of BCR-ABL gene and corresponding protein with deregulated tyrosine kinase (TK) activity as crucial for malignant transformation in CML, led to synthesis of the small-molecule drugs designed to interfere with Bcr-Abl TK activation. The first TKI introduced into clinical practice in 1998, was imatinib mesylate, which became the first choice drug in chronic phase CML. However, approximately 20%-25% of patients initially successfully treated with imatinib, develop resistance to this drug, mainly because of selection of clones expressing mutant forms of BCR-ABL with impairing imatinib binding. Dasatinib is 325-fold more potent than imatinib against cell expressing wild-type BCR-ABL and showing activity against most imatinib-resistant Bcr-Abl mutants. Several clinical trials demonstrated that dasatinib is effective and generally well tolerated in imatinib resistant or intolerant CML and represents a promising therapeutic option for these patients.
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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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Imatinib Mesylate
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BCR-ABL, a constitutively active tyrosine kinase, causes chronic myeloid leukaemia (CML). Rational development of drugs targeting BCR-ABL has significantly improved the treatment of CML. Imatinib (a BCR-ABL tyrosine kinase inhibitor) produces haematological and cytogenetic remissions across all phases of CML and is the present standard of care. Imatinib resistance occurs in a significant proportion of patients and mechanisms of resistance include BCR-ABL mutations and activation of alternate oncogenic pathways. Dasatinib is a novel, potent, multi-targeted oral kinase inhibitor. Preclinical and clinical investigations demonstrate that dasatinib effectively overcomes imatinib resistance and has further improved the treatment of CML. Dasatinib was recently approved by the FDA for use in Philadelphia-positive leukaemias in patients who are resistant or intolerant to imatinib.
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