Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dasatinib, an oral inhibitor of multiple tyrosine kinases, including BCR-ABL, Src, and platelet-derived growth factor receptor, was approved for patients with imatinib-resistant or -intolerant chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Dasatinib demonstrated efficacy with a well-tolerated safety profile in all phases of CML and Ph+ ALL, which led to its 2006 approval by the U.S. Food and Drug Administration for clinical use. However, although most adverse events are grade 1 or 2, a number of adverse events require management and monitoring to ensure that patients can continue receiving the treatment. This review discusses the appropriate nursing management of key adverse events (cytopenias, fluid retention, bleeding, gastrointestinal toxicity, and cardiotoxicity) to ensure that patients gain maximum benefit from this multitargeted agent.
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PMID:Practical management of dasatinib for maximum patient benefit. 1950 92

Deregulated BCR-ABL tyrosine kinase (TK) activity is the molecular marker for chronic myeloid leukemia (CML), which provides an identifiable target for developing therapeutic agents. Imatinib mesylate, a BCR-ABL TK inhibitor, is the frontline therapy for CML. Despite the stunning efficacy of this agent, a small number of patients develop a suboptimal response or resistance to imatinib. In newly diagnosed patients with chronic phase CML, the rate of resistance to imatinib at 4 years was up to 20%, increasing to 70% to 90% for patients in the accelerated/blastic phase. Resistance to imatinib led to the development of novel TK inhibitors such as dasatinib. Several clinical trials have reported more durable complete hematologic and cytogenetic responses with this agent in patients who are resistant or intolerant to imatinib. Dasatinib is well tolerated and has broad efficacy, resulting in durable responses in patients with any BCR-ABL mutation except for T3151 and mutations in codon 317 - most commonly F317L - including mutations that were highly resistant to imatinib, such as L248, Y253, E255, F359, and H396. Dasatinib is recommended for CML in chronic, blastic or accelerated phase that is resistant or intolerant to imatinib. Dasatinib was approved by the FDA at 100 mg once daily as the starting dose in patients with chronic phase CML and at 70 mg twice daily in patients with accelerated or blastic phase CML. Various clinical trial results provided evidence that resistance to one TK inhibitor can be reversed with the use of a different TK inhibitor (TKI). Other second-generation TKIs with activity in CML include nilotinib, bosutinib and INNO 406. New molecules, such as the inhibitor of Aurora family serine-threonine kinases, MK0457, which has antileukemic activity in CML associated with a T315I mutation, are being investigated. Allogeneic hematopoietic stem cell transplantation remains an option for selected patients.
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PMID:Dasatinib in chronic myeloid leukemia: a review. 1953 17

Dasatinib is a highly potent BCR-ABL inhibitor that has shown durable efficacy in patients with chronic phase (CP) chronic myeloid leukemia (CML) after resistance, suboptimal response, or intolerance to prior imatinib. In patients with CML, BCR-ABL transcript measurement is the most sensitive method for assessing minimal residual disease. Here, molecular responses were analyzed in 1067 patients with CML-CP treated with dasatinib during phase II/III trials. After 3, 6, 12, and 24 months of follow-up, a major molecular response (MMR) was achieved by 12, 22, 35, and 40% of patients, respectively. The 24-month MMR rate was 34% in patients with resistance or suboptimal response to imatinib (n=829) and 63% in imatinib-intolerant patients (n=238). Among patients who had achieved a complete cytogenetic response (CCyR), 72% also achieved MMR. Responses with dasatinib 100 mg once daily were similar to other doses. In landmark analyses, 24-month progression-free survival was higher in patients who had achieved MMR or CCyR at 12 months than in those without MMR or CCyR at 12 months. MMR at 12 months was associated with a longer duration of CCyR. Overall, this analysis shows that dasatinib treatment results in high MMR rates in patients with CML-CP after imatinib failure.
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PMID:Dasatinib-associated major molecular responses in patients with chronic myeloid leukemia in chronic phase following imatinib failure: response dynamics and predictive value. 1964 27

Protein kinases catalyze the transfer of the gamma-phosphoryl group of adenosine triphosphate (ATP) to the hydroxyl groups of protein side chains, and they play critical roles in regulating cellular signal transduction and other biochemical processes. They are attractive targets for today's drug discovery and development, and many pharmaceutical companies are intensively developing various kinds of protein kinase inhibitors. A good example is the recent success with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (Gleevec) in the treatment of chronic myeloid leukemia. Though imatinib has dramatically improved the treatment of Bcr-Abl-positive chronic myeloid leukemia, resistance is often found in patients with advanced-stage disease. Several mechanisms have been proposed to explain this resistance, including point mutations within the Abl kinase domain, amplification of the bcr-abl gene, overexpression of the corresponding mRNA, increased drug efflux mediated by P-glycoprotein, and activation of the Src-family kinase (SFK) Lyn. We set out to develop a novel drug whose affinity for Abl is higher than that of imatinib and whose specificity in inhibiting Lyn is higher than that of SFK/Abl inhibitors such as dasatinib (Sprycel) or bosutinib (SKI-606). Our work has led to the development of NS-187 (INNO-406), a novel Abl/Lyn dual tyrosine kinase inhibitor with clinical prospects. To provide an overview of how a selective kinase inhibitor has been developed, this review presents chemical-modification studies carried out with the guidance of molecular modeling, the structural basis for the high potency and selectivity of NS-187 based on the X-ray structure of the NS-187/Abl complex, and the biological profiling of NS-187, including site-directed mutagenesis experiments.
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PMID:NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. 1966 83

Dasatinib, a dual Src/Abl tyrosine kinase inhibitor, has significant antileukemic effects against various imatinib mesylate-resistant BCR/ABL mutants. Despite well-documented inhibitory effects of dasatinib on BCR/ABL kinase, the exact downstream cellular events leading to generation of its potent antileukemic effects remain to be defined. We provide evidence that p38 Map kinase (MAPK) pathway is activated leading to increased upregulation of mixed lineage kinase 3, MKK3/6, MSK1, and Mapkapk2, upon treatment of BCR/ABL expressing cells with dasatinib, including cells expressing various imatinib-resistant mutants, except for T315I. Our data demonstrate that such dasatinib-dependent activation of p38 MAPK and its effectors plays a critical role in the generation of antileukemic responses, since pharmacological inhibition of p38 or siRNA-mediated knockdown of its expression reverse dasatinib-mediated apoptosis, cell cycle arrest, and anti-proliferative effects. p38 MAPK inhibition also reversed dasatinib-induced suppression of CML patient-derived leukemic colony-forming units progenitor growth in vitro, as well as BCR/ABL expressing KT-1 cell-derived leukemic progenitor growth. Altogether, our findings suggest a critical role for p38 MAPK pathway in the generation of antileukemic effects of dasatinib, and raise the possibility that development of novel means to enhance p38 MAPK activation in BCR/ABL expressing cells may be an approach to promote antileukemic responses and, possibly, reverse T315I mutation-mediated resistance.
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PMID:Activation of the p38 Map kinase pathway is essential for the antileukemic effects of dasatinib. 2000 Dec 44

The development of imatinib for the treatment of chronic myeloid leukemia (CML) has proven to be an example of medical success in the era of targeted therapy. However, imatinib resistance or intolerance occurs in a substantial number of patients. Additionally, patients who have progressed beyond the chronic phase of CML do relatively poorly with imatinib therapy. Mechanisms of imatinib resistance include BCR-ABL point mutations resulting in decreased imatinib binding, as well as mutation-independent causes of resistance such as SRC family kinase dysregulation, BCR-ABL gene amplification, drug influx/efflux mechanisms and other poorly understood processes. The options for therapy in these patients include stem cell transplantation, imatinib dose escalation as well as the use of second-generation tyrosine kinase inhibitors. Dasatinib is a second-generation multi-kinase inhibitor with several theoretical and mechanistic advantages over imatinib. Moreover, several studies have evaluated dasatinib in patients who have progressed on imatinib therapy with encouraging results. Other novel agents such as mTOR inhibitors, bosutinib and INNO 406 have also shown promise in this setting. Although treatment options have increased, the choice of second-line therapy in patients with CML is influenced by concerns surrounding the duration of response as well as toxicity. Consequently, there is no agreed upon optimal second-line agent. This paper reviews the current data and attempts to address these issues.
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PMID:Dasatinib in the treatment of imatinib refractory chronic myeloid leukemia. 1970 9

Dasatinib is a BCR-ABL inhibitor with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Imatinib failure is commonly caused by BCR-ABL mutations. Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR-ABL mutations after prior imatinib. Among 1043 patients, 39% had a preexisting BCR-ABL mutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-threedifferent BCR-ABL mutations affecting 49 amino acids were detected at baseline, with G250, M351, M244, and F359 most frequently affected. After 2 years of follow-up, dasatinib treatment of imatinib-resistant patients with or without a mutation resulted in notable response rates (complete cytogenetic response: 43% vs 47%) and durable progression-free survival (70% vs 80%). High response rates were achieved with different mutations except T315I, including highly imatinib-resistant mutations in the P-loop region. Impaired responses were observed with some mutations with a dasatinib median inhibitory concentration (IC(50)) greater than 3nM; among patients with mutations with lower or unknown IC(50), efficacy was comparable with those with no mutation. Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844.
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PMID:Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. 1996 2

The introduction of the BCR-ABL inhibitor imatinib revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, resistance to imatinib has become a clinically significant issue, limiting its long-term efficacy. Numerous mechanisms have been associated with imatinib resistance, including mutations to the BCR-ABL gene, increased production of BCR-ABL, and activation of BCR-ABL-independent pathways (e.g., SRC-family kinases [SFKs]). Resistance to imatinib has driven the development of second-line therapies, such as dasatinib, a dual BCR-ABL/SFK inhibitor more potent than imatinib at targeting BCR-ABL. Dasatinib is approved for the treatment of patients with imatinib-resistant and -intolerant CML and Philadelphia chromosome-positive acute lymphoblastic leukemia. Nilotinib, an analog of imatinib, more potent than its parent compound, is another approved agent for patients with imatinib-resistant or -intolerant CML in the chronic or accelerated phase. Nurses must be aware of what constitutes a requirement for treatment change and the mechanisms of resistance that inform the choice of second-line agents. Oncology nurses also must ensure that patients have been educated appropriately to understand imatinib resistance and second-line treatment options. This article explores the mechanisms and identification of resistance and treatment options for when resistance occurs, as well as nursing implications.
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PMID:Treatment of chronic myeloid leukemia following imatinib resistance: a nursing guide to second-line treatment options. 1979 9

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.
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PMID:Suboptimal responses to imatinib in chronic myelogenous leukemia: what are they and how do they affect treatment? 1979 10

Chronic myeloid leukemia (CML) is characterized by a Philadelphia chromosome which contains an oncogene, bcr-abl. This oncogene encodes a tyrosine kinase which is constitutively activated. Imatinib, a tyrosine kinase inhibitor (TKI), has been widely used in the treatment of CML. Dasatinib and nilotinib were recently approved for the treatment of CML. Other TKIs, such as bosutinib, erlotinib, and sunitinib, are under study for the treatment of CML as well as other hematologic and solid malignancies. Skin rash has been reported as one of the most common side effects of the TKIs. Here we present a case of severe skin rash together with unusual symptoms of high fever and diarrhea induced by imatinib in a CML patient. The dermatologic toxicities from a variety of tyrosine kinase inhibitors are reviewed and general principles of management are also discussed.
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PMID:Severe toxicity of skin rash, fever and diarrhea associated with imatinib: case report and review of skin toxicities associated with tyrosine kinase inhibitors. 1992 Sep 8


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