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TKIs in CML

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https://www.readbyqxmd.com/read/29456888/an-observational-study-on-risk-of-secondary-cancers-in-chronic-myeloid-leukemia-patients-in-the-tki-era-in-the-united-states
#1
Vivek Kumar, Mohit Garg, Neha Chaudhary, Abhinav Binod Chandra
Introduction: The treatment with tyrosine kinase inhibitors (TKIs) has drastically improved the outcome of chronic myeloid leukemia (CML) patients. This study was conducted to examine the risk of secondary cancers (SCs) in the CML patients who were diagnosed and treated in the TKI era in the United States. Methods: The surveillance epidemiology and end results (SEER) database was used to identify CML patients who were diagnosed and received treatment during January 2002-December 2014...
2018: PeerJ
https://www.readbyqxmd.com/read/29455672/non-abl-directed-inhibitors-as-alternative-treatment-strategies-for-chronic-myeloid-leukemia
#2
REVIEW
Michele Massimino, Stefania Stella, Elena Tirrò, Chiara Romano, Maria Stella Pennisi, Adriana Puma, Livia Manzella, Antonino Zanghì, Fabio Stagno, Francesco Di Raimondo, Paolo Vigneri
The introduction of ABL Tyrosine Kinase Inhibitors (TKIs) has significantly improved the outcome of Chronic Myeloid Leukemia (CML) patients that, in large part, achieve satisfactory hematological, cytogenetic and molecular remissions. However, approximately 15-20% fail to obtain optimal responses according to the current European Leukemia Network recommendation because of drug intolerance or resistance.Moreover, a plethora of evidence suggests that Leukemic Stem Cells (LSCs) show BCR-ABL1-independent survival...
February 19, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29455643/chronic-myeloid-leukemia-the-paradigm-of-targeting-oncogenic-tyrosine-kinase-signaling-and-counteracting-resistance-for-successful-cancer-therapy
#3
REVIEW
Simona Soverini, Manuela Mancini, Luana Bavaro, Michele Cavo, Giovanni Martinelli
Deregulated activity of BCR-ABL1, a nonreceptor tyrosine kinase encoded by the fusion gene resulting from the t(9;22)(q34;q11) chromosomal translocation, is thought to be the driver event responsible for initiation and maintenance of chronic myeloid leukemia (CML). BCR-ABL1 was one of the first tyrosine kinases to be implicated in a human malignancy and the first to be successfully targeted. Imatinib mesylate, the first tyrosine kinase inhibitor (TKI) to be approved for therapeutic use, was hailed as a magic bullet against cancer and remains one of the safest and most effective anticancer agents ever developed...
February 19, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29454474/cardiovascular-pulmonary-and-metabolic-toxicities-complicating-tyrosine-kinase-inhibitor-therapy-in-chronic-myeloid-leukemia-strategies-for-monitoring-detecting-and-managing
#4
REVIEW
Bruno C Medeiros, Jennifer Possick, Michael Fradley
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, the incidence of which increases with age. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML treatment, including imatinib, nilotinib, dasatinib, bosutinib, and ponatinib. Beyond matching patient disease profiles with TKI specificity, differences in the efficacy and toxicity profiles and a patient's comorbid risk factors should be considered when selecting the most appropriate agent. Our objectives are to review the incidence and severity of cardiovascular, metabolic, and pulmonary disorders associated with these TKIs, highlighting differences in adverse event profiles, suggested risk-mitigation strategies, and guidance for TKI selection in different settings...
February 3, 2018: Blood Reviews
https://www.readbyqxmd.com/read/29448857/therapy-free-remission-in-chronic-myeloid-leukemia-possible-mechanism
#5
Robert Peter Gale, Andreas Hochhaus
Chronic myeloid leukemia (CML) can be cured using tyrosine kinase-inhibitors (TKIs) when cure is defined as achieving a life-expectancy similar or even better than sex- and age-matched persons without CML. Most deaths in persons with CML are now from non-leukemia-related causes including heart disease, diabetes other cancers and stroke. Contrary to expectation, 40-50 percent of persons with CML treated for a few years with TKIs and who achieve a deep molecular response can stop TKI-therapy without leukemia recurrence for several years, some possibly indefinitely...
February 15, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29442179/efficacy-and-safety-of-nilotinib-therapy-in-patients-with-newly-diagnosed-chronic-myeloid-leukemia-in-the-chronic-phase
#6
Michihide Tokuhira, Yuta Kimura, Keiji Sugimoto, Tomonori Nakazato, Maho Ishikawa, Isao Fujioka, Tomoiku Takaku, Noriyoshi Iriyama, Eriko Sato, Hiroyuki Fujita, Yoshihiro Hatta, Norio Komatsu, Norio Asou, Masahiro Kizaki, Tatsuya Kawaguchi
ABL1-tyrosine kinase inhibitors (TKIs) have led to dramatic changes in treatment strategies for chronic myeloid leukemia in the chronic phase (CML-CP). However, clinical studies have highlighted increasing numbers of adverse events (AE) with TKIs. Although TKI modification plays a key role in AE management, this process is poorly understood, particularly in terms of the TKI nilotinib. In the present study, we retrospectively analyzed the records of 70 patients with newly diagnosed (ND)-CML-CP who were treated with nilotinib to investigate the drug potency of nilotinib and treatment management...
February 13, 2018: Medical Oncology
https://www.readbyqxmd.com/read/29435021/long-lasting-memory-of-cellular-immunity-in-a-chronic-myeloid-leukemia-patient-maintains-molecular-response-5-after-cessation-of-dasatinib
#7
Tatsuro Jo, Kazuhiro Noguchi, Shizuka Hayashi, Sadaharu Irie, Risa Hayase, Haruna Shioya, Youhei Kaneko, Kensuke Horio, Jun Taguchi
Tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib and nilotinib are primarily used in the initial treatment of chronic phase (CP)-chronic myeloid leukemia (CML), as CMLs harbor the BCR-ABL fusion product. An increased number of lymphocytes and large granular lymphocytes (LGLs) have been observed in patients treated with dasatinib, but not other TKIs. The LGLs have been reported to be primarily natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). In the present study, a CP-CML patient who has maintained molecular response 5 for >2...
March 2018: Oncology Letters
https://www.readbyqxmd.com/read/29429960/adam8-is-an-antigen-of-tyrosine-kinase-inhibitor-resistant-chronic-myeloid-leukemia-cells-identified-by-patient-derived-induced-pluripotent-stem-cells
#8
Masashi Miyauchi, Junji Koya, Shunya Arai, Sho Yamazaki, Akira Honda, Keisuke Kataoka, Akihide Yoshimi, Kazuki Taoka, Keiki Kumano, Mineo Kurokawa
Properties of cancer stem cells involved in drug resistance and relapse have significant effects on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myeloid leukemia (CML), TKIs have not fully cured CML due to TKI-resistant CML stem cells. Moreover, relapse after discontinuation of TKIs has not been predicted in CML patients with the best TKI response. In our study, a model of CML stem cells derived from CML induced pluripotent stem cells identified ADAM8 as an antigen of TKI-resistant CML cells...
February 6, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29418079/concise-review-chronic-myeloid-leukemia-stem-cell-niche-and-response-to-pharmacologic-treatment
#9
REVIEW
Elena Arrigoni, Marzia Del Re, Sara Galimberti, Giuliana Restante, Eleonora Rofi, Stefania Crucitta, Claudia Baratè, Mario Petrini, Romano Danesi, Antonello Di Paolo
Nowadays, more than 90% of patients affected by chronic myeloid leukemia (CML) survive with a good quality of life, thanks to the clinical efficacy of tyrosine kinase inhibitors (TKIs). Nevertheless, point mutations of the ABL1 pocket occurring during treatment may reduce binding of TKIs, being responsible of about 20% of cases of resistance among CML patients. In addition, the presence of leukemic stem cells (LSCs) represents the most important event in leukemia progression related to TKI resistance. LSCs express stem cell markers, including active efflux pumps and genetic and epigenetic alterations together with deregulated cell signaling pathways involved in self-renewal, such as Wnt/β-catenin, Notch, and Hedgehog...
February 8, 2018: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/29415932/-management-of-cardiovascular-complications-in-cml-patients-treated-with-tyrosine-kinase-inhibitors
#10
Itaru Matsumura
Tyrosine kinase inhibitors (TKIs) have significantly improved the clinical outcomes of patients with chronic myeloid leukemia (CML). However, patients with CML need to receive TKI therapy for several years. Hence, the safety of long-term TKI treatment warrants utmost attention. Among various adverse events caused by TKI therapy, cardiovascular events (CVEs), such as acute myocardial infarction, cerebral infarction, and pulmonary hypertension, are the most serious with high mortality. TKIs inhibit various off-target molecules involved in the occurrence of CVEs such as c-Kit, platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and Tie-2/Tec...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29411417/chronic-myeloid-leukemia-2018-update-on-diagnosis-therapy-and-monitoring
#11
Elias Jabbour, Hagop Kantarjian
DISEASE OVERVIEW: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome...
March 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29400343/inhibition-of-siah2-ubiquitin-ligase-by-vitamin-k3-attenuates-chronic-myeloid-leukemia-chemo-resistance-in-hypoxic-microenvironment
#12
Jixian Huang, Ziyuan Lu, Yajuan Xiao, Bolin He, Chengyun Pan, Xuan Zhou, Na Xu, Xiaoli Liu
BACKGROUND A hypoxic microenvironment is associated with resistance to tyrosine kinase inhibitors (TKIs) and a poor prognosis in chronic myeloid leukemia (CML). The E3 ubiquitin ligase Siah2 plays a vital role in the regulation of hypoxia response, as well as in leukemogenesis. However, the role of Siah2 in CML resistance is unclear, and it is unknown whether vitaminK3 (a Siah2 inhibitor) can improve the chemo-sensitivity of CML cells in a hypoxic microenvironment. MATERIAL AND METHODS The expression of Siah2 was detected in CML patients (CML-CP and CML-BC), K562 cells, and K562-imatinib-resistant cells (K562-R cells)...
February 5, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29388307/chronic-myeloid-leukaemia-and-tyrosine-kinase-inhibitor-therapy-assessment-and-management-of-cardiovascular-risk-factors
#13
REVIEW
David M Ross, Chris Arthur, Kate Burbury, Brian S Ko, Anthony K Mills, Jake Shortt, Karam Kostner
Several BCR-ABL1 tyrosine kinase inhibitors (TKIs) are approved for the first-line treatment of chronic phase chronic myeloid leukaemia (CML). Disease control is achieved in the vast majority of patients and disease-specific survival is excellent. Consequently, there is now emphasis on managing comorbidities and minimising treatment-related toxicity. Second-generation TKIs have cardiovascular risks that are greater than with imatinib treatment, but these risks must be balanced against the superior CML responses encountered with more potent TKIs...
February 2018: Internal Medicine Journal
https://www.readbyqxmd.com/read/29385394/practical-management-of-toxicities-associated-with-bosutinib-in-patients-with-philadelphia-chromosome-positive-chronic-myeloid-leukemia
#14
H J Khoury, C Gambacorti-Passerini, T H Brümmendorf
Bosutinib (SKI-606) is an oral, dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) that is resistant or intolerant to prior TKI therapy or for whom other TKIs are not appropriate choices. The objective of this review is to provide a longitudinal summary of toxicities that may arise during treatment with second-line or later bosutinib in patients with Ph+ chronic phase CML and to provide strategies for managing these toxicities...
January 27, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29385210/abcc6-plays-a-significant-role-in-the-transport-of-nilotinib-and-dasatinib-and-contributes-to-tki-resistance-in-vitro-in-both-cell-lines-and-primary-patient-mononuclear-cells
#15
Laura N Eadie, Phuong Dang, Jarrad M Goyne, Timothy P Hughes, Deborah L White
ATP Binding Cassette family efflux proteins ABCB1 and ABCG2 have previously been demonstrated to interact with Tyrosine Kinase Inhibitors (TKIs); however, evidence for the interaction of other potentially relevant drug transporters with TKIs is lacking. Through Taqman transporter array technology we assessed the impact of nilotinib on mRNA expression of ABC transporters, with ABCC6 identified as a transporter of interest. Additionally, increased expression of ABCC6 mRNA was observed during in vitro development of nilotinib resistance in BCR-ABL1-expressing cell lines...
2018: PloS One
https://www.readbyqxmd.com/read/29383451/chronic-myeloid-leukemia-what-is-the-best-strategy-to-start-and-monitor-treatment-outside-academic-centers
#16
REVIEW
Carolina Pavlovsky, Maria Jose Mela Osorio
The introduction of tyrosine kinase inhibitors (TKI) has dramatically changed the outcome of chronic myeloid leukemia (CML). Over the last decade, imatinib positioned itself as the gold standard of care, until second-generation TKIs were introduced as first-line treatment. Multiple therapeutic options available today in CML make the decision of the first-line therapy a difficult choice. However, a gap still exists, in the management of CML outside academic centers. Important advances in molecular monitoring have been developed worldwide; nevertheless, monitoring in the "real world" continues to be a challenge in part because international scale (IS) standardized laboratories are not available worldwide, and also because physicians still have some resource barriers and lack of familiarity restricting guideline adoption and consider optimal molecular monitoring a challenge...
January 30, 2018: Current Oncology Reports
https://www.readbyqxmd.com/read/29380058/patients-and-hematologists-concerns-regarding-tyrosine-kinase-inhibitor-therapy-in-chronic-myeloid-leukemia
#17
Qian Jiang, Lu Yu, Robert Peter Gale
PURPOSE: To explore patients' and hematologists' concerns regarding tyrosine kinaseinhibitor (TKI)-therapy and identify variables associated these concerns. Methods A cross-sectional questionnaire including 16 common issues related to TKI-therapy was distributed to adults with chronic myeloid leukemia (CML) receiving TKIs and hematologists treating CML patients and answered anonymously. RESULTS: Data from 1518 patient respondents receiving TKI-therapy ≥ 3 months were analyzed...
January 29, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29358661/anthelmintic-niclosamide-suppresses-transcription-of-bcr-abl-fusion-oncogene-via-disabling-sp1-and-induces-apoptosis-in-imatinib-resistant-cml-cells-harboring-t315i-mutant
#18
Bei Jin, Chengyan Wang, Yingying Shen, Jingxuan Pan
Tyrosine kinase BCR-ABL fusion protein is the driver in patients with chronic myeloid leukemia (CML). The gate-keeper mutation T315I is the most challenging mutant due to its resistance to most tyrosine kinase inhibitors (TKIs). The third generation TKI ponatinib is the only effective TKI to treat CML patients harboring T315I-BCR-ABL mutation, but with high rate of major arterial thrombotic events. Alternative strategies to specifically target T315I-BCR-ABL are needed for the treatment of CML patients harboring such a mutation...
January 22, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29334667/lithium-a-classic-drug-in-psychiatry-improves-nilotinib-mediated-antileukemic-effects
#19
Janaína Peixoto-da-Silva, Andrana K Calgarotto, Katiucha R Rocha, Caroline Palmeira-Dos-Santos, Soraya S Smaili, Gustavo J S Pereira, Fernando V Pericole, Adriana da Silva S Duarte, Sara T O Saad, Claudia Bincoletto
Although Tyrosine kinase inhibitors (TKIs) that target Bcr-Abl play a key role in Chronic Myeloid Leukemia (CML) therapy, they do not eradicate CML-initiating cells, which lead to the emergence of drug resistance. Here we used the lithium, a GSK-3 inhibitor, to attempt to potentiate the effects of nilotinib against leukemia cells. For this purpose, a K562 leukemia cell line and bone marrow cells from untreated Chronic Myeloid Leukemia (CML) patients, prior to any exposure to TKIs, were used as a model. Our results demonstrated that the combination of lithium + nilotinib (L + N) induced K562-cell death and cleaved caspase-3 when compared to lithium or nilotinib alone, accompanied by GSK-3β phosphorylation and Bcr-Abl oncoprotein levels reduction...
January 12, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29334406/dasatinib-induced-pulmonary-arterial-hypertension
#20
REVIEW
Nurgül Özgür Yurttaş, Ahmet Emre Eşkazan
Drug-induced (Group 1) pulmonary hypertension (PH) is an important subgroup of PH involving dasatinib as a likely related agent, which is a second-generation tyrosine kinase inhibitor (TKI), that is used in the treatment of chronic myeloid leukemia (CML). The mechanism of dasatinib-induced pulmonary arterial hypertension (PAH) is unclear. However, the occurence of PAH at a late onset in CML patients suggests a chronic pathological mechanism with an insidious onset rather than an acute inflammatory or cardiac etiology...
January 15, 2018: British Journal of Clinical Pharmacology
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