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TKIs in CML

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https://www.readbyqxmd.com/read/29665902/-mean-corpuscular-volume-can-be-a-predictor-for-therapeutic-response-of-patients-with-chronic-myeloid-leukemia
#1
Luo Lu, Chun Qiao, Ming Hong, Yan-Ru Li, Liang-Qin Pan, Si-Xuan Qian, Yu Zhu, Jian-Yong Li
OBJECTIVE: The past studies found that the treatment of chronic myeloid leukemia (CML) with imatinib can induce the macrocytic anemia, moreover the incidence of anemia increases along with enhancement of imatinib concentration. This study was aimed to evaluate the potential relation of erythrocyte mean corpuscular volume (MCV) increase after the treatment with tyrosine kinase inhibitors (TKI) with the therapeutic response in patients with CML-chronic phase (CML-CP). METHODS: The clinical and hematologic data including MCV, molecular and cytogenetic response of 119 patients with CML-CP were collected after treatment with TKIs, and the relation of MCV changes after treatment with the clinical characteristics and therapeutic efficacy for patients with CML-CP was analyzed...
April 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29663362/cd69-partially-inhibits-apoptosis-and-erythroid-differentiation-via-cd24-and-their-knockdown-increase-imatinib-sensitivity-in-bcr-abl-positive-cells
#2
Shih-Yun Huang, Yu-Hsiu Liu, Yi-Ju Chen, Yi-Yen Yeh, Huei-Mei Huang
Chronic myeloid leukemia (CML) is caused by a constitutively active BCR-ABL tyrosine kinase. Tyrosine kinase inhibitors (TKIs) imatinib and its derivatives represent a breakthrough for CML therapy, but the use of TKI alone is ineffective for many CML patients. CD69, an early activation marker of lymphocytes, participates in immune and inflammatory responses. Previous studies revealed that BCR-ABL upregulates CD69 expression; however, the role of CD69 in CML cells is unknown. Here, we demonstrate that BCR-ABL induced CD69 promoter activity and mRNA and protein expression via the NF-κB pathway...
April 16, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29660177/severe-adverse-events-by-tyrosine-kinase-inhibitors-decrease-survival-rates-in-patients-with-newly-diagnosed-chronic-phase-chronic-myeloid-leukemia
#3
Shuichi Ota, Toshihiro Matsukawa, Satoshi Yamamoto, Ito Shinichi, Motohiro Shindo, Kazuya Sato, Takeshi Kondo, Kyuhei Kohda, Hajime Sakai, Akio Mori, Tohru Takahashi, Hiroshi Ikeda, Hiroyuki Kuroda, Yoshihito Haseyama, Masaki Yamamoto, Takeo Sarashina, Makoto Yoshida, Ryoji Kobayashi, Mitsufumi Nishio, Toshimichi Ishihara, Yasuo Hirayama, Yasutaka Kakinoki, Hajime Kobayashi, Takashi Fukuhara, Masahiro Imamura, Mitsutoshi Kurosawa
OBJECTIVE: This multicenter cooperative study aimed to analyze the adverse events (AEs) associated with tyrosine kinase inhibitors (TKIs) used as initial treatment for chronic-phase chronic myeloid leukemia (CML-CP) and their impact on outcome. METHODS: We retrospectively evaluated 450 patients with CML-CP who received TKIs between 2004 and 2014. RESULTS: The 5-year overall survival (OS) and event-free survival (EFS) rates were 95.1% and 89...
April 16, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29651584/anxiety-and-depression-associated-with-tyrosine-kinase-inhibitor-discontinuation-in-patients-with-chronic-myeloid-leukemia
#4
Rintaro Sogawa, Sakiko Kimura, Ryota Yakabe, Yasuhito Mizokami, Masanobu Tasaki, Naoko Sueoka-Aragane, Yutaka Narisawa, Shinya Kimura
BACKGROUND: ABL tyrosine kinase inhibitors (TKIs) significantly changed the prognosis of patients with chronic myeloid leukemia (CML), and clinical trials demonstrated that TKIs can be discontinued in approximately 50% of patients after a period of deep molecular response (DMR). However, in some patients, TKI discontinuation leads to anxiety and depression. Here, we analysed the incidence of anxiety and depression in patients who stop TKI therapy. METHODS: Anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale (HADS) in 32 patients with CML...
April 12, 2018: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29622860/laboratory-monitoring-of-chronic-myeloid-leukemia-in-patients-on-tyrosine-kinase-inhibitors
#5
REVIEW
Richa Chauhan, Sudha Sazawal, H P Pati
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by translocation of genetic material from chromosome 9 to chromosome 22 to form a fusion gene (BCR-ABL1) that is responsible for abnormal tyrosine kinase activity and alteration of various downstream signaling pathways. In addition to morphological diagnosis of CML phase, it is essential to detect BCR-ABL1 fusion by either metaphase cytogenetics or reverse transcriptase polymerase chain reaction that also determines type of mRNA transcript...
April 2018: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/29620253/cotylenin-a-and-tyrosine-kinase-inhibitors-synergistically-inhibit-the-growth-of-chronic-myeloid-leukemia-cells
#6
Fumiyoshi Ikejiri, Yoshio Honma, Takahiro Okada, Takeshi Urano, Junji Suzumiya
The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has substantially extended patient survival. However, TKIs do not effectively eliminate CML stem cells. In fact, CML stem cells persist and cause relapse in the majority of patients upon discontinuation of the drug treatment. Transcriptomic and proteomic analyses have revealed that p53 and c-Myc play defining roles in CML stem cell survival, suggesting that the dual targeting of p53 and c-Myc may selectively eliminate stem cells in patients with CML...
April 2, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29593936/oral-effects-and-early-implant-survival-results-after-imatinib-discontinuation-therapy-for-chronic-myelogenous-leukemia-a-case-report
#7
Douglas R Dixon, Alaa Yassin
Introduction: Little is known regarding the success, failure, or complication rates of advanced implant procedures in patients after discontinuation therapy of long-term medications for the treatment of chronic myelogenous leukemia (CML). This case report presents initial results of a case involving implant placement in the mandible and maxilla as well as reduction of palatal oral pigmentation in a patient discontinuing long-term tyrosine kinase inhibitor (TKI) therapy for CML. Case Presentation: A 57-year-old male was referred to the Department of Periodontics, University of Washington, Seattle, Washington, for an assessment of edentulous areas (tooth sites #3 and #14) and failing tooth #19...
August 2017: Clinical Advances in Periodontics
https://www.readbyqxmd.com/read/29581839/excellent-outcomes-of-2g-tki-therapy-after-imatinib-failure-in-chronic-phase-cml-patients
#8
Mario Tiribelli, Massimiliano Bonifacio, Gianni Binotto, Alessandra Iurlo, Francesca Cibien, Elena Maino, Anna Guella, Gianluca Festini, Claudia Minotto, Ercole De Biasi, Federico De Marchi, Luigi Scaffidi, Luca Frison, Cristina Bucelli, Marta Medeot, Elisabetta Calistri, Rosaria Sancetta, Manuela Stulle, Nicola Orofino, Mauro Krampera, Filippo Gherlinzoni, Gianpietro Semenzato, Giovanni Pizzolo, Achille Ambrosetti, Renato Fanin
Second-generation tyrosine kinase inhibitors (2G-TKIs) dasatinib and nilotinib produced historical rates of about 50% complete cytogenetic response (CCyR) and about 40% major molecular response (MMR) in chronic myeloid leukaemia (CML) patients failing imatinib. Direct comparisons between dasatinib and nilotinib are lacking, and few studies addressed the dynamics of deep molecular response (DMR) in a "real-life" setting. We retrospectively analyzed 163 patients receiving dasatinib ( n = 95) or nilotinib ( n = 68) as second-line therapy after imatinib...
March 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29562466/-the-molecular-cytogenetic-characterization-and-tyrosine-kinase-inhibitors-efficacy-in-newly-diagnosed-chronic-phase-cml-patients-with-variant-philadelphia-chromosomes
#9
J J Zhao, Y L Zhang, S J Zhang, J Zhou, F K Yu, Y L Zu, H F Zhao, Z Li, Y P Song
Objective: To investigate the molecular-cytogenetic characterization and impact on tyrosine kinase inhibitors (TKIs) therapy in chronic phase of chronic myeloid leukemia (CML-CP) patients with variant Ph chromosome (vPh). Methods: The clinical data of 32 patients with vPh chromosomes were collected and compared with 703 patients with typical Ph chromosome in newly diagnosed CML-CP who were on first-line imatinib (IM) and with BCR-ABL transcript of P210. Results: There was no significant difference in demographic and hematological characteristics between vPh and classic Ph patients...
March 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29531660/safety-and-efficacy-of-nilotinib-in-routine-clinical-practice-in-patients-with-chronic-myeloid-leukemia-in-chronic-or-accelerated-phase-with-resistance-or-intolerance-to-imatinib-results-from-the-novel-study
#10
Ching-Yuan Kuo, Po-Nan Wang, Wen-Li Hwang, Cheng-Hwai Tzeng, Li-Yaun Bai, Jih-Luh Tang, Ming-Chih Chang, Sheng-Fung Lin, Tsai-Yun Chen, Yeu-Chin Chen, Tran-Der Tan, Chih-Yi Hsieh, Chinjune Lin, Clinton Lai, Darko Miljkovic, Cheng-Shyong Chang
Background: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), is approved for the treatment of patients with chronic myeloid leukemia (CML) in many countries, including Taiwan. Though a number of controlled clinical trials have demonstrated the safety and efficacy of nilotinib, studies assessing the safety and efficacy of nilotinib in routine clinical practice are limited. Methods: The current study was an open-label, single-arm study conducted across 12 centers in Taiwan in adult patients with CML in chronic or accelerated phase with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to one or more previous TKIs...
March 2018: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/29522367/novel-tyrosine-kinase-inhibitors-for-the-treatment-of-chronic-myeloid-leukemia-safety-and-efficacy
#11
Fulvio Massaro, Gioia Colafigli, Matteo Molica, Massimo Breccia
Chronic myeloid leukemia (CML) is characterized by a pathognomonic chromosomal translocation, which leads to the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus 1 (ABL1) genes, generating an oncoprotein with deregulated tyrosine kinase activity. Areas covered: In the last two decades, BCR/ABL1 kinase has become the molecular target for tyrosine kinase inhibitors (TKIs), a class of drugs that impressively improved overall survival. Despite these results, a proportion of patients experiences resistance to TKIs and need to change treatment...
April 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29521048/imatinib-in-the-treatment-of-chronic-myeloid-leukemia-in-children-and-adolescents-is-effective-and-well-tolerated-report-of-the-polish-pediatric-study-group-for-the-treatment-of-leukemias-and-lymphomas
#12
Małgorzata Janeczko-Czarnecka, Maryna Krawczuk-Rybak, Irena Karpińska-Derda, Maciej Niedźwiecki, Katarzyna Musioł, Magdalena Ćwiklińska, Katarzyna Drabko, Katarzyna Mycko, Tomasz Ociepa, Katarzyna Pawelec, Danuta Januszkiewicz-Lewandowska, Marek Ussowicz, Blanka Rybka, Renata Ryczan-Krawczyk, Andrzej Kołtan, Grażyna Karolczyk, Agnieszka Zaucha-Prażmo, Wanda Badowska, Krzysztof Kałwak
BACKGROUND: Chronic myeloid leukemia (CML) constitutes only 2-3% of all leukemias in pediatric patients. Philapelphia chromosome and BCR-ABL fusion are genetic hallmarks of CML, and their presence is crucial for targeted molecular therapy with tyrosine kinase inhibitors (TKIs), which replaced hematopoietic stem cell transplantation (HSCT) as a standard first-line therapy. The disease in pediatric population is rare, and despite molecular and clinical similarities to CML in adults, different approach is needed, due to the long lifetime expectancy and distinct developmental characteristics of affected children...
January 2018: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
https://www.readbyqxmd.com/read/29511948/current-information-and-recommendations-on-the-discontinuation-of-tki-inhibitors-in-chronic-myeloid-leukemia
#13
REVIEW
Massimo Breccia, Robin Foà
PURPOSE OF REVIEW: Discontinuation of tyrosine kinase inhibitors (TKIs) in chronic phase chronic myeloid leukemia (CP-CML) patients has become a reality. Treatment-free remission (TFR) is the term that identifies success after discontinuation. RECENT FINDINGS: Several trials have demonstrated that with imatinib about 40% of patients discontinuing treatment in deep and stable molecular response remain disease-free. Second-generation TKIs have improved the rate of deep molecular responses and allowed to increase the percentage of patients attempting treatment discontinuation...
March 6, 2018: Current Oncology Reports
https://www.readbyqxmd.com/read/29511345/targeting-pfkfb3-sensitizes-chronic-myelogenous-leukemia-cells-to-tyrosine-kinase-inhibitor
#14
Yu Zhu, Luo Lu, Chun Qiao, Yi Shan, Huapeng Li, Sixuan Qian, Ming Hong, Huihui Zhao, Jianyong Li, Zhongfa Yang, Yaoyu Chen
Resistance to the BCR-ABL tyrosine kinase inhibitor (TKI) remains a challenge for curing the disease in chronic myeloid leukemia (CML) patients as leukemia cells may survive through BCR-ABL kinase activity-independent signal pathways. To gain insight into BCR-ABL kinase activity-independent mechanisms, we performed an initial bioinformatics screen and followed by a quantitative PCR screen of genes that were elevated in CML samples. A total of 33 candidate genes were identified to be highly expressed in TKIs resistant patients...
March 7, 2018: Oncogene
https://www.readbyqxmd.com/read/29510895/effect-of-abcg2-oct1-and-abcb1-mdr1-gene-expression-on-treatment-free-remission-in-a-euro-ski-subtrial
#15
Sébastien Rinaldetti, Markus Pfirrmann, Kirsi Manz, Joelle Guilhot, Christian Dietz, Panayiotidis Panagiotidis, Birgit Spiess, Wolfgang Seifarth, Alice Fabarius, Martin Müller, Maria Pagoni, Maria Dimou, Jolanta Dengler, Cornelius F Waller, Tim H Brümmendorf, Regina Herbst, Andreas Burchert, Carsten Janβen, Maria Elisabeth Goebeler, Philipp J Jost, Stefan Hanzel, Philippe Schafhausen, Gabriele Prange-Krex, Thomas Illmer, Viktor Janzen, Martine Klausmann, Robert Eckert, Gerd Büschel, Alexander Kiani, Wolf-Karsten Hofmann, François-Xavier Mahon, Susanne Saussele
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial...
February 8, 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29507701/ptprg-and-ptprc-modulate-nilotinib-response-in-chronic-myeloid-leukemia-cells
#16
Julia Drube, Thomas Ernst, Markus Pfirrmann, Benadict Vincent Albert, Sebastian Drube, Daniela Reich, Anne Kresinsky, Kathrin Halfter, Claudio Sorio, Christian Fabisch, Andreas Hochhaus, Frank-D Böhmer
The introduction of second-generation tyrosine kinase inhibitors (TKIs) targeting the protein-tyrosine kinase (PTK) BCR-ABL1 has improved treatment response in chronic myeloid leukemia (CML). However, in some patients response still remains suboptimal. Protein-tyrosine phosphatases (PTPs) are natural counter-actors of PTK activity and can affect TKI sensitivity, but the impact of PTPs on treatment response to second-generation TKIs is unknown. We assessed the mRNA expression level of 38 PTPs in 66 newly diagnosed CML patients and analyzed the potential relation with treatment outcome after 9 months of nilotinib medication...
February 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29506666/exploring-stem-cell-heterogeneity-in-chronic-myeloid-leukemia
#17
Chinmay Munje, Mhairi Copland
Until very recently, understanding the complexity of the stem cell (SC) compartment in both normal and leukemic hematopoiesis has been challenging due to the inability to separate and study normal and leukemic SCs at the single-cell level. Recent advances in cell-sorting techniques and single-cell technologies now make this possible, with the identification of a population of highly quiescent chronic myeloid leukemia (CML) SCs that is enriched following therapy with tyrosine kinase inhibitors (TKIs).
March 2018: Trends in Cancer
https://www.readbyqxmd.com/read/29505034/bone-marrow-niche-trafficking-of-mir-126-controls-the-self-renewal-of-leukemia-stem-cells-in-chronic-myelogenous-leukemia
#18
Bin Zhang, Le Xuan Truong Nguyen, Ling Li, Dandan Zhao, Bijender Kumar, Herman Wu, Allen Lin, Francesca Pellicano, Lisa Hopcroft, Yu-Lin Su, Mhairi Copland, Tessa L Holyoake, Calvin J Kuo, Ravi Bhatia, David S Snyder, Haris Ali, Anthony S Stein, Casey Brewer, Huafeng Wang, Tinisha McDonald, Piotr Swiderski, Estelle Troadec, Ching-Cheng Chen, Adrienne Dorrance, Vinod Pullarkat, Yate-Ching Yuan, Danilo Perrotti, Nadia Carlesso, Stephen J Forman, Marcin Kortylewski, Ya-Huei Kuo, Guido Marcucci
Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals...
March 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29500416/sipa1-deficiency-unleashes-a-host-immune-mechanism-eradicating-chronic-myelogenous-leukemia-initiating-cells
#19
Yan Xu, Satoshi Ikeda, Kentaro Sumida, Ryusuke Yamamoto, Hiroki Tanaka, Nagahiro Minato
Chronic myelogenous leukemia (CML) caused by hematopoietic stem cells expressing the Bcr-Abl fusion gene may be controlled by Bcr-Abl tyrosine kinase inhibitors (TKIs). However, CML-initiating cells are resistant to TKIs and may persist as minimal residual disease. We demonstrate that mice deficient in Sipa1, which encodes Rap1 GTPase-activating protein, rarely develop CML upon transfer of primary hematopoietic progenitor cells (HPCs) expressing Bcr-Abl, which cause lethal CML disease in wild-type mice. Resistance requires both T cells and nonhematopoietic cells...
March 2, 2018: Nature Communications
https://www.readbyqxmd.com/read/29500381/gdna-qpcr-is-statistically-more-reliable-than-mrna-analysis-in-detecting-leukemic-cells-to-monitor-cml
#20
Alessia Rainero, Fabrizio Angaroni, Andrea Conti, Cristina Pirrone, Giovanni Micheloni, Lucia Tararà, Giorgia Millefanti, Emanuela Maserati, Roberto Valli, Orietta Spinelli, Ksenija Buklijas, Anna Michelato, Rosario Casalone, Cristina Barlassina, Matteo Barcella, Silvia Sirchia, Eleonora Piscitelli, Massimo Caccia, Giovanni Porta
Chronic Myeloid Leukemia (CML) is a stem cell cancer that arises when t(9;22) translocation occurs in a hematopoietic stem cells. This event results in the expression of the BCR-ABL1 fusion gene, which codes for a constitutively active tyrosine kinase that is responsible for the transformation of a HSC into a CML stem cell, which then gives rise to a clonal myeloproliferative disease. The introduction of Tyrosine Kinase Inhibitors (TKIs) has revolutionized the management of the disease. However, these drugs do not seem to be able to eradicate the malignancy...
March 2, 2018: Cell Death & Disease
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