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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
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...
March 9, 2018: Expert Review of Hematology
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
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
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
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
K Lewandowski, M Gniot, M Wojtaszewska, Z Kanduła, R Becht, E Paczkowska, E Mędraś, E Wasilewska, M Iwoła
INTRODUCTION: There are 7 designated conditions under the category of myeloproliferative neoplasms (MPN), including chronic myelogenous leukemia (CML) and classical MPN, that is, polycythemia vera (PV), essential thrombocythaemia (ET), and primary myelofibrosis (PMF). Recently, reports about Philadelphia and JAK2 V617F-positive MPN cases have been described in literature. The coexistence of different molecular defects may change the clinical and laboratory manifestation of MPN and may result in an inappropriate interpretation of the response to treatment with tyrosine kinase inhibitors in CML patients...
March 6, 2018: International Journal of Laboratory Hematology
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
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
Devendra Hiwase, Peter Tan, James D'Rozario, John Taper, Anthony Powell, Ian Irving, Matthew Wright, Susan Branford, David T Yeung, Luke Anderson, Othon Gervasio, Carly Levetan, Will Roberts, Ann Solterbeck, Robert Traficante, Timothy Hughes
BACKGROUND: Some patients receiving a tyrosine kinase inhibitor (TKI) for the first-line treatment of chronic phase chronic myeloid leukemia (CML-CP) experience intolerable adverse events. Management strategies include dose adjustments, interrupting or discontinuing therapy, or switching to an alternative TKI. METHODS: This multicenter, single-arm, Phase IIIb study included CML-CP patients intolerant of, but responsive to, first-line treatment with imatinib or dasatinib...
February 21, 2018: Leukemia Research
Anna Chorzalska, Nagib Ahsan, R Shyama Prasad Rao, Karim Roder, Xiaoqing Yu, John Morgan, Alexander Tepper, Steven Hines, Peng Zhang, Diana O Treaba, Ting C Zhao, Adam J Olszewski, John Reagan, Olin Liang, Philip A Gruppuso, Patrycja M Dubielecka
The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a chronic disease with long-term survival exceeding 85%. However, resistance of CML stem cells to TKI may contribute to the 50% relapse rate observed after TKI discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr-Abl1 protein and activity levels while maintaining proliferative potential...
February 27, 2018: Molecular Oncology
Doralina do Amaral Rabello, Vivian D'Afonseca da Silva Ferreira, Maria Gabriela Berzoti-Coelho, Sandra Mara Burin, Cíntia Leticia Magro, Maira da Costa Cacemiro, Belinda Pinto Simões, Felipe Saldanha-Araujo, Fabíola Attié de Castro, Fabio Pittella-Silva
Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm whose pathogenesis is linked to the Philadelphia chromosome presence that generates the BCR - ABL 1 fusion oncogene. Tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM) dramatically improved the treatment efficiency and survival of CML patients by targeting BCR-ABL tyrosine kinase. The disease shows three distinct clinical-laboratory stages: chronic phase, accelerated phase and blast crisis...
2018: Cancer Cell International
S Lejniece, I Udre, A Rivkina
BACKGROUND: Imatinib is tyrosine kinase inhibitor (TKI) and as a targeted anti-cancer agent has significantly changed chronic myeloid leukemia (CML) prognosis and patient survival. Currently TKI is the main therapy in CML Philadelphia chromosome-positive (Ph-positive) cases. When generics of imatinib appeared in the pharmaceuticals market, reimbursement policies in many countries switched to using generics or encouraged use of generic imatinib to lower the expenses. Cost savings were substantial; however, for doctors and CML patients the efficacy, safety and quality of generic imatinib were an issue of concern...
July 2017: Experimental Oncology
Simon Kavanagh, Aisling Nee, Jeffrey H Lipton
BCR-ABL-directed tyrosine kinase inhibitors (TKIs) have revolutionised therapy for chronic myeloid leukemia. However, despite the availability and efficacy of this class of agents, lifelong treatment is still required in a significant proportion of patients Areas covered: We give an overview of the currently available BCR-ABL-directed TKIs and other conventional therapies for CML. We proceed to review the current market and some of the scientific rationale for new drug development before outlining a number of novel therapies, considered broadly as immunotherapies and targeted agents...
March 2018: Expert Opinion on Emerging Drugs
Esra Terzi Demirsoy, Ozgur Mehtap, Elif Birtas Atesoglu, Pinar Tarkun, Necmi Eren, Ayfer Gedük, Abdullah Hacihanefioglu
Most commonly seen side effects with Tyrosine kinase inhibitors (TKI's) are hematologic toxicities. Besides, with dasatinib autoimmune side effects can be seen. Thrombotic thrombocytopenic purpura (TTP) is a life- threatening disease that can be related to various causes mainly autoimmune disorders or antineoplastic drugs. Few cases of TKI associated secondary thrombotic microangiopathies (TMA) have been reported in literature. Most of cases were diagnosed as hemolytic uremic syndrome (HUS) rather than TTP...
February 9, 2018: Transfusion and Apheresis Science
Daniela Dörfel, Christian J Lechner, Simone Joas, Tanja Funk, Michael Gutknecht, Julia Salih, Julian Geiger, Korbinian N Kropp, Stefanie Maurer, Martin R Müller, Hans-Georg Kopp, Helmut R Salih, Frank Grünebach, Susanne M Rittig
In chronic myeloid leukemia (CML), the translocation t(9;22) results in the fusion protein BCR-ABL (breakpoint cluster region-abelson murine leukemia), a tyrosine kinase mediating oncogenic signaling which is successfully targeted by treatment with BCR-ABL inhibitors like imatinib. However, BCR-ABL inhibitors may also affect antitumor immunity. For instance, it was reported that imatinib impairs the function of dendritic cells (DCs) that play a central role in initiating and sustaining T cell responses. Meanwhile, second generation BCR-ABL inhibitors like nilotinib, which inhibits BCR-ABL with enhanced potency have become standard of treatment, at least in patients with BCR-ABL kinase domain mutations...
February 21, 2018: Cancer Immunology, Immunotherapy: CII
Massimo Breccia, Francesca Palandri, Luigiana Luciano, Giulia Benevolo, Massimiliano Bonifacio, Giovanni Caocci, Fausto Castagnetti, Giuseppe A Palumbo, Alessandra Iurlo, Francesco Landi
The incidence of cancer, including myeloproliferative neoplasms (MPNs), is projected to increase significantly due to the growing proportion of people aged > 65 years. These older individuals are a heterogeneous population in terms of fitness, comorbidity, and psychological reserve. Therefore, age per se does not always provide an accurate indication of condition in patients with cancer. Frailty has been proposed as an alternative measure of vulnerability that might better indicate which patients can tolerate standard cancer treatment and those who may benefit from treatment adjustment...
February 22, 2018: Annals of Hematology
Kiran Naqvi, Jorge E Cortes, Raja Luthra, Susan O'Brien, William Wierda, Gautam Borthakur, Tapan Kadia, Guillermo Garcia-Manero, Farhad Ravandi, Mary Beth Rios, Sara Dellasala, Sherry Pierce, Elias Jabbour, Keyur Patel, Hagop Kantarjian
Kinase domain (KD) mutations of ABL1 represent the most common resistance mechanism to tyrosine kinase inhibitors (TKI) in CML. Besides T315I, mutations in codon 255 are highly resistant mutations in vitro to all TKI. We aimed to study the incidence, prognosis, and response to treatment in patients with E255K/V. We evaluated 976 patients by sequencing of BCR-ABL1 fusion transcript for ABL1 KD mutations. We identified KD mutations in 381 (39%) patients, including E255K/V in 48 (13% of all mutations). At mutation detection, 14 patients (29%) were in chronic phase (CP), 12 (25%) in accelerated phase (AP), and 22 (46%) in blast phase (BP)...
February 20, 2018: International Journal of Hematology
Marlise R Luskin, Daniel J DeAngelo
Chronic myeloid leukemia (CML), a myeloproliferative neoplasm defined by the t(9;22)(q34;q11) chromosomal translocation, primarily affects older adults. Historically, effective treatment options were not available for older CML patients ineligible for curative allogeneic stem cell transplant, and the disease was therefore usually fatal within several years of diagnosis. The development of tyrosine kinase inhibitors (TKIs) that effectively target the constitutively active mutant tyrosine kinase in CML has dramatically improved outcomes for all patients with CML, including older patients...
February 18, 2018: Journal of Geriatric Oncology
Osvaldo Contreras, Maximiliano Villarreal, Enrique Brandan
BACKGROUND: Tyrosine kinase inhibitors (TKIs) are effective therapies with demonstrated antineoplastic activity. Nilotinib is a second-generation FDA-approved TKI designed to overcome Imatinib resistance and intolerance in patients with chronic myelogenous leukemia (CML). Interestingly, TKIs have also been shown to be an efficient treatment for several non-malignant disorders such fibrotic diseases, including those affecting skeletal muscles. METHODS: We investigated the role of Nilotinib on skeletal myogenesis using the well-established C2C12 myoblast cell line...
February 20, 2018: Skeletal Muscle
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