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TKI CML

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https://www.readbyqxmd.com/read/28186983/differentiation-status-of-primary-chronic-myeloid-leukemia-cells-affects-sensitivity-to-bcr-abl1-inhibitors
#1
Paavo O Pietarinen, Christopher A Eide, Pilar Ayuda-Durán, Swapnil Potdar, Heikki Kuusanmäki, Emma I Andersson, John P Mpindi, Tea Pemovska, Mika Kontro, Caroline A Heckman, Olli Kallioniemi, Krister Wennerberg, Henrik Hjorth-Hansen, Brian J Druker, Jorrit M Enserink, Jeffrey W Tyner, Satu Mustjoki, Kimmo Porkka
Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1-positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1-positive leukemia (n = 40) and healthy controls (n = 12)...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28184964/absorption-metabolism-and-excretion-of-14-c-ponatinib-after-a-single-oral-dose-in-humans
#2
Yihua E Ye, Caroline N Woodward, Narayana I Narasimhan
PURPOSE: Ponatinib is a novel tyrosine kinase inhibitor (TKI) specifically designed to inhibit native and mutated BCR-ABL. In the United States, ponatinib has received accelerated approval for adults with T315I-positive chronic myeloid leukemia (CML) or T315I (gatekeeper mutation)-positive, Philadelphia chromosome-positive, acute lymphoblastic leukemia (Ph + ALL), and patients with CML or Ph + ALL for whom no other TKI therapy is indicated. The objective of this phase 1, mass balance study was to evaluate the absorption, metabolism, and excretion of [(14)C]ponatinib in healthy subjects...
February 9, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28169304/targeted-therapies-remembrance-of-things-past-discontinuation-of-second-generation-tki-therapy-for-cml
#3
Timothy P Hughes, David M Ross
No abstract text is available yet for this article.
February 7, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28159740/the-chronic-myeloid-leukemia-stem-cell-stemming-the-tide-of-persistence
#4
Tessa L Holyoake, David Vetrie
Chronic myeloid leukaemia (CML) is caused by the acquisition of the tyrosine kinase BCR-ABL1 in a haemopoietic stem cell (HSC), transforming it into a leukaemic stem cell (LSC) that self-renews, proliferates and differentiates to give rise to a myeloproliferative disease. While tyrosine kinase inhibitors (TKI) that target the kinase activity of BCR-ABL1 have transformed CML from a once fatal disease to a manageable one for the vast majority of patients, only ~10% of those who present in chronic phase (CP) can discontinue TKI treatment and maintain a therapy-free remission...
February 3, 2017: Blood
https://www.readbyqxmd.com/read/28135648/current-approach-to-the-treatment-of-chronic-myeloid-leukaemia
#5
REVIEW
Ivan Pasic, Jeffrey H Lipton
Of all the cancers, chronic myeloid leukaemia (CML) has witnessed the most rapid evolution of the therapeutic milieu in recent decades. The introduction of tyrosine kinase inhibitors (TKIs) as a therapeutic option has profoundly changed patient experience and outcome. The availability of multiple new highly effective therapies has increasingly underscored the importance of a good understanding of the underlying pathophysiological basis in CML, as well as patient-specific factors in choosing the right treatment for every individual...
January 11, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28135325/early-bcr-abl1-transcript-decline-after-1-month-of-tyrosine-kinase-inhibitor-therapy-as-an-indicator-for-treatment-response-in-chronic-myeloid-leukemia
#6
Mohamed El Missiry, Henrik Hjorth-Hansen, Johan Richter, Ulla Olson-Strömberg, Leif Stenke, Kimmo Porkka, Anna Kreutzman, Satu Mustjoki
In chronic myeloid leukemia (CML), early treatment prediction is important to identify patients with inferior overall outcomes. We examined the feasibility of using reductions in BCR-ABL1 transcript levels after 1 month of tyrosine kinase inhibitor (TKI) treatment to predict therapy response. Fifty-two first-line TKI-treated CML patients were included (imatinib n = 26, dasatinib n = 21, nilotinib n = 5), and BCR-ABL1 transcript levels were measured at diagnosis (dg) and 1, 3, 6, 12, 18, 24, and 36 months. The fold change of the BCR-ABL1 transcripts at 1 month compared to initial BCR-ABL1 transcript levels was used to indicate early therapy response...
2017: PloS One
https://www.readbyqxmd.com/read/28125373/health-care-resource-utilization-and-costs-in-patients-with-chronic-myeloid-leukemia-with-better-adherence-to-tyrosine-kinase-inhibitors-and-increased-molecular-monitoring-frequency
#7
Dominick Latremouille-Viau, Annie Guerin, Patrick Gagnon-Sanschagrin, Katherine Dea, Benjamin G Cohen, George J Joseph
BACKGROUND: Frequent molecular monitoring (qPCR tests), as recommended by evidence-based monitoring guidelines, is associated with higher adherence to tyrosine kinase inhibitors (TKIs) in the management of chronic myeloid leukemia (CML); both factors have been associated with better clinical and economic outcomes. OBJECTIVES: To (a) estimate the effect of more frequent qPCR tests on health care resource utilization (HRU) and associated costs, including direct (effect of qPCR test frequency on HRU) and indirect (through TKI adherence) effects, and (b) develop an economic model applicable to multiple clinical practice scenarios...
February 2017: Journal of Managed Care & Specialty Pharmacy
https://www.readbyqxmd.com/read/28122740/single-cell-molecular-analysis-defines-therapy-response-and-immunophenotype-of-stem-cell-subpopulations-in-cml
#8
Rebecca Warfvinge, Linda Geironson Ulfsson, Mikael N E Sommarin, Stefan Lang, Christine Karlsson, Teona Roschupkina, Leif Stenke, Jesper Stentoft, Ulla Olsson-Strömberg, Henrik Hjorth-Hansen, Satu Mustjoki, Shamit Soneji, Johan Richter, Göran Karlsson
Understanding leukemia heterogeneity is critical for the development of curative treatments as the failure to eliminate therapy-persistent leukemic stem cells (LSCs) may result in disease relapse. Here we have combined high-throughput immunophenotypic screens with large-scale single-cell gene expression analysis to define the heterogeneity within the LSC-population in chronic phase chronic myeloid leukemia (CML) patients at diagnosis and following conventional tyrosine kinase inhibitor (TKI) treatment. Our results reveal substantial heterogeneity within the putative LSC population in CML at diagnosis and demonstrate differences in response to subsequent TKI-treatment between distinct subpopulations...
January 25, 2017: Blood
https://www.readbyqxmd.com/read/28117336/cd5-molecule-like-and-transthyretin-as-putative-biomarkers-of-chronic-myeloid-leukemia-an-insight-from-the-proteomic-analysis-of-human-plasma
#9
Iram Fatima, Saima Sadaf, Syed Ghulam Musharraf, Naghma Hashmi, Muhammad Waheed Akhtar
Better and sensitive biomarkers are needed to help understand the mechanism of disease onset, progression, prognosis and monitoring of the therapeutic response. Aim of this study was to identify the candidate circulating markers of chronic-phase chronic myeloid leukemia (CP-CML) manifestations, having potential to develop into predictive- or monitoring-biomarkers. A proteomic approach, two-dimensional gel electrophoresis in conjunction with mass spectrometry (2DE-MS), was employed for this purpose. Based on the spot intensity measurements, six proteins were found to be consistently dysregulated in CP-CML subjects compared to the healthy controls [false discovery rate (FDR) threshold ≤0...
January 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28109974/incidences-and-outcomes-of-therapy-related-chronic-myeloid-leukemia-in-the-era-of-tyrosine-kinase-inhibitors-surveillance-of-the-cml-cooperative-study-group
#10
Noriyoshi Iriyama, Michihide Tokuhira, Tomoiku Takaku, Eriko Sato, Maho Ishikawa, Tomonori Nakazato, Kei-Ji Sugimoto, Hiroyuki Fujita, Isao Fujioka, Yoshihiro Hatta, Masahiro Kizaki, Norio Komatsu, Norio Asou, Tatsuya Kawaguchi
This study was performed to investigate the features and outcome of patients with therapy-related chronic myeloid leukemia (TR-CML) who were treated with tyrosine kinase inhibitors (TKIs). The analysis included 308 patients with CML in the chronic phase who were extracted from the CML Cooperative Study Group database. Of these patients, 11 (3.6%) were identified as having TR-CML. No differences in age, sex, white blood cell count, hemoglobin level, platelet count, or European Treatment and Outcome Study risk were observed between patients with TR-CML vs...
January 5, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28103766/long-term-exposure-to-imatinib-mesylate-downregulates-hippo-pathway-and-activates-yap-in-a-model-of-chronic-myelogenous-leukemia
#11
Anna Chorzalska, Javier Flores Kim, Karim Roder, Alexander Tepper, Nagib Ahsan, R Shyama Prasad Rao, Adam J Olszewski, Xiaoqing Yu, Dmitry Terentyev, John Morgan, Diana O Treaba, Ting Zhao, Olin Liang, Philip Gruppuso, Patrycja Dubielecka
Despite the success of tyrosine kinase inhibitor (TKI) therapy in chronic myelogenous leukemia (CML), leukemic stem/progenitor cells remain detectable even in the state of deep molecular remission. Mechanisms that allow them to persist despite continued kinase inhibition remain unclear. We have previously shown that prolonged exposure to imatinib mesylate results in dysregulation of Akt/Erk 1/2 signaling, upregulation of miR-181a, enhanced adhesiveness, and resistance to high imatinib mesylate. In order to characterize the molecular basis and reversibility of those effects, we applied gene and protein expression analysis, quantitative phosphoproteomic, and direct miR-181a inhibition to our cellular model of CML cells subjected to prolonged exposure to imatinib mesylate...
January 19, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28099274/can-any-patients-with-chronic-myeloid-leukemia-outside-of-a-clinical-trial-have-their-tyrosine-kinase-inhibitor-discontinued
#12
Michael J Mauro
PURPOSE OF REVIEW: This article critically appraises the state of treatment-free remission as a strategy for patients with chronic myeloid leukemia (CML) in deep remission after therapy with tyrosine kinase inhibitors (TKIs). RECENT FINDINGS: Approximately half of patients with CML defined fairly narrowly by trial criteria - TKI sensitive, in deep molecular remission for a defined period - can successfully maintain protective levels of response after TKI cessation...
March 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28079885/mirna182-regulates-percentage-of-myeloid-and-erythroid-cells-in-chronic-myeloid-leukemia
#13
Deepak Arya, Sasikala P Sachithanandan, Cecil Ross, Dasaradhi Palakodeti, Shang Li, Sudhir Krishna
The deregulation of lineage control programs is often associated with the progression of haematological malignancies. The molecular regulators of lineage choices in the context of tyrosine kinase inhibitor (TKI) resistance remain poorly understood in chronic myeloid leukemia (CML). To find a potential molecular regulator contributing to lineage distribution and TKI resistance, we undertook an RNA-sequencing approach for identifying microRNAs (miRNAs). Following an unbiased screen, elevated miRNA182-5p levels were detected in Bcr-Abl-inhibited K562 cells (CML blast crisis cell line) and in a panel of CML patients...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28074067/expression-of-the-ctla-4-ligand-cd86-on-plasmacytoid-dendritic-cells-pdc-predicts-risk-of-disease-recurrence-after-treatment-discontinuation-in-cml
#14
C Schütz, S Inselmann, S Sausslele, C T Dietz, M C Mu Ller, E Eigendorff, C A Brendel, S K Metzelder, T H Bru Mmendorf, C Waller, J Dengler, M E Goebeler, R Herbst, G Freunek, S Hanzel, T Illmer, Y Wang, T Lange, F Finkernagel, R Hehlmann, M Huber, A Neubauer, A Hochhaus, J Guilhot, F Xavier Mahon, M Pfirrmann, A Burchert
It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86(+)pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86(+)pDC (n=12)...
January 27, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28052354/evaluation-of-long-term-chronic-myeloid-leukemia-treatment-practices-with-tyrosine-kinase-inhibitors-in-a-national-cohort-of-veterans
#15
Eugene D Kreys, Christopher R Frei, Sarah M Villarreal, Mary J Bollinger, Xavier Jones, Jim M Koeller
STUDY OBJECTIVE: To evaluate nationwide chronic myeloid leukemia treatment practices over an extended period and across multiple lines of tyrosine kinase inhibitor (TKI) therapy with imatinib, dasatinib, and nilotinib. DESIGN: Retrospective cohort study. DATA SOURCE: Veterans Health Administration (VHA) national database. PATIENTS: A total of 2,873 VHA beneficiaries aged 18-89 years who had at least one encounter at any of the approximately 150 VHA hospitals and 800 VHA clinics, had a diagnosis code for chronic myeloid leukemia, and filled at least one prescription for imatinib, nilotinib, or dasatinib between October 1, 2001, and September 30, 2010...
January 4, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28049640/cml-patients-with-deep-molecular-responses-to-tki-have-restored-immune-effectors-decreased-pd-1-and-immune-suppressors
#16
Amy Hughes, Jade Clarson, Carine Tang, Ljiljana Vidovic, Deborah L White, Timothy P Hughes, Agnes S M Yong
Immunological control may contribute to achievement of deep molecular response in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitor (TKI) therapy and may promote treatment free remission (TFR). We investigated effector and suppressor immune responses in CML patients at diagnosis (n=21), on TKI (imatinib, nilotinib, dasatinib) prior to achieving major molecular response (pre-MMR, BCR-ABL1 >0.1%, n=8), MMR (BCR-ABL1 ≤0.1%, n=20), molecular response(4.5) (MR(4.5), BCR-ABL1 ≤0.0032%, n=16) and sustained TFR (BCR-ABL1 undetectable following cessation of TKI therapy, n=13)...
January 3, 2017: Blood
https://www.readbyqxmd.com/read/28024517/-role-of-bone-marrow-mesenchymal-stem-cells-in-resistance-of-chronic-myeloid-leukemia-to-tyrosine-kinase-inhibitors-review
#17
Xiao-Yan Zhang, Qian Wan, Li-Jun Fang, Jian Li
Chronic myeloid leukemia (CML) is a disease originated from malignant hematopoietic stem cell disorder. In CML, mesenchymal stem cells(MSC) have been changed in the bone marrow microenvironment, which can protect the leukemia cells from apoptosis induced by tyrosine kinase inhibitors (TKI) and lead to the resistance to TKI by the secretion of soluble factors, involvement in cell-cell adhesion, and so on. This review mainly focuses on the changes of the bone marrow mesenchymal stem cells in CML, as well as the role and mechanism of MSC in the CML resistance of TKI...
December 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28024513/-a-new-goal-for-tyrosine-kinase-inhibitor-therapy-in-chronic-myeloid-leukemia-treatment-free-remission-review
#18
Lan Yang, Bian-Hong Wang, Xiang-Shu Jin, Yu Jing, Li Yu
Tyrosine kinase inhibitor (TKI) therapy significantly improved the prognosis and outcome of patients with chronic myeloid leukemia(CML). Long-term therapy of TKI drugs was often accompanied with financial burden and the rise of chronic adverse effects. At present, the treatment-free remission (TFR) has been gradually regarded as the new ultimate aim to the patients with long-term CML. In clinical trials, the patients with the therapy of imatinib stopping TKI treatment after acquired deep molecular reaction still maintained remission...
December 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28011678/enhanced-targeting-of-cml-stem-and-progenitor-cells-by-inhibition-of-porcupine-acyltransferase-in-combination-with-tki
#19
Puneet Agarwal, Bin Zhang, Yinwei Ho, Amy Cook, Ling Li, Fady M Mikhail, Youzhen Wang, Margaret E McLaughlin, Ravi Bhatia
Tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) has limited efficacy against leukemia stem cells (LSC) responsible for disease propagation, and most CML patients require continued TKI treatment to maintain remission. LSC maintenance is related, at least in part, to signals from the bone marrow microenvironment (BMM). Our previous studies have shown that Wnt signaling from the BMM contributes to preservation of CML LSC following TKI treatment. Secretion of Wnt ligands requires their modification by the O-acyl transferase Porcupine (PORCN)...
December 23, 2016: Blood
https://www.readbyqxmd.com/read/28009456/the-impact-of-socioeconomic-factors-on-treatment-choice-and-mortality-in-chronic-myeloid-leukaemia
#20
Gunnar Larfors, Fredrik Sandin, Johan Richter, Anders Själander, Leif Stenke, Mats Lambe, Martin Höglund
PURPOSE: To evaluate the influence of socioeconomic variables on treatment selection and survival of patients with chronic myeloid leukaemia (CML). METHODS: Using information available in population-based Swedish registries we evaluated indices of health, education and economy from the 980 patients in the Swedish CML register diagnosed between 2002 and 2012. Apart from internal comparisons, five age-, gender- and region-matched control subjects per patient served as control cohort...
December 23, 2016: European Journal of Haematology
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