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https://www.readbyqxmd.com/read/29675611/ponatinib-as-second-line-treatment-in-chronic-phase-chronic-myeloid-leukemia-patients-in-real-life-practice
#1
Massimo Breccia, Elisabetta Abruzzese, Fausto Castagnetti, Massimiliano Bonifacio, Domenica Gangemi, Federica Sorà, Alessandra Iurlo, Luigiana Luciano, Antonella Gozzini, Massimo Gentile, Monica Bocchia, Debora Luzi, Alessandro Maggi, Nicola Sgherza, Alessandro Isidori, Monica Crugnola, Patrizia Pregno, Anna Rita Scortechini, Isabella Capodanno, Michele Pizzuti, Robin Foà
Scarce information is available on the use of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients resistant and/or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. We collected data from 29 CML patients, with a median age of 54 years (range 32-72). Eleven patients had received dasatinib, 15 patients received nilotinib, and 3 patients received imatinib as first-line treatment. Forty-five percent of patients started ponatinib for secondary resistance, 38% for primary resistance, 7% for severe intolerance associated to a molecular warning, 7% due to the presence of a T315I mutation, and 3% for severe intolerance...
April 19, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29662665/molecular-mechanism-of-action-and-potential-biomarkers-of-growth-inhibition-of-synergistic-combination-of-afatinib-and-dasatinib-against-gefitinib-resistant-non-small-cell-lung-cancer-cells
#2
Miao Wang, Alex Yuang-Chi Chang
Epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) is the first choice of treatment for advanced non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, single agent usually has limited efficacy due to heterogeneous resistant mechanisms of cancer cells. Thus drug combination therapy would offer more benefits by synergistic interactions and avoidance of resistance emergence. In this study, we selected 8 NSCLC cell lines with different genetic characteristics as research models to investigate the efficacy of 4 agents (gefitinib, cetuximab, afatinib and dasatinib) and their combinations...
March 27, 2018: Oncotarget
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/29658958/treatment-with-src-inhibitor-dasatinib-results-in-elevated-metastatic-potential-in-the-4t1-murine-mammary-carcinoma-model
#4
Veronica S Hughes, Dietmar W Siemann
Introduction: The src inhibitor Dasatinib has been widely studied as an anti-metastatic agent. The aims of this study were to examine the effect of Src inhibition on the metastatic potential of the 4T1 murine mammary carcinoma. Context: Src is a non-receptor tyrosine kinase well-known to contribute to the metastatic potential of tumour cells. It does so through alteration of signalling pathways important to metastasis. Elevated levels of Src are common in many cancer types, and have been correlated with tumour progression and poor patient prognosis...
2018: Tumor & microenvironment
https://www.readbyqxmd.com/read/29616864/a-phase-1-study-of-dasatinib-plus-all-trans-retinoic-acid-in-acute-myeloid-leukemia
#5
Robert L Redner, Jan H Beumer, Patricia Kropf, Mounzer Agha, Michael Boyiadzis, Kathleen Dorritie, Rafic Farah, Jing-Zhao Hou, Annie Im, Seah H Lim, Anastasios Raptis, Alison Sehgal, Susan M Christner, Daniel Normolle, Daniel E Johnson
Src family kinases (SFKs) are hyperactivated in acute myeloid leukemia (AML). SFKs impede the retinoic acid receptor, and SFK inhibitors enhance all-trans retinoic acid (ATRA)-mediated cellular differentiation in AML cell lines and primary blasts. To translate these findings into the clinic, we undertook a phase-I dose-escalation study of the combination of the SFK inhibitor dasatinib and ATRA in patients with high-risk myeloid neoplasms. Nine subjects were enrolled: six received 70 mg dasatinib plus 45 mg/m2 ATRA daily, and three received 100 mg dasatinib plus 45 mg/m2 ATRA daily for 28 days...
April 4, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29610029/final-3-year-results-of-the-dasatinib-discontinuation-trial-in-patients-with-chronic-myeloid-leukemia-who-received-dasatinib-as-a-second-line-treatment
#6
Masaya Okada, Jun Imagawa, Hideo Tanaka, Hirohisa Nakamae, Masayuki Hino, Kazunori Murai, Yoji Ishida, Takashi Kumagai, Seiichi Sato, Kazuteru Ohashi, Hisashi Sakamaki, Hisashi Wakita, Nobuhiko Uoshima, Yasunori Nakagawa, Yosuke Minami, Masahiro Ogasawara, Tomoharu Takeoka, Hiroshi Akasaka, Takahiko Utsumi, Naokuni Uike, Tsutomu Sato, Sachiko Ando, Kensuke Usuki, Syuichi Mizuta, Satoshi Hashino, Tetsuhiko Nomura, Masato Shikami, Hisashi Fukutani, Yokiko Ohe, Hiroshi Kosugi, Hirohiko Shibayama, Yasuhiro Maeda, Toshihiro Fukushima, Hirohito Yamazaki, Kazuo Tsubaki, Toshimasa Kukita, Yoko Adachi, Toshiki Nataduka, Hiroto Sakoda, Hisayuki Yokoyama, Takahiro Okamoto, Yukari Shirasugi, Yasushi Onishi, Masaharu Nohgawa, Satoshi Yoshihara, Satoshi Morita, Junichi Sakamoto, Shinya Kimura
INTRODUCTION: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. PATIENTS AND METHODS: The DADI trial was a prospective, multicenter trial conducted in Japan...
March 15, 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29609532/design-and-rationale-for-the-life-after-stopping-tyrosine-kinase-inhibitors-last-study-a-prospective-single-group-longitudinal-study-in-patients-with-chronic-myeloid-leukemia
#7
Ehab Atallah, Charles A Schiffer, Kevin P Weinfurt, Mei-Jie Zhang, Jerald P Radich, Vivian G Oehler, Javier Pinilla-Ibarz, Michael W N Deininger, Li Lin, Richard A Larson, Michael J Mauro, Joseph O Moore, Ellen K Ritchie, Neil P Shah, Richard T Silver, Martha Wadleigh, Jorge Cortes, James Thompson, Jessica Guhl, Mary M Horowitz, Kathryn E Flynn
BACKGROUND: Treatment of chronic myeloid leukemia with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet nevertheless is associated with reduced health-related quality of life and very high cost. Several small studies from Europe and Australia suggested that discontinuing TKIs with regular monitoring was safe. METHODS: The Life After Stopping TKIs (LAST) study is a large, U.S.-based study that aims to improve the evidence for clinical decision making regarding TKI discontinuation with monitoring in patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy...
April 2, 2018: BMC Cancer
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/29568367/the-new-allosteric-inhibitor-asciminib-is-susceptible-to-resistance-mediated-by-abcb1-and-abcg2-overexpression-in-vitro
#9
Laura N Eadie, Verity A Saunders, Susan Branford, Deborah L White, Timothy P Hughes
Asciminib (previously ABL001), which binds the myristate-binding pocket of the Bcr-Abl kinase domain, is in phase I clinical trials as monotherapy and in combination with imatinib, nilotinib and dasatinib for the treatment of patients with refractory CML or Ph+ ALL. Asciminib sensitivity was evaluated in asciminib naïve BCR-ABL1+ cell lines K562 (negligible ABCB1/ABCG2 expression), K562-Dox (ABCB1-overexpressing through doxorubicin exposure) and K562-ABCG2 (ABCG2 overexpression via transduction) with results demonstrating asciminib efflux by both ABCB1 and ABCG2 transporters...
March 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29567798/ponatinib-efficacy-and-safety-in-philadelphia-chromosome-positive-leukemia-final-5-year-results-of-the-phase-2-pace-trial
#10
Jorge E Cortes, Dong-Wook Kim, Javier Pinilla-Ibarz, Philipp D le Coutre, Ronald Paquette, Charles Chuah, Franck E Nicolini, Jane F Apperley, H Jean Khoury, Moshe Talpaz, Daniel J DeAngelo, Elisabetta Abruzzese, Delphine Rea, Michele Baccarani, Martin C Müller, Carlo Gambacorti-Passerini, Stephanie Lustgarten, Victor M Rivera, Frank G Haluska, François Guilhot, Michael W Deininger, Andreas Hochhaus, Timothy P Hughes, Neil P Shah, Hagop M Kantarjian
Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I The pivotal phase 2 PACE trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia resistant/intolerant to dasatinib or nilotinib, or with BCR ABL1T315I This analysis focuses on chronic-phase CML (CP-CML) patients (n=270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and MR4...
March 22, 2018: Blood
https://www.readbyqxmd.com/read/29562444/-efficacy-comparison-of-sequential-treatment-with-first-line-administration-of-second-generation-and-first-generation-tyrosine-kinase-inhibitors-in-patients-with-ph-acute-lymphoblastic-leukemia-followed-by-allogeneic-hematopoietic-stem-cell-transplantation
#11
F Yang, W Z Cai, X D Yang, S N Chen, X W Tang, A N Sun, D P Wu, W Q Qian, H Y Qiu
Objective: To investigate the efficacy of sequential treatment with first-line administration of second-generation tyrosine kinase inhibitors (TKI) and first-generation TKI (imatinib) in patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Retrospective analysis of clinical features and prognosis of 76 newly diagnosed Ph+ ALL patients from June 2011 to December 2015 treated by allo-HSCT combined with first-line administration of second-generation or first-generation TKI was performed and the efficacy compared...
February 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29556695/outcomes-of-switching-to-dasatinib-after-imatinib-related-low-grade-adverse-events-in-patients-with-chronic-myeloid-leukemia-in-chronic-phase-the-dasperse-study
#12
Dong-Wook Kim, Susanne Saussele, Loretta A Williams, Hesham Mohamed, Yuanxin Rong, Teresa Zyczynski, Javier Pinilla-Ibarz, Elisabetta Abruzzese
Chronic, low-grade adverse events are common in patients with chronic myeloid leukemia who are treated with imatinib. These events may decrease patient quality of life and adherence, and may ultimately contribute to a suboptimal response. Alternative, second-generation tyrosine kinase inhibitors, such as dasatinib, are available with the potential to reduce adverse events, improve tolerability, and support long-term treatment goals. We present the final, primary analysis of DASPERSE/CA180-400 (NCT01660906), an open-label, multicenter, phase IV study designed to determine whether chronic, low-grade nonhematologic adverse events in imatinib-treated patients improve after switching to dasatinib, without affecting efficacy...
March 20, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29551130/acquired-resistance-to-drugs-targeting-tyrosine-kinases
#13
Steven A Rosenzweig
Resistance to chemotherapeutic drugs exemplifies the greatest hindrance to effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over 50 years and have revealed the lack of a single cause, but instead, multiple mechanisms including induced expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system, and altered metabolism. Treatment of cancer patients/cancer cells with chemotherapeutic agents and/or molecularly targeted drugs is accompanied by acquisition of resistance to the treatment administered...
2018: Advances in Cancer Research
https://www.readbyqxmd.com/read/29549929/local-anesthetic-drug-inhibits-growth-and-survival-in-chronic-myeloid-leukemia-through-suppressing-pi3k-akt-mtor
#14
Qinghong Zheng, Xiaohong Peng, Hai Yu
BACKGROUND: Apart from the known anesthetic and antiarrhythmic effects, recent studies also highlight the anticancer activities of local anesthetics. In line with the findings, our work shows that ropivacaine, an amide-linked local anesthetic drug, targets chronic myeloid leukemia (CML) via inhibiting PI3K/Akt/mTOR. MATERIALS AND METHODS: The effects of ropivacaine in CML cell lines and primary stem or progenitor cells were investigated using apoptosis, proliferation and colony formation assays...
March 2018: American Journal of the Medical Sciences
https://www.readbyqxmd.com/read/29545943/dasatinib-overrides-the-differentiation-blockage-in-a-patient-with-mutant-kit-d816v-positive-cbf%C3%AE-myh11-leukemia
#15
Kerstin M Kampa-Schittenhelm, Wichard Vogel, Irina Bonzheim, Falko Fend, Marius Horger, Lothar Kanz, Martin Soekler, Marcus M Schittenhelm
Activating KIT D816V mutations are frequently found in CBF AML, which predicts for an unfavorable outcome. Dasatinib is a potent inhibitor of wildtype and mutant-KIT isoforms - including D816V. We now provide proof of antileukemic efficacy in a patient with relapsing mutant- KIT D816V CBF AML. Importantly, this effect is mediated via overriding the differentiation blockage of the leukemia clone. In addition, we show that dasatinib is capable to induce pulmonary differentiation syndrome - and therefore needs close monitoring of patients under therapy...
February 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29545424/chronic-myelogenous-leukaemia-with-a-p53-mutation-demonstrated-neutrophilic-granulocytes-with-nuclear-hypolobation-pseudo-pelger-h%C3%A3-et-anomaly-and-hypogranulation-in-the-peripheral-blood-smear
#16
Motoharu Shibusawa, Jiro Tadokoro, Masaru Kojima, Makoto Kashimura
A 70-year-old man visited our emergency department, whose laboratory test results revealed leucocytosis, anaemia, thrombocytopenia and high levels of serum lactate dehydrogenase. In addition, the peripheral blood smear revealed neutrophilic granulocytes with nuclear hypolobation (pseudo-Pelger-Hüet anomaly), hypogranulation and no myeloperoxidase reactivity. Genetic testing of the peripheral blood sample was as follows: G-band, 46XY,t(9;22)(q34;q11.2) (20/20); fluorescence in situ hybridisation BCR/ABL fusion signal, 97%; and analysis of exons 5-9 of the p53 gene, mutation (Pro72Arg) in exon 4 protein...
March 15, 2018: BMJ Case Reports
https://www.readbyqxmd.com/read/29541231/co-existence-of-isodicentric-ph-chromosomes-and-the-three-way-ph-chromosome-variant-t-3-9-22-p21-q34-q11-in-a-rare-case-of-chronic-myeloid-leukemia
#17
Qian Li, Xiao-Ji Lin, Hui Chen, Jian Gong, Zhen Li, Xiang-Nan Chen
More than 90% of patients with chronic myeloid leukemia (CML) have the chromosomal translocation t(9;22)(q34;q11), while 5-8% of patients have complex variant translocations that have previously been thought not to affect the efficacy of imatinib therapy. The present study reports a patient with CML in B-lymphoid blast crisis who had a rare three-way Philadelphia (Ph) variant t(3;9;22)(p21;q34;q11), in addition to isodicentric Ph chromosomes. The patient was initially treated with imatinib for >2 months with a very poor response...
April 2018: Oncology Letters
https://www.readbyqxmd.com/read/29535838/targeting-loss-of-the-hippo-signaling-pathway-in-nf2-deficient-papillary-kidney-cancers
#18
Carole Sourbier, Pei-Jyun Liao, Christopher J Ricketts, Darmood Wei, Youfeng Yang, Sarah M Baranes, Benjamin K Gibbs, Lernik Ohanjanian, L Spencer Krane, Bradley T Scroggins, J Keith Killian, Ming-Hui Wei, Toshiki Kijima, Paul S Meltzer, Deborah E Citrin, Len Neckers, Cathy D Vocke, W Marston Linehan
Papillary renal cell carcinomas (PRCC) are a histologically and genetically heterogeneous group of tumors that represent 15-20% of all kidney neoplasms and may require diverse therapeutic approaches. Alteration of the NF2 tumor suppressor gene, encoding a key regulator of the Hippo signaling pathway, is observed in 22.5% of PRCC. The Hippo signaling pathway controls cell proliferation by regulating the transcriptional activity of Yes-Associated Protein, YAP1. Loss of NF2 results in aberrant YAP1 activation...
February 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29526392/dasatinib-in-paediatric-chronic-myeloid-leukaemias
#19
Priya Venkatesan
No abstract text is available yet for this article.
March 8, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29519619/efficacy-of-ponatinib-versus-earlier-generation-tyrosine-kinase-inhibitors-for-front-line-treatment-of-newly-diagnosed-philadelphia-positive-acute-lymphoblastic-leukemia
#20
Elias Jabbour, Maral DerSarkissian, Mei Sheng Duh, Nora McCormick, Wendy Y Cheng, Lisa J McGarry, Ariadne Souroutzidis, Hui Huang, Susan O'Brien, Farhad Ravandi, Hagop M Kantarjian
INTRODUCTION: Complete molecular response (CMR) and 2- and 3-year overall survival (OS) were compared for patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) who had undergone front-line combination chemotherapy plus ponatinib versus combination therapy plus earlier generation tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, and nilotinib). PATIENTS AND METHODS: We identified 26 Ph+ ALL studies: 25 of earlier generation TKIs and 1 of ponatinib...
February 17, 2018: Clinical Lymphoma, Myeloma & Leukemia
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