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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
#1
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/29423110/potential-for-subsets-of-wt-npm1-primary-aml-blasts-to-respond-to-retinoic-acid-treatment
#2
Rodica P Bunaciu, Robert J MacDonald, Feng Gao, Lynn M Johnson, Jeffrey D Varner, Xin Wang, Sarah Nataraj, Monica L Guzman, Andrew Yen
Acute myeloid leukemia (AML) has high mortality rates, perhaps reflecting a lack of understanding of the molecular diversity in various subtypes and a lack of known actionable targets. There are currently 12 open clinical trials for AML using combination therapeutic modalities including all-trans retinoic acid (RA). Mutant nucleophosmin-1, proposed as a possible marker for RA response, is the criterion for recruiting patients in three active RA phase 3 clinical trials. We tested the ability of RA alone or in combination with either bosutinib (B) or 6-formylindolo(3,2-b) carbazole (F) to induce conversion of 12 de novo AML samples toward a more differentiated phenotype...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29415932/-management-of-cardiovascular-complications-in-cml-patients-treated-with-tyrosine-kinase-inhibitors
#3
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
#4
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/29385394/practical-management-of-toxicities-associated-with-bosutinib-in-patients-with-philadelphia-chromosome-positive-chronic-myeloid-leukemia
#5
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/29381234/balancing-early-access-with-uncertainties-in-evidence-for-drugs-authorized-by-prospective-case-series-systematic-review-of-reimbursement-decisions
#6
Susanna M Wallerstedt, Martin Henriksson
AIMS: To review clinical and cost-effectiveness evidence underlying reimbursement decisions relating to drugs whose authorization mainly is based on evidence from prospective case series. METHODS: A systematic review of all new drugs evaluated in 2011-2016 within a health care profession-driven resource prioritization process, with a market approval based on prospective case series, and a reimbursement decision by the Swedish Dental and Pharmaceutical Benefits Board (TLV)...
January 30, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29316665/towards-comprehension-of-the-abcb1-p-glycoprotein-role-in-chronic-myeloid-leukemia
#7
REVIEW
Raquel C Maia, Flavia C Vasconcelos, Paloma S Souza, Vivian M Rumjanek
Abstract: The introduction of imatinib (IM), a BCR-ABL1 tyrosine kinase inhibitor (TKI), has represented a significant advance in the first-line treatment of chronic myeloid leukemia (CML). However, approximately 30% of patients need to discontinue IM due to resistance or intolerance to this drug. Both resistance and intolerance have also been observed in treatment with the second-generation TKIs-dasatinib, nilotinib, and bosutinib-and the third-generation TKI-ponatinib. The mechanisms of resistance to TKIs may be BCR-ABL1-dependent and/or BCR-ABL1-independent...
January 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29274040/lc-ms-ms-method-for-the-quantification-of-masitinib-in-rlms-matrix-and-rat-urine-application-to-metabolic-stability-and-excretion-rate
#8
Sawsan M Amer, Adnan A Kadi, Hany W Darwish, Mohamed W Attwa
Masitinib (MST) is a selective tyrosine kinase inhibitor. Validated liquid chromatography tandem mass spectrometric method (LC-MS/MS) was developed for the quantification of MST in rat liver microsomes (RLMs) matrix. The developed method was applied to metabolic stability and excretion rate studies. Reversed phase liquid chromatography was used for resolution of MST and bosutinib (IS) using C18 (50 mm × 2.1 mm, 1.8 μm). Binary solvent system consisted of 35% solvent A (0.1% formic acid in H2O, pH: 3...
December 22, 2017: Chemistry Central Journal
https://www.readbyqxmd.com/read/29220734/high-throughput-routine-determination-of-17-tyrosine-kinase-inhibitors-by-lc-ms-ms
#9
Camille Merienne, Marine Rousset, Dominique Ducint, Nadège Castaing, Karine Titier, Mathieu Molimard, Stéphane Bouchet
Several studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKI) can improve their benefit in cancer. An analytical tool has been developed in order to quantify 17 tyrosine kinase inhibitors and 2 metabolites in human plasma (afatinib, axitinib, bosutinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, ponatinib, regorafenib, regorafenib M2, regorafenib M5, ruxolitinib, sorafenib, sunitinib, vandetanib). Drugs were arranged in four groups, according to their plasma concentration range: 0...
November 28, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29212964/simple-determination-of-plasma-ponatinib-concentration-using-hplc
#10
Takeo Yasu, Kenji Momo, Shunsuke Kobayashi, Seiichirou Kuroda, Arinobu Tojo
Ponatinib, a novel tyrosine kinase inhibitor marketed in 2016, is a key drug used for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. This study aimed to develop a simple method for determining plasma ponatinib concentration. The analysis required extraction of a 400-μL sample of plasma and precipitation of proteins using an Oasis HLB cartridge. Ponatinib and bosutinib, which is used as an internal standard, were separated by HPLC using a mobile phase of acetonitrile: 0...
December 6, 2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29202231/identification-of-novel-aurora-kinase-a-aurka-inhibitors-via-hierarchical-ligand-based-virtual-screening
#11
Yue Kong, Andreas Bender, Aixia Yan
Aurora kinases are essential for cell mitosis, amplified and overexpressed in various human malignancies. Therefore, Aurora kinases have been promising targets for anticancer therapies, which has prompted an intensive search for their small-molecule inhibitors. In this work, we performed a hierarchical and time-efficient virtual screening cascade for scaffold hopping, aiming to obtain structurally novel and highly potent hit compounds targeting Aurora kinases. The cascade consisted of a shape- and an electrostatic-based protocol, combined with a QSAR-based selection protocol...
December 4, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29185155/successful-treatment-of-follicular-lymphoma-with-second-generation-tyrosine-kinase-inhibitors-administered-for-coexisting-chronic-myeloid-leukemia
#12
Shin-Ichiro Fujiwara, Yuya Shirato, Takashi Ikeda, Shin-Ichiro Kawaguchi, Yumiko Toda, Shoko Ito, Shin-Ichi Ochi, Takashi Nagayama, Kiyomi Mashima, Kento Umino, Daisuke Minakata, Hirofumi Nakano, Kaoru Morita, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Masahiro Ashizawa, Chihiro Yamamoto, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Kazuo Muroi, Yoshinobu Kanda
Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic myeloid leukemia (CML). However, the effects of these agents on mature B cell lymphoma are not well known. We describe a 50-year-old man who was diagnosed with CML in the chronic phase and treated with imatinib. After 3 years of imatinib therapy that achieved a complete cytogenetic response of CML, he developed Philadelphia-negative follicular lymphoma (FL). Rituximab monotherapy induced a partial response of FL, and he subsequently achieved a major molecular response (MMR) of CML...
November 28, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/29138996/ichthyosiform-pityriasis-rubra-pilaris-like-eruption-secondary-to-ponatinib-therapy-case-report-and-literature-review
#13
Ariel E Eber, Alyx Rosen, Kate E Oberlin, Alessio Giubellino, Paolo Romanelli
Tyrosine kinase inhibitors have revolutionized the chemotherapy arena as targeted therapies for a multitude of malignancies. They are more selective than conventional chemotherapy, and often elicit fewer systemic adverse events, however toxicities still exist. Cutaneous toxicities are common and their management presents a novel challenge to physicians and patients. Ponatinib is a third-generation tyrosine kinase inhibitor increasingly reported to cause cutaneous eruption. A 50-year-old woman with a history of chronic myelogenous leukemia presented with a 4-month history of worsening atrophic and ichthyosiform pink plaques involving the axillae, thighs and abdomen; red patches were also observed on the cheeks and forehead...
November 14, 2017: Drug Safety—Case Reports
https://www.readbyqxmd.com/read/29129440/bosutinib-more-effective-than-imatinib-in-cml
#14
Elizabeth Gourd
No abstract text is available yet for this article.
November 9, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29101238/glucocorticoid-resistance-is-reverted-by-lck-inhibition-in-pediatric-t-cell-acute-lymphoblastic-leukemia
#15
Valentina Serafin, Giorgia Capuzzo, Gloria Milani, Sonia Anna Minuzzo, Marica Pinazza, Roberta Bortolozzi, Silvia Bresolin, Elena Porcù, Chiara Frasson, Stefano Indraccolo, Giuseppe Basso, Benedetta Accordi
Pediatric T-acute lymphoblastic leukemia (T-ALL) patients often display resistance to glucocorticoid (GC) treatment. These patients, classified as prednisone poor responders (PPR), have poorer outcome than do the other pediatric T-ALL patients receiving a high-risk adapted therapy. Because glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to improving the outcome for these patients. Mechanisms underlying resistance are not yet fully unraveled; thus our research focused on the identification of deregulated signaling pathways to point out new targeted approaches...
December 21, 2017: Blood
https://www.readbyqxmd.com/read/29091516/bosutinib-versus-imatinib-for-newly-diagnosed-chronic-myeloid-leukemia-results-from-the-randomized-bfore-trial
#16
Jorge E Cortes, Carlo Gambacorti-Passerini, Michael W Deininger, Michael J Mauro, Charles Chuah, Dong-Wook Kim, Irina Dyagil, Nataliia Glushko, Dragana Milojkovic, Philipp le Coutre, Valentin Garcia-Gutierrez, Laurence Reilly, Allison Jeynes-Ellis, Eric Leip, Nathalie Bardy-Bouxin, Andreas Hochhaus, Tim H Brümmendorf
Purpose Bosutinib is a potent dual SRC/ABL kinase inhibitor approved for adults with Philadelphia chromosome-positive chronic myeloid leukemia (CML) resistant and /or intolerant to prior therapy. We assessed the efficacy and safety of bosutinib versus imatinib for first-line treatment of chronic-phase CML. Methods In this ongoing, multinational, phase III study, 536 patients with newly diagnosed chronic-phase CML were randomly assigned 1:1 to receive 400 mg of bosutinib once daily (n = 268) or imatinib (n = 268)...
November 1, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29072772/long-term-patient-reported-outcomes-from-an-open-label-safety-and-efficacy-study-of-bosutinib-in-philadelphia-chromosome-positive-chronic-myeloid-leukemia-patients-resistant-or-intolerant-to-prior-therapy
#17
Hagop M Kantarjian, Carla M Mamolo, Carlo Gambacorti-Passerini, Jorge E Cortes, Tim H Brümmendorf, Yun Su, Arlene L Reisman, Mark Shapiro, Jeff H Lipton
BACKGROUND: Health-related quality of life (HRQOL) in patients with chronic-phase chronic myeloid leukemia (CML) is important because of the requirement for long-term treatment. This study assessed HRQOL in bosutinib-treated patients with Philadelphia chromosome-positive CML and resistance or intolerance to 1 (chronic-phase second-line [CP2L]) or more (chronic-phase third-line [CP3L]) tyrosine kinase inhibitors who had 264 weeks or more of follow-up (ClinicalTrials.gov identifier NCT00261846)...
October 26, 2017: Cancer
https://www.readbyqxmd.com/read/29058816/absolute-bioavailability-of-bosutinib-in-healthy-subjects-from-an-open-label-randomized-2-period-crossover-study
#18
Poe-Hirr Hsyu, Daniela Soriano Pignataro, Kyle Matschke
This study evaluated the absolute bioavailability of bosutinib and assessed its safety and tolerability after single-dose oral and intravenous administration. In this phase 1 open-label, 2-sequence, 2-period crossover study, healthy, fed subjects aged 18-55 years were randomized to 1 of 2 treatment sequences (n = 7/sequence): oral bosutinib (100 mg × 5) followed by intravenous bosutinib (120 mg in approximately 240 mL over 1 hour), with a ≥14-day washout, or intravenous bosutinib and then oral bosutinib...
October 23, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/29018127/bosutinib-attenuates-inflammation-via-inhibiting-salt-inducible-kinases-in-experimental-model-of-intracerebral-hemorrhage-on-mice
#19
Li Ma, Anatol Manaenko, Yi-Bo Ou, An-Wen Shao, Shu-Xu Yang, John H Zhang
BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a subtype of stroke with highest mortality and morbidity. Pronounced inflammation plays a significant role in the development of the secondary brain injury after ICH. Recently, SIK-2 (salt-inducible kinase-2) was identified as an important component controlling inflammatory response. Here we sought to investigate the role of SIK-2 in post-ICH inflammation and potential protective effects of SIK-2 inhibition after ICH. METHODS: Two hundred and ninety-three male CD-1 mice were used...
November 2017: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/28990873/third-line-treatment-with-second-generation-tyrosine-kinase-inhibitors-dasatinib-or-nilotinib-in-patients-with-chronic-myeloid-leukemia-after-two-prior-tkis-real-life-data-on-a-single-center-experience-along-with-the-review-of-the-literature
#20
Seniz Ongoren, Ahmet Emre Eskazan, Veysel Suzan, Sercan Savci, Isil Erdogan Ozunal, Selin Berk, Fevzi Fırat Yalniz, Tugrul Elverdi, Ayse Salihoglu, Yucel Erbilgin, Sibel Aylin Iseri, Muhlis Cem Ar, Zafer Baslar, Yildiz Aydin, Nukhet Tuzuner, Ugur Ozbek, Teoman Soysal
OBJECTIVES: Newer tyrosine kinase inhibitors (TKIs) (bosutinib, ponatinib) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be utilized as a salvage therapy in patients with chronic myeloid leukemia (CML) who failed two lines (imatinib → nilotinib or imatinib → dasatinib) of TKI therapy. However, these TKIs are not available in many countries and not all patients can undergo allo-HSCT. METHODS: In this study, CML patients who received dasatinib or nilotinib as a third-line treatment were retrospectively evaluated...
October 9, 2017: Hematology (Amsterdam, Netherlands)
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