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https://www.readbyqxmd.com/read/28646676/multicenter-phase-2-study-of-combination-therapy-with-ruxolitinib-and-danazol-in-patients-with-myelofibrosis
#1
K Gowin, H Kosiorek, A Dueck, J Mascarenhas, R Hoffman, C Reeder, J Camoriano, R Tibes, K Gano, J Palmer, R Mesa
Myelofibrosis is a myeloproliferative neoplasm that is characterized by splenomegaly, profound symptom burden, and cytopenias. JAK inhibitor therapy offers improvements in splenomegaly, symptom burden, and potentially survival; however, cytopenias remain a significant challenge. Danazol has previously demonstrated improvements in myelofibrosis-associated anemia. We conducted a phase II clinical trial evaluating the efficacy and tolerability of combination therapy with ruxolitinib, an oral JAK inhibitor, and danazol...
June 13, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28645562/anti-myeloma-effects-of-ruxolitinib-combined-with-bortezomib-and-lenalidomide-a-rationale-for-jak-stat-pathway-inhibition-in-myeloma-patients
#2
Mariana B de Oliveira, Veruska L Fook-Alves, Angela I P Eugenio, Rodrigo C Fernando, Luiz Felipe G Sanson, Mariana F de Carvalho, Walter M T Braga, Faith E Davies, Gisele W B Colleoni
JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells; therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI-8226 and U266 MM cell lines. 57% of patients presented overexpression of JAK2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubG0 phase...
June 20, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28635319/a-case-of-topical-ruxolitinib-treatment-failure-in-alopecia-areata
#3
Maya Deeb, Renée A Beach
Alopecia areata (AA) is an autoimmune-mediated, nonscarring form of hair loss. Despite its prevalence, current management options are limited, especially when the disease has progressed to alopecia totalis (AT) or alopecia universalis (AU). Recent evidence that janus kinase (JAK) signaling contributes to AA pathogenesis prompted the investigation of JAK inhibitors such as tofacitinib and ruxolitinib as possible oral treatments. However, the potential for significant adverse effects with systemic JAK inhibition makes local administration a more attractive option...
June 1, 2017: Journal of Cutaneous Medicine and Surgery
https://www.readbyqxmd.com/read/28628689/aggressive-skin-cancers-occurring-in-patients-treated-with-the-janus-kinase-inhibitor-ruxolitinib
#4
Adam B Blechman, Christine E Cabell, Christine H Weinberger, Anna Duckworth, Justin J Leitenberger, Fiona O Zwald, Mark A Russell
<p>The Food and Drug Administration approved Ruxolitinib in 2011 for the treatment of primary myelofibrosis. Five-year safety data showed a higher incidence of skin cancer in patients treated with Ruxolitinib compared to best available therapy for myelofibrosis. This report presents a series of five patients with history of myelofibrosis treated with Ruxolitinib who subsequently developed numerous skin cancers with aggressive biological behavior. Each patient in this report was treated by a Mohs surgeon affiliated with an academic institution...
May 1, 2017: Journal of Drugs in Dermatology: JDD
https://www.readbyqxmd.com/read/28622305/the-thrombopoietin-mpl-axis-is-activated-in-the-gata1-low-mouse-model-of-myelofibrosis-and-is-associated-with-a-defective-rps14-signature
#5
M Zingariello, L Sancillo, F Martelli, F Ciaffoni, M Marra, L Varricchio, R A Rana, C Zhao, J D Crispino, A R Migliaccio
Myelofibrosis (MF) is characterized by hyperactivation of thrombopoietin (TPO) signaling, which induces a RPS14 deficiency that de-regulates GATA1 in megakaryocytes by hampering its mRNA translation. As mice carrying the hypomorphic Gata1(low) mutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1(low) mice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1(low) LSKs expressed levels of Mpl mRNA (five times greater than normal) and protein (two times lower than normal) similar to those expressed by LSKs from TPO-treated wild-type mice...
June 16, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28619982/jak1-2-and-bcl2-inhibitors-synergize-to-counteract-bone-marrow-stromal-cell-induced-protection-of-aml
#6
Riikka Karjalainen, Tea Pemovska, Mihaela Popa, Minxia Liu, Komal K Javarappa, Muntasir M Majumder, Bhagwan Yadav, David Tamborero, Jing Tang, Dmitrii Bychkov, Mika Kontro, Alun Parsons, Minna Suvela, Mireia Mayoral Safont, Kimmo Porkka, Tero Aittokallio, Olli Kallioniemi, Emmet McCormack, Bjørn T Gjertsen, Krister Wennerberg, Jonathan Knowles, Caroline A Heckman
The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be due to the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the impact of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions...
June 15, 2017: Blood
https://www.readbyqxmd.com/read/28606598/practical-measures-of-clinical-benefit-with-ruxolitinib-therapy-an-exploratory-analysis-of-comfort-i
#7
Carole B Miller, Rami S Komrokji, Ruben A Mesa, William Sun, Michael Montgomery, Srdan Verstovsek
BACKGROUND: The phase III COMFORT (Controlled Myelofibrosis Study With Oral JAK inhibitor Treatment)-I and COMFORT-II trials in patients with intermediate-2 or high-risk myelofibrosis (MF) showed that ruxolitinib was superior to placebo and best available therapy, respectively, for improvements in spleen volume, MF-related symptoms, and overall survival (OS). However, patients managed in community settings might not have access to the methods used in the COMFORT trials. In this exploratory analysis we summarize efficacy findings of COMFORT-I using practical, community-oriented measures of patient outcomes...
May 12, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28602585/janus-kinase-2-inhibitor-fedratinib-in-patients-with-myelofibrosis-previously-treated-with-ruxolitinib-jakarta-2-a-single-arm-open-label-non-randomised-phase-2-multicentre-study
#8
Claire N Harrison, Nicolaas Schaap, Alessandro M Vannucchi, Jean-Jacques Kiladjian, Ramon V Tiu, Pierre Zachee, Eric Jourdan, Elliott Winton, Richard T Silver, Harry C Schouten, Francesco Passamonti, Sonja Zweegman, Moshe Talpaz, Joanne Lager, Zhenming Shun, Ruben A Mesa
BACKGROUND: Myelofibrosis is a chronic myeloproliferative neoplasm characterised by splenomegaly, cytopenias, bone marrow fibrosis, and debilitating symptoms including fatigue, weight loss, and bone pain. Mutations in Janus kinase-2 (JAK2) occur in approximately 50% of patients. The only approved JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib. 58-71% of patients treated with ruxolitinib in clinical trials so far have not achieved the primary endpoint of 35% or more reduction in spleen volume from baseline assessed by MRI or CT...
June 8, 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28598077/-the-effect-of-ruxolitinib-on-the-expression-of-vegf-and-hif-1%C3%AE-in-leukemia-hel-cells
#9
Qian Xu, Gui-Min Liu, Feng-Yun Wang, Li-Jun Zhang, Wen-Tong Liang, Zhi-Yong Cheng
OBJECTIVES: To investigate the effect of Ruxolitinib on the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 α (HIF-1α) in HEL cells. METHODS: he HEL cells were treated with Ruxolitinib in different concentrations (1 nmol/L, 5 nmol/L, 10 nmol/L, 50 nmol/L, 100 nmol/L, 500 nmol/L). The growth inhibition of Ruxolitinib on HEL cells was detected by CCK-8 assay;the mRNA expression level ofJAK2 were measured by RT-PCR and the protein level of p-JAK2, VEGF, HIF-1α were observed by Western blot after treated with Ruxolitinib for 24,48,72 h...
September 2016: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28586756/inhibitors-of-the-pi3k-mtor-pathway-prevent-stat5-phosphorylation-in-jak2v617f-mutated-cells-through-pp2a-cip2a-axis
#10
Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
May 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28579852/treatment-of-myelofibrosis-old-and-new-strategies
#11
REVIEW
Alessandra Iurlo, Daniele Cattaneo
Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm that is mainly characterised by reactive bone marrow fibrosis, extramedullary haematopoiesis, anaemia, hepatosplenomegaly, constitutional symptoms, leukaemic progression, and shortened survival. As such, this malignancy is still orphan of curative treatments; indeed, the only treatment that has a clearly demonstrated impact on disease progression is allogeneic haematopoietic stem cell transplantation, but only a minority of patients are eligible for such intensive therapy...
2017: Clinical Medicine Insights. Blood Disorders
https://www.readbyqxmd.com/read/28571503/managing-side-effects-of-jak-inhibitors-for-myelofibrosis-in-clinical-practice
#12
Iram Saeed, Donal McLornan, Claire N Harrison
Myelofibrosis (MF) is characterized by bone marrow fibrosis, abnormalities in peripheral counts, extramedullary hematopoiesis, splenomegaly and an increased risk of transformation to acute myeloid leukaemia. The disease course is often heterogeneous and management can range from observation alone through to allogeneic stem cell transplantation. As of 2017, the only approved medication for MF remains the JAK Inhibitor (JAKi), ruxolitinib (Novartis Pharmaceuticals, Basel, Switzerland; Incyte, Wilmington, Detroit, USA) although several others have reached advanced stages of clinical trials...
June 19, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28566376/ruxolitinib-and-polycation-combination-treatment-overcomes-multiple-mechanisms-of-resistance-of-pancreatic-cancer-cells-to-oncolytic-vesicular-stomatitis-virus
#13
Sébastien A Felt, Gaith N Droby, Valery Z Grdzelishvili
Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV). Although VSV is effective against a majority of pancreatic ductal adenocarcinoma (PDAC) cell lines, some PDAC cell lines are highly resistant to VSV, and the mechanisms of the resistance are still unclear. JAK 1/2 inhibitors (such as ruxolitinib and JAK Inhibitor 1) strongly stimulate VSV replication and oncolysis in all resistant cell lines, but only partially improve susceptibility of resistant PDACs to VSV. VSV tumor tropism is generally dependent on the permissiveness of malignant cells to viral replication, rather than on receptor specificity, with several ubiquitously expressed cell-surface molecules to play a role in VSV attachment to host cells...
May 31, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28554272/angiogenesis-in-jak2-v617f-positive-myeloproliferative-neoplasms-and-ruxolitinib-decrease-vegf-hif-1-enesis-in-jak2-v617f-positive-cells
#14
Zhiyong Cheng, Jianzhu Fu, Guimin Liu, Lijun Zhang, Qian Xu, Su-Yun Wang
Angiogenesis and JAK2 V617F mutation are common in BCR-ABL1 negative myeloproliferative neoplasms (MPNs). Ruxolitinib, a JAK inhibitor, is an effective treatment for some MPNs. However, the relationship between angiogenesis and JAK2 V617F and the effects of ruxolitinib on angiogenesis are still unknown. Here, we observed the correlation of JAK2 V617F mutation burden with VEGF, HIF-1a and microvascular density (MVD) in MPNs. We investigate the effect of ruxolitinib on the expression of VEGF and HIF-1α in JAK2 V617F positive cells...
May 30, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28540737/investigational-drugs-in-phase-i-and-phase-ii-clinical-trials-for-thalassemia
#15
Irene Motta, Natalia Scaramellini, Maria Domenica Cappellini
Regular transfusion and iron chelation are the current treatment of severe forms of thalassemia. As a consequence of this demanding supportive treatment, there are several unmet therapeutic needs. Due to a deeper understanding in the pathophysiology of thalassemia, new therapeutic strategies have been developed that are now in pre-clinical and clinical trials. Areas covered: Activin receptor ligand traps (luspatercept and sotatercept), drugs targeting ineffective erythropoiesis, showed encouraging results in Phase I and II clinical trials...
June 5, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28515254/nccn-debuts-new-guidelines-for-myeloproliferative-neoplasms
#16
Ruben A Mesa
For the first time, NCCN has published guidelines specifically geared toward treating myeloproliferative neoplasms (MPNs). The first set of guidelines was developed for myelofibrosis (MF), and was presented at the NCCN 22nd Annual Conference. Future guidelines will be issued for polycythemia vera, essential thrombocytopenia, and atypical MPNs. Patients with MF can have an unpredictable course, one that is largely dependent on the presence of certain molecular alterations. Models are currently emerging that take into account molecular factors...
May 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28512865/efficacy-and-safety-of-ruxolitinib-in-intermediate-1-ipss-risk-myelofibrosis-patients-results-from-an-independent-study
#17
Francesca Palandri, Mario Tiribelli, Giulia Benevolo, Alessia Tieghi, Francesco Cavazzini, Massimo Breccia, Micaela Bergamaschi, Nicola Sgherza, Nicola Polverelli, Monica Crugnola, Alessandro Isidori, Gianni Binotto, Florian H Heidel, Francesco Buccisano, Bruno Martino, Roberto Latagliata, Marco Spinsanti, Lydia Kallenberg, Giuseppe Alberto Palumbo, Elisabetta Abruzzese, Luigi Scaffidi, Antonio Cuneo, Michele Cavo, Nicola Vianelli, Massimiliano Bonifacio
Patients with myelofibrosis at intermediate-1 risk according to the International Prognostic Score System are projected to a relatively long survival; nonetheless, they may carry significant splenomegaly and/or systemic constitutional symptoms that hamper quality of life and require treatment. Since registrative COMFORT studies included only patients at intermediate-2/high International Prognostic Score System risk, safety and efficacy data in intermediate-1 patients are limited. We report on 70 intermediate-1 patients treated with ruxolitinib according to standard clinical practice that were evaluated for response using the 2013 IWG-MRT criteria...
May 17, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28500170/jak2-inhibitors-for-myeloproliferative-neoplasms-what-is-next
#18
Prithviraj Bose, Srdan Verstovsek
Since its approval in 2011, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant/intolerant polycythemia vera (PV) is steadily increasing. A number of other JAK2 inhibitors have entered clinical testing, but none has been approved yet, and many discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, where survival is short...
May 12, 2017: Blood
https://www.readbyqxmd.com/read/28496202/inhibition-of-jak-stat-signaling-reduces-the-activation-of-pancreatic-stellate-cells-in-vitro-and-limits-caerulein-induced-chronic-pancreatitis-in-vivo
#19
Hannah M Komar, Gregory Serpa, Claire Kerscher, Erin Schwoegl, Thomas A Mace, Ming Jin, Ming-Chen Yang, Ching-Shih Chen, Mark Bloomston, Michael C Ostrowski, Phil A Hart, Darwin L Conwell, Gregory B Lesinski
Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28491265/experience-with-ruxolitinib-in-the-treatment-of-polycythaemia-vera
#20
REVIEW
Samah Alimam, Claire Harrison
Polycythaemia vera (PV) is a myeloproliferative neoplasm classically characterized by an erythrocytosis and is associated with a high risk of thromboembolic events, constitutional symptoms burden and risk of transformation to myelofibrosis and acute myeloid leukaemia. Therapy is directed at the haematocrit (HCT) to reduce the risk of thrombotic events and usually comprises low-dose aspirin and phlebotomy to maintain HCT at >45%. Frequently in addition, cytoreductive therapy is indicated in high-risk patients for normalizing haematological parameters to mitigate the occurrence of thromboembolic events...
April 2017: Therapeutic Advances in Hematology
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