FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2264962020> ?p ?o ?g. }

• W2264962020 endingPage "327" @default.
• W2264962020 startingPage "324" @default.
• W2264962020 abstract "Approval for use of the JAK1/2 inhibitor ruxolitinib (Novartis Pharmaceuticals, Basel, Switzerland) for myelofibrosis (MF) was granted in 2011. This followed two large Phase III trials [Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment (COMFORT)-I and II] that demonstrated significant improvements in quality of life with spleen reduction compared to both placebo and best available therapy (Harrison et al, 2012; Verstovsek et al, 2012). However, the efficacy and safety of ruxolitinib as a therapeutic agent in the spectrum of mast cell disorders remains unknown. We report that ruxolitinib objectively improved symptom burden and splenomegaly in a patient with Systemic Mastocytosis (SM) with associated clonal haematological non-mast cell lineage disease (SM-AHNMD). A 63-year-old female presented with diarrhoea, fatigue, night sweats requiring daily changes in clothes, early satiety and progressive dyspnea. Examination demonstrated bulky splenomegaly with no associated hepatomegaly. Laboratory investigations revealed haemoglobin 102 g/l, mean cell volume 97 fl, leucocytosis 24 × 109/l (predominant neutrophilia) and platelet count 202 × 109/l. The patient was referred to our centre with a presumed diagnosis of MF, However, investigation revealed a leucoerythroblastic blood film with <1% circulating blasts and markedly dysplastic neutrophils. Serum tryptase level was elevated at 20·1 μg/l and cytogenetic analysis revealed a normal karyotype. Trephine biopsy was hypercellular for age with marked dyserythropoietic features. Granulopoiesis was expanded with many neutrophils showing abnormal nuclear folding. Megarkaryocyte nuclear hyper- and hypo-lobulation was prominent. Approximately 50% of the remaining marrow was replaced by either hypercellular interstitial nodules of spindle-shaped mast cells, which expressed mast cell tryptase, CD117, CD25, CD68 and weak positivity for CD30, or extensive paratrabecular zones of reticulin fibrosis. Overall histopathological features were in keeping with SM with Refractory Cytopenia with Multilineage Dysplasia (Fig 1A–C). Mutation analyses demonstrated no evidence of JAK2, KIT, MPL or CALR mutations. Furthermore, a next generation sequencing (NGS) panel for 24 genes commonly mutated in myeloid disorders did not reveal any additional pathogenetic mutations. The patient was commenced on H1/H2- histamine receptor blockers and sodium cromoglycate. Her diarrhoea improved, however, over a 6-month period the patient developed increasingly symptomatic splenomegaly, continued early satiety and still had persistent night sweats. Blood counts revealed stable haemoglobin (103 g/l), progressive leucocytosis (90 × 109/l; predominant neutrophilia) and a platelet count of 121 × 109/l. An empirical trial of imatinib for a 3-month period produced no benefit. At this stage, the patient was displaying progressive constitutional symptoms. Given her profound symptom burden, ruxolitinib 5 mg twice daily was commenced. Within 2 weeks, her symptom burden as regards fatigue had markedly improved. At 1 month she continued to have clinical improvement and ruxolitinib was increased to 10 mg twice daily. By 2 months, her weight had stabilised and there had been abatement of both sweats and pyrexia. Although not yet fully validated for use in SM, we utilized the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) to assess symptom burden during the first 5 weeks of therapy (Emanuel et al, 2012). Sequential analyses demonstrated marked symptom amelioration (Fig 2). By month 4 of ruxolitinib treatment the spleen length had improved, from 11 cm to 8 cm below the costal margin. Blood count analysis revealed a haemoglobin of 100 g/l, leucocyte count of 34 × 109/l and platelet count of 114 × 109/l. Repeat marrow demonstrated no significant change in mast cell burden or fibrosis. No adverse events were experienced during ruxolitinib therapy and cytopenias were not evident. Due to an improved performance status the patient successfully underwent an allogeneic stem cell transplant. Ruxolitinib was tapered slowly over a 10-day period prior to commencement of conditioning therapy with no symptom flare. Systemic Mastocytosis is heterogeneous with clinical phenotypes ranging from indolent disorders through to aggressive subtypes that rapidly transform to leukaemic variants. A retrospective study of 342 SM patients assessed over a 31-year period revealed that 138 (40%) were classified as SM-AHNMD (Lim et al, 2009). Median survival for those with SM-AHNMD was poor, at only 24 months. Treatment is often complex-dictated by the co-existing AHNMD in addition to addressing the SM component. It is well established that mast cells are a source of multiple cytokines/chemokines including FGF, VEGF, IL6, IL5, IL16, TNFα and GM-CSF (reviewed in Katsanos et al, 2008). Many of these pro-inflammatory cytokines utilize the JAK1/JAK2-STAT pathway for signalling. In addition, STAT5 has been shown as a regulator of mast cell proliferation, homeostasis and release of mediator substances (Shelburne et al, 2002). Mayado et al (2015) measured serum levels of IL1β, IL6, IL13, CCL23 and clusterin in 75 patients with SM (66 indolent SM and 9 with aggressive SM) and described that rising IL6 levels correlated with disease progression, particularly in those with a KIT mutation. However, comprehensive cytokine-clinical phenotype correlative studies are currently lacking in SM. Nonetheless, it seems likely that there was cytokine disruption in our patient which was responsible for the systemic symptoms and their abatement with ruxolitinib. In MF, Tefferi et al (2011) demonstrated that levels of pro-inflammatory cytokines are directly proportional to the presence or absence of constitutional symptoms and cachexia. Specific cytokine signatures correlated with both prognosis and degree of splenomegaly. Ruxolitinib has been shown to induce a rapid decrease in multiple MF-associated inflammatory cytokine levels including IL1RA, MIP1β, TNFα, VEGF, IL6 and IL8 (Verstovsek et al, 2012). In addition, Quintás-Cardama et al (2010) documented that ruxolitinib induces downregulation of phosphorylated STAT3 and STAT5 in a dose-dependent manner. Given the pivotal role of STAT5 in mast cell homeostasis, coupled with blockade of proinflammatory cytokine-mediated signalling, this provides a potential rationale for the use of JAK inhibitors in SM. Of specific interest, the JAK inhibitor SAR302503 inhibited KIT D816V-dependent growth in mast cell leukaemia cells (Lasho et al, 2010). Of note, this case lacked the KIT D816V mutation. The marrow mast cell infiltration appeared unchanged after 4 months of treatment despite improvements in symptoms. This may well be explained by the fact that although ruxoloitinib may mediate down-regulation of STAT5 activity this may be insufficient to induce mast cell growth inhibition. Alternatively, the ruxolitinib may have been mediating its effects on the AHNMD component. The potential beneficial properties of ruxolitinib therapy require further exploration in SM, coupled with correlative cytokine studies, in a clinical trial setting. All authors (RD, MI, DM, CH and DR) contributed to the writing of this article and contributed to patient care." @default.
• W2264962020 created "2016-06-24" @default.
• W2264962020 creator A5017537622 @default.
• W2264962020 creator A5018505446 @default.
• W2264962020 creator A5028061272 @default.
• W2264962020 creator A5034548009 @default.
• W2264962020 creator A5046827092 @default.
• W2264962020 creator A5049437631 @default.
• W2264962020 date "2016-02-05" @default.
• W2264962020 modified "2023-10-17" @default.
• W2264962020 title "Beneficial effects of JAK inhibitor therapy in Systemic Mastocytosis" @default.
• W2264962020 cites W1981419431 @default.
• W2264962020 cites W1987263365 @default.
• W2264962020 cites W2079645940 @default.
• W2264962020 cites W2111141291 @default.
• W2264962020 cites W2115351357 @default.
• W2264962020 cites W2121216306 @default.
• W2264962020 cites W2123633897 @default.
• W2264962020 cites W2141249732 @default.
• W2264962020 cites W935880247 @default.
• W2264962020 doi "https://doi.org/10.1111/bjh.13951" @default.
• W2264962020 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26847591" @default.
• W2264962020 hasPublicationYear "2016" @default.
• W2264962020 type Work @default.
• W2264962020 sameAs 2264962020 @default.
• W2264962020 citedByCount "8" @default.
• W2264962020 countsByYear W22649620202017 @default.
• W2264962020 countsByYear W22649620202018 @default.
• W2264962020 countsByYear W22649620202019 @default.
• W2264962020 countsByYear W22649620202020 @default.
• W2264962020 countsByYear W22649620202021 @default.
• W2264962020 crossrefType "journal-article" @default.
• W2264962020 hasAuthorship W2264962020A5017537622 @default.
• W2264962020 hasAuthorship W2264962020A5018505446 @default.
• W2264962020 hasAuthorship W2264962020A5028061272 @default.
• W2264962020 hasAuthorship W2264962020A5034548009 @default.
• W2264962020 hasAuthorship W2264962020A5046827092 @default.
• W2264962020 hasAuthorship W2264962020A5049437631 @default.
• W2264962020 hasBestOaLocation W22649620201 @default.
• W2264962020 hasConcept C121608353 @default.
• W2264962020 hasConcept C126322002 @default.
• W2264962020 hasConcept C16005928 @default.
• W2264962020 hasConcept C185926286 @default.
• W2264962020 hasConcept C2780007613 @default.
• W2264962020 hasConcept C2780581156 @default.
• W2264962020 hasConcept C530470458 @default.
• W2264962020 hasConcept C71924100 @default.
• W2264962020 hasConceptScore W2264962020C121608353 @default.
• W2264962020 hasConceptScore W2264962020C126322002 @default.
• W2264962020 hasConceptScore W2264962020C16005928 @default.
• W2264962020 hasConceptScore W2264962020C185926286 @default.
• W2264962020 hasConceptScore W2264962020C2780007613 @default.
• W2264962020 hasConceptScore W2264962020C2780581156 @default.
• W2264962020 hasConceptScore W2264962020C530470458 @default.
• W2264962020 hasConceptScore W2264962020C71924100 @default.
• W2264962020 hasIssue "2" @default.
• W2264962020 hasLocation W22649620201 @default.
• W2264962020 hasLocation W22649620202 @default.
• W2264962020 hasOpenAccess W2264962020 @default.
• W2264962020 hasPrimaryLocation W22649620201 @default.
• W2264962020 hasRelatedWork W2012245921 @default.
• W2264962020 hasRelatedWork W2264962020 @default.
• W2264962020 hasRelatedWork W2278279314 @default.
• W2264962020 hasRelatedWork W2443517091 @default.
• W2264962020 hasRelatedWork W2912404883 @default.
• W2264962020 hasRelatedWork W3026902890 @default.
• W2264962020 hasRelatedWork W3030437504 @default.
• W2264962020 hasRelatedWork W4287582753 @default.
• W2264962020 hasRelatedWork W4297184974 @default.
• W2264962020 hasRelatedWork W4366142243 @default.
• W2264962020 hasVolume "176" @default.
• W2264962020 isParatext "false" @default.
• W2264962020 isRetracted "false" @default.
• W2264962020 magId "2264962020" @default.
• W2264962020 workType "article" @default.