Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"6134",leadTitle:null,fullTitle:"Intermetallic Compounds - Formation and Applications",title:"Intermetallic Compounds",subtitle:"Formation and Applications",reviewType:"peer-reviewed",abstract:"Intermetallic compounds are usually brittle with high melting points. Their properties are often found among ceramic and metallic materials. In most cases, their hot corrosion resistance and simultaneously hardness are important. One of the main applications of intermetallic compounds is for superalloy turbine blades in which they show appropriate high-temperature-related properties. This book collects new developments about intermetallic compounds and their recent usages.",isbn:"978-1-78923-179-3",printIsbn:"978-1-78923-178-6",pdfIsbn:"978-1-83881-298-0",doi:"10.5772/intechopen.68256",price:119,priceEur:129,priceUsd:155,slug:"intermetallic-compounds-formation-and-applications",numberOfPages:226,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"d417aabc209ed4ce28dee750fd15c479",bookSignature:"Mahmood Aliofkhazraei",publishedDate:"May 30th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6134.jpg",numberOfDownloads:11876,numberOfWosCitations:37,numberOfCrossrefCitations:21,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:52,numberOfDimensionsCitationsByBook:2,hasAltmetrics:0,numberOfTotalCitations:110,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 9th 2017",dateEndSecondStepPublish:"May 30th 2017",dateEndThirdStepPublish:"August 26th 2017",dateEndFourthStepPublish:"November 24th 2017",dateEndFifthStepPublish:"January 23rd 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"155413",title:"Dr.",name:"Mahmood",middleName:null,surname:"Aliofkhazraei",slug:"mahmood-aliofkhazraei",fullName:"Mahmood Aliofkhazraei",profilePictureURL:"https://mts.intechopen.com/storage/users/155413/images/3939_n.jpg",biography:"Dr. Mahmood Aliofkhazraei works in the corrosion and surface engineering group at the Tarbiat Modares University. He is the head of Aliofkhazraei research group (www.aliofkhazraei.com). Dr. Aliofkhazraei has received several honors, including the Khwarizmi award and the best young nanotechnologist award of Iran. He is a member of the National Association of Surface Sciences, Iranian Corrosion Association, and National Elite Foundation of Iran. His research focuses on materials science, nanotechnology, and its use in surface and corrosion science.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"13",institution:{name:"Tarbiat Modares University",institutionURL:null,country:{name:"Iran"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"950",title:"Solid-State Chemistry",slug:"metals-and-nonmetals-solid-state-chemistry"}],chapters:[{id:"59839",title:"FeAl Intermetallic Alloy: Its Heat-Resistant and Practical Application",doi:"10.5772/intechopen.73184",slug:"feal-intermetallic-alloy-its-heat-resistant-and-practical-application",totalDownloads:1254,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Intermetallic phases, as a group of materials which have a great practical importance, both in the past and in the present day, are subject of research on the basis of physicochemical and mechanical properties. The presented studies were conducted for Fe40Al5Cr0.2TiB intermetallic alloy, their purpose was to determine the corrosion resistance of this alloy in an oxidizing environment, at temperatures up to 1373 K. The test material was made of Fe40Al5Cr0.2TiB intermetallic alloy after plastic processing. The kinetics of corrosion, allotropic variants according to the temperature of the process and the surface condition after corrosion were determined during the study. Based on the results obtained, the verification was performed under operating conditions. Taking into account the properties of the FeAl alloys, the working conditions and material requirements of turbochargers, studies have been undertaken to determine the possibility of the use of Fe40Al5Cr0.2TiB intermetallic alloys for components of the hot turbocharger of the automobile with compression ignition engines. The components of the hot turbocharger parts were used from the test material. The tests distance of turbocharger was 80,000 km.",signatures:"Janusz Cebulski and Dorota Pasek",downloadPdfUrl:"/chapter/pdf-download/59839",previewPdfUrl:"/chapter/pdf-preview/59839",authors:[{id:"210940",title:"Ph.D.",name:"Janusz",surname:"Cebulski",slug:"janusz-cebulski",fullName:"Janusz Cebulski"},{id:"210942",title:"MSc.",name:"Dorota",surname:"Pasek",slug:"dorota-pasek",fullName:"Dorota Pasek"}],corrections:null},{id:"58937",title:"Intermetallics Formation and Their Effect on Mechanical Properties of Al-Si-X Alloys",doi:"10.5772/intechopen.73188",slug:"intermetallics-formation-and-their-effect-on-mechanical-properties-of-al-si-x-alloys",totalDownloads:1990,totalCrossrefCites:12,totalDimensionsCites:25,hasAltmetrics:0,abstract:"This study focuses on primary impurities, called intermetallics, in the microstructure of Al-Si-X alloys, their formation, effects and treatments to eliminate or ameliorate their deleterious effects. Intermetallic compounds are usually formed when alloying elements, such as Fe, Cu, Mn, Mg and Sr. are added to Al-Si based alloys. These elements are depicted by X in the alloys formation expression. The chapter noted that the most common intermetallics are iron (Fe) based, and several of these Fe-phases, including the most harmful Fe-phase, β-Al5SiFe, are listed and discussed. Fe-phase intermetallics are deleterious to the mechanical properties of Al-alloys; however, addition of <0.7% Fe helps prevent soldering in die casting mould. The effects of Fe-phase and other intermetallics formed by Cu, Mg and Mn were examined. Further, some techniques of eliminating or mitigating the negative influences of intermetallics were discussed.",signatures:"Williams S. Ebhota and Tien-Chien Jen",downloadPdfUrl:"/chapter/pdf-download/58937",previewPdfUrl:"/chapter/pdf-preview/58937",authors:[{id:"206268",title:"Dr.",name:"Williams",surname:"Ebhota",slug:"williams-ebhota",fullName:"Williams Ebhota"},{id:"214786",title:"Prof.",name:"Tien-Chien",surname:"Jen",slug:"tien-chien-jen",fullName:"Tien-Chien Jen"}],corrections:null},{id:"60256",title:"Intermetallic Bonding for High-Temperature Microelectronics and Microsystems: Solid-Liquid Interdiffusion Bonding",doi:"10.5772/intechopen.75139",slug:"intermetallic-bonding-for-high-temperature-microelectronics-and-microsystems-solid-liquid-interdiffu",totalDownloads:1203,totalCrossrefCites:5,totalDimensionsCites:7,hasAltmetrics:0,abstract:"Solid-liquid interdiffusion (SLID) bonding for microelectronics and microsystems is a bonding technique relying on intermetallics. The high-melting temperature of intermetallics allows for system operation at far higher temperatures than what solder-bonded systems can do, while still using similar process temperatures as in common solder processes. Additional benefits of SLID bonding are possibilities of fine-pitch bonding, as well as thin-layer metallurgical bonding. Our group has worked on a number of SLID metal systems. We have optimized wafer-level Cu-Sn SLID bonding to become an industrially feasible process, and we have verified the reliability of Au-Sn SLID bonding in a thermally mismatched system, as well as determined the actual phases present in an Au-Sn SLID bond. We have demonstrated SLID bonding for very high temperatures (Ni-Sn, having intermetallics with melting points up to 1280°C), as well as SLID with low process temperatures (Au-In, processed at 180°C, and Au-In-Bi, processed at 90–115°C). We have verified experimentally the high-temperature stability for our systems, with quantified strength at temperatures up to 300°C for three of the systems: Cu-Sn, Au-Sn and Au-In.",signatures:"Knut E. Aasmundtveit, Thi-Thuy Luu, Hoang-Vu Nguyen, Andreas\nLarsson and Torleif A. Tollefsen",downloadPdfUrl:"/chapter/pdf-download/60256",previewPdfUrl:"/chapter/pdf-preview/60256",authors:[{id:"216490",title:"Dr.",name:"Knut",surname:"Aasmundtveit",slug:"knut-aasmundtveit",fullName:"Knut Aasmundtveit"},{id:"239422",title:"Dr.",name:"Thi-Thuy",surname:"Luu",slug:"thi-thuy-luu",fullName:"Thi-Thuy Luu"},{id:"239424",title:"Dr.",name:"Hoang-Vu",surname:"Nguyen",slug:"hoang-vu-nguyen",fullName:"Hoang-Vu Nguyen"},{id:"239426",title:"MSc.",name:"Andreas",surname:"Larsson",slug:"andreas-larsson",fullName:"Andreas Larsson"},{id:"239427",title:"Dr.",name:"Torleif A.",surname:"Tollefsen",slug:"torleif-a.-tollefsen",fullName:"Torleif A. Tollefsen"}],corrections:null},{id:"61032",title:"The Importance of the Fluorine Effect on the Oxidation of Intermetallic Titanium Aluminides",doi:"10.5772/intechopen.75696",slug:"the-importance-of-the-fluorine-effect-on-the-oxidation-of-intermetallic-titanium-aluminides",totalDownloads:1026,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Due to the low Al activity within technical titanium aluminides and the similar thermodynamic stabilities of Al- and Ti-oxide these alloys always form a mixed oxide scale at elevated temperatures consisting of TiO2, Al2O3 and also nitrides if the exposure takes place in air. This mixed scale does not provide any oxidation protection especially under thermocyclic load or in water vapor containing environments. Thus accelerated oxidation occurs. Alloying of additional elements such as Nb improves the oxidation behavior if the additions stay within a certain concentration range but such additions cannot suppress non-protective mixed scale formation. Coatings are another way to protect these materials but several obstacles and new degradation mechanisms exist such as delamination e.g. due to CTE mismatch or development of brittle intermetallic phases due to interdiffusion. Therefore, other suitable protective measures have to be undertaken to make sure a protective oxide scale will develop. The so called halogen effect is a very promising way to change the oxidation mechanism from mixed scale formation to alumina formation. After optimized halogen treatment the alumina layer is very protective up to several thousand hours even under thermocyclic load and in atmospheres containing water vapor or SO2.",signatures:"Alexander Georg Donchev and Mathias Christian Galetz",downloadPdfUrl:"/chapter/pdf-download/61032",previewPdfUrl:"/chapter/pdf-preview/61032",authors:[{id:"174362",title:"Dr.",name:"Mathias",surname:"Galetz",slug:"mathias-galetz",fullName:"Mathias Galetz"},{id:"222128",title:"Dr.",name:"Alexander",surname:"Donchev",slug:"alexander-donchev",fullName:"Alexander Donchev"}],corrections:null},{id:"60516",title:"Structural and Mechanical Behaviour of Al-Fe Intermetallics",doi:"10.5772/intechopen.73944",slug:"structural-and-mechanical-behaviour-of-al-fe-intermetallics",totalDownloads:1519,totalCrossrefCites:3,totalDimensionsCites:10,hasAltmetrics:0,abstract:"In this chapter, results of our recent investigations on Al-25%Fe (at.%), Al-30%Fe and Al-34.5%Fe alloys close to Al3Fe, Al5Fe2 and Al2Fe intermetallic phases have been discussed. The effect of process parameters on structural aspects and mechanical behaviour of Al-Fe intermetallics has been studied. The high melting intermetallics that are difficult to prepare by conventional processing technique are easily synthesized in nanocrystalline state with a homogeneous structure by mechanical means. In this process, we have come out with a single orthorhombic Al5Fe2 nanocrystalline intermetallic phase. Hardness measurements of intermetallic revealed an increase in hardness with a decreasing grain size up to a critical grain size, followed by a decrease. A decrease in hardness with a grain size refinement, an indication of softening behaviour, demonstrating the Inverse Hall-Petch (IHP)-like phenomenon has been observed in intermetallic compounds. The deviation from the regular Hall-Petch (HP) behaviour has been discussed using various deformation models based on the dislocations and grain boundary-mediated processes. The study is focused on investigations of Al-rich iron aluminide intermetallics to understand the structure property correlations.",signatures:"Mohammed Ishaq Raviathul Basariya and Nilay Krishna\nMukhopadhyay",downloadPdfUrl:"/chapter/pdf-download/60516",previewPdfUrl:"/chapter/pdf-preview/60516",authors:[{id:"220122",title:"Dr.",name:"M. Raviathul",surname:"Basariya",slug:"m.-raviathul-basariya",fullName:"M. Raviathul Basariya"},{id:"220646",title:"Dr.",name:"N. K.",surname:"Mukhopadhyay",slug:"n.-k.-mukhopadhyay",fullName:"N. K. Mukhopadhyay"}],corrections:null},{id:"61063",title:"Technological Aspects of Production and Processing of Functional Materials Based on Intermetallic Fe-Al",doi:"10.5772/intechopen.76701",slug:"technological-aspects-of-production-and-processing-of-functional-materials-based-on-intermetallic-fe",totalDownloads:979,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The problems of this paper relate to a possibility to affect the structure and properties of new alloys with an intermetallic phase matrix of the Fe-Al system by improvements in casting and hot plastic working processes. The studies were focused on selection of an optimum chemical composition and parameters of the casting and heat treatment processes for further hot plastic working process. The primary goal was to obtain semifinished products in the forms of sheets and bars with specified set of mechanical and physical properties. The works included several selected alloys with various Al content and variable contents of alloying elements influencing the formation of intermetallic phases. A series of characteristics of mechanical, physical, and chemical properties of alloys containing 28 and 38% of Al were developed. The result of the work consists in the development of a technology for hot forming of flat and round products.",signatures:"Magdalena Jabłońska, Iwona Bednarczyk, Anna Śmiglewicz and\nTomasz Mikuszewski",downloadPdfUrl:"/chapter/pdf-download/61063",previewPdfUrl:"/chapter/pdf-preview/61063",authors:[{id:"211483",title:"Associate Prof.",name:"Magdalena",surname:"Jabłońska",slug:"magdalena-jablonska",fullName:"Magdalena Jabłońska"}],corrections:null},{id:"59086",title:"Inter-Diffusion of Nickel and Palladium with Germanium",doi:"10.5772/intechopen.73190",slug:"inter-diffusion-of-nickel-and-palladium-with-germanium",totalDownloads:1014,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Nickel and palladium germanides are the most promising candidates for nano-electronic contact materials to active areas of germanium-based devices. Solid-state reactions were thermally induced in conventional thin film couples of the Ni/Ge and Pd/Ge systems in order to study the sequence of phase formation. By embedding a thin layer of tantalum or tungsten as an inert marker between coupling thin film layers and observing its movement during phase formation, the dominant diffusing species were identified and monitored. In the Ni/Ge system, Ni5Ge3 was the first phase to form followed by NiGe. The results showed that during Ni5Ge3 formation, Ni was the sole diffusing species. During NiGe formation, both Ni and Ge diffused with the Ge diffusion prominent during the early stages, while the later stage of growth was dominated by Ni diffusion. The only phases observed to form in the Pd/Ge system were PdGe and Pd2Ge, the latter being the first. Palladium was the dominant diffusing species during both phase formations. Lateral diffusion couples were also prepared by the deposition of thick rectangular islands of germanium on to thin films of nickel and palladium. Several aspects of thermally induced lateral (as opposed to vertical) growth of phases were studied.",signatures:"Adrian Habanyama and Craig M. Comrie",downloadPdfUrl:"/chapter/pdf-download/59086",previewPdfUrl:"/chapter/pdf-preview/59086",authors:[{id:"211243",title:"Dr.",name:"Adrian",surname:"Habanyama",slug:"adrian-habanyama",fullName:"Adrian Habanyama"},{id:"220838",title:"Prof.",name:"Craig",surname:"Comrie",slug:"craig-comrie",fullName:"Craig Comrie"}],corrections:null},{id:"58790",title:"Transition Metal Aluminide Coatings and Initial Steps on Additive Manufacturing",doi:"10.5772/intechopen.72582",slug:"transition-metal-aluminide-coatings-and-initial-steps-on-additive-manufacturing",totalDownloads:1191,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"During the last decades, Fe-, Ni- and Ti-based aluminides have been studied in terms of bulk materials with an effort to develop alloying and processing strategies to overcome their low ductilities and toughness compared to conventional alloys. Whenever significant improvements can be addressed in this direction, they will be opened to an extensive range of industrial applications, especially those related to high temperature resistance requirements. In parallel, progressing interest has also been focused on their application as protective layers. This chapter is intended to provide a review of the evolution that has been made mainly during the last two decades of the several coating technologies devoted for this purpose. From thick to thin coatings are revised, with insight into coating microstructures and properties as well. Lack of space has forced the selection of those technologies arising most interest within last years; therefore, the content will follow this order: joining (laser cladding and electrospark deposition), thermal spraying (high velocity oxygen fuel and cold spraying) and physical vapor deposition (magnetron sputtering and cathodic arc deposition).",signatures:"Núria Cinca i Luis",downloadPdfUrl:"/chapter/pdf-download/58790",previewPdfUrl:"/chapter/pdf-preview/58790",authors:[{id:"209969",title:"Dr.Ing.",name:"Núria",surname:"Cinca",slug:"nuria-cinca",fullName:"Núria Cinca"}],corrections:null},{id:"59014",title:"Physical Properties of Yttrium-Rhodium and Yttrium-Copper B2-Type Rare Earth Intermetallic Compounds: First Principles Study",doi:"10.5772/intechopen.73189",slug:"physical-properties-of-yttrium-rhodium-and-yttrium-copper-b2-type-rare-earth-intermetallic-compounds",totalDownloads:837,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The electronic structure of B2-YCu and YRh intermetallic compounds which crystallize in the CsCl structure has attracted the attention of the scientific world because of their excellent mechanical properties. The advantage of studying these materials is to answer of some industrial request in the materials that resist for high temperature and high oxidation resistance. However, high ductility has been observed in these compounds at room temperature. In this present work, we employed ab initio calculation methods while basing on the full-potential linearized augmented plane wave (FP-LAPW) method within density functional theory implanted in the Wien-2 k code, which is used to examine the various properties of these materials (YCu, YRh) like structural, electronic, and elastic properties. The results obtained are in good agreement with those found in other theoretical studies and experimental data.",signatures:"Abdessamad Sekkal, Mohamed Sahlaoui and Abdelnour Benzair",downloadPdfUrl:"/chapter/pdf-download/59014",previewPdfUrl:"/chapter/pdf-preview/59014",authors:[{id:"210648",title:"Dr.",name:"Abdessamad",surname:"Sekkal",slug:"abdessamad-sekkal",fullName:"Abdessamad Sekkal"}],corrections:null},{id:"60530",title:"Effect on Heat Treatment and Doping of Cubic NaZn13-Type La0.7Pr0.3(Fe,Si)13 for Magnetic Refrigerator Application",doi:"10.5772/intechopen.75607",slug:"effect-on-heat-treatment-and-doping-of-cubic-nazn13-type-la0-7pr0-3-fe-si-13-for-magnetic-refrigerat",totalDownloads:864,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Soft ferromagnetic cubic NaZn13-type La0.7Pr0.3Fe11.4Si1.6 has turned out to be a standout amongst the most fascinating compounds for investigating substantial magnetocaloric effect (MCE) on the grounds that the attractive properties of this compound shows large enough spontaneous magnetization for applications, strongly doping dependent, and as well as delicate soft ferromagnetism. These impacts can be attributed to the itinerant electron metamagnetic (IEM) transition especially around the first-order magnetic transition region. However, this compound is difficult to frame by the basic cementing process because of the inherent deficiency of the peritectic response, Υ-Fe + La → La(Fe,Si)13(τ1a), which frequently brings about a blended microstructure of α-Fe + La(Fe,Si)13(τ1a) + LaFeSi(τ4). Additionally, dependability of La(FexSi1−x)13 is no middle-of-the-road stage and common solvency amongst Fe and La in the Fe-La framework as a reality is represented by response dispersion as indicated by magnetic and electronic states’ contribution. From this point of view, the structure, attractive properties and MCE of this compound have been talked about in detail as indicated by various temperatures and times of the annealing treatment. In addition, efficiently contemplating on the doping impact from various concentrations of transition metal elements such as Copper (Cu) and Chromium (Cr) on Iron (Fe) in the La0.7Pr0.3Fe11.4Si1.6 compound is likewise discussed.",signatures:"Muhamad Faiz Md Din, Jianli Wang and Mohd Taufiq Ishak",downloadPdfUrl:"/chapter/pdf-download/60530",previewPdfUrl:"/chapter/pdf-preview/60530",authors:[{id:"209538",title:"Dr.",name:"Muhamad Faiz",surname:"Md Din",slug:"muhamad-faiz-md-din",fullName:"Muhamad Faiz Md Din"},{id:"212495",title:"Dr.",name:"Jianli",surname:"Wang",slug:"jianli-wang",fullName:"Jianli Wang"},{id:"212496",title:"Dr.",name:"Mohd Taufiq",surname:"Ishak",slug:"mohd-taufiq-ishak",fullName:"Mohd Taufiq Ishak"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"3817",title:"Developments in Corrosion Protection",subtitle:null,isOpenForSubmission:!1,hash:"8ff86fac7ac8bce142fdc3c0e5a79f30",slug:"developments-in-corrosion-protection",bookSignature:"M. Aliofkhazraei",coverURL:"https://cdn.intechopen.com/books/images_new/3817.jpg",editedByType:"Edited by",editors:[{id:"155413",title:"Dr.",name:"Mahmood",surname:"Aliofkhazraei",slug:"mahmood-aliofkhazraei",fullName:"Mahmood Aliofkhazraei"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3558",title:"Advances in Graphene Science",subtitle:null,isOpenForSubmission:!1,hash:"f3a2158260a79c0fc8a4298864aa7dcd",slug:"advances-in-graphene-science",bookSignature:"Mahmood Aliofkhazraei",coverURL:"https://cdn.intechopen.com/books/images_new/3558.jpg",editedByType:"Edited by",editors:[{id:"155413",title:"Dr.",name:"Mahmood",surname:"Aliofkhazraei",slug:"mahmood-aliofkhazraei",fullName:"Mahmood Aliofkhazraei"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5319",title:"Wetting 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Dunn",authors:[{id:"18367",title:"Dr.",name:"Robert",middleName:null,surname:"Dunn",fullName:"Robert Dunn",slug:"robert-dunn"}]},{id:"15789",title:"Seed Storage Proteins; Strategies for Developing Crops Promoting Human Health",slug:"seed-storage-proteins-strategies-for-developing-crops-promoting-human-health",signatures:"Nobuyuki Maruyama, Takayasu Motoyama, Masaaki Yoshikawa, Fumio Takaiwa and Shigeru Utsumi",authors:[{id:"18385",title:"Dr.",name:"Nobuyuki",middleName:null,surname:"Maruyama",fullName:"Nobuyuki Maruyama",slug:"nobuyuki-maruyama"}]},{id:"15790",title:"Soybean Seeds Produced in Out Season in West of Paraná State – Brazil",slug:"soybean-seeds-produced-in-out-season-in-west-of-paran-state-brazil",signatures:"Marizangela Rizzatti Ávila, Alessandro de Lucca e Braccini, Leandro Paiola Albrecht and Carlos Alberto Scapim",authors:[{id:"21047",title:"Dr.",name:"Marizangela",middleName:null,surname:"Ávila",fullName:"Marizangela Ávila",slug:"marizangela-avila"},{id:"21048",title:"Dr.",name:"Alessandro",middleName:null,surname:"Lucca Braccini",fullName:"Alessandro Lucca Braccini",slug:"alessandro-lucca-braccini"},{id:"21049",title:"Dr.",name:"Carlos",middleName:null,surname:"Scapim",fullName:"Carlos Scapim",slug:"carlos-scapim"},{id:"23525",title:"Dr.",name:"Leandro",middleName:null,surname:"Albrecht",fullName:"Leandro Albrecht",slug:"leandro-albrecht"}]},{id:"15829",title:"The Alternatives to Soybeans for Animal Feed in the Tropics",slug:"the-alternatives-to-soybeans-for-animal-feed-in-the-tropics",signatures:"Archimède H, Régnier C, Marie-Magdeleine Chevry C, Gourdine JL, Rodriguez L and Gonzalez E",authors:[{id:"17514",title:"Dr.",name:"Harry",middleName:null,surname:"Archimède",fullName:"Harry Archimède",slug:"harry-archimede"}]},{id:"15791",title:"Application of Nondestructive Measurement to Improve Soybean Quality by Near Infrared Reflectance Spectroscopy",slug:"application-of-nondestructive-measurement-to-improve-soybean-quality-by-near-infrared-reflectance-sp",signatures:"Jeong-Dong Lee, J. 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Vadlani",authors:[{id:"17592",title:"Dr.",name:"Praveen V",middleName:null,surname:"Vadlani",fullName:"Praveen V Vadlani",slug:"praveen-v-vadlani"},{id:"21150",title:"Mr",name:"Khushal",middleName:null,surname:"Brijwani",fullName:"Khushal Brijwani",slug:"khushal-brijwani"}]},{id:"15830",title:"Immunoquantitative Measurement of Soybean Aeroallergen Emissions",slug:"immunoquantitative-measurement-of-soybean-aeroallergen-emissions",signatures:"María-Jesús Cruz and Susana Gómez-Ollé",authors:[{id:"17507",title:"Dr.",name:"Maria-Jesus",middleName:null,surname:"Cruz",fullName:"Maria-Jesus Cruz",slug:"maria-jesus-cruz"},{id:"21495",title:"Dr.",name:"Susana",middleName:null,surname:"Gómez-Ollés",fullName:"Susana Gómez-Ollés",slug:"susana-gomez-olles"}]},{id:"15793",title:"Recovery of Phytosterols from Waste Residue of Soybean Oil Deodorizer Distillate",slug:"recovery-of-phytosterols-from-waste-residue-of-soybean-oil-deodorizer-distillate",signatures:"Feng Yan, Haojun Yang, Daogeng Wu, Ming Huo and Jianxin Li",authors:[{id:"17113",title:"Prof.",name:"Jianxin",middleName:null,surname:"Li",fullName:"Jianxin Li",slug:"jianxin-li"},{id:"18646",title:"Prof.",name:"Feng",middleName:null,surname:"Yan",fullName:"Feng Yan",slug:"feng-yan"},{id:"18647",title:"Ms.",name:"Haojun",middleName:null,surname:"Yang",fullName:"Haojun Yang",slug:"haojun-yang"},{id:"18648",title:"Mr.",name:"Daogeng",middleName:null,surname:"Wu",fullName:"Daogeng Wu",slug:"daogeng-wu"},{id:"18649",title:"Ms.",name:"Ming",middleName:null,surname:"Huo",fullName:"Ming Huo",slug:"ming-huo"}]},{id:"15794",title:"Soybean-based Surfactants and Their Applications",slug:"soybean-based-surfactants-and-their-applications",signatures:"Qingyi Xu, Mitsutoshi Nakajima, Zengshe Liu and Takeo Shiina",authors:[{id:"18905",title:"Dr.",name:"Qingyi",middleName:null,surname:"Xu",fullName:"Qingyi Xu",slug:"qingyi-xu"},{id:"22088",title:"Dr.",name:"Mitsutoshi",middleName:null,surname:"Nakajima",fullName:"Mitsutoshi Nakajima",slug:"mitsutoshi-nakajima"},{id:"22089",title:"Dr.",name:"Zengshe",middleName:null,surname:"Liu",fullName:"Zengshe Liu",slug:"zengshe-liu"},{id:"22090",title:"Dr.",name:"Takeo",middleName:null,surname:"Shiina",fullName:"Takeo Shiina",slug:"takeo-shiina"}]},{id:"15795",title:"Polymerization of Soybean Oil with Superacids",slug:"polymerization-of-soybean-oil-with-superacids",signatures:"Ionescu Mihail and Petrović S. Zoran",authors:[null]},{id:"15796",title:"Sourdough and Bread Properties as Affected by Soybean Protein Addition",slug:"sourdough-and-bread-properties-as-affected-by-soybean-protein-addition",signatures:"Josué Peñaloza- Espinosa, Gloria J. De La Rosa-Angulo, Rosalva Mora-Escobedo, Jorge Chanona-Pérez, Reynold Farrera-Rebollo and Georgina Calderón-Domínguez",authors:[{id:"19018",title:"Dr.",name:"Rosalva",middleName:null,surname:"Mora Escobedo",fullName:"Rosalva Mora Escobedo",slug:"rosalva-mora-escobedo"},{id:"21263",title:"Dr.",name:"Georgina",middleName:null,surname:"Calderón-Domínguez",fullName:"Georgina Calderón-Domínguez",slug:"georgina-calderon-dominguez"},{id:"22034",title:"Ing",name:"Josue",middleName:null,surname:"Peñaloza-Espinoza",fullName:"Josue Peñaloza-Espinoza",slug:"josue-penaloza-espinoza"},{id:"22035",title:"Dr.",name:"Reynold",middleName:null,surname:"Farrera-Rebollo",fullName:"Reynold Farrera-Rebollo",slug:"reynold-farrera-rebollo"},{id:"22694",title:"Ing",name:"Gloria J.",middleName:null,surname:"De la Rosa-Angulo",fullName:"Gloria J. De la Rosa-Angulo",slug:"gloria-j.-de-la-rosa-angulo"},{id:"22695",title:"Dr.",name:"Jorge",middleName:null,surname:"Chanona-Pérez",fullName:"Jorge Chanona-Pérez",slug:"jorge-chanona-perez"}]}]}],publishedBooks:[{type:"book",id:"495",title:"Soybean",subtitle:"Physiology and Biochemistry",isOpenForSubmission:!1,hash:"09e5f0af30214d460498f8d770e985cf",slug:"soybean-physiology-and-biochemistry",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/495.jpg",editedByType:"Edited by",editors:[{id:"54719",title:"Prof.",name:"Hany",surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1014",title:"Food Additive",subtitle:null,isOpenForSubmission:!1,hash:"d5d05e31d794c4697626a5616a9fe077",slug:"food-additive",bookSignature:"Yehia El-Samragy",coverURL:"https://cdn.intechopen.com/books/images_new/1014.jpg",editedByType:"Edited by",editors:[{id:"81644",title:"Prof.",name:"Yehia",surname:"El-Samragy",slug:"yehia-el-samragy",fullName:"Yehia El-Samragy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2082",title:"Food Industrial Processes",subtitle:"Methods and Equipment",isOpenForSubmission:!1,hash:"b0aef25c18dea1ab87af9c3e72c952e0",slug:"food-industrial-processes-methods-and-equipment",bookSignature:"Benjamin Valdez",coverURL:"https://cdn.intechopen.com/books/images_new/2082.jpg",editedByType:"Edited by",editors:[{id:"65522",title:"Dr.",name:"Benjamin",surname:"Valdez",slug:"benjamin-valdez",fullName:"Benjamin Valdez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5412",title:"Biological Activities and Application of Marine Polysaccharides",subtitle:null,isOpenForSubmission:!1,hash:"c0859ef7d4b56525b985dfec6bc26192",slug:"biological-activities-and-application-of-marine-polysaccharides",bookSignature:"Emad A. Shalaby",coverURL:"https://cdn.intechopen.com/books/images_new/5412.jpg",editedByType:"Edited by",editors:[{id:"76214",title:"Dr.",name:"Emad",surname:"Shalaby",slug:"emad-shalaby",fullName:"Emad Shalaby"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5701",title:"Superfood and Functional Food",subtitle:"The Development of Superfoods and Their Roles as Medicine",isOpenForSubmission:!1,hash:"0c3c4e9924a0f6c2fe2df43d5dfc50fb",slug:"superfood-and-functional-food-the-development-of-superfoods-and-their-roles-as-medicine",bookSignature:"Naofumi Shiomi and Viduranga Waisundara",coverURL:"https://cdn.intechopen.com/books/images_new/5701.jpg",editedByType:"Edited by",editors:[{id:"163777",title:"Dr.",name:"Naofumi",surname:"Shiomi",slug:"naofumi-shiomi",fullName:"Naofumi Shiomi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],publishedBooksByAuthor:[]},onlineFirst:{chapter:{type:"chapter",id:"81569",title:"Impact of Interferon Alpha/Beta in the Management of Chronic Myeloproliferative Disorders",doi:"10.5772/intechopen.104501",slug:"impact-of-interferon-alpha-beta-in-the-management-of-chronic-myeloproliferative-disorders",body:'Chronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Source | Type of trial | Interferon | Diagnosis | No. | Prior treatment status | Response rate |
---|---|---|---|---|---|---|
Yacoubet al. [15] | Phase II, multicenter | Pegylated IFN alfa-2a | PV | 50 | Resistance to HU or HU intolerance | CR:22% PR:38% |
ET | 65 | CR:43% PR:26% | ||||
Masarova et al. [16] | Phase II, single-center | Pegylated IFN alfa-2a | PV | 43 | Untreated or previously treated with cytoreductive therapy | CR:77% PR:7% |
ET | 40 | CR:73% PR:3% | ||||
Samuelsson et al. [18] | Phase II | Pegylated IFN alfa-2b | PV | 21 | Untreated or previously treated with cytoreductive therapy | CR: 69% for the entire group |
ET | 21 | |||||
Huang BT et al. [19] | Open label, multicenter | IFN alfa-2b | PV | 136 | Untreated or previously treated with cytoreductive therapy | OHR:70% Molecular response:54.7% |
ET | 123 | OHR (JAK2+ patients):83% CHR:23 cases OHR (JAK2-patients): 61.4% CHR:12 cases | ||||
Gisslinger et al. [23] | phase III, multicenter | Ropeginterferon | PV | 257 | Previously treated | OHR:53% |
Quintás-Cardama et al. [26] | phase II | Pegylated IFN alfa-2a | PV | 40 | Untreated or previously treated with cytoreductive therapy | OHR:80% CR:70% Molecular remission:54% |
ET | 39 | OHR:81% CR:76% Molecular remission:38% | ||||
Sørensen et al. [36] | Phase III, multicenter, COMBI | Pegylated IFN alfa-2a with ruxolitinib or Pegylated IFN alfa-2b with ruxolitinib | PV | 32 | Untreated or previously treated with cytoreductive therapy | OHR:44% CR:28% |
MF | 18 | OHR:31% CR:9% | ||||
Casassus et al. [40] | Open label, multicenter | IFN alpha-2b | Mastocytosis | 20 | Untreated and previously treated | PR:35% Minor remission: 30% |
Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; HU: hydroxycarbamide/hydroxyurea; CR: complete remission; PR: partial remission; and OHR: overall hematological response.
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
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\\n\\nWe started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\nIn the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n2004
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\n\n2008
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