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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:"7117",leadTitle:null,fullTitle:"Psychosis - Biopsychosocial and Relational Perspectives",title:"Psychosis",subtitle:"Biopsychosocial and Relational Perspectives",reviewType:"peer-reviewed",abstract:"This book collects chapters from a number of scientists all over the world, giving their contribution to the comprehension and clinical management of psychosis. The book adopts a perspective that respects the complexity of the human person and his/her relationships. It devotes a space both to the deepening of the more strictly biological aspects, the psychological aspects and the social aspects. Each section of the book (biological, psychological, social) reveals a deep connection with the themes of the other sections, showing the strength of this biopsychosocial interweaving. The relationship and the interweaving between these different areas is certainly a foundation of our existence and constitutes a law to which we cannot escape, so it is necessary that the biopsyosocial model is always considered in the interventions for the psychotic patient. This book also focuses on some specific and very innovative topics such as the importance of psychosocial factors and family factors, complementary approaches to psychosis managment, subclinical psychosis and relational aspects of psychosis.",isbn:"978-1-78984-020-9",printIsbn:"978-1-78984-019-3",pdfIsbn:"978-1-83881-762-6",doi:"10.5772/intechopen.73912",price:119,priceEur:129,priceUsd:155,slug:"psychosis-biopsychosocial-and-relational-perspectives",numberOfPages:112,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"3cfc852c7ecc10618bca94b1a559c9cd",bookSignature:"Floriana Irtelli",publishedDate:"October 17th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/7117.jpg",numberOfDownloads:8193,numberOfWosCitations:7,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:12,numberOfDimensionsCitationsByBook:1,hasAltmetrics:0,numberOfTotalCitations:25,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 14th 2018",dateEndSecondStepPublish:"March 7th 2018",dateEndThirdStepPublish:"May 6th 2018",dateEndFourthStepPublish:"July 25th 2018",dateEndFifthStepPublish:"September 23rd 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"174641",title:"Dr.",name:"Floriana",middleName:null,surname:"Irtelli",slug:"floriana-irtelli",fullName:"Floriana Irtelli",profilePictureURL:"https://mts.intechopen.com/storage/users/174641/images/system/174641.jpeg",biography:"Floriana Irtelli is a psychoanalyst/psychotherapist and member of the International Association for Relational Psychoanalysis and Psychotherapy (IARPP) who has been lecturing for several years at the Catholic University of the Sacred Heart, Milan, Italy. She has worked at Fatebenefratelli Hospital in Milan performing research and clinical activities. She is among the authors of several books, including A Fresh Look at Anxiety Disorders and Psychopathy - New Updates on an Old Phenomenon, and has published articles for the Journal of Affective Disorders, Research in Psychotherapy, and the Journal for Psychiatric and Mental Health Nursing. She has participated in numerous conferences, seminars, and congresses. Dr. Irtelli is the sole author of the books Illuminarsi di Ben-essere, Familiar-mente, and Contemporary Perspectives on Relational Wellness.",institutionString:"Catholic University of the Sacred Heart",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"Catholic University of the Sacred Heart",institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1061",title:"Psychiatry",slug:"mental-and-behavioural-disorders-and-diseases-of-the-nervous-system-psychiatry"}],chapters:[{id:"62216",title:"Subtypes of Psychotic-Like Experiences and Their Significance for Mental Health",doi:"10.5772/intechopen.78691",slug:"subtypes-of-psychotic-like-experiences-and-their-significance-for-mental-health",totalDownloads:3192,totalCrossrefCites:3,totalDimensionsCites:5,hasAltmetrics:0,abstract:"More recently, the interest in studying subclinical psychosis has increased, as it might provide critical information regarding mechanisms that are implicated in the exacerbation of subclinical symptoms and the maintenance of mental health. However, psychosis research has tended to focus on clinical outcomes and not to differentiate between subtypes of psychotic-like experiences (PLE) that might differ regarding their psychopathological significance. Importantly, this might have obscured a more accurate picture of the complex structure of psychosis and the significance of particular risk and protective factors. Notably, while studies point toward a continuity of psychotic experiences and accompanying factors across the general population, there is evidence indicating that some PLE in healthy individuals might also be associated with a weaker expression of other subclinical symptoms, increased well-being and even resilience to some degree. Importantly, such findings might have implications on strategies in psychosis prevention and therapy, early detection, as well as the construction of continuum models of psychosis. The present chapter aims at drawing together findings that necessitate a more differentiated view and assessment of PLE. It intends to provoke new questions that might offer starting points for future investigations, such as longitudinal studies investigating the interplay of subclinical symptoms.",signatures:"Lui Unterrassner",downloadPdfUrl:"/chapter/pdf-download/62216",previewPdfUrl:"/chapter/pdf-preview/62216",authors:[{id:"245870",title:"Ph.D. Student",name:"Lui",surname:"Unterrassner",slug:"lui-unterrassner",fullName:"Lui Unterrassner"}],corrections:null},{id:"61984",title:"From Vulnerability to Resilience: A Coping Related Approach to Psychosis",doi:"10.5772/intechopen.78385",slug:"from-vulnerability-to-resilience-a-coping-related-approach-to-psychosis",totalDownloads:1286,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Many of us may have to face stressful events during life. How we are affected by these events depends on our vulnerability limit and our coping mechanisms. Both vulnerability-stress models and cognitive-behavioral theories of psychosis consider biological, psychological, and social factors together as determinants of our vulnerability limit. This point of view enables us to handle the psychotic disorders as a continuity of normality. In addition, coping mechanisms have an important role in the maintenance and/or recovery of psychotic symptoms. Therefore, the objective of this chapter is to summarize coping-related explanations that facilitate understanding the symptomatology of psychosis and defining the adaptive ways to challenge it.",signatures:"Oya Mortan Sevi",downloadPdfUrl:"/chapter/pdf-download/61984",previewPdfUrl:"/chapter/pdf-preview/61984",authors:[{id:"247063",title:"Ph.D.",name:"Oya",surname:"Mortan Sevi",slug:"oya-mortan-sevi",fullName:"Oya Mortan Sevi"}],corrections:null},{id:"62504",title:"Cognitive Impairment in Schizophrenia: Description and Cognitive Familiar Endophenotypes. A Review of the Literature",doi:"10.5772/intechopen.78948",slug:"cognitive-impairment-in-schizophrenia-description-and-cognitive-familiar-endophenotypes-a-review-of-",totalDownloads:1406,totalCrossrefCites:3,totalDimensionsCites:7,hasAltmetrics:0,abstract:"The presence of cognitive deficits in schizophrenia is a fact widely confirmed by a more than abundant literature. The existence of these deficits cannot be ignored, given their presence even with stabilized symptoms and their proven correlation with the functioning of the subject. The following chapter focuses on describing the main affected cognitive domains most frequently described in this pathology, mutually before and after the appearance of the clinical signs, as well as reviewing the presence of these affected domains in first-degree relatives of these patients. The existence of these deficits in relatives reveals that these alterations can not only be considered as markers of heritability and risk for the development of the pathology, but that their ignorance, in the family context, is also related to an important stain in the perception of the quotidian aspects, in the healthy interaction between relatives and an impact on the overall functionality of the subject.",signatures:"Eduardo García-Laredo",downloadPdfUrl:"/chapter/pdf-download/62504",previewPdfUrl:"/chapter/pdf-preview/62504",authors:[{id:"245937",title:"Ph.D.",name:"Eduardo",surname:"García-Laredo",slug:"eduardo-garcia-laredo",fullName:"Eduardo García-Laredo"}],corrections:null},{id:"62587",title:"The Ambit of Phytotherapy in Psychotic Care",doi:"10.5772/intechopen.79547",slug:"the-ambit-of-phytotherapy-in-psychotic-care",totalDownloads:1264,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The rate of psychosis has drastically increased in recent years and the number of prescriptions for psychiatric medications has made an even bigger jump. With the worrisome side effects of the medications, which can pose serious health risks and make medication compliance difficult, coupled with the prohibitive cost for many patients, there is an obvious need for alternative solutions. This review presents the ambit of phytotherapy in psychotic care. Interestingly, the review revealed that, plant-based medicines are rich in phytonutrients of antipsychotic importance and may be effective as stand-alone treatments or supplementary to conventional interventions. Despite the emerging interest in phytotherapy for mental disorders, the majority of the formulations are yet to be clinically certified. However, simply disregarding them for this reason might be consequential and as such, for better and improved mental health, research into phytotherapeutic care for psychosis must remain to be continuously explored as a promising niche.",signatures:"Abdulwakeel Ayokun-nun Ajao, Saheed Sabiu, Fatai Oladunni\nBalogun, Damilare Adedayo Adekomi and Sefiu Adekilekun Saheed",downloadPdfUrl:"/chapter/pdf-download/62587",previewPdfUrl:"/chapter/pdf-preview/62587",authors:[{id:"200124",title:"Dr.",name:"Fatai Oladunni",surname:"Balogun",slug:"fatai-oladunni-balogun",fullName:"Fatai Oladunni Balogun"},{id:"248272",title:"Dr.",name:"Abdulwakeel",surname:"Ayokun-nun Ajao",slug:"abdulwakeel-ayokun-nun-ajao",fullName:"Abdulwakeel Ayokun-nun Ajao"},{id:"259661",title:"Dr.",name:"Damilare",surname:"Adedayo Adekomi",slug:"damilare-adedayo-adekomi",fullName:"Damilare Adedayo Adekomi"},{id:"259663",title:"Dr.",name:"Sefiu",surname:"Adekilekun Saheed",slug:"sefiu-adekilekun-saheed",fullName:"Sefiu Adekilekun Saheed"},{id:"300406",title:"Dr.",name:"Saheed",surname:"Sabiu",slug:"saheed-sabiu",fullName:"Saheed Sabiu"}],corrections:null},{id:"63341",title:"Insight in Psychosis: An Integrated Perspective",doi:"10.5772/intechopen.79368",slug:"insight-in-psychosis-an-integrated-perspective",totalDownloads:1047,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Insight in psychosis is a multidimensional concept with each component being influenced by various biological, individual and cultural factors. The study and understanding of such a concept needs to be done at various levels and with needed emphasis on the personal and interpersonal aspects of the people suffering with psychotic disorders, as this is routinely neglected in the clinical discourse in favor of reductionist biological models. An adequate understanding of the nature of human person should undergird a complex effort like the inquiry into the higher concepts of human experience such as delusion and insight into illness, which in turn should guide the therapeutic, administrative and legal management of people with psychotic illness.",signatures:"Starlin Vijay Mythri and Johann Alex Ebenezer",downloadPdfUrl:"/chapter/pdf-download/63341",previewPdfUrl:"/chapter/pdf-preview/63341",authors:[{id:"246230",title:"Dr.",name:"Starlin",surname:"Vijay Mythri",slug:"starlin-vijay-mythri",fullName:"Starlin Vijay Mythri"},{id:"249046",title:"Dr.",name:"Johann",surname:"Alex Ebenezer",slug:"johann-alex-ebenezer",fullName:"Johann Alex Ebenezer"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"7810",title:"Quality of Life",subtitle:"Biopsychosocial Perspectives",isOpenForSubmission:!1,hash:"0392d2712c58885b729bd943f9aac37f",slug:"quality-of-life-biopsychosocial-perspectives",bookSignature:"Floriana Irtelli, Federico Durbano and Simon George Taukeni",coverURL:"https://cdn.intechopen.com/books/images_new/7810.jpg",editedByType:"Edited by",editors:[{id:"174641",title:"Dr.",name:"Floriana",surname:"Irtelli",slug:"floriana-irtelli",fullName:"Floriana Irtelli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8864",title:"Family Therapy",subtitle:"New Intervention Programs and Researches",isOpenForSubmission:!1,hash:"e50bb9cef36aeaef4ba976554b3dd141",slug:"family-therapy-new-intervention-programs-and-researches",bookSignature:"Floriana Irtelli",coverURL:"https://cdn.intechopen.com/books/images_new/8864.jpg",editedByType:"Edited by",editors:[{id:"174641",title:"Dr.",name:"Floriana",surname:"Irtelli",slug:"floriana-irtelli",fullName:"Floriana Irtelli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9052",title:"Psychoanalysis",subtitle:"A New Overview",isOpenForSubmission:!1,hash:"69cc7a085f5417038f532cf11edee22f",slug:"psychoanalysis-a-new-overview",bookSignature:"Floriana Irtelli, Barbara Marchesi and Federico Durbano",coverURL:"https://cdn.intechopen.com/books/images_new/9052.jpg",editedByType:"Edited by",editors:[{id:"174641",title:"Dr.",name:"Floriana",surname:"Irtelli",slug:"floriana-irtelli",fullName:"Floriana Irtelli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"510",title:"Anxiety Disorders",subtitle:null,isOpenForSubmission:!1,hash:"183445801a9be3bfbce31fe9752ad3db",slug:"anxiety-disorders",bookSignature:"Vladimir Kalinin",coverURL:"https://cdn.intechopen.com/books/images_new/510.jpg",editedByType:"Edited by",editors:[{id:"31572",title:null,name:"Vladimir V.",surname:"Kalinin",slug:"vladimir-v.-kalinin",fullName:"Vladimir V. 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Importantly, knowledge gained from model plants can be generally translated to other related plant species because many key cellular and molecular processes are conserved and regulated by ‘blueprint’ genes inherited from a common ancestor. Model Organisms in Plant Genetics addresses characteristics of model plants such as Arabidopsis, moss, soybean, maize, and cotton, highlighting their advantages and limitations as well as their importance in studies of plant development, plant genome polyploidization, adaptive selection, evolution, and domestication, as well as their importance in crop improvement.",isbn:"978-1-83969-750-0",printIsbn:"978-1-83969-749-4",pdfIsbn:"978-1-83969-751-7",doi:"10.5772/intechopen.94797",price:119,priceEur:129,priceUsd:155,slug:"model-organisms-in-plant-genetics",numberOfPages:112,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"f6624b58571ac10c9b636c5d85ec5e54",bookSignature:"Ibrokhim Y. Abdurakhmonov",publishedDate:"June 23rd 2022",coverURL:"https://cdn.intechopen.com/books/images_new/10774.jpg",keywords:null,numberOfDownloads:723,numberOfWosCitations:0,numberOfCrossrefCitations:2,numberOfDimensionsCitations:3,numberOfTotalCitations:5,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 26th 2021",dateEndSecondStepPublish:"May 27th 2021",dateEndThirdStepPublish:"July 26th 2021",dateEndFourthStepPublish:"October 14th 2021",dateEndFifthStepPublish:"December 13th 2021",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a year",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:"Dr. Abdurakhmonov was elected as The World Academy of Sciences Fellow (2014) in Agricultural Science and a member and Vice-president of the Academy of Sciences of Uzbekistan. He was appointed (2017) as a Minister of Innovative Development of Uzbekistan.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"213344",title:"Prof.",name:"Ibrokhim Y.",middleName:null,surname:"Abdurakhmonov",slug:"ibrokhim-y.-abdurakhmonov",fullName:"Ibrokhim Y. Abdurakhmonov",profilePictureURL:"https://mts.intechopen.com/storage/users/213344/images/system/213344.jpg",biography:'Ibrokhim Y. Abdurakhmonov received a BS in Biotechnology from the National University, California, in 1997, an MS in Plant Breeding from Texas A&M University in 2001, and a Ph.D. in Molecular Genetics, DSc in Genetics, and a full professorship in Molecular Genetics and Molecular Biotechnology from the Academy of Sciences of Uzbekistan in 2002, 2009, and 2011, respectively. He founded the Center of Genomics and Bioinformatics of Uzbekistan in 2012. He received the 2010 prize from The World Academy of Sciences (TWAS) and \\"ICAC Cotton Researcher of the Year 2013\\" for his outstanding contribution to cotton genomics and biotechnology. He was elected as a fellow to TWAS in 2014 and as a member of the Academy of Sciences of Uzbekistan in 2017. In the same year, he was appointed Minister of Innovative Development of Uzbekistan.',institutionString:"Academy of Sciences of Uzbekistan",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"14",totalChapterViews:"0",totalEditedBooks:"13",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"311",title:"Plant Genetics",slug:"agronomy-plant-genetics"}],chapters:[{id:"81301",title:"Introductory Chapter: Model Plants for Discovering the Key Biological Processes in Plant Research",slug:"introductory-chapter-model-plants-for-discovering-the-key-biological-processes-in-plant-research",totalDownloads:11,totalCrossrefCites:0,authors:[{id:"213344",title:"Prof.",name:"Ibrokhim Y.",surname:"Abdurakhmonov",slug:"ibrokhim-y.-abdurakhmonov",fullName:"Ibrokhim Y. 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Traore"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"418965",firstName:"Nera",lastName:"Butigan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/418965/images/16899_n.jpg",email:"nera@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors.\nFrom chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors, and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing or reviewing.\nI assist authors in preparing their full chapter submissions and track important deadlines to ensure they are met. I help to coordinate internal processes such as linguistic review and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"3800",title:"World Cotton Germplasm Resources",subtitle:null,isOpenForSubmission:!1,hash:"c8454ec008f1d20ebe7387b1be02b2db",slug:"world-cotton-germplasm-resources",bookSignature:"Ibrokhim Y. Abdurakhmonov",coverURL:"https://cdn.intechopen.com/books/images_new/3800.jpg",editedByType:"Edited by",editors:[{id:"213344",title:"Prof.",name:"Ibrokhim Y.",surname:"Abdurakhmonov",slug:"ibrokhim-y.-abdurakhmonov",fullName:"Ibrokhim Y. Abdurakhmonov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5297",title:"Cotton Research",subtitle:null,isOpenForSubmission:!1,hash:"2066d7af6611d6ee68d42608dba4e3d6",slug:"cotton-research",bookSignature:"Ibrokhim Y. 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Hypercholesterolemia is an important determinant of cardiovascular disease (CVD), the leading cause of death globally [1]. Cholesterol, among other lipids, is carried in the bloodstream from the liver to different parts of the body by lipoproteins, complex particles composed of lipids and proteins. There are four major lipoproteins that can be classified on the basis of their density: chylomicrons, very low‐density lipoprotein (VLDL), low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL) [2]. Chylomicrons, VLDL and LDL are larger particles with densities ranging from 0.95 to 1.063 g/ml. HDL is a mixture of spherical particles ranging in size from 7 to 12 nm in diameter and 1.063–1.21 g/ml in density. Epidemiological studies have established an inverse relationship between HDL cholesterol and CVD risk [3, 4]. Thus, a reduction in plasma HDL levels represents an important risk factor for CVD. Results of clinical trials demonstrate that lowering LDL levels reduces CVD risk [5, 6]. Evidence supporting a role for elevated HDL in reducing CVD risk, however, is still forthcoming. Clinical trials have shown that torcetrapib, dalcetrapib and extended‐release niacin significantly increase circulating HDL levels; however, this was not associated with improved outcomes [7–9]. On the other hand, raising plasma HDL by infusion or overexpression of apoA‐I in murine models was shown to reduce atherogenic lesion progression [10]. One hypothesis to explain this disparity proposes that the “quality” or functional status of HDL may be a better indicator of CVD risk than plasma levels of HDL per se [11]. This review will focus on the structure‐function relationship of HDL and how it influences responses to the lipoprotein in the context of inflammation.
\nHDL particles have a neutral core of cholesteryl ester and triglycerides (TG) surrounded by a monolayer of phospholipids, free cholesterol (FC) and protein. ApoA‐I is the major protein associated with HDL particles and is synthesized in the liver and small intestine. Phospholipids and cholesterol are transferred to apoA‐I by a process mediated by the ATP‐binding cassette transporter type 1 (ABCA1) [12, 13] resulting in the formation of a lipid poor, dense particle called preβ‐HDL. This particle plays an important role in reverse cholesterol transport, a process by which cholesterol is removed from cells. Although these particles have been predominantly studied under in vitro conditions, little information is available regarding the presence or functional significance of preβ‐HDL in vivo [14]. HDL isolated from plasma by sequential ultracentrifugation yields two major subpopulations: HDL2, a large, light, lipid‐rich particle (d1.063–1.125 g/ml), and HDL3, a smaller, denser protein‐rich particle (d1.125–1.21 g/ml). These two particles can be further subdivided into five distinct populations: HDL2b, HDL2a, HDL3a, HDL3b and HDL3c [15]. These heterogeneous particles vary in their lipid and protein composition, forming particles of varying density, charge, and antigenicity. They also possess discrete functional properties.
Sphingolipids are also well‐represented in HDL particles. Sphingomyelin (SM) accounts for 5–10% by weight of total HDL lipids [15]. SM is converted to ceramide by sphingomyelinase [16]. Ceramide constitutes 0.05% by weight of total HDL lipids. Ceraminidase converts ceramide to sphingosine. Finally, the enzyme sphingosine kinase converts sphingosine to sphingosine 1‐phosphate (S1P) [16]. S1P, as well as ceramide‐1‐phosphate, are carried by HDL and are potent signaling molecules that regulate cell growth, survival and differentiation [17]. S1P plays an important role in the suppression of inflammation [17]. S1P binding to HDL requires its physical interaction with apo M [17, 18]. Sphingosylphosphorylcholine and lysosulfatide are additional, biologically active lysosphingolipids carried by HDL [15]. The principal lipids associated with HDL particles are summarized in Table 1.
Proteins | Lipids |
---|---|
Apolipoproteins (AI‐II, A‐V, C‐I‐IV, D, E, F, M, H, O) | Phospholipids: |
CETP | PC, PE, PI, PG, PS, PA |
PAF‐AH | |
PLTP | Sphingolipids: |
LCAT | SM |
PON1, PON3 | Ceramides |
SAA1, SAA2, SAA4 | S1P |
Albumin | Sphingosylphosphorylcholine |
Transthyretin | Lysosulfatide |
Hemoglobin | |
Hemopexin | |
Transferrin | |
Ceruloplasmin | |
Vitamin D binding protein | |
Complement |
Normal protein and lipid components of HDL.
ApoA‐I is likely the major HDL protein species involved in the removal of LOOH moieties from LDL. The methionine (Met) residues 112 and 148 of apoA‐I can reduce LOOHs to inactive lipid hydroxides (LOH) [28]. In addition, apoA‐I removes seeding LOOH molecules from LDL [29]. In addition to apoA‐I, other apolipoprotein and enzyme components of HDL, such as, apo E, apo J, apo A‐II, apo L‐1, apo F, apo A‐IV, PON1/3, PLTP and PAF‐AH, play a role in its antioxidant function. Proteomic analyses from the Davidson laboratory [30] demonstrate that HDL3c contains all these proteins along with apo M, apo D, apo A‐II, SAA1,2 and 4 and apo C‐I and apo C‐II. This corroborates earlier studies showing that HDL3c has more potent antioxidant activity than other HDL subspecies [31, 32]. Thus, both lipid and protein components of HDL3c contribute to its antioxidant activity. Kontush et al. [32] have hypothesized that the protein components of HDL3c form a pocket which enables the transfer of LOOH from LDL which is further reduced by the concerted action of apolipoproteins and enzymes in this pocket [26].
\nIn the presence of ox‐LDL and other oxidized lipids, the mitochondrion increases the formation of ROS, which can damage the mitochondria and other organelles causing cellular dysfunction and death. HDL, by virtue of its antioxidant properties, can decrease the cellular damage caused by oxidized lipids. The HDL protein PON1 hydrolyzes cholesterol esters and phospholipids in oxidized lipoproteins [52, 57, 58] thus inhibiting mitochondrial damage in the presence of oxidized lipids [58]. Further, HDL‐associated apoA-I has been implicated in electron transport chain maintenance and repair [59]. In apoA‐I null mice (apoA‐I-/-), an increase in coronary ischemia‐reperfusion injury is observed compared to wild‐type mice [59] and is associated with a decrease in the content of the mitochondrial protein Coenzyme Q (CoQ) in cardiomyocytes. CoQ normally supports oxidative phosphorylation by shuttling electrons from Complex II to Complex III. Exogenous administration of CoQ to apo‐A‐I-/- mice attenuated myocardial infarct size compared to the injury response in untreated mice. These data indicate the importance of HDL, and specifically, apoA‐I in preserving mitochondrial structure and function.
\nPotential mechanisms by which HDL preserves mitochondrial function include activation of the Reperfusion Injury Salvage Kinase (RISK) pathway and the Survivor Activating Factor Enhancement (SAFE) cascade. These are cell survival pathways which are known to prevent mitochondrial damage in models of ischemic pre‐ and postconditioning [60]. Activation of STAT3 is an important component of the SAFE pathway and results in the downregulation of pro‐apoptotic factors Bax and Bad and upregulation of antiapoptotic factor Bcl‐2 and the antioxidants manganese superoxide dismutase and metallothionein [60, 61]. Further, STAT3 is transported to the mitochondrion by the GRIM‐19 chaperone where it inhibits the release of cytochrome c and reduces cell death [62–64]. In a rodent model of coronary artery occlusion, the administration of apoA‐I was shown to decrease infarct size and inhibit mitochondrial morphological changes seen in the heart [60]. Further analyses showed that apoA‐I increased the phosphorylation of
The S1P component of HDL is also able to activate the RISK And SAFE pathways [51, 52, 65]. Interestingly, studies conducted in neonatal rat cardiomyocytes showed that S1P is critically required for the phosphorylation of STAT3. In contrast, STAT3 phosphorylation was absent in cells treated with HDL that was deficient in S1P [65]. In addition, S1P stimulates the phosphorylation of the transcription factor, forkhead box O‐1 (FOXO‐1), which inhibits ROS formation and apoptosis in the phosphorylated form [66, 67]. These data suggest that HDL activates RISK and SAFE pathways and inhibits ROS, mitochondrial dysfunction and cell death.
\nInterestingly, S1P has also been shown to regulate mitochondrial Complex IV assembly and cellular respiration by interacting with mitochondrial prohibitin‐2 (PBH‐2) [68]. PBH‐2 acts as a scaffolding protein for mitochondria and its interaction with S1P during ischemic pre‐conditioning of cardiomyocytes is essential for cardioprotection [68–70]. These data suggest that S1P can stabilize mitochondrial complexes and inhibit ROS formation, suggesting an alternate cardioprotective mechanism of S1P action.
\nRecent studies have suggested that other HDL‐associated apolipoproteins play a role in preserving mitochondrial structure and function. ApoJ is expressed ubiquitously and is present on small dense HDL3 particles [71–73]. It is considered to be an antioxidant due to the presence of disulfide bonds that inhibit ROS‐induced injury and preserve mitochondrial function [74]. Further, apoJ has been implicated in activating
Changes in HDL sub‐species and their function have been reported in several disease states, including atherosclerosis [4], rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) [81, 82], diabetes [83], hypertension [84] and psoriasis [85–87]. Inflammation/infection triggers an APR that causes a reduction in HDL quantity and alterations in both its lipid and protein composition. Van Lenten and colleagues [88] first reported that HDL loses its ability to inhibit LDL oxidation during the APR, demonstrating that inflammation affects the structure and function of HDL.
\nProteinsa | Lipidsb | ||
---|---|---|---|
Increased | Decreased | Increased | Decreased |
Serum Amyloid A (SAA) | Apo A‐I | Triglycerides | Total lipid |
Apo J | Apo A‐II | FC | Phospholipids |
sPLA2 | Apo C | LPC | CE |
Apo E | Apo M | FFA | SM |
Ceruloplasmin | LCAT | ||
PAF‐AH | CETP | ||
LBP | Transferrin | ||
Apo A‐IV | Hepatic lipase | ||
Apo A‐V | Paraoxanase I |
The presence of apoM in HDL particles is thought to contribute to atheroprotection [103]. LPS and inflammatory cytokines, however, attenuate apoM mRNA levels and protein expression in Hep3B cells [104]. A decrease in serum apoM is also observed in patients with sepsis and HIV infections [104]. Further, a reduction in apoM reduces the association of S1P with HDL resulting in degradation of anti‐inflammatory function [103].
\nThe association of other apolipoproteins with HDL may impair the function of the lipoprotein. ApoO is incorporated by HDL, LDL and VLDL particles [105]. Data suggest that apoO provides structural stability for mitochondria by stabilizing the inner mitochondrial membrane and cristae [105]. Other data, however, show that overexpression of apoO degrades mitochondrial protein and increases cardiac dysfunction in hypercholesterolemic mice [106]. In cardiomyocyte cultures, upregulation of apoO was associated with an increase in ROS and apoptosis compared to control cells that were apoO‐deficient [106]. ApoC is an additional, exchangeable apolipoprotein associated with HDL and apoB‐containing lipoproteins. In isolated rat liver mitochondria, addition of the apoC‐III isoform was shown to inhibit mitochondrial oxygen consumption and attenuate ATP formation [107]. Another study showed that enrichment of HDL with apoC‐I stimulates cytochrome c release, caspase 3 cleavage and cell death in human aortic smooth muscle cells [108]. Finally, apoC‐I enrichment of HDL is associated with a reduction in HDL‐associated apoA‐I, suggesting that loss of apoA‐I and its cytoprotective effects is a component of apoC‐I‐mediated cell injury [107, 108]. Clearly, additional in vitro and in vivo studies are required to define the mechanistic role of specific apolipoprotein species in the development of inflammatory injury.
Changes in HDL lipid and protein composition induced by the APR impair normal HDL function resulting in the formation of “dysfunctional” HDL.
\nHDL plays an important role in regulating atherogenesis
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.
This is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
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From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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