Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"Milestone",originalUrl:"/media/original/124"}},components:[{type:"htmlEditorComponent",content:'
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:"7867",leadTitle:null,fullTitle:"Drug Discovery and Development - New Advances",title:"Drug Discovery and Development",subtitle:"New Advances",reviewType:"peer-reviewed",abstract:"The process of drug discovery and development is a complex multistage logistics project spanned over 10-15 years with an average budget exceeding 1 billion USD. Starting with target identification and synthesizing anywhere between 10k to 15k synthetic compounds to potentially obtain the final drug that reaches the market involves a complicated maze with multiple inter- and intra-operative fields. Topics described in this book emphasize the progresses in computational applications, pharmacokinetics advances, and molecular modeling developments. In addition the book also contains special topics describing target deorphaning in Mycobacterium tuberculosis, therapy treatment of some rare diseases, and developments in the pediatric drug discovery process.",isbn:"978-1-78923-976-8",printIsbn:"978-1-78923-975-1",pdfIsbn:"978-1-78985-219-6",doi:"10.5772/intechopen.77685",price:119,priceEur:129,priceUsd:155,slug:"drug-discovery-and-development-new-advances",numberOfPages:164,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"5dd2483e8a643b7da16c4be006fd61cf",bookSignature:"Vishwanath Gaitonde, Partha Karmakar and Ashit Trivedi",publishedDate:"March 11th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/7867.jpg",numberOfDownloads:12145,numberOfWosCitations:44,numberOfCrossrefCitations:45,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:95,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:184,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 6th 2018",dateEndSecondStepPublish:"November 26th 2018",dateEndThirdStepPublish:"January 25th 2019",dateEndFourthStepPublish:"April 15th 2019",dateEndFifthStepPublish:"June 14th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"221897",title:"Dr.",name:"Vishwanath",middleName:null,surname:"Gaitonde",slug:"vishwanath-gaitonde",fullName:"Vishwanath Gaitonde",profilePictureURL:"https://mts.intechopen.com/storage/users/221897/images/system/221897.jfif",biography:"Education: Doctor of Philosophy in Chemistry, University of Toledo, Toledo, OH, USA\r\nCurrent Position: Senior Research Scientist, Chemical Research and Development, Cambrex High Point, Inc., High Point, NC, USA.\r\n\r\nAt Cambrex, Dr. Gaitonde design, develop and optimize chemical processes for multi-kilo scale cGMP and nGMP production campaigns to support clinical trials and Phase I to Phase III manufacturing. Prior to joining Cambrex, Dr. Gaitonde worked at GlaxoSmithKline - Antiviral Medicinal Chemistry, on the development and optimization of a lead molecule targeted towards broad-spectrum viral respiratory disease. Dr. Gaitonde’s Ph.D. research was focused on understanding tuberculosis disease condition and the development of carbohydrate-based molecules as biochemical tools to probe the Mtb GlgE mechanistic aspect. Additionally, his Ph.D. research involved the development of a low molecular weight novel amorphous polyester material based on sustainable chemistry.",institutionString:"Cambrex High Point, Inc.",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"268945",title:"Dr.",name:"Partha",middleName:null,surname:"Karmakar",slug:"partha-karmakar",fullName:"Partha Karmakar",profilePictureURL:"https://mts.intechopen.com/storage/users/268945/images/system/268945.jpg",biography:"Dr. Partha Karmakar is Doctor of Philosophy in Chemistry, University of Toledo, Toledo, Ohio, USA. Currently he is a Post-Doctoral Research Associate, Washington University School of Medicine, St. Louis, MO, USA.\nDr. Karmakar\\'s research at the Washington University School of Medicine St. Louis involves the development of new therapeutic strategy for cancer treatment that involves development of small molecules, bioconjugates and nanoparticle-based photosensitizer and radionuclide probes, in-vitro and in-vivo efficacy study and moving towards clinical translation. Prior to this, he worked at GlaxoSmithKline – Pennsylvania-Antibacterial drug discovery, on the development and optimization of a lead molecule targeting bacterial colony growth mechanism. Dr. Karmakar\\'s PhD research involves development of glycopeptide-based vaccines and their in-vivo immunological evaluation.",institutionString:"University of Washington School of Medicine St. Louis",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Abzena (United States)",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:{id:"268948",title:"Dr.",name:"Ashit",middleName:null,surname:"Trivedi",slug:"ashit-trivedi",fullName:"Ashit Trivedi",profilePictureURL:"https://mts.intechopen.com/storage/users/268948/images/system/268948.jpg",biography:"Dr. Ashit Trivedi is Doctor of Philosophy in Pharmaceutical Sciences, University of Tennessee Health Science Campus, Memphis, TN, USA. Currently he is Sr. Scientist at Clinical Pharmacology Modeling and Simulations, Amgen, Thousand Oaks, CA.\nDr. Trivedi joined Amgen as a Scientist in the Clinical Pharmacology Modeling and Simulations group in September 2015. He has worked in different therapeutic areas including oncology and neurosciences. His current focus is on cardiovascular diseases. As a clinical pharmacologist, Dr. Trivedi participated in multifunctional study teams to design and conduct clinical pharmacology studies to support the global registration of pipeline drugs, perform PK and exposure-response analysis to inform dose selection, summarize and interpret PK, PK/PD, and clinical pharmacology results for internal/external presentations, study reports, and regulatory documents and interact with the line-management and different functions to implement strategies for drug label.",institutionString:"Amgen Inc.",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1195",title:"Drug Discovery",slug:"pharmacology-toxicology-and-pharmaceutical-science-pharmacology-drug-discovery"}],chapters:[{id:"70934",title:"Introductory Chapter: The Modern-Day Drug Discovery",doi:"10.5772/intechopen.90922",slug:"introductory-chapter-the-modern-day-drug-discovery",totalDownloads:929,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:null,signatures:"Partha Karmakar, Ashit Trivedi and Vishwanath Gaitonde",downloadPdfUrl:"/chapter/pdf-download/70934",previewPdfUrl:"/chapter/pdf-preview/70934",authors:[{id:"221897",title:"Dr.",name:"Vishwanath",surname:"Gaitonde",slug:"vishwanath-gaitonde",fullName:"Vishwanath Gaitonde"}],corrections:null},{id:"70982",title:"Past, Present, and Future of Molecular Docking",doi:"10.5772/intechopen.90921",slug:"past-present-and-future-of-molecular-docking",totalDownloads:1295,totalCrossrefCites:4,totalDimensionsCites:9,hasAltmetrics:0,abstract:"The interface of any given ligand and protein—normally considered a macromolecule—of a known or predicted/modeled structure can be computed by determining each potential ligand position, resulting in an array of possibilities which are finally expressed in numerical energy values based on their thermodynamic affinity. Over the past few decades, this premier approach technique has proved to be crucial as an automated method in drug design and discovery, as well as in other fields. Data are retrieved from contour surface calculations for each ligand probe and can be analyzed to delineate regions of attraction on the basis of energy levels. Negative energy levels from contours are used to infer protein-ligand affinity clefts and are therefore relevant to drug design. Accordingly, molecular docking, framed as the “new microscope,” is part of a group of in silico computational techniques that enable the behavior of molecular chemistry to be analyzed and predicted in an inexpensive manner. From the starting point of framing the key terms in the binomial macromolecule-ligand docking approach, this chapter presents an introductory description of the progress made in this field of research over the past several years, in addition to present and future perspectives. This chapter presents a broad plethora of possibilities arising from the old docking alternatives to the current software technology and critically dissects and discusses the emerging trends. Despite the emergence of more degrees of freedom, a number of flexible conglomerates have not been well developed, and there are still computational limitations to solve, including several features in the focused technique. The present goals, such as molecular flexibility, binding entropy, and the presence of ions and solute conditions, are revisited with the purpose of anticipating the challenges, goals, and achievements in this field over the next few years or decades.",signatures:"Thuluz Meza Menchaca, Claudia Juárez-Portilla and Rossana C. Zepeda",downloadPdfUrl:"/chapter/pdf-download/70982",previewPdfUrl:"/chapter/pdf-preview/70982",authors:[{id:"219266",title:"Dr.",name:"Rossana C",surname:"Zepeda",slug:"rossana-c-zepeda",fullName:"Rossana C Zepeda"},{id:"219492",title:"Dr.",name:"Claudia",surname:"Juárez-Portilla",slug:"claudia-juarez-portilla",fullName:"Claudia Juárez-Portilla"},{id:"277080",title:"Dr.",name:"Thuluz",surname:"Meza-Menchaca",slug:"thuluz-meza-menchaca",fullName:"Thuluz Meza-Menchaca"}],corrections:null},{id:"67939",title:"Molecular Docking in Modern Drug Discovery: Principles and Recent Applications",doi:"10.5772/intechopen.85991",slug:"molecular-docking-in-modern-drug-discovery-principles-and-recent-applications",totalDownloads:3901,totalCrossrefCites:27,totalDimensionsCites:60,hasAltmetrics:1,abstract:"The process of hunt of a lead molecule is a long and a tedious process and one is often demoralized by the endless possibilities one has to search through. Fortunately, computational tools have come to the rescue and have undoubtedly played a pivotal role in rationalizing the path to drug discovery. Of all techniques, molecular docking has played a crucial role in computer aided drug design and has swiftly gained ranks to secure a valuable position in the modern scenario of structure-based drug design. In this chapter, the principle, sampling algorithms, scoring functions and diverse available software’s for molecular docking have been summarized. We demonstrate the interplay of docking, classical techniques of structure-based design and X-ray crystallography in the process of drug discovery. In addition, we dwell upon some of the limitations faced in docking studies. Finally, several success stories of molecular docking approaches in drug discovery have been highlighted, concluding with remarks on molecular docking for the future.",signatures:"Aaftaab Sethi, Khusbhoo Joshi, K. Sasikala and Mallika Alvala",downloadPdfUrl:"/chapter/pdf-download/67939",previewPdfUrl:"/chapter/pdf-preview/67939",authors:[{id:"252956",title:"Dr.",name:"Mallika",surname:"Alvala",slug:"mallika-alvala",fullName:"Mallika Alvala"},{id:"287101",title:"Mr.",name:"Aaftaab",surname:"Sethi",slug:"aaftaab-sethi",fullName:"Aaftaab Sethi"},{id:"295049",title:"Ms.",name:"Khusbhoo",surname:"Joshi",slug:"khusbhoo-joshi",fullName:"Khusbhoo Joshi"},{id:"295050",title:"Ms.",name:"Sasikala",surname:"K",slug:"sasikala-k",fullName:"Sasikala K"}],corrections:null},{id:"64654",title:"Computational Deorphaning of Mycobacterium tuberculosis Targets",doi:"10.5772/intechopen.82374",slug:"computational-deorphaning-of-mycobacterium-tuberculosis-targets",totalDownloads:1129,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Tuberculosis (TB) continues to be a major health hazard worldwide due to the resurgence of drug discovery strains of Mycobacterium tuberculosis (Mtb) and co-infection. For decades drug discovery has concentrated on identifying ligands for ~10 Mtb targets, hence most of the identified essential proteins are not utilised in TB chemotherapy. Here computational techniques were used to identify ligands for the orphan Mtb proteins. These range from ligand-based and structure-based virtual screening modelling the proteome of the bacterium. Identification of ligands for most of the Mtb proteins will provide novel TB drugs and targets and hence address drug resistance, toxicity and the duration of TB treatment.",signatures:"Lorraine Yamurai Bishi, Sundeep Chaitanya Vedithi, Tom L. Blundell and Grace Chitima Mugumbate",downloadPdfUrl:"/chapter/pdf-download/64654",previewPdfUrl:"/chapter/pdf-preview/64654",authors:[{id:"261230",title:"Prof.",name:"Grace",surname:"Mugumbate",slug:"grace-mugumbate",fullName:"Grace Mugumbate"},{id:"262105",title:"MSc.",name:"Lorraine Yamurai",surname:"Bishi",slug:"lorraine-yamurai-bishi",fullName:"Lorraine Yamurai Bishi"},{id:"271045",title:"Dr.",name:"Dr Sundeep Chaitanya",surname:"Vedithi",slug:"dr-sundeep-chaitanya-vedithi",fullName:"Dr Sundeep Chaitanya Vedithi"},{id:"271046",title:"Prof.",name:"Tom L.",surname:"Blundell",slug:"tom-l.-blundell",fullName:"Tom L. Blundell"}],corrections:null},{id:"64593",title:"Revisiting Pharmacokinetics and Pharmacogenetics of Methadone in Healthy Volunteers",doi:"10.5772/intechopen.82426",slug:"revisiting-pharmacokinetics-and-pharmacogenetics-of-methadone-in-healthy-volunteers",totalDownloads:1181,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Methadone acts as a μ opioid agonist, a serotonin and norepinephrine reuptake inhibitor, and a noncompetitive N-methyl-D-aspartate receptor antagonist. These actions altogether are responsible for its efficacy in the management of chronic pain. It is available as a racemic mixture of (R)- and (S)-methadone, both being stereoisomers responsible for its analgesic effect. Methadone elimination occurs mainly through metabolism in the liver by CYP3A4, CYP2B6, and CY2C19 and to a lesser extent by CYP2D6 and in the intestine by CYP3A4. The relative intestinal content of CYP2B6 and CY2C19 is unknown but it seems that CYP2B6 is not present at the intestine. CYP3A4, CYP2B6, and CYP2C19 convert methadone mainly into 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine(EDDP). CYP2B6 and CYP2C19 are stereoselective to S- and R-enantiomer, respectively. The pharmacokinetic study carried out in healthy volunteers by our research group confirmed that MTD undergoes recirculation via gastric secretion and intestinal reabsorption and revealed that the drug is extensively metabolized in the liver but intestinal metabolism is not only relevant but also stereoselective. Polymorphisms of the CYP2B6 and CYP2C19 isoenzymes and their relationship with the pharmacokinetics of MTD were also assessed.",signatures:"Natalia Guevara, Marianela Lorier, Marta Vázquez, Pietro Fagiolino, Iris Feria-Romero and Sandra Orozco-Suarez",downloadPdfUrl:"/chapter/pdf-download/64593",previewPdfUrl:"/chapter/pdf-preview/64593",authors:[{id:"69773",title:"Prof.",name:"Marta",surname:"Vázquez",slug:"marta-vazquez",fullName:"Marta Vázquez"},{id:"73431",title:"Prof.",name:"Pietro",surname:"Fagiolino",slug:"pietro-fagiolino",fullName:"Pietro Fagiolino"},{id:"109165",title:"Dr.",name:"Iris",surname:"Feria-Romero",slug:"iris-feria-romero",fullName:"Iris Feria-Romero"},{id:"198119",title:"Dr.",name:"Sandra",surname:"Orozco-Suarez",slug:"sandra-orozco-suarez",fullName:"Sandra Orozco-Suarez"},{id:"259026",title:"Mrs.",name:"Natalia",surname:"Guevara",slug:"natalia-guevara",fullName:"Natalia Guevara"},{id:"259027",title:"Mrs.",name:"Marianela",surname:"Lorier",slug:"marianela-lorier",fullName:"Marianela Lorier"}],corrections:null},{id:"66969",title:"ADME Profiling in Drug Discovery and a New Path Paved on Silica",doi:"10.5772/intechopen.86174",slug:"adme-profiling-in-drug-discovery-and-a-new-path-paved-on-silica",totalDownloads:1678,totalCrossrefCites:7,totalDimensionsCites:16,hasAltmetrics:1,abstract:"The drug discovery and development pipeline have more and more relied on in vitro testing and in silico predictions to reduce investments and optimize lead compounds. A comprehensive set of in vitro assays is available to determine key parameters of absorption, distribution, metabolism, and excretion, for example, lipophilicity, solubility, and plasma stability. Such test systems aid the evaluation of the pharmacological properties of a compound and serve as surrogates before entering in vivo testing and clinical trials. Nowadays, computer-aided techniques are employed not just in the discovery of new lead compounds but embedded as part of the entire drug development process where the ADME profiling and big data analyses add a new layer of complexity to those systems. Herein, we give a short overview of the history of the drug development pipeline presenting state-of-the-art ADME in vitro assays as established in academia and industry. We will further introduce the underlying good practices and give an example of the compound development pipeline. In the next step, recent advances at in silico techniques will be highlighted with special emphasis on how pharmacogenomics and in silico PK profiling can enhance drug monitoring and individualization of drug therapy.",signatures:"Arne Krüger, Vinicius Gonçalves Maltarollo, Carsten Wrenger and Thales Kronenberger",downloadPdfUrl:"/chapter/pdf-download/66969",previewPdfUrl:"/chapter/pdf-preview/66969",authors:[{id:"75830",title:"Prof.",name:"Carsten",surname:"Wrenger",slug:"carsten-wrenger",fullName:"Carsten Wrenger"},{id:"175204",title:"Dr.",name:"Thales",surname:"Kronenberger",slug:"thales-kronenberger",fullName:"Thales Kronenberger"},{id:"278208",title:"MSc.",name:"Arne",surname:"Krüger",slug:"arne-kruger",fullName:"Arne Krüger"},{id:"278209",title:"Prof.",name:"Vinicius Gonçalves",surname:"Maltarollo",slug:"vinicius-goncalves-maltarollo",fullName:"Vinicius Gonçalves Maltarollo"}],corrections:null},{id:"69483",title:"Successive Drug Therapy for a Very Rare Autosomal Diseases",doi:"10.5772/intechopen.89583",slug:"successive-drug-therapy-for-a-very-rare-autosomal-diseases",totalDownloads:675,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"It is very rare to find reports concerning a drug therapy successively treating chromosomal abnormalities. In this paper, we are reporting a successive use of nitisinone in treating a fatal and very rare autosomal disease called hereditary tyrosinemia type-1 [HT-1]. HT-1 is affecting about one person in 100,000 to 120,000 births worldwide. It is due to a genetic defect in the enzyme fumarylacetoacetate hydroxylase (FAH), which is responsible for the final degradation of tyrosine. Accumulation of tyrosine metabolites is responsible for tissue damage such as liver, kidney, and neural tissues, finally causing the death of the newborn babies in their early months of life if not treated. Fumarylacetoacetate hydrolase gen has mapped on chromosome 15q23-15q25. Since 1992, the initiation of treating HT-1 with nitisinone (NTBC) has become the medical therapy of choice in combination with diet. NTBC therapy has shown a direct correlation between age of initiation and subsequent clinical course. We are reporting three brothers treated safely and successively with NTBC in combination with diet. All of them are in very good conditions. The elder brother is on NTBC since 27 years ago.",signatures:"Mohammed Chyad Al-Noaemi and Hassan Ali Daghriri",downloadPdfUrl:"/chapter/pdf-download/69483",previewPdfUrl:"/chapter/pdf-preview/69483",authors:[{id:"307586",title:"Prof.",name:"Mohammed Chyad",surname:"Al-Noaemi",slug:"mohammed-chyad-al-noaemi",fullName:"Mohammed Chyad Al-Noaemi"}],corrections:null},{id:"66531",title:"Challenges and New Frontiers in the Paediatric Drug Discovery and Development",doi:"10.5772/intechopen.85635",slug:"challenges-and-new-frontiers-in-the-paediatric-drug-discovery-and-development",totalDownloads:1359,totalCrossrefCites:5,totalDimensionsCites:6,hasAltmetrics:0,abstract:"Drug discovery and development advances in the last decades allowed to find a treatment for many preventable diseases. However, all too often, children are excluded from these progresses since most of the new medicines have been discovered and developed for the adult population. Even if paediatricians routinely give drugs to children ‘off-label’, researchers have demonstrated that children do not respond to medications in the same way as adults. Furthermore, certain specific disorders are unique to children or occur in children differently than in adults. Besides specifically testing medicines in children in proper clinical studies taking into due account the peculiarity of this population, there is a growing recognition of the need to develop paediatric medicines having in mind the specificities of this vulnerable population. In this chapter, we will provide an overview on the drug discovery and development path for children highlighting challenges and new frontiers of each phase from the discovery to the preclinical and clinical development as well as we will provide a slightest hint about paediatric biomarkers discovery, age-appropriate formulation, pregnancy, and perinatal pharmacology and in silico pharmacology. Finally, pricing and reimbursement policies for medicines and new and existing research initiatives in the field will be discussed.",signatures:"Angelica Intini, Donato Bonifazi and Giovanni Migliaccio",downloadPdfUrl:"/chapter/pdf-download/66531",previewPdfUrl:"/chapter/pdf-preview/66531",authors:[{id:"218024",title:"Mr.",name:"Donato",surname:"Bonifazi",slug:"donato-bonifazi",fullName:"Donato Bonifazi"},{id:"233341",title:"Dr.",name:"Angelica",surname:"Intini",slug:"angelica-intini",fullName:"Angelica Intini"},{id:"294876",title:"Dr.",name:"Giovanni",surname:"Migliaccio",slug:"giovanni-migliaccio",fullName:"Giovanni Migliaccio"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"671",title:"Drug Discovery and Development",subtitle:"Present and Future",isOpenForSubmission:!1,hash:"74072e600a9fb54b8257355a7954399e",slug:"drug-discovery-and-development-present-and-future",bookSignature:"Izet M. 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Habib",reviewType:"peer-reviewed",authors:[null]},{id:"69",type:"chapter",title:"Feasibility Study on an Excavation-Type Demining Robot PEACE",slug:"feasibility_study_on_an_excavation-type_demining_robot_peace",totalDownloads:2958,totalCrossrefCites:1,signatures:"Yoshikazu Mori",reviewType:"peer-reviewed",authors:[null]},{id:"70",type:"chapter",title:"Attitude Compensation of Space Robots for Capturing Operation",slug:"attitude_compensation_of_space_robots_for_capturing_operation",totalDownloads:2895,totalCrossrefCites:1,signatures:"Panfeng Huang and Yangsheng Xu",reviewType:"peer-reviewed",authors:[null]},{id:"71",type:"chapter",title:"Omni-directional Mobile Microrobots on a Millimeter Scale for a Microassembly System",slug:"omni-directional_mobile_microrobots_on_a_millimeter_scale_for_a_microassembly_system",totalDownloads:3267,totalCrossrefCites:0,signatures:"Zhenbo Li and Jiapin Chen",reviewType:"peer-reviewed",authors:[null]},{id:"72",type:"chapter",title:"Study of Dance Entertainment Using Robots",slug:"study_of_dance_entertainment_using_robots",totalDownloads:4232,totalCrossrefCites:1,signatures:"Kuniya Shinozaki, Akitsugu Iwatani and Ryohei Nakatsu",reviewType:"peer-reviewed",authors:[null]},{id:"73",type:"chapter",title:"Experimental Robot Musician",slug:"experimental_robot_musician",totalDownloads:3457,totalCrossrefCites:0,signatures:"Tarek Sobh, Kurt Coble and Bei Wang",reviewType:"peer-reviewed",authors:[null]},{id:"74",type:"chapter",title:"On the Analogy in the Emergent Properties of Evolved Locomotion Gaits of Simulated Snakebot",slug:"on_the_analogy_in_the_emergent_properties_of_evolved_locomotion_gaits_of_simulated_snakebot",totalDownloads:2227,totalCrossrefCites:0,signatures:"Ivan Tanev, Thomas Ray and Katsunori Shimohara",reviewType:"peer-reviewed",authors:[null]},{id:"75",type:"chapter",title:"A Novel Autonomous Climbing Robot for Cleaning an Elliptic Half-Shell",slug:"a_novel_autonomous_climbing_robot_for_cleaning_an_elliptic_half-shell",totalDownloads:4767,totalCrossrefCites:0,signatures:"Houxiang Zhang, Rong Liu, Guanghua Zong and Jianwei Zhang",reviewType:"peer-reviewed",authors:[null]}]},relatedBooks:[{type:"book",id:"3759",title:"Particle Swarm Optimization",subtitle:null,isOpenForSubmission:!1,hash:"85447c3d76565043803bbf8de76e5729",slug:"particle_swarm_optimization",bookSignature:"Aleksandar Lazinica",coverURL:"https://cdn.intechopen.com/books/images_new/3759.jpg",editedByType:"Edited by",editors:[{id:"12392",title:"Mr.",name:"Alex",surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"6251",title:"Novel Binary Particle Swarm Optimization",slug:"novel_binary_particle_swarm_optimization",signatures:"Mojtaba Ahmadieh Khanesar, Hassan Tavakoli, Mohammad Teshnehlab and Mahdi Aliyari Shoorehdeli",authors:[null]},{id:"6252",title:"Swarm Intelligence Applications in Electric Machines",slug:"swarm_intelligence_applications_in_electric_machines",signatures:"Amr M. 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Fikret Ercan",authors:[null]},{id:"6260",title:"A Particle Swarm Optimization Technique used for the Improvement of Analogue Circuit Performances",slug:"a_particle_swarm_optimization_technique_used_for_the_improvement_of_analogue_circuit_performances",signatures:"Mourad Fakhfakh, Yann Cooren, Mourad Loulou and Patrick Siarry",authors:[null]},{id:"6261",title:"Particle Swarm Optimization Applied for Locating an Intruder by an Ultra-Wideband Radar Network",slug:"particle_swarm_optimization_applied_for_locating_an_intruder_by_an_ultra-wideband_radar_network",signatures:"Rodrigo M. S. de Oliveira, Carlos L. S. S. Sobrinho, Josivaldo S. Araujo and Rubem G. 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Elkamchouchi",authors:[null]}]}],publishedBooks:[{type:"book",id:"3609",title:"Mobile Robots",subtitle:"State of the Art in Land, Sea, Air, and Collaborative Missions",isOpenForSubmission:!1,hash:null,slug:"mobile-robots-state-of-the-art-in-land-sea-air-and-collaborative-missions",bookSignature:"XiaoQi Chen, Y.Q. Chen and J.G. Chase",coverURL:"https://cdn.intechopen.com/books/images_new/3609.jpg",editedByType:"Edited by",editors:[{id:"81536",title:"PhD.",name:"XiaoQi",surname:"Chen",slug:"xiaoqi-chen",fullName:"XiaoQi Chen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3624",title:"Robot Soccer",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"robot-soccer",bookSignature:"Vladan Papić",coverURL:"https://cdn.intechopen.com/books/images_new/3624.jpg",editedByType:"Edited by",editors:[{id:"34038",title:"Prof.",name:"Vladan",surname:"Papić",slug:"vladan-papic",fullName:"Vladan Papić"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6111",title:"Mobile Robots",subtitle:"towards New Applications",isOpenForSubmission:!1,hash:"75544814a08a51504dd52ee155eff99d",slug:"mobile_robots_towards_new_applications",bookSignature:"Aleksandar Lazinica",coverURL:"https://cdn.intechopen.com/books/images_new/6111.jpg",editedByType:"Edited by",editors:[{id:"12392",title:"Mr.",name:"Alex",surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],publishedBooksByAuthor:[]},onlineFirst:{chapter:{type:"chapter",id:"81569",title:"Impact of Interferon Alpha/Beta in the Management of Chronic Myeloproliferative Disorders",doi:"10.5772/intechopen.104501",slug:"impact-of-interferon-alpha-beta-in-the-management-of-chronic-myeloproliferative-disorders",body:'Chronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Source | Type of trial | Interferon | Diagnosis | No. | Prior treatment status | Response rate |
---|---|---|---|---|---|---|
Yacoubet al. [15] | Phase II, multicenter | Pegylated IFN alfa-2a | PV | 50 | Resistance to HU or HU intolerance | CR:22% PR:38% |
ET | 65 | CR:43% PR:26% | ||||
Masarova et al. [16] | Phase II, single-center | Pegylated IFN alfa-2a | PV | 43 | Untreated or previously treated with cytoreductive therapy | CR:77% PR:7% |
ET | 40 | CR:73% PR:3% | ||||
Samuelsson et al. [18] | Phase II | Pegylated IFN alfa-2b | PV | 21 | Untreated or previously treated with cytoreductive therapy | CR: 69% for the entire group |
ET | 21 | |||||
Huang BT et al. [19] | Open label, multicenter | IFN alfa-2b | PV | 136 | Untreated or previously treated with cytoreductive therapy | OHR:70% Molecular response:54.7% |
ET | 123 | OHR (JAK2+ patients):83% CHR:23 cases OHR (JAK2-patients): 61.4% CHR:12 cases | ||||
Gisslinger et al. [23] | phase III, multicenter | Ropeginterferon | PV | 257 | Previously treated | OHR:53% |
Quintás-Cardama et al. [26] | phase II | Pegylated IFN alfa-2a | PV | 40 | Untreated or previously treated with cytoreductive therapy | OHR:80% CR:70% Molecular remission:54% |
ET | 39 | OHR:81% CR:76% Molecular remission:38% | ||||
Sørensen et al. [36] | Phase III, multicenter, COMBI | Pegylated IFN alfa-2a with ruxolitinib or Pegylated IFN alfa-2b with ruxolitinib | PV | 32 | Untreated or previously treated with cytoreductive therapy | OHR:44% CR:28% |
MF | 18 | OHR:31% CR:9% | ||||
Casassus et al. [40] | Open label, multicenter | IFN alpha-2b | Mastocytosis | 20 | Untreated and previously treated | PR:35% Minor remission: 30% |
Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; HU: hydroxycarbamide/hydroxyurea; CR: complete remission; PR: partial remission; and OHR: overall hematological response.
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
IntechOpen - where academia and industry create content with global impact
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