Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
\r\n\t
",isbn:"978-1-83768-132-7",printIsbn:"978-1-83768-131-0",pdfIsbn:"978-1-83768-133-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"8e41aab8223c29ce69c00e8c8f6f560d",bookSignature:"Prof. Vlassios Hrissanthou and Assistant Prof. Vasilis Bellos",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12059.jpg",keywords:"Reservoir, Check Dam, River Flow, River Sediment Transport, Stilling Basin, Weir, Bridge Pier, Scouring, Reservoir Volume Capacity, Dimensioning Flood, Dimensioning Hydrograph, Length of Spillway",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 20th 2022",dateEndSecondStepPublish:"July 21st 2022",dateEndThirdStepPublish:"September 19th 2022",dateEndFourthStepPublish:"December 8th 2022",dateEndFifthStepPublish:"February 6th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Prof. Hrissanthou is the author and co-author of 48 publications in scientific journals, 88 publications in conference proceedings, and 12 book chapters published in English, Greek, and German. 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Vlassios Hrissanthou is an Emeritus Professor at the Civil Engineering Department of Democritus University of Thrace (DUTH), Xanthi, Greece. He studied Civil Engineering at the Aristotle University of Thessaloniki (AUTH), Greece, obtaining the diploma of Civil Engineer in 1972. He then undertook postgraduate and doctoral studies on Hydrology and Hydraulic Structures at the University of Karlsruhe (KIT), Germany. Subsequently, he completed a postdoctoral study on Hydraulics and Hydraulic Structures at the University of the Armed Forces Munich (UniBw München), Germany. His teaching work includes the following graduate and postgraduate study courses: Fluid Mechanics, Hydraulics, Engineering Hydrology, River Engineering, Hydropower Engineering, Water Resources Management, Open Channel Hydraulics, Hydrology of Groundwater, Advanced Engineering Hydrology, Sediment Transport, Reservoir Design, Time Series Analysis, Selected Chapters of Hydropower Engineering, and Hydraulics of Stratified Flows. He has supervised a plethora of diploma, postgraduate and doctoral dissertations. He has participated as principal investigator in several competitive international, german and greek research projects, dealing amongst others with soil erosion and sediment transport. Professor Hrissanthou is the author and co-author of 48 publications in scientific journals, 88 publications in conference proceedings, as well as 12 publications in book chapters in English, Greek and German. 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In 1971,
Healthcare providers supply products (e.g., iron or multivitamin supplements for infants, condoms for sex workers, and contraceptives for teenagers) and provide services (e.g., pap smear testing for early detection of cervical cancer, mammography for diagnosis of breast cancer, and chest X-ray for patients suspected with tuberculosis). But, that is not all. In healthcare systems, the people as consumers or clients are encouraged to perform healthy behaviors and avoid non-healthy behaviors. We ask them have enough physical activity, reduce their salt intake, consume enough fruit and vegetables, and quit smoking.
Health behavior is a behavior directed at promoting, protecting, and maintaining health, as well as reducing disease risks and early death. It includes personal attributes such as beliefs, expectations, values, perceptions, prevention, behavior patterns, actions, and habits that relate to health maintenance, restoration, and improvement [6]. In public health, education, marketing, and law enforcement are three main approaches applied to achieve behavior change. For people who consider the behavior change but do not have the required knowledge or skills, education is effective. Enforcement of laws and regulation is appropriate for the entrenched people who have no desire to change and resist deliberately. Marketing can be useful to bridge the gap between these two approaches and will be a good solution for those who are aware of the need to change but have not considered changing [7].
Health can be considered as a real market in which consumers pay the monetary and non-monetary costs and obtain the benefits of health products, services, or behaviors. If the marketing principles and techniques are applied, we can expect to be successful in selling our products, especially health behaviors. This chapter will address the theoretical concepts and practical steps for planning, implementing, and evaluating the interventions based on the social marketing approach for health.
Health interventions to be considered as social marketing programs need to fulfill some criteria. The benchmark criteria provide a useful framework for assessing the extent to which an intervention is consistent with the social marketing approach and for identifying opportunities to potentially increase the impact of an intervention. Kotler and Lee explained some features of the social marketing approach: (1) focusing on understanding the perspectives of the full range of target audiences necessary to bring about change; (2) developing a research-based program, relying on formative research to develop and test concepts with members of the target audience; and (3) recognizing the need to include all elements of the marketing mix (i.e., product, price, place, promotion) to bring about behavior change [8]:
The National Social Marketing Centre has developed a set of eight social marketing benchmark criteria to promote the understanding and use of core social marketing concepts. They are behavior, customer orientation, theory, insight, exchange, competition, segmentation, and methods mix [9]. According to Andreasen’s benchmark criteria [10], for an intervention to be classified as social marketing, at least one of the following components is needed. They are considered as the key concepts of the social marketing approach:
Behavioral change: Determining the objective aiming to achieve behavioral change as the main focus of social marketing interventions.
Formative research: Using audience research to understand target audiences, pre-test interventions and monitor their delivery; it is fundamental in social marketing interventions.
Segmentation: Dividing a general target audience into smaller and homogenous segments based on the shared characteristics.
Marketing mix: Adopted from the commercial sector is the marketing mix, also known as the 4Ps: product, price, place, and promotion [11]. These four key elements of social marketing are central to the planning and implementation of an integrated marketing strategy. Each of these four components should be present in a marketing plan. However, it is the science of correctly using these elements in combination with one another that provides the effective “marketing mix.” To have an effective social marketing program, we must have a product developed based on the consumers’ wants, needs, and preferences, priced realistically, distributed through convenient channels, and actively promoted to customers.
Exchange: Social marketing programs aim to change behavior by establishing an exchange between the consumers and the program developer based on the consumers’ wants and needs. In this exchange, consumers give up something of value and receive something of equal or greater value. Target audiences have opportunities to exchange their monetary and non-monetary resources for attractive tangible and/or intangible benefits. They are looking for the benefits of the product and have to pay its cost. Exchange forms voluntarily. Consumers want to fulfill their felt needs or desires and are ready to pay the costs and the social, economic, and physical costs (price). The costs must not be more than the perceived gains and benefits of the product.
Competition: In a dynamic marketplace, commercial or social, there are different priorities and choices. So, competition is always present. If the target audience is not ready or willing to buy our promoted products, or we do not provide the products which the target audience wants, the marketing attempts will fail. In other words, the consumer will exit our market and go somewhere else. In case of social marketing, particular decisions are faced with some barriers that may result in highlighted desirability or perceived relative value of other options. So, thinking about competition is a major requirement in a successful social marketing program.
A health intervention defined as: “Any health-related measure taken to improve the health of an individual or a community; this may involve diagnosing, preventing, treating, and managing disease conditions, injury, or disability” [6]. In practice, understanding the key components of social marketing is not sufficient and we need to use social marketing planning models. Some of these models are the Social Marketing Assessment and Response Tool (SMART) model of Neiger & Thackeray (1998), Andreasen’s model (1995), a framework suggested by Walsh, Rudd, Moeykens, and Moloney [15], and Weinreich’s model (1999) [12]. All of them have practical phases and researchers can design the intervention step by step. The SMART model is a social marketing planning model developed by Neiger in 1998 and is applied to some researches in the health field [13, 14]. This model has seven phases as below:
Preliminary planning includes identification of the intended health problem, developing the goals, preparing the evaluation plan, and estimating the program costs. Like other programs, the first step is determining the health problems and selecting the prioritized ones. To get ready, behavioral aspects of the intended health problem were considered and the target health behavior was determined. According to this health behavior, we set the program goals. Evaluation planning, or determining measures of success, would include identifying and comparing measures before and after the intervention. Social marketers must estimate the monetary and non-monetary costs and try to provide them. Remember that social marketing programs are usually expensive interventions and advocacy with decision-makers is required.
Formative research findings provide the primary idea for intervention. This data determines the target audience and its properties, the specific objectives, the primary idea for intervention, and communicating manners to the audience. Data are collected through qualitative approaches (focus group discussions (FGDs) and in-depth interviews) and quantitative surveys. After collecting and analyzing the formative research data, social marketers describe the target audience: who they are, what is important to them, what influences their behavior, and what would enable them to engage in the desired behavior. Formative research consists of audience, channels, and market analysis as below:
Audience analysis: In this step, identification of the general target audience, segmentation, defining the special target segment, and then studying their needs, wants, and preferences were done. Learning about demographic, psychosocial, and behavioral variables through qualitative and quantitative methods is necessary for segmenting the primary general target audience into smaller and more homogenous subgroups and developing the particular interventions needed to modify risky behaviors. When we have a general and heterogeneous audience, their points of view about the target behavior, benefits, and barriers to perform behavior, and channels for communicating to the audience, are different. So, the segmentation of a general and large audience group to small and relatively homogeneous subgroups helps the planners to design an effective program. In this way, it is possible to develop marketing strategies customized to the unique characteristics of each subgroup and have better outcomes. We will discuss about segmentation later in formative research and market analysis. The target audiences were asked about the costs and benefits of performing the intended behavior, desires, and values. Qualitative and quantitative studies provide data for knowing the consumer’s perspective before starting the strategy design. The data can be collected through surveys, focus groups, and in-depth interviews.
Market analysis: For analyzing the market, the partners, the competitors, and the components of marketing mix are identified. Partners are those people or organizations who can help achieve the program goals. They have common, but not the same, goals and can provide the resources and support the activities. Competitors are those who provide similar products and services and may lose their benefits during our programs. So, they are vying for individual audience members’ time and attention. Market analysis is not completed without marketing mix establishment. Marketing mix is also referred to as the 4Ps: product, price, place, and promotion. Product refers to the set of benefits associated with the desired behavior or service usage. To be successful, the product must provide a solution to problems that consumers consider important and must offer them a benefit they truly value. So, we need to research to understand people’s wants, needs, and preferences. The marketing objective is to discover which benefits have the greatest appeal to the target audience and to design a product that provides those benefits. The product can be a tangible good or an intangible one. In the case of social marketing, behaviors are common products. The product can include ideas and behavior changes or something offered to the consumer to satisfy a want or need. Examples may include educational programs, screenings, environmental changes, self-care programs, and so on. Price refers to the cost for the promised benefits or the barriers that may prevent the consumer from taking action. This cost is always considered from the consumer’s point of view. Costs can include money, time, opportunity, energy, social, behavioral, geographic, physical, structural, psychological factors, and convenience or pleasure. So, price is not always monetary and usually encompasses intangible costs. In setting the right price, it is important to know if consumers prefer to pay more to obtain “value-added” benefits and if they think that products given away or priced low are inferior to more expensive ones. Place: For tangible goods, place refers to the distribution system and the location of sales and for intangible products such as services or behaviors, it refers to the location where consumers can obtain information about the product. Promotion is often the most visible component of marketing. It includes the type of persuasive communication that marketers use to deliver the product benefits of tangible goods or intangible products and services. Promotional activities may encompass advertising, public relations, printed materials, promotional items, signage, special events and displays, face-to-face selling, and entertainment media [15]. For the exchange to take place, the social marketer must understand consumers’ preferences regarding the 4Ps.
Channel analysis: Identification of the best way to communicate to the target audience and know about their preferred sources of information is the main mission of channel analysis. Channels can be people, institutions, organizations, and specific communication techniques, such as mass media, personal communication, or public events. Social marketers may consider printed materials (e.g., pamphlet and brochures), printed media (e.g., newspapers and magazines), and mass media (e.g., radio and television programs, websites contents, social networks, and mobile applications).
During the formative research, the main ideas for intervention are determined, and primary materials develop. Before completing the production of messages and materials for implementation, it is required to pretest the key elements including methods, communications, and strategies. They are presented to some members of the target audience and receive their feedback. Modifications are made based on the feedback. Typical methods for pretesting include focus groups, interviews, and surveys.
Implementation is the activation of all strategies, tactics, and methods that were developed to achieve the designated goals and objectives. Activities such as the initiation of a mass-media awareness campaign, offerings of small-group self-management classes, or creation of a community coalition to improve the health behavior in a neighborhood are included in this phase.
Evaluation determines the program’s success. It is done during and at the end of the intervention. When the quality of the program is assessed by documenting the extent to which it was implemented as designed,
Gordon et al. [17] described three systematic reviews and primary studies that evaluate social marketing effectiveness. They concluded that social marketing provides a very promising framework for improving health both at the individual level and at the wider environmental and policy levels [17]. Morris and Clarkson [18] reviewed the studies using a social marketing framework for changing healthcare practice. They found social marketing as a useful solution-focused framework for systematically understanding barriers to individual behavior change and designing interventions accordingly. They argued that the social marketing approaches being adopted in public health may also provide a potent strategy for achieving change from practitioners and concluded that this approach provides a single framework to analyze and address the complex problem of behavior change, systematically using methods proven in commercial marketing [18]. Firestone et al. [19] reviewed the evidence of the effectiveness of social marketing in low- and middle-income countries, focusing on major areas of investment in global health: HIV, reproductive health, child survival, malaria, and tuberculosis. They concluded that social marketing can influence health behaviors and health outcomes in global health; however, evaluations assessing health outcomes remain comparatively limited. Evidence exists that social marketing can influence health behaviors and health outcomes [19]. Luca and Suggs [20] reviewed systematically 17 articles published after 1990. These articles reported social marketing interventions for the prevention or management of some diseases and behavioral risk factors, conducted evaluations, and met the six social marketing benchmarks’ criteria. They concluded that there is an ongoing lack of use or underreporting of the use of theory in social marketing interventions and focused on applying and reporting theory to guide and evaluate interventions [20].
To obtain newer findings, we searched PubMed database using “social marketing “and found that 1655 articles have been published since 2010 till now. By limiting the search to “Systematic Reviews,” 120 articles were determined, and by limiting the search more to behaviors, it showed that in 65 systematic review articles, social marketing interventions focused on behaviors. Application of social marketing to reduce tobacco use (19 articles) and alcohol consumption (18 articles), modify the nutritional practice (16 articles), promote physical activity (14 articles), and increase the condom usage (7 articles) were the most common subjects. Some particular systematic reviews in which “social marketing” has been mentioned in their titles are explained as below:
Xia et al. [21] reviewed 92 social marketing interventions published during 1997–2013. They concluded that if the six benchmarks of social marketing interventions (behavior change, consumer research, segmentation and targeting, exchange, competition, and marketing mix) are considered, and if the researchers analyze the audience, make the target behavior tangible, and promote the desired behavior, it is an effective approach in promoting physical activity among adults [21]. In another systematic review done by Luecking et al. [22], they searched PubMed, ISI Web of Science, PsycInfo, and the Cumulative Index of Nursing and Allied Health systematically to identify interventions targeting nutrition and/or physical activity behaviors of children enrolled in early care centers between 1994 and 2016. They concluded that social marketing could be an important strategy for preventing early childhood obesity through promoting physical activity and nutrition modification [22].
Aceves-Martins et al. [23] reviewed 38 non-randomized and randomized controlled trials conducted from 1990 to April 2014 in participants aged 5–17. They searched the PubMed, Cochrane, and ERIC databases to find the studies that contained social marketing strategies to reduce youth obesity in European school-based interventions. They concluded that the inclusion of at least five social marketing benchmark criteria in school-based interventions could be effective to prevent obesity in young people [23].
Sweat et al. [24] searched the National Library of Medicine’s Gateway (includes Medline and AIDSline), PsycINFO, Sociological Abstracts, CINAHL, and EMBASE to study the effectiveness of social marketing for promoting condom use. Their meta-analyses showed a positive and statistically significant effect on increasing condom use, and all individual studies showed positive trends. They concluded that the cumulative effect of condom social marketing over multiple years could be substantial [24].
Janssen et al. [25] reviewed six papers extracted through searching PubMed, PsychInfo, Cochrane, and Scopus to describe the effects of an alcohol prevention intervention developed according to one or more principles of social marketing. Based on this review, the effect of applying the principles of social marketing in alcohol prevention in changing alcohol-related attitudes or behavior could not be assessed [25].
Wei et al. [26] searched the following electronic databases for results from January 1, 1980 to the search date July 14, 2010: Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, LILACS (Latin America and Brazil), PsycINFO, PubMed, Web of Science/Web of Social Science, Chinese National Knowledge Infrastructure (CNKI), and CQ VIP (China). This review provided limited evidence that multi-media social marketing campaigns can promote HIV testing among men who have sex with men (MSM) in developed countries. Future evaluations of social marketing interventions for MSM should employ more rigorous study designs. Long-term impact evaluations (changes in HIV or STI incidence over time) are also needed. Implementation research, including detailed process evaluation, is needed to identify elements of social marketing interventions that are most effective in reaching the target population and changing behaviors [26].
Social marketing is an approach to change health behaviors. It can provide a useful framework for systematically understanding barriers to and benefits of the targeted health products.
Social marketing programs are based on the six benchmark criteria: focusing on behavior change, consumer research, audience segmentation, exchange, competition thinking, and establishing the marketing mix or 4Ps. For applying social marketing in practice, we need some planning models that contain operational steps and constructs. The SMART model is one of these planning models.
Formative research is the heart of social marketing programs, and audience, market, and channel analysis are three fundamental components of formative research.
Using social marketing to promote health behaviors is growing, but answering this question that whether the social marketing framework provides an effective means of bringing about behavior change remains an empirical question which still has to be tested in practice. However, many lessons have been learned in recent years.
In Iran, the mortality rate due to road traffic crashes is considerably high, and risky driving behavior by road users is an important factor influencing this health problem. However, many attempts have been made to reduce risky driving behaviors; they have been limited to education and enforcement. In this study, researchers designed and implemented an intervention based on the SMART (Social Marketing Assessment and Response Tool) model to reduce two specific risky driving behaviors, tailgating and non-driving between lines, among taxi drivers in Tehran, Iran. The target audience were the professional drivers in two municipality regions with the highest rate of traffic violations as recorded by the Tehran Driving Police. Formative research inclusive of a qualitative study and a quantitative survey was designed and implemented to determine intervention components. In a qualitative study, opinions and views of 42 taxi drivers in 4 focus group discussions were explored. They talked about the current driving in Tehran, causes of risky driving behaviors, suggested practices for modification of risky driving behaviors, appropriate places for introducing products and services, and appropriate channels to communicate and influence taxi drivers. Taxi drivers believed that if they concentrate on driving, they can avoid risky driving behaviors. Most of them suggested reminding messages for drivers and using materials containing these messages. Getting help from taxi route supervisors was suggested by taxi drivers as influencing people and effective communication channels.
Based on the formative research, the social marketing-based intervention was designed. The product was the reminder message for concentrating on the avoidance of two target behaviors, and the messages containing stickers were developed and installed on the glass before the driver’s eyes. In addition, developing and distributing the message containing pamphlets, and justifying taxi route supervisors as opinion leaders to communicate messages to taxi drivers, were done. After 6 weeks, two target risky driving behaviors were assessed by checklists and compared.
Before the intervention, 68.3% of drivers in the intervention group and 77.1% of drivers in the control group committed tailgating, while after the intervention, these percentages were 36.9 and 67.9% in intervention and control groups respectively. For non-driving between lines, it was similar. Before the intervention, 60.9% of drivers in the intervention group and 59.0% of drivers in the control group committed non-driving between lines, while after the intervention, these percentages were 38.9 and 52.4%, respectively. The interventions resulted in statistically significant reductions in the two target behaviors in the intervention group as compared with the control group. Furthermore, logistic regression showed that the odds ratio for avoiding tailgating and non-driving between lines increased significantly in the intervention group: 2.34 (1.30–4.21) and 1.83 (1.06–3.17), respectively [27].
Workplace injury is the second leading cause of fatal injuries in Iran. However, many programs have been implemented to reduce workplace injuries; a majority of the interventions had been designed based on viewpoints of health and industry experts and were not consumer orientated. These interventions were usually focused on education and enforcement. In other words, for people who face a choice with attractive alternatives, or barriers, a third approach is needed; there was not any solution. In this study, an intervention based on the SMART model was designed and implemented to persuade workers in two constructing subway stations to use personal protective equipment (PPE) at the workplaces in Isfahan, Iran. This study is a quasi-experimental intervention based on the SMART model. A total of 44 employees in two separate subway stations under construction in Isfahan were assigned into intervention and control groups. All constructing subway stations were listed and one of them was selected as an intervention station randomly. By considering the similarities in the number and composition of employees in all stations, another one was considered as the control station. Intervention and control stations were in the north and center regions of Isfahan, respectively. Formative research included a qualitative study and a quantitative survey was designed. In the qualitative study, focus group discussions (FGDs) were used to explore viewpoints of the audience about PPE usage. The participants were asked to talk about the importance of using PPE, factors that influence their use and strategies to increase the use of PPE. In the quantitative study, attitudes and self-reported behaviors were measured by a 28-item questionnaire. Workers in both intervention and control stations completed the questionnaires and a 10-item checklist was used by two trained observers to record observed behaviors regarding PPE use. Based on initial findings, a free package containing a well-designed light-weighted helmet, a dust mask and safety gloves were delivered to workers in the intervention group. A sticker with an emotionally tailored message reminding them of the importance of caring for themselves because of their families was attached to the helmet. This message was developed based on concerns expressed by the workers during FGDs. They had told that their families were the most important reason for using PPE because injuries would result in problems not only for themselves but also for their families. Providing and delivering a free and suitable package containing PPE in the workplace and promoting the product through personal communication and applying printed materials were its main components. The intervention was done in the workplace, and stickers with the message “I take care of myself because of my family” were attached to all helmets. In the package, we also put a simple tailored pamphlet including messages related to the advantages of using PPE and the risks they can reduce. For people who were unschooled, face-to-face counseling was held. The intervention was implemented for 4 weeks in the intervention station. Engineers and foremen supervised the use of PPE and reminded and warned the employees to use the package content. After 6 weeks, the use of PPE in both intervention and control stations were checked by checklists. Behaviors in the intervention and control stations were measured using an observational checklist. After the intervention, the percentage of workers who used PPE at the intervention station increased significantly. Before the intervention, none of the workers in intervention station used helmet and safety masks, and 4 and 12% of them in the control station used these PPEs. After the intervention, 43.5% of the intervention group and 27.3% of the control group used helmets, and 39.1% of the intervention group and 18.2% of the control group used safety masks and these percentages were 36.9 and 67.9% in intervention and control groups respectively. The intervention resulted in statistically significant reductions in the two target behaviors in the intervention group as compared with the control group [28].
Mammography has an important role in early detection of breast cancer. So, the health sector tries to persuade women to do that. A majority of the interventions are based on education and information and there has been less attention to making mammography cost beneficent. This study aimed at assessing the effect of a social marketing-based intervention to persuade one to do mammography in Bojnord, Iran. In this study, two villages which had similar demographic characteristics such as population, sex ration, and socioeconomic status, considered as intervention and comparison groups randomly. All women of 35 years and older consisted of 343 women (151 in intervention and 191 in comparison groups) and were included in the study. To obtain the main idea for intervention, and exploring the viewpoints of the target group about mammography, a formative research combined of a quantitative survey and a qualitative study was done. It was completed by the women to assess their attitudes, and four focus group discussions were established to gather qualitative data. The quantitative study showed that time for referring and waiting in hospitals, financial costs, forgetting mammography, and fear of exposure to x-ray are more prominent. In the qualitative study, expending time and high economical costs are considered as two main factors related to not taking up mammography. According to the formative research findings, an intervention focused on the main barriers that were designed. Women who chose mammography were registered in health houses. After arranging the appointments with the local hospital, women were picked up in groups and brought to the hospital. A person who was familiar with the process of mammography welcomed them and coordinated the service. Mammography was not free, but a significant discount had been considered by the hospital. This program was implemented for 4 consecutive weeks. One week after the intervention, the number of mammograms in two villages was determined and compared. After the intervention, 48.1% of the women in the intervention group went for mammography and there were no changes in the comparison group [29].
The rate of Cesarean sections in Iran is higher than the acceptable rate recommended by the World Health Organization. Regardless of implementing many educational programs to reduce Cesarean section rates, some barriers are influencing the choices of pregnant women. This field trial was done in Yasuj, Iran, and 39 3–4 months pregnant primigravida were included in the study as the target audience. They chose Cesarean section for delivery. A formative research combined of a quantitative survey and a qualitative study was done to achieve the social marketing mix, and based on the results a tailored intervention was designed and pretested on the subjects. The product was a promoting package that consisted of a short-time instruction, messages for brief interventions in public health facilities, and a phone counseling service managed by trained midwives. The final intervention was implemented for a period of 1 month and its effectiveness was assessed after at least 1 month by a proportion test. One month after the intervention 30 pregnant women expressed willingness and intentions to have a normal delivery, which was a statistically significant change [30].
Education, marketing, and law enforcement are three key solutions for changing behaviors. For people who consider the behavior change but do not have the required knowledge or skills, education is effective. Enforcement of laws and regulation is appropriate for the entrenched people who have no desire to change and resist deliberately. Marketing can be useful to bridge the gap between these two approaches and will be a good solution for those who are aware of the need to change but have not considered changing. Healthcare system supplies the health products (e.g., iron or multivitamin supplements for infants, condoms for sex workers, and contraceptives for women who want to do family planning), provides the health services (e.g., pap smear testing for early detection of cervical cancer in women, mammography for early detection of breast cancer, and chest X-ray for patients suspected with tuberculosis), and encourages people to perform the right health behaviors (e.g., having enough physical activity, smoking cessation, and reducing salt intake). So, healthcare providers have something to offer their consumers and expect the audiences to take them. Health is an important social market in which the principles and key elements of commercial marketing are applied. To be successful in the health market, it is required to consider the key principles and techniques of social marketing such as consumer research, audience segmentation, exchange theory, competition thinking, and marketing mix by decision-makers, managers, and care providers. So, the future policy must be focused on empowering them to apply this approach as an important solution for health issues.
Although, attention to using the social marketing for health problems is expanding, there are some controversies about the long-term of the social marketing based programs yet. We need to conduct more and more trials to be sure. If the decision-makers in health systems want to solve their problems, they have to pay attention to social marketing as a new and innovative choice.
The author does not have any conflict of interest.
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.
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