Test results showing proportions of failure mechanisms for given
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\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:"1007",leadTitle:null,fullTitle:"Xenotransplantation",title:"Xenotransplantation",subtitle:null,reviewType:"peer-reviewed",abstract:"Accompanied by the advent of animal cloning, the technique of nuclear transfer produced alpha1,3-galactosyltransferase-knockout (Gal-KO) pigs in many institutes, including the ones in Japan, at the beginning of 21st Century. In addition, the controversy of the risks of PERV has gradually minimized, because of the fact that there are no cases of PERV infections reported in humans. Furthermore, a large clinical wave for islet allotransplantation resumed the interest of xenotransplantation, especially porcine islet transplantation and some exceptions. Clinical trials were done in many countries so far, such as Sweden, China, Mexico, USA (Inventory of Human Xenotransplantation Practices - IXA and HUG in collaboration with WHO). 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After graduating at Hokkaido University Medical School, he finished clinical training in the first Department of Surgery, Osaka University Medical School. \r\nHe obtained his Ph.D. degree in transplantation immunology from the same university in 1989. Dr. Shuji Miyagawa worked at the University of Texas Medical School in Houston as a research associate from 1988 to 1990. He became an assistant professor in 1995 and associate professor at Osaka University in 1998. His works have been presented in numerous international meetings, especially the International Xenotransplantation Association (IXA), and he held the IXA-2013 in Osaka as the president. \r\nHe was a councilor of IXA, 2013 to 2017, and now the president of Japanese Society for Xenotransplantation (JSX).",institutionString:"Osaka University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Osaka University",institutionURL:null,country:{name:"Japan"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1152",title:"Reconstructive Surgery",slug:"reconstructive-surgery"}],chapters:[{id:"27902",title:"Anti-Gal and Anti-Non Gal Antibody Barriers in Xenotransplantation",doi:"10.5772/28180",slug:"anti-gal-and-anti-non-gal-antibody-barriers-in-xenotransplantation",totalDownloads:1849,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:null,signatures:"Uri Galili",downloadPdfUrl:"/chapter/pdf-download/27902",previewPdfUrl:"/chapter/pdf-preview/27902",authors:[{id:"72986",title:"Prof.",name:"Uri",surname:"Galili",slug:"uri-galili",fullName:"Uri Galili"}],corrections:null},{id:"27903",title:"Piscine Islet Xenotransplantation",doi:"10.5772/27547",slug:"piscine-islet-xenotransplantation",totalDownloads:1382,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"James R. 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Through a series of case studies, historical considerations, and reflections, different communities of gender and sexual minority groups will be explored. The book will give an overview of the wide variety of experiences that people who identify as gender and sexual minority group members have used in the formation of community, both online and in person. We will see that some of these creations of the community are a reaction to the exclusion by the larger society in which members are embedded. We will also see that people create a community in the face of oppression, engage in dialogue and activities (political and social), and create meaning in their identities. We will witness how these spaces give voice to change, resilience, and survival. For all of us who are queer and trans, community means at a minimum the place in which we can thrive and be seen.
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"55859",title:"Reliability Prediction Considering Multiple Failure Mechanisms",doi:"10.5772/intechopen.69500",slug:"reliability-prediction-considering-multiple-failure-mechanisms",body:'\nTraditional high‐temperature operational life (HTOL) test strategy is based on the outdated JEDEC standard that has not been supported or updated for many years. The major drawback of this method is that it is not based on a model that predicts failures in the field. Nonetheless, the electronics industry continues to provide data from tests of fewer than 100 parts, subjected to their maximum allowed voltages and temperatures for as many as 1000 h. The result based on zero, or a maximum of one, failure out of the number of parts tested does not actually predict. This null result is then fit into an average acceleration factor (AF), which is the product of a thermal factor and a voltage factor. The result is a reported failure rate as described by the standard failure in time (FIT) model, which is the number of expected failures per billion part hours of operation. FIT is still an important metric for failure rate in today’s technology; however, it does not account for the fact that multiple failure mechanisms simply cannot be averaged for either thermal or voltage acceleration factors.
\nOne of the major limitations of advanced electronic systems qualification, including advanced microchips and components,is providing reliability specifications that match the variety of user applications. The standard HTOL qualification that is based on a single high‐voltage and high‐temperature burn‐in does not reflect actual failure mechanisms that would lead to a failure in the field. Rather, the manufacturer is expected to meet the system’s reliability criteria without any real knowledge of the possible failure causes or the relative importance of any individual mechanism. More than this, as a consequence of the non‐linear nature of individual mechanisms, it is impossible for the dominant mechanism at HTOL test reflect the expected dominant mechanism at operating conditions, essentially sweeping the potential cause of failure under the rug while generating an overly optimistic picture for the actual reliability.
\nTwo problems exist with the current HTOL approach, as recognized by JEDEC in publication JEP122G:
Multiple failure mechanisms actually compete for dominance in our modern electronic devices and
Each mechanism has a vastly different voltage and temperature acceleration factors depending on the device operation.
This more recent JEDEC publication recommends explicitly that multiple mechanisms should be addressed in a sum‐of‐failure‐rates approach. We agree that a single point HTOL test with zero failures can, by no means, account for a multiplicity of competing mechanisms.
\nIn order to address this fundamental limitation, we developed a special multiple‐mechanism qualification approach that allows companies to tailor specifications to a variety of customer’s needs. We call this approach the multiple temperature operational life (MTOL) test at multiple conditions and match the results with the foundry’s reliability models to make accurate FIT calculations based on specific customer’s environments including voltage, temperature, and speed. The basic strategy is outlined in Figure 1. Time to fail models are put into the matrix as failure rates (
Matrix methodology for reliability prediction.
This new MTOL system allows the FIT value to be calculated with the assumption of not just one but multiple degradation mechanisms that are characterized by multiple acceleration factors. This chapter will describe the advantages of considering multiple failure mechanisms and how they can be linearly combined with a simple matrix solution that accounts for each mechanism proportionally based on data rather than based on a zero‐failure result.
\nThe semiconductor industry provides an expected FIT for every product that is sold based on operation within the specified conditions of voltage, frequency, heat dissipation, etc. Hence, a system reliability model is a prediction of the expected MTBF’s, or as we will use here, mean time to fail (MTTF), for a system that is not replaced as the sum of the FIT rates for every component.
\nA FIT is defined in terms of an acceleration factor (AF) and MTTF as:
\nwhere #failures and #tested are the numbers of actual failures that occurred as a fraction of the total number of units subjected to an accelerated test per total test time in hours. From a statistical perspective, this calculation would be correct if there is only a single known mechanism that is completely characterized by a single acceleration factor, AF. However, if multiple mechanisms are present, there is no way to average the acceleration factor, and thus, the denominator cannot be characterized as one AF for any set of operating conditions. The true AF must be based on the physics of the actual mechanisms, including different activation energies for different physical processes. Without testing at multiple accelerated conditions, a standard HTOL qualification cannot distinguish effects of more than one thermally activated process, rather only give an approximation for the dominant mechanism at the test condition. The test consists of stressing some number of parts, usually around 77, for an extended time, usually 1000 h, at an accelerated voltage and temperature.
\nIn order to excite multiple mechanisms, testing must be performed at multiple conditions of accelerated stress in order to obtain sufficient statistical data. Furthermore, there needs to be a statistically significant number of observed or extrapolated failures during the testing so that a proper average can be obtained. We cannot rely on a “zero failure” pass criterion when multiple mechanisms are involved since there needs to be a distinction between the effects of different accelerated stress conditions. The qualification tests are designed inevitably to result in zero failures, which allows the assumption (with only 60% confidence!) that no more than ½ a failure occurred during the accelerated test. The only fallacy with this approach is that the assumption is that the only dominant mechanism that would be seen during the test is the one with the reported AF. However, if that mechanism is not modelled or observed, there is no way to prove that this mechanism would actually be the cause of a field failure.
\nWe don’t need to prove that in most systems, multiple failure mechanisms contribute to the overall reliability of a system. Reliability mathematics assumes that the influences are time‐independent, occurring at a constant rate, while each is independent of the others. In reality, most systems experience failures at approximately a constant rate, at least for the first few “random” occurrences. When we consider that the defects responsible for earlier failures are generally distributed in time, the assumption of multiple failure mechanisms makes valid sense as to why the random failures occurring during the useful life of a product will be, in fact, caused by not a single mechanism, but rather by a proportional combination of all the likely failure and wear‐out mechanisms. However, due to the physics involved with each cause of failure, each will be accelerated differently depending on the thermal, electrical, or environmental stresses that are responsible for each mechanism. Hence, when an accelerated test is performed at an arbitrary voltage and temperature for acceleration based only on a single failure mechanism, then, only that mechanism will be accelerated. When the failure rate (FIT) is calculated based on the non‐occurrence of a failure (i.e., zero failure assumption), then it is naturally over‐estimating the reliability by whatever factor was not introduced by the second or third mechanism that was not accounted for in the model.
\nUnfortunately for the test and qualification industry, the final test procedure and failure rate calculation have not kept pace with the depth of understanding that we have today about the actual failure mechanisms. Also, manufacturing processes are so tightly controlled that each known mechanism is designed to be theoretically non‐existent in the field. Thus, naturally, since there is no single mechanism that will cause a known end‐of‐life, so it is logical that multiple mechanisms will affect the final failure rate. Furthermore, HTOL tests are known to reveal multiple failure mechanisms during final qualification, which would suggest also that no single failure mechanism would dominate FIT in the field. Thus, finally, in order to make a more accurate model for FIT, a preferable approximation should be that all mechanisms contribute and the resulting overall failure distribution resembles combination of
The key innovation of the multiple temperature operational life (MTOL) testing method is its ability to separate different failure mechanisms so that predictions can be made for any user defined operating conditions. This is opposed to the common approach for assessing device reliability today, using high‐temperature operating life (HTOL) testing [1], which is based on the assumption that just one dominant failure mechanism is responsible for a failure of the device in the field [2]. However, it is known that, in reality, multiple failure mechanisms act simultaneously on any system that causes failure based on more than a single mechanism at any time [3].
\nOur new approach, MTOL, deals with this issue [4]. This method predicts the reliability of electronic components by combining separately measured FITS of multiple failure mechanisms [5]. Our data reveal that different failure mechanisms act on a component in different regimes of operation causing different mechanisms to dominate, depending on the stress and the particular technology. When multiple mechanisms are known to affect the failure a product, then JEDEC standard publication JEP‐122G states that “
Because failure rates are linear and sum linearly only if they are all considered as constant rate processes, they can be combined linearly to calculate the actual reliability as measured in FIT of the system based on the physics of degradation at specific operating conditions. In a more recent publication [6], we present experimental results of the MTOL method tested on both 45 and 28 nm FPGA devices from Xilinx that were processed at TSMC (according to the Xilinx data sheets). The FPGAs were tested over a range of voltages, temperature and frequencies. We measured ring frequencies of multiple asynchronous ring oscillators simultaneously during stress in a single FPGA. Hundreds of oscillators and the corresponding frequency counters were burned into a single FPGA to monitor of statistical information in real time. Since the frequency of a ring oscillator itself monitors the device speed and performance, there is no recovery effect, giving a true measure for the effects of all the failure mechanisms in real time. Our results produced an acceleration factor (AF) for each failure mechanism as a function of core voltage, temperature and frequency.
\nThe failure rates of all of the mechanisms were then combined using a matrix to normalize the AF of the mechanisms to find the overall failure in time or FIT of the device. In other words, we found an accurate estimate of the device’s mean lifetime and thus the reliability that can be conveniently transposed to other technologies and ASICs and not necessarily only FPGAs, as was the basis of our previous work. In this chapter, we show that the MTOL methodology is general and can apply to any system that is characterized by multiple failure mechanisms, which can individually be treated as approximately occurring at a constant rate, having its own FIT per mechanism.
\nThe acceleration of the rate of occurrence of a single failure mechanism is a highly non‐linear function of temperature and/or voltage as is well known through studies of the physics of failure [3–5]. The temperature acceleration factor (
Calculated acceleration factors (AF) are universally used as the industry standard for device qualification. However, it only approximates a single dielectric breakdown type of failure mechanism and does not correctly predict the acceleration of other mechanisms. Similarly, an acceleration factor can be determined using any other type of stress applied, for example, vibration, radiation, number of cycles, etc. However, when only a single AF is assumed to contribute to the expected time to fail based on the high temperature, high voltage acceleration, there is no way to account for the effect of multiple mechanisms.
\nThe goal here is to improve the approach from standard HTOL to a one where a true “sum of failure rates” model is considered based on a proportional contribution of each mechanism based on its relative influence. Each one mechanism acts on the system in combination with others to cause an eventual failure. When more than one mechanism affects the reliability of a system or component, then the relative acceleration of each one must be defined and calculated at the applied condition. Every potential failure mechanism should be identified, and its unique AF should then be relatively known at a given temperature and voltage so the FIT rate can be approximated separately for each mechanism. Thus, the actual FIT will be the sum of the failure rates per mechanism, as is described by:
\nwhereby each mechanism is described by its own FIT, which leads to its own expected failure unit per mechanism, FIT
The qualification of device reliability, as reported by a FIT rate, must be based on an acceleration factor, which represents the failure model for the tested device. Since multiple mechanisms are known to lead to degradation and thus failure in any complex system, it is obvious that a single mechanism model with a single AF assumption will never produce a useful result for reliability prediction. This will be explained by way of example. Suppose there are two identifiable, constant rate competing failure modes (assume an exponential distribution). One failure mode is accelerated only by temperature. We denote its failure rate as AF
where the measured Mean Time To Fail (MTTF) (measured in hours) would be different for each mechanism. However, since only one condition of Voltage and Temperature is applied, yet the calculated FIT is based on a combination of two mechanisms, each with its own acceleration factor, then there is now way to determine which mechanism dominates. Because the effective acceleration factor for any given set of test conditions is related to the inverse of the acceleration factor, without separately testing each mechanism, the resulting FIT will have no relation to the actual tested results.
\nDue to the exponential nature of the acceleration factor as a function of
A test system was built in off‐the‐shelf Xilinx FPGA evaluation boards. The system ran hundreds of internal oscillators at several different frequencies asynchronously, allowing independent measurements across the chip and the separation of current versus voltage induced degradation effects. In order to create a measurable accelerating system, ring oscillators (ROs) consisting of inverter chains were used. The last inverter in the chain is connected to the first, forming a cycle/ring (Figure 2). When the number of stages is odd, every sampled cell in the chain will invert its logic level. Additionally, as no clock is fed into the RO, the frequency of the alternating logical states depends just on the internal delay of the cells and the latency of the connections between them, where the frequency of each RO is given by ½
Ring oscillator is made of 2
For optimal testing and chip coverage, different sized ROs were selected, ranging from three inverters, giving the maximum frequency possible in accordance with the intrinsic delays of the FPGA employed (400–700 MHz), and up to 1001‐inverter oscillators, giving a much lower frequency (around 800 KHz). The system implemented on the chip starts operating immediately when the FPGA core voltage is connected. Using a wide range of ROs enabled us to measure the frequency and the internal delay of a real, de‐facto system on a chip. This allows seeing the frequency dependence of each failure mechanism without any recovery effect. The set of ROs consisted of:
150 oscillators of 3 stages
50 oscillators of 5 stages
20 oscillators of 33 stages
3 oscillators of 333 stages
1 oscillator of 1001 stages
It is important to note, here, that the size of the ring determines the interdependence of any degradation. The shortest oscillators containing only three stages will have the greatest variability as well as the highest frequency. This is because a shorter critical electrical path will be much more sensitive to minor variations that lead to greater or smaller degradation over time. This means that the lower frequency oscillators containing as many as 1001 stages will average out the effects of individual degradations. Furthermore, the random statistical variability of individual devices will be exaggerated by the statistical distribution in wear‐out slopes seen at high frequencies. Thus, we made 150 of the smallest ring size devices, which would need to be averaged to find the average degradation at those frequencies exhibiting more random times to fail. Interestingly, we see that the variability of three‐ring oscillators is quite diverse, nearly randomly distributed about an average, whereas the lower frequency rings are much more narrowly distributed, indicating a more predictable time to fail, as compared to circuits having a much shorter critical path.
\nThe testing system was synthesized and downloaded to the FPGA card. The test conditions were predefined for allowing separation and characterization of the relative contributions of the various failure mechanisms by controlling voltage, temperature, and frequency. Extreme core voltages and environmental temperatures, beyond the specifications, were imposed to cause failure acceleration of individual mechanisms to dominate others at each condition, for example, sub‐zero temperatures, at very high operating voltages, to exaggerate HCI.
\nFor each test, the FPGA board was placed in a temperature‐controlled oven, dedicated to the MTOL testing, with an appropriate voltage set at the FPGA core. The board was connected to a computer via USB and the external clock signal was fed into the chip. The tests performed for 200–500 h, while the device was working in the accelerated conditions. Frequencies of every ring oscillator, of different sizes, were measured. Initial sampling started after one working‐hour in the accelerated environment, and then, samples were taken automatically at 5‐min intervals. The frequency measurement data were stored in a database from which one could draw statistical information about the degradation in the device performance.
\nThe acceleration conditions for each failure mechanism allowed us to examine the specific effect of voltage and temperature versus frequency on that particular mechanism at the system level and thus define its unique physical characteristics even from a finished product. A close inspection of test results yielded more precise parameters for the acceleration factors (AF) equations and allowed adjusting them to the device under test. Finally, after completing the tests, some of the experiments with different frequency, voltage and temperature conditions were chosen to construct the MTOL Matrix.
\nOur tests for various mechanisms included exposing the core of the FPGA to accelerating voltages above nominal. About 45 nm defines the nominal voltage at 1.2 V and for 28 and 20 nm, 1.0 V. Our method of separating mechanisms allowed the evaluation of actual activation energies for the three failure mechanisms, which are hot carrier injection (HCI), bias temperature instability (BTI) and electromigration (EM). We plotted the degradation in frequency and attributed it to one of the three failure mechanisms.
\nWe need to justify our approach for accounting for current in the devices. Both‐and HCI have
The results of our experiments give both
The degradation slope, α, is measured as the degradation from initial frequency as an exponential decay, approximated by taking the difference in frequency, and divided by initial frequency over the time. In our experiments, we found that when the decay was dominated by BTI, the decay was proportional to the fourth root of time, while HCI and EM, being diffusion‐related mechanisms, have decay that is proportional to the square root of time [2], as seen in Figure 3.
\nTypical frequency versus square root of time showing degradation slope
In the 45 nm boards each oscillator, the ring frequency was measured and plotted against the square root of time in 45 nm devices. The slope, α, was then converted to a FIT for each test as determined by extrapolating the degradation slope to 10% degradation from its initial value. Each set is plotted as an exponential decay dependent on the square root of time as shown by example in Figure 3. This slope is then used to find the time to fail as seen in the development of FIT below (Eqs. (8)–(11)). We defined the exponent as 1/
The time to fail (TTF) was then calculated for as the square of the inverse slope times the failure criterion, which is 10% degradation in the 45 nm technology [1]. Hence, the FIT for each slope is simply determined as the (10*
Two typical degradation plots are shown in Figure 4(a and b), the FITs, determined by the slopes, are plotted against frequency in two different experiments. The data demonstrate the clear advantage of RO generated frequencies in a single chip [4]. In the examples of Figure 4, we see that FIT is directly proportional to frequency [6], consistent with Eq. (5). Figure 4(b) shows a chip that was stressed at high voltage and temperature showing a strong BTI degradation at low frequency and a much shallower slope due to EM in combination with a small HCI effect. Such curves were made for each experiment, incorporating all the oscillators across the chip spanning the range of frequencies, reflecting also the averaging effect of the longer chains. Hence, the variability is much lower than at higher frequencies, demonstrating that the averaging of many variations results in a consistent mean degradation. The slope of FIT versus frequency is then related at low temperatures as occurring only from HCI, while at higher voltages and temperatures, it can be due to BTI [6] and EM. BTI is only responsible for low frequency degradation.
\nFailure rate, FIT/1000, versus frequency in MHz for (a) HCI, stressed at −35°C with 2.0 V core voltage and (b) BTI, stressed at 145°C with 2.4 V at the core.
In order to determine the dependence of each mechanism, the activation energy as relating to the temperature factor (
We verified that the measurement to 1% degradation over relatively shorter times gives the same slope as longer term measurement that were carried all the way to 1000 h. We found that the failure criterion of 10% degradation was reached in these ring oscillators. This is seen in Figure 5, where the frequency was recorded at accelerated conditions all the way to 1000 h at various voltage and temperatures. The slopes are all very close to
1000 h degradation data for 28 nm devices over a range of core voltages from 1.3 to 1.6 V at 30 and 120°C as indicated.
We assume here that the linear, Poisson, model for constant rate is associated with the probability of failure for each separable mechanism. As we showed in Eq. (3) above, each FIT adds linearly to the other FITs in order to obtain an average system failure rate. By observation of the procedure in Figure 1, it is clear that each FIT will have its own value that is uniquely determined by the acceleration factor for each mechanism depending on the voltage (
This approach is exactly what JEDEC describes as a sum of failure rates methodology as it sums the expected failure rate of each mechanism distinctly from the other mechanisms. The combination results from actual accelerated life tests where there is an extrapolated mean time to fail based on the known operating conditions of
Of course, we assume that each component is composed of multiple sub‐components, for example, a certain percentage is effectively ring‐oscillator, static SRAM, DRAM, etc. Each type of circuit, based on its operation, can be seen to affect the potential steady‐state (defect related) failure mechanisms differently based on the accelerated test conditions. However, unlike traditional reliability systems, rather than treat each sub‐system or component as an individual source with a known failure rate, we separate the system into distinct mechanisms that is known to have its own acceleration factor with voltage, temperature, frequency, cycles, etc. Hence, the standard system reliability FIT can be modeled using traditional MIL‐handbook‐217 type of algorithms and adapted to known system reliability tools; however, instead of treating each component as individuals, we propose treating each complex component as a series system of various mechanisms, each with its own reliability.
\nThe matrix is arranged as in Table 1. The three most left‐hand columns show the temperature,
The second from the right‐hand column shows the ratio of the extrapolated failure rate and the calculated FIT. These values serve to show the closeness of fit to the model parameters by comparing the other measured FIT values with the calculations. This matrix will have a unique solution that will fit the percentages of each mechanism (
HCI | \nBTI | \nEM | \nMeasured | \nRatio | \nFIT | \n|||
---|---|---|---|---|---|---|---|---|
−62.5 | \n1.2 | \n1 | \n99.99% | \n0.01% | \n0.00% | \n30 | \n94% | \n2.83E + 01 | \n
125 | \n1.2 | \n1 | \n0.00% | \n86.86% | \n13.14% | \n997.4 | \n102% | \n1.01E + 03 | \n
153 | \n1.2 | \n1 | \n0.00% | \n63.79% | \n36.21% | \n3672 | \n100% | \n3.67E + 03 | \n
−35 | \n2.5 | \n0.5 | \n100.00% | \n0.00% | \n0.00% | \n23,750,000 | \n100% | \n2.38E + 07 | \n
154 | \n1.2 | \n0 | \n0.00% | \n100.00% | \n0.00% | \n2420 | \n100% | \n2.42E + 03 | \n
140 | \n2.2 | \n0 | \n0.00% | \n100.00% | \n0.00% | \n66,200 | \n102% | \n6.76E + 04 | \n
−22.5 | \n2.8 | \n1 | \n100.00% | \n0.00% | \n0.00% | \n240,000,000 | \n101% | \n2.43E + 08 | \n
7.3 | \n3 | \n1 | \n100.00% | \n0.00% | \n0.00% | \n156,000,000 | \n106% | \n1.66E + 08 | \n
Test results showing proportions of failure mechanisms for given
Once the parameters for the three mechanisms have been calculated and verified against the other test data, a full set of extrapolated values for FIT can then be calculated using the equations for each mechanism times the same
\n | \nInverse matrix | \n\n | \n\n | \n|
---|---|---|---|---|
−4.36972 E−29 | \n4.76285 E−18 | \n−1.10403 E−20 | \n\n | \n1.13118 E−10 | \n
0 | \n0 | \n10,946.04333 | \n\n | \n26,489,424.87 | \n
1.19767E + 14 | \n−2040.515932 | \n−1.15932E + 14 | \n\n | \n1.59226E + 17 | \n
Inverse matrix (left three columns) and respective
Since the matrix is linear, as are the calculations for FIT at any given
Reliability curves for 45 nm technology showing FIT versus temperature for voltages. These curves are for 1.0, 1.2, and 1.4 V core voltage at 10 MHz (dashed) and at 1 GHz (solid).
HCI | \nBTI | \nEM | \nFIT | \n|||
---|---|---|---|---|---|---|
−50 | \n1.2 | \n2 | \n1.45382E + 11 | \n2.84438 E−10 | \n1.99008 E−27 | \n16.5 | \n
−10 | \n1.2 | \n2 | \n6,131,362,305 | \n1.61083 E−08 | \n2.65294 E−23 | \n1.1 | \n
20 | \n1.2 | \n2 | \n1,006,254,891 | \n1.61337 E−07 | \n6.00169 E−21 | \n4.4 | \n
30 | \n1.2 | \n2 | \n596,524,778.1 | \n3.14239 E−07 | \n2.8808 E−20 | \n8.4 | \n
40 | \n1.2 | \n2 | \n365,644,331.1 | \n5.86524 E−07 | \n1.2509 E−19 | \n15.6 | \n
50 | \n1.2 | \n2 | \n231,020,972.9 | \n1.05325 E−06 | \n4.95957 E−19 | \n28.0 | \n
80 | \n1.2 | \n2 | \n68,110,854.71 | \n4.99845 E−06 | \n1.9353 E−17 | \n135.5 | \n
100 | \n1.2 | \n2 | \n33,650,811.61 | \n1.22819 E−05 | \n1.60476 E−16 | \n350.9 | \n
Calculated FIT based on the solved matrix for typical use conditions.
The unique solution that solves all three equations with the three extrapolated acceleration factors gives a percentage contribution for each of the failure mechanisms. We report the reliability as FIT, which is 109/MTTF for each condition. The percentages for each mechanism are shown, based on the relative contributions that were extrapolated from the physics of failure equations normalized to the measured FIT of each test. Seeing the dispersion of FIT values per test proves that the approximation of a constant rate, meaning a random distribution in time, is the proper statistical model for these results. Figure 6 shows the resulting FIT as plotted versus temperature (°C) for the measured 45 nm technology FPGA.
\nOne advantage of plotting our data as failure rate versus temperature allows one to determine effective activation energy as a function of temperature and stressor parameters,
If we assume that
Hence, if we plot the change in
The advantage of this representation allows a designer to consider the temperature rage as a function of stressor factors that would affect the reliability of a product, especially under extreme conditions. We see very clearly that at low frequencies, the reliability is completely dominated by BTI where the activation energy is around 0.53 eV, whereas at very high temperatures and very low temperatures, the effect of frequency becomes dominant. At the very low temperatures, a negative activation energy is seen for higher frequency operation, while at high temperatures, the EM effect becomes more important, both of which are current‐related effects; hence, they are frequency dependent.
\nWhat is most important to understand about this Matrix solution to linear, constant, failure rate models is that this methodology is not limited to only microelectronics. We must understand that all that is needed are the appropriate physics of failure relations to whatever stresses will be experienced during the expected life of the product. It is also important to know that this method of combining mechanisms is limited to failure mechanisms that have a generally constant rate over time. That is to say that the slope from a Weibull distribution is close to 1. If, however, the failure distribution of a particular mechanism is known to be highly predictable, that is with a wear‐out characteristic, having a Weibull slope of 2 or more, then this methodology will not properly work to combine mechanisms. On the other hand, if one mechanism is known to dominate or be the limitation, that one mechanism can be separated from the other more random mechanisms, as shown in Figure 7 and based on our extrapolation from Table 3.
\nActivation energy versus temperature based on the data above in
One clear proof from this graph is that it is not possible to choose simply one accelerating temperature and voltage, or any one condition for any accelerated test, expecting that a simple extrapolation can be made based on a single failure mechanism. The mechanisms interact such that any accelerated test will surely give incorrect results, and, thus, the traditional HTOL test is obviously not sufficient for reliability prediction. Furthermore, the MTOL, multiple stressor qualification will give accurate prediction for the failure rate under any given operating conditions from a fraction of the number of samples tested over a much shorter period of time. Hence, this methodology will save a large proportion of the standard qualification procedure and give much more accurate and meaningful results.
\nChronic 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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The theme is discussed first at a general level for each type of enterprise and subsequently with particular reference to the global firm, with regard to which considerations are developed as to the most suitable approach to CSI in light of the worldwide spread of values and principles for conducting business, and of the global importance of social and environmental problems. 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Attention is drawn to the fact that social enterprises implementing governmental programmes for the employment of persons with disabilities are oriented only to the guarantees of the physical working conditions, but the issues of psychological safety, psychological well-being, and social exclusion are not dealt with. The latter questions are not discussed neither in the government programme nor in policies of the enterprises; therefore, they are dealt with depending on the established business management culture. The management personnel of companies with the status of social enterprises perceives the function of the enterprise as a certain niche in the market, receiving the state aid for the implemented requirements to employ disabled persons and adapt the physical environment for them. This approach highlights such side effects as unaddressed (suppressed) discriminatory attitude towards employees with disabilities in enterprises, organisational weakness in dealing with interpersonal conflicts, the lack of competence of the managerial staff and the lack of systematic knowledge on work with personnel. In this case, there is a debatable question of whether the efforts of the state will reach the desired goal, i.e. the fully-fledged work and social integration of the people who the investments are intended for, or continue the traditions of silent social segregation? This study shows that it is necessary to critically evaluate the selected model for fostering businesses to integrate into the labour market, in which the issues of psycho-social welfare and social initiative of enterprises are underestimated.",book:{id:"5145",slug:"social-enterprise-context-dependent-dynamics-in-a-global-perspective",title:"Social Enterprise",fullTitle:"Social Enterprise - Context-Dependent Dynamics In A Global Perspective"},signatures:"Jolita Vveinhardt",authors:[{id:"179629",title:"Prof.",name:"Jolita",middleName:null,surname:"Vveinhardt",slug:"jolita-vveinhardt",fullName:"Jolita Vveinhardt"}]},{id:"50229",title:"Social Entrepreneurship by Community-Based Organizations: Innovations and Learning through Partnerships",slug:"social-entrepreneurship-by-community-based-organizations-innovations-and-learning-through-partnershi",totalDownloads:1910,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"This chapter examines the social entrepreneurship potentials of community-based organizations (CBOs) linked to nongovernmental organizations (NGOs) in the implementation of development programs. The conceptual framework of the study draws on the existing literature on social entrepreneurship and cooperatives. The study highlights the social and ecological roles and significance of CBOs in the creation of social value at the local community level. The research findings reveal that NGO-CBO partnerships help to transform CBOs into social enterprises by creating revenue generation streams. Such partnerships also catalyze social innovations and social learning outcomes. In this chapter, three case studies from Bangladesh are examined, which demonstrate how the social entrepreneurial roles of these CBOs have been instrumental in the management of local natural resources and in fostering social learning. The case studies reveal that institutional support and favorable public policies are crucial in sustaining social entrepreneurship by CBOs.",book:{id:"5145",slug:"social-enterprise-context-dependent-dynamics-in-a-global-perspective",title:"Social Enterprise",fullTitle:"Social Enterprise - Context-Dependent Dynamics In A Global Perspective"},signatures:"A.K.M. Shahidullah and C. Emdad Haque",authors:[{id:"179555",title:"Ph.D. Student",name:"Akm",middleName:null,surname:"Shahidullah",slug:"akm-shahidullah",fullName:"Akm Shahidullah"},{id:"179612",title:"Prof.",name:"C. Emdad",middleName:null,surname:"Haque",slug:"c.-emdad-haque",fullName:"C. Emdad Haque"}]},{id:"50075",title:"A Comparative Study of Social Enterprises: North vs. South Perspectives",slug:"a-comparative-study-of-social-enterprises-north-vs-south-perspectives",totalDownloads:1778,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Social entrepreneurship as a practice that integrates economic and social value creation has a strong global presence. This chapter capitalizes on the evolution of the concept of social enterprise in the Western literature to analyze its manifestation in the Middle East and North Africa (MENA) region. Specifically, using empirical evidence from seven Arab countries, this chapter documents the understanding and application of social enterprises in the MENA region. Through the voices of social entrepreneurs who are working across the MENA countries, we document how social enterprise is displayed in practice along with both the constraints and the opportunities facing social entrepreneurs across this region. This new context-specific approach is then used to shed light on the similarities and differences of social enterprise practices across the international scene and the MENA region. The findings presented highlight the uniqueness of social enterprise in the MENA context, combining elements of both European and American approaches, in addition to some context-specific features.",book:{id:"5145",slug:"social-enterprise-context-dependent-dynamics-in-a-global-perspective",title:"Social Enterprise",fullTitle:"Social Enterprise - Context-Dependent Dynamics In A Global Perspective"},signatures:"Dima Jamali, Nadine Mohanna, Dina H. Sherif and Salma El Sayeh",authors:[{id:"179628",title:"Prof.",name:"Dima",middleName:null,surname:"Jamali",slug:"dima-jamali",fullName:"Dima Jamali"},{id:"179775",title:"M.Sc.",name:"Nadine",middleName:null,surname:"Mohanna",slug:"nadine-mohanna",fullName:"Nadine Mohanna"},{id:"184857",title:"MSc.",name:"Salma",middleName:null,surname:"El Sayeh",slug:"salma-el-sayeh",fullName:"Salma El Sayeh"},{id:"184858",title:"MSc.",name:"Dina",middleName:null,surname:"H. Sherif",slug:"dina-h.-sherif",fullName:"Dina H. Sherif"}]},{id:"50101",title:"Corporate Credibility, Religion and Customer Support Intention toward Social Enterprises",slug:"corporate-credibility-religion-and-customer-support-intention-toward-social-enterprises",totalDownloads:2015,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Social enterprise (SE) outputs are not merely a result of the social entrepreneur’s personal vision, but an accumulation of resources and support from multiple stakeholders, particularly customers. Although marketing communication studies have long established the effects of corporate credibility on consumer attitudes and behaviors, it is worth noting that corporate credibility comprises three distinct dimensions, namely trustworthiness, expertise and dynamism, which do not necessarily have equal levels of influence on the endogenous variables. Additionally, from a social entrepreneurship perspective, the relationship between corporate credibility and consumer psychology requires a deeper inspection because of the role of religion in charitable and care-giving activities. Most religions stress the importance of spirituality, which may override their concern with the business aspects of the SE. In other words, for religious customers, it is likely that trustworthiness has a higher influence on their attitudes and support intention than expertise and dynamism. These conceptual relationships among corporate credibility, religion and consumer psychology in social entrepreneurship are elaborated in this article through a literature review, followed by the development of a theoretical framework and its associated propositions. The article concludes with some implications for SE governance, distinguishing societies with different religious backgrounds.",book:{id:"5145",slug:"social-enterprise-context-dependent-dynamics-in-a-global-perspective",title:"Social Enterprise",fullTitle:"Social Enterprise - Context-Dependent Dynamics In A Global Perspective"},signatures:"Aida Idris and Sri Rahayu Hijrah Hati",authors:[{id:"178264",title:"Associate Prof.",name:"Aida",middleName:null,surname:"Idris",slug:"aida-idris",fullName:"Aida Idris"},{id:"183170",title:"Dr.",name:"Sri Rahayu",middleName:null,surname:"Hijrah Hati",slug:"sri-rahayu-hijrah-hati",fullName:"Sri Rahayu Hijrah Hati"}]}],onlineFirstChaptersFilter:{topicId:"1314",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:7,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",slug:"alexandros-tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",slug:"lulu-wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:"Shenzhen Technology University",institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",slug:"reda-r.-gharieb",fullName:"Reda R. 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He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. 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