Optimization of the inverted V antenna.
\r\n\tThis book chapter’s main theme will be focused on transmission dynamics, pathogenesis, mechanisms of host interaction and response, epigenetics and markers, molecular diagnosis, RNA interacting proteins, RNA binding proteins, advanced development of tools for diagnosis, possible development of concepts for vaccines and anti drugs for RNA viruses, immunological mechanisms, treatment, prevention and control.
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There is a strong research activity in Antarctica in the fields of geophysics, meteorology, wildlife, flora, oceanography, and environment, among others. This research activity often involves the installation of sensors in remote places under severe/extreme weather conditions. Most of those sensors are operated with a data logger that stores the data between campaigns until it is recovered after several months.
If we need either to have access to the data throughout the year, or to install a sensor far away from the Antarctic station, we should install a radio transmission system. The standard VHF radios have a reach up to 50 km with line of sight. As the installation of a repeater station is not an option in Antarctica, it only remains to install either a satellite link or an HF link. The satellite services are expensive and are provided mostly by geostationary satellites. The geostationary orbits around the equator are not always easily visible from the poles, so the link is not fully reliable.
The HF band (3–30 MHz) is well known from the beginning of the age of the radio. The ionization of the upper layers of the atmosphere changes the direction of the radio waves in that band, so the ionosphere behaves as a mirror for a certain set of frequencies. The reflection is strongly dependent on the solar activity, the solar radiation at any time, the terrestrial magnetic field, and the angle of incidence of the wave [1]. For oblique incidence, a range up to 3000 km for a single hop can be achieved, so we can establish a link all over the planet with a few hops. The antenna in those applications should have a maximum of radiation toward the horizon.
For near vertical incidence skywave (NVIS), we can achieve a circular coverage area with a radius up to 250 km without the need of line of sight. The most suitable frequency for vertical incidence is lower than in oblique incidence, so a larger size of the antenna is needed. The antenna should have a maximum of radiation upward, so horizontal dipoles, inverted V, and loops are the best options [2]. As the distance is much lower, the transmission power required can be reduced to tens of Watt, so the application to remote sensors with power restrictions is straightforward. In the world where an increasing number of devices are going to be interconnected in an Internet of Things paradigm, a system able to communicate sensors located hundreds of kilometers away without any additional infrastructure is really welcomed.
A first step when developing a new physical layer is the sounding and characterization of the channel. Apart from the classical model of Watterson [3] for narrowband communications and Mastrangelo [4] for wideband communications, a significant amount of research has been done in ionospheric channels for a single hop at high latitudes in the Arctic [5, 6, 7]. However, few works can be found about channel sounding for long-range links with multiple hops from the Antarctica.
For the last 15 years, our research group has been working in the application of HF communications (3–30 MHz) with ionospheric reflection for data collection of remote sensors in Antarctica. In particular, we have developed a system to communicate the Spanish Antarctic Station (SAS) Juan Carlos I at Livingston Island (62.6°S, 60.4°W) and the Ebre Observatory in Roquetes (Tarragona, Spain) (40.8°N, 0.5°E). It is a 12,700 km link with multiple hops and without the use of any repeater. First, we started to sound the channel and estimate the main parameters of the channel [8, 9, 10, 11, 12]. Then, we have developed and tested a wide range of modulations, with its frame structure, the radio-modem, and several antennas for both the long range with oblique incidence and the near vertical incidence scenario [13, 14, 15, 16, 17]. We are also developing a self-organized network of NVIS nodes that can handle the delays and the unavailability of the ionospheric channel. The NVIS nodes may behave as a hub able to collect data from other neighboring sensors and transmit the joint data to the central node.
This chapter is organized as follows. In Section 2, the evolution of the hardware of the radio-modem and the antennas is presented. The modem is prepared for both channel sounding and data transmission and has evolved to low-cost software radio platforms. In Section 3, the results of more than 15 years of experience in channel sounding are presented, for both the oblique and the vertical sounding. The variability of the channel as a function of time, season, and year is summarized. In Section 4, the physical layer of the communication system of the modem is introduced. The modulation, the frame structure, and the synchronization techniques for both the long-range modem and the NVIS modem are described. The performance in terms of bit rate and bit-error rate is presented. In Section 5, new routing strategies for NVIS networks are explained. The NVIS node has to collect the data from the sensors nearby and establish a delay tolerant network (DTN) with the rest of the nodes. Finally, Section 6 contains the conclusions and some other applications of HF communications.
From the beginning of the project, we pursued a software-defined radio (SDR) hardware platform which was able to both sound the ionospheric channel and implement different modulation schemes without changing the hardware. This kind of platform was not available 15 years ago, so we had to develop our own platform with the FPGAs Virtex-IV and Spartan-II and the fastest ADC and DAC of that time. The control of the whole system and the rest of peripherals was performed by an embedded PC [10]. For the long-range link between the SAS and Spain, the system was able to transmit along the whole HF band (3–30 MHz), 24 hours a day, with two synchronized receivers connected to two wideband antennas: a monopole with antenna tuner and a wideband inverted V. The transmission power was 250 W and the system was designed to work, connected with the main power. The author is referred to [11] for further details of that system.
NVIS communication between remote sensors and the SAS is a quite different challenge. The sensor will be often battery-powered so the transmission power should be as low as possible. Although we started developing our own platform for NVIS [18], we can now find different compact SDR platforms that include FPGA, embedded microprocessor, and AD/DA converters in a very cost-effective platform. The implementation of the low-cost transceiver for remote sensors using NVIS is detailed in the following section.
The hardware of the system (see Figure 1) is composed by three parts: a Red Pitaya (RP), a Raspberry Pi 3 (Rpi3), and different peripherals.
Block diagram of the NVIS communication system for remote sensors.
The RP (FPGA board) is a low-cost SDR platform dedicated to the transmission and reception of the radiofrequency signals, converting them from analog to digital with an ADC of 14 bits, decreasing the frequency of the signal carrier, processing the signal, and sending the low-pass IQ components to the Rpi3 via Ethernet. Similarly, the Rpi3 can send the IQ components to the RP for the transmission. The sampling rate is 125 Ms/s at the RF plane, while it is 100 ks/s at the IQ plane.
Internally, the RP contains a Zynq® 7010, based on the Xilinx System on Chip (SoC) architecture. These products integrate a feature-rich dual-core or single-core ARM® processing system (PS) and a Xilinx programmable logic (PL) in a single device. On the PS, there is a Linux operating system for controlling the PL, where there are all the hardware configurations that allow the different transmission modes.
Although there is a true microprocessor inside the RP, it is not able to handle all the control functions, since the biggest part of the RP is dedicated to the real-time processing in the PL part. That is the reason for adding the Rpi3, a single-board computer that controls the overall system operation. Rpi3 is able to collect data from many wireless sensors connected via Zigbee and encapsulate them on a single frame to be sent through the NVIS channel. In our case, we have used the solution of Libelium [19], with a maximum range between 1 and 8 km, depending on the chosen solution. When Rpi3 either stores 1000 bytes of data or a defined time lapse runs out, it sends the baseband IQ components of the frame to the RP to be transited to the SAS. On the other side, the RP is waiting for reception. When the preamble of the transmission is found, the RP sends the received IQ components to the Rp3, which demodulates all the data frames and extracts the data from all the sensors.
As mentioned before, the transmission power has to be less than 10 W to ensure a proper operation in a battery-powered scenario. As the maximum output power of the DAC is 0 dBm, we need a linear minimum amplification of 40 dB. The power amplifier is controlled by an electronic circuit that switches the supply voltages of the power stages in the proper order. This hardware measures the forward and reverse power, so the Rpi3 could switch the transmission off in case of mismatch. Finally, a band pass filter (BPF) attenuates the out-of-band emissions.
At the receiver site, another BPF from 2 to 7 MHz is placed close to the antenna to filter all the unwanted noise and interferences typical of the HF band, such as AM broadcast stations. As the received signal may be around −90 dBm, an amplifier of 30 dB is needed in order to take the maximum advantage of the dynamic range of the ADC, without saturating the converter. Finally, the received data are stored in a solid-state disk.
The total measured power consumption of the system is about 7.2 W in sleep mode, which is the dominant mode. Once every hour, the transceiver transmits and receives a few seconds with a power consumption of 96 W. Under these conditions, the transceiver will operate for 2 weeks with a battery of 110 Ah.
When working in the HF band, we have to expect large-size antennas if we want to achieve dimensions close to half wavelength. If we are going to install the antennas in Antarctica, we will have strict environmental conditions, so no complex installations can be built. Moreover, if the antennas are for remote sensors powered by batteries, we should try to maximize the gain of the antennas in order to reduce the transmission power of the amplifier at minimum. Taking all this into consideration, the best choice are monopoles or wire antennas that need only one elevated point at most.
There is a great difference between the long range with oblique incidence and the near vertical incidence scenario. In the first case, we need a maximum of radiation toward the horizon, so a vertical monopole is the simplest option. In the second case, we need a radiation lobe with elevation angles between 70 and 90
The monopole is the simplest antenna for long-range HF communications. It is easy to carry and install and is very robust against adverse weather conditions. As a wideband antenna, we need an antenna tuner that has to be tuned a low power before every frequency change. As the conductivity of the soil gets worse, the angle of maximum radiation is not 0
Diagram of radiation of a 7.5 m monopole with radials over permafrost.
Installation of the monopole with radials in the SAS.
For NVIS applications, the horizontal dipole would be one of the best antennas, but it needs one mast at either end. The inverted V, however, achieves a similar performance with only one mast at the center. For the V of Figure 4, we have optimized the height of the antenna (Mast h), the heights of the end (Min h), and the distance from the center to the end (Yf). The length of the V changes accordingly. In Table 1, we can see the results for three types of soil: ideal (infinite σ, εr = 6), rural (σ = 0.01, εr = 15), and permafrost (σ = 0.00005, εr = 3), where σ and εr stand for the conductivity and the dielectric constant, respectively, and j is the imaginary unit. The conductivity of the permafrost causes a drop up to 5.5 dB in the gain with respect to the ideal ground. We need a mast height of 13 m to achieve a gain of 1.3 dB. As we want to have a minimum power consumption, we will operate at a single frequency and try to maximize the gain at that frequency. So, we do not intend to have a wideband antenna in this scenario. Checking the reports of ionograms of the last decade from Ebre Observatory [20] and Lowell Digisonde International [21], we came to the conclusion that the best frequency for maximum availability would be 4.5 MHz.
Simulation parameters of the inverted V.
Soil type | Optimization algorithm | Gain (dBi) | SWR | Impedance (Ω) | Mast h. (m) | Min h. (m) | Yf (m) |
---|---|---|---|---|---|---|---|
Ideal | Evolve | 6.8 | 1.96 | 25.6 + 3.2j | 11.01 | 2.00 | 12.39 |
Rural | Evolve | 3.8 | 1.05 | 47.7 + 0.4j | 10.81 | 1.87 | 12.39 |
Permafrost | Evolve | 1.3 | 1.27 | 63.3 – 1.0j | 13.08 | 2.00 | 11.51 |
Optimization of the inverted V antenna.
It is important to note that the optimization of the gain is a key factor for the transmission, while the radiation diagram with a maximum around 90° and a minimum at the rest of elevation angles is the most important issue in reception, because we minimize the noise and interference from the nondesired directions [22].
As far as the horizontal dipole is concerned, there is a 3 dB gain improvement, bearing in mind that two mast installations are needed. The optimum height, as discussed in [23], is between 0.16 and 0.22λ depending on the type of soil.
The ionosphere is one of the layers of the upper atmosphere situated between about 90 and 400 km above the surface. Thanks to its atomic composition, the ionic charge allows radiofrequency signals to rebound and go back to the terrestrial surface, thus creating a communication channel. The ionization of this layer is caused by solar radiation producing the apparition of free electrons that change the refraction index of the medium. As more radiation there is, more ions are exited and the maximum reflected frequency increases. As the sun radiation is the major cause of frequency variation, daily, monthly, seasonal, and yearly variations have to be taken into account. Apart from the variation between day and night, one of the most significant variations is caused by the solar cycle reaching maximum and minimum levels approximately about every 11 years. The sunspot number (SSN) measures the number of spots visible on the face of the sun. The higher the number, the more radiation ionizes this layer of the atmosphere. Figure 5 shows the variation of the solar cycle radiation from 1995 to 2017, and the estimation until 2019. We can point out that in the current year (2018), solar radiation is in minimum levels. This minimum level causes that the frequency used for the transmissions is much lower than in previous years (between 4.5 and 6.5 MHz during the day).
Evolution of the sunspot number (SSN) [
The ionosphere is observed throughout the world by a set of observatories. Most of them have an ionosonde developed by Lowell Digisonde International [21] and publish the ionogram in a common webpage [25], enabling the parameterization of the ionosphere behavior along the day in quasi-real time.
As the ionosphere is divided into several layers (D, E, F1, and F2), which are always moving, the ionospheric channel behaves as a slow fading multipath channel, similar to the wireless channels for mobile communications. Hence, the ionosphere can be characterized by the following parameters: time dispersion (multipath, delay spread), frequency dispersion (Doppler shift, Doppler spread), noise, interferences, and channel availability [26].
All these factors will allow us to determine the best modulations, size of the frame, and occupied bandwidth to optimize the transmission in both the long-range and the NVIS case. In the next two following points, we aim to describe the results of the sounding of both types of communications.
When we try to characterize a channel, we have to distinguish between the narrowband analysis and the wideband analysis. The narrowband analysis allows us to determine the channel availability and the signal-to-noise ratio (SNR). This sounding is performed with tones that range from 2 to 30 MHz with steps of 500 Hz and are measured with a 10 Hz bandwidth during a time interval of 10 s. We concluded that a good quality of service is achieved for a SNR larger than 6 dB in a 10 Hz of bandwidth [8]. The SNR is measured after filtering the signal with some different windows (Hanning, Blackman, Flattop, Kaiser) defined in [11]. In Figure 6, we can see the evolution of the signal envelope during the 10 s transmission interval for each window. The SNR is measured as the ratio between the average of the signal power in case of absence of interference and the noise power measured in the seconds where there is no transmission. The Kaiser window turned out to be the best filtering technique.
Time evolution of the signal envelope for narrowband analysis.
The SNR and the channel availability (defined in [8]) are studied as a function of frequency and the time of day (see Figure 7). The big differences between day and night and between sunrise and sunset are explained in detail in [11].
SNR as a function of frequency and time of day (February 17, 2014) during the campaign 2013–2014.
The wideband analysis allows the characterization of the rest of the channel parameters such as time and frequency dispersion and wideband SNR. This analysis is performed by sending a pseudorandom noise (PN) sequence that allows us to obtain an estimation of the channel response as a function of time. The channel matrix, that is, the evolution of the channel impulse response over time, is calculated correlating the received signal with the original PN sequence. Then, the scattering function is calculated as the fast Fourier transform (FFT) of the channel matrix. A detailed analysis of the scattering function is key to determine modulation, frame length, separation between data block and data corrector, and other issues of the physical layer [9].
In Figure 8, we can see the averaged channel parameters for the campaign 2013–2014. During daytime, high frequencies (20–30 MHz) show the highest delay spread (up to 4 ms) and Doppler spread (up to 1.5 Hz). That means a bigger amount of intersymbolic interference and a higher degree of variability. Sunset and sunrise are the most unstable moments because the ionosphere is changing due to the ion formation or ion recombination. They are, therefore, the least suitable periods for the transmissions. Finally, nighttime is the most stable moment from 19 to 06 UTC.
Wideband channel measurements during the campaign 2013–2014: (a) mean of delay spread (in ms);(b) mean of Doppler spread (in Hz).
For the NVIS channel, there are a few factors to be taken into account. For the narrowband analysis, we only have to check the nearby ionograms and choose the optimum working frequency as the 0.85 × foF2, being foF2 the critical frequency of the upper layer of the ionosphere [27]. For the wideband analysis, we have to notice that the NVIS channel is the same channel that affects the ionosonde when it is measuring the height of the different layers to build the ionogram. The ionosonde temporarily stores a file with the IQ components that is used to calculate the critical frequency, virtual height, and total electron content of each layer. If we have access to this raw data file, we can have an initial estimation of the wideband channel parameters [28]. Of course, an ad hoc channel sounding will yield to better results. In Table 2, we can see the studies performed with the raw data of the ionosonde of Ebre Observatory. As expected, both the delay spread and the Doppler spread are lower than in the oblique sounding, so the modulation, the length of the frame, and many other parameters will allow a physical layer with higher transmission capabilities.
October 24, 2012 | March 5, 2013 | ||||
---|---|---|---|---|---|
Parameters | Wave | Mean | Variance | Mean | Variance |
Doppler spread (Hz) | Ordinary | 0.681 | 0.094 | 0.378 | 0.199 |
Extraordinary | 0.123 | 0.095 | 0.081 | 0.061 | |
Doppler shift (Hz) | Ordinary | −0.088 | 0.554 | −0.025 | 0.208 |
Extraordinary | −0.073 | 0.478 | −0.222 | 0.177 | |
Multipath spread (μs) | Ordinary | 710.71 | 2.83 | 496.01 | 2.02 |
Extraordinary | 921.41 | 4.46 | 712.47 | 3.19 |
NVIS sounding results from data of the ionosonde at Ebre Observatory.
HF communications are often designed to operate with high-power amplifiers at the transmitter side, with typical values from 1 to 10 kW. When thinking about remote sensors supplied by batteries or solar panels, the transmitted power has to be much lower. For long-range transmissions between the Antarctic stations and Europe, a power value less than 150 W is desirable, while a value less than 30 W is expected for unattended remote sensors installed around the stations.
In a low-power scenario, the modulation has to be extremely robust with respect to noise and interference. Several replicas of the transmitted signal arrive to the receiver due to the reflection at the different layers of the ionosphere. As the layers are in constant motion, the HF channel behaves as a slow-frequency selective channel, so as the mobile channel for wireless communications. Hence, some of the latest techniques applied to the world of mobile telephony can be adapted to HF communications.
For the long-range link (about 12,760 km) with oblique incidence, the SNR at the receiver is extremely poor, often with negative values. In that situation, we defined two different modulation schemes: (i) the robust mode, for SNRs negative or close to zero and (ii) the fast mode, when the SNR is positive, and the bit rate can increase significantly.
In the robust mode, a modulation based on direct-sequence spread spectrum (DS-SS) was designed. The effective net data rate is very low (hundreds of bps), but the data can be demodulated under high levels of noise and interference. In the fast mode, the single carrier-frequency domain equalization (SC-FDE) modulation was used, since it can handle higher data rates (up to 3 kbps) if the different subcarriers can be received at a positive SNR.
For the NVIS link with vertical incidence, the situation is much more suitable. Although the transmitted power is lower, the received signal is higher while the level of interference and noise coming from the vertical direction is reduced significantly. With a SNR between 10 and 20 dB with an available bandwidth of 3 kHz, a narrowband phase shift keying (PSK) or frequency shift keying (FSK) is proposed, achieving bit rates of tens of kbps that ensure another range of applications, such as messaging, e-mail, and digital voice transmission.
When a node is working in an asynchronous mode, the receiver has to be waiting for an incoming signal continuously. A robust signal detector with low false alarm probability has to be developed, with strict requirements of energy consumption. The following subsections deal with the different modulations and the signal detector in detail.
In the oblique transmission from Antarctica, two modulations have been designed for the two reception modes [13]: (i) a DS signaling [15] was designed for high robustness mode and (ii) a SC-FDE for high throughput mode [16].
The spread spectrum tests were performed using a DS-SS signaling modulation. It consists of the use of a whole family of PN sequences [26] and associating each of them to a symbol. The information about the transmission will be contained in the own sequence by means of the use of a codebook. The receiver also has the codebook available and uses it as a dictionary to obtain the transmitted information. The PN sequences used for these tests were gold sequences [29], taking advantage of their low cross-correlation in each family.
The results for the cumulative density function of the bit error rate (BER) results for two thresholds of 5 and 10% are shown in Table 3. They present bit rates around hundreds of bits per second—enough for data to be transmitted—and with a reasonable quality assuming that we are facing the most hostile time zone of the channel, the daytime. We found out that the best possible combination is a Gold PN sequence family 2047 length, using a bandwidth of 16.6 kHz and a final bit rate of 89 bps.
PN length | Ts (ms) | BW (kHz) | Bit rate (bps) | BER (5%) | BER (10%) |
---|---|---|---|---|---|
1023 | 123 | 8.3 | 81 | 0.66 | 0.79 |
511 | 127 | 4 | 73 | 0.64 | 0.78 |
255 | 127 | 2 | 65 | 0.53 | 0.67 |
Cumulative density function of the BER results for two thresholds of 5 and 10%. Best BER values in bold.
The first tests using SC-FDE were conducted in [16], with the aim of minimizing the problems generated by the peak-to-average power ratio (PAPR) and interchannel interference (ICI) of the previous works using OFDM [17]. The single carrier-frequency domain equalization has been designed with several parameter modifications in comparison with [17], such as variable bandwidth, different length of blocks, and several constellations. The reader is referred to [14] for the results of the extensive tests in SC-FDE, and a synthesis of the best results in terms of the cumulative distribution function (CDF) for a BER greater than 0.05% for a bandwidth of 400 Hz can be found in Table 4.
Constellation | Tb (ms) | Bit rate (bps) | Spectral efficiency (bps/Hz) | BER (>0.05) |
---|---|---|---|---|
PSK | 10 | 296.3 | 0.74 | 0.54 |
PSK | 70 | 381.0 | 0.95 | 0.39 |
Cumulative SC-FDE results for PSK constellation. Best results in bold.
From the results presented in Table 4, the best possible configuration in terms of bit rate and cumulative density function of BER is the proposal with a bit time of 50 ms, in close competence with the proposal of 30 ms. The PSK using 50 ms was finally chosen because the ratio between the bit rate and the spectral efficiency against the BER was slightly higher than the same metric for 30 ms. That configuration was finally proposed to implement the high throughput mode of the oblique Antarctic transmission system.
The transmission system using NVIS has to be power efficient in order to attain the requirements of the battery. The tests performed are designed to optimize the required power for bit rates lower than 3 kbps, which cover the major part of remote sensing applications. The tests compare the performance of simple modulations, that is, 2-FSK, 2-PSK, 4-FSK, and 4-QAM (quadrature amplitude modulation), to find out the best modulation to be used with low transmission power, from 0.3 to 24 W. The duration for each test is adjusted so as the same amount of bits is sent for each modulation. The occupied bandwidth is 2.3 kHz to be consistent with the most common HF standards [30]. The results presented are derived from a 4-month survey between February and May 2018. The tests were performed between our premises in Barcelona (41°24′33.62″ N, 2°7′48.82″ E) and a field laboratory in Cambrils (41°4′57.22″ N, 1°4′4.61″ E) placed 96 km away. The frequency was fixed to 4.5 MHz after a detailed analysis of the ionograms from the Ebre Observatory in Roquetes, situated 80 km from Cambrils. We have only performed the transmissions during the day, so the system only uses one frequency. Figure 9 shows the cumulative density function of the BER for a transmission power of 0.7 and 24 W. For low power transmission (0.7 W), PSK outperforms the rest of the modulations, presenting a BER less than 10−3 the 55% of the time and a BER less than 10−2 the 80% of the time. For high power (24 W), 2-FSK, 2-PSK, and 4-PSK behave in the same way, while 4-FSK has a much poorer performance. This is because FSK needs a higher bandwidth in order to keep the carrier spacing, and we have made all the tests under the same conditions.
CDF of the BER for an NVIS link with a TX power of 0.7 W (a) and 24 W (b).
In every telecommunication system, a precise time and frequency synchronization is a key issue in order to receive and demodulate the signal in the best conditions. The classical approach to time synchronization uses a PN sequence, finding the starting point of the frame by simple correlation. In practice, the clock differences between transmitter and receiver as well as the Doppler introduced by the channel may cause frequency shifts up to ±50 Hz. It follows that the received signal is rotated in phase and, therefore, hampers the correlation. An initial frequency synchronization in narrowband has to be done first. Hence, a tone of 600 Hz (with respect to the carrier) is added to detect which global frequency appears during the signal transmission. A tone of 600 Hz is often masked by the huge levels of noise and interference that are typical in the HF band. Therefore, we need a way to detect in a robust way that the signal is present with a low probability of false alarm. A known sequence of appearance of the 600 Hz tone is added at the beginning of the frame. Once the frequency shift is corrected, next step is synchronization. As the low-cost hardware is limited in speed, memory capacity, and programmable space of the FPGA, the design of the PN sequence is based on achieving correlation with the use of the smallest possible size, in the fastest way and requiring the minimum memory. A PN m-sequence of order 6 (64 chips) and 11 kHz of bandwidth was selected. The final header structure can be seen in Figure 10.
Synchronization header for the NVIS frame.
The development of a wide area network of sensors around the Spanish Antarctic Station (or SAS) needs not only a robust physical layer, but also a robust protocol able to provide reliability, security, and tolerance to latency. In fact, we can see a remote sensor in Antarctica as a particular case of the Internet of Things paradigm. In this context, it is not wise to extend the traditional networking infrastructure based on routers to these networks for cost, efficiency, and protocol complexity reasons.
The presented work deals with the issues of utmost importance to achieve quality of service-aware (QoS-aware) communication in wireless and wired sensor networks based on standard communication protocols for the sensor networks around the SAS. The network consists of a system of distributed sensor nodes that interact among them and with infrastructure depending on applications in order to acquire, process, transfer, and provide information extracted from the physical world [31]. Those sensor nodes can be located anywhere and form an ad hoc network, which does not require a communication infrastructure. Sensor nodes are small enough to guarantee pervasiveness in the Antarctic environment and may be able to observe a certain phenomenon, measure its physical properties, quantify this observation, and finally, transmit gathered data. Sensor nodes could also have processing and routing capabilities using either a wireless or a wired medium. In this environment, sensor networks must dynamically provide the necessary QoS depending on the type of information transmitted by sensor nodes in a multihop topology, and then, the information should be transmitted to central station through NVIS by implementing a delay tolerant network.
As the network is composed of an extensive mesh of spread nodes, they must be located in the same link layer domain to communicate among themselves. Therefore, they will use link layer mechanisms instead of network layer techniques such as IP networks or routing protocols. Consequently, communications become faster and time response turns tighter.
Each type of data may require specific requirements, for example, a critical alarm may demand strict real-time requirements while monitoring reports may not need latency requirements. In order to face these demands, network architecture must deal with several QoS profiles and it should allow discriminating and/or enforcing specific traffic differentiation.
Taking all the above into account, the ICT requirements identified for the system are as follows:
Distributed system: the system itself is to be distributed and it must allow distributed applications.
Simplicity: the number of protocols and APIs, and the number of different types of interfaces are kept to a minimum.
Open system: open to other technologies (future proof) by applying existing standards whenever possible to avoid as much as possible proprietary solutions.
High interoperability: intertechnology mesh networking between personal area network (PAN) and NVIS backhaul.
Easy configuration: automatic neighbor discovery and plug and play capability.
Security: security confinement (to avoid the spreading of vulnerabilities).
Due to the large scenario in which the research project is going to be deployed, different technologies will be needed in order to cover all the areas. Some technologies based on IEEE 802.15.4 are presented as wireless communication candidate technologies that work within mesh networks and they are useful for Antarctic local area network coverage. The result has to be able to support large, geographically diverse networks with minimal infrastructure, with potential millions of fixed endpoints. In the upper layers, there may be technologies such as Zigbee or 6LoWPAN.
When working at Layer2 (second layer of the open system interconnection protocol stack), the communication between two different technology domains (IEEE 802.15.4 and NVIS) involves a gateway, enabling the communication between two separate IEEE 802.15.4 domains across a NVIS domain. A Layer2 routing multihop algorithm capable of working over the obtained topology database is needed in complex network topologies. The multihop algorithm is in charge of determining the neighbors to reach a destination, and the communication with that destination will be requested from the link layer. It is important to bear in mind that the information used by the multihop algorithm can be filtered by the topology control algorithm (valid/nonvalid neighbors).
In this chapter, we have reviewed all the recent activities around the application of HF communications for the research community in Antarctica. The long-range transequatorial link aims to communicate the Antarctic station directly to the home country as an alternative to satellite communications for low bit rate applications. For a transmission power up to 250 W, two different transmission modes have been developed, the robust mode and the high throughput mode. The robust mode, which uses spread spectrum modulation, is suited for extreme channel conditions and achieves 85 bps for a bandwidth of 16 kHz for the spread signal. The high throughput mode, which uses multicarrier modulation and achieves 370 bps for a bandwidth of 400 Hz, is suited for good channel conditions. Although these bit rates are low, they are enough for most of the current sensors installed around the Antarctic stations.
The NVIS link can provide coverage in a surface of approximately 200–250 km radius without the need of line of sight. The main goal of the proposed system is to extend the influence area of the Antarctic stations with the deployment of a wide-area sensor network. When the sensors are distributed in distant zones, it is a hard work to collect the data regularly, and the data are often accessed once or twice a year. With the NVIS solution, all the researchers may get a report of the sensor data in the SAS every day, with no need of direct vision between the sensor and the SAS. The NVIS node has an internal memory that stores the data until the ionosphere conditions allow the transmission. The nodes are intended to be battery powered so the transmission power is kept to a minimum (below 10 W). For NVIS links, the bit rate ranges from 2.3 to 4.6 kbps, depending on channel conditions. On this basis, digital voice and low-resolution images can be sent apart from data from most of the sensors available on the market.
In addition to the use in the Antarctica or any other remote places, NVIS communications have a straightforward application in case of natural disasters, terrorist acts, and communications for developing countries. During a natural disaster or terrorist attack, all the conventional communication systems such as GPRS, 3G, and 4G can be seriously damaged and the communication systems will stop working properly. Our proposed NVIS system may help sanitary assistants, firefighters, police, and other emergency services to communicate during the event of a disaster. In that case, the ease in putting this system up and not needing direct vision between the nodes would be a good solution to save lives.
On the other hand, some parts of the world do not have any communication infrastructures, either because they are uninhabited areas or simply because people cannot afford the price of a conventional communication system. In places where there is no any telecom operator, the communication can only be made via HF and satellite. The NVIS system, based on a low-cost platform, allows the population of developing countries to have access to primary services, such as e-health and education.
Finally, there is a great deal of applications, which can use the proposed communication protocol architecture. They can be classified in detection (e.g., detection of temperatures exceeding a particular threshold, of unauthorized access), tracking (e.g., the tracking of workers in dangerous work environments), and monitoring (e.g., monitoring of inhospitable environments).
Chronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Source | Type of trial | Interferon | Diagnosis | No. | Prior treatment status | Response rate |
---|---|---|---|---|---|---|
Yacoubet al. [15] | Phase II, multicenter | Pegylated IFN alfa-2a | PV | 50 | Resistance to HU or HU intolerance | CR:22% PR:38% |
ET | 65 | CR:43% PR:26% | ||||
Masarova et al. [16] | Phase II, single-center | Pegylated IFN alfa-2a | PV | 43 | Untreated or previously treated with cytoreductive therapy | CR:77% PR:7% |
ET | 40 | CR:73% PR:3% | ||||
Samuelsson et al. [18] | Phase II | Pegylated IFN alfa-2b | PV | 21 | Untreated or previously treated with cytoreductive therapy | CR: 69% for the entire group |
ET | 21 | |||||
Huang BT et al. [19] | Open label, multicenter | IFN alfa-2b | PV | 136 | Untreated or previously treated with cytoreductive therapy | OHR:70% Molecular response:54.7% |
ET | 123 | OHR (JAK2+ patients):83% CHR:23 cases OHR (JAK2-patients): 61.4% CHR:12 cases | ||||
Gisslinger et al. [23] | phase III, multicenter | Ropeginterferon | PV | 257 | Previously treated | OHR:53% |
Quintás-Cardama et al. [26] | phase II | Pegylated IFN alfa-2a | PV | 40 | Untreated or previously treated with cytoreductive therapy | OHR:80% CR:70% Molecular remission:54% |
ET | 39 | OHR:81% CR:76% Molecular remission:38% | ||||
Sørensen et al. [36] | Phase III, multicenter, COMBI | Pegylated IFN alfa-2a with ruxolitinib or Pegylated IFN alfa-2b with ruxolitinib | PV | 32 | Untreated or previously treated with cytoreductive therapy | OHR:44% CR:28% |
MF | 18 | OHR:31% CR:9% | ||||
Casassus et al. [40] | Open label, multicenter | IFN alpha-2b | Mastocytosis | 20 | Untreated and previously treated | PR:35% Minor remission: 30% |
Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; HU: hydroxycarbamide/hydroxyurea; CR: complete remission; PR: partial remission; and OHR: overall hematological response.
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
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