Experimental methods used in placenta research.
\r\n\t
\r\n\tThe aim of this book project is to compile the updated research work on medicinal applications of noble metal complexes mainly focusing the structure activity relationship of metal complexes with targeting biological components.
The core of cell proliferation is the division of cells and replication of chromosomes. Among other factors, it is also regulated by the length of telomeres since short telomeres will either recruit telomerase, or, in the absence of telomerase, induce senescence, apoptosis, or genome instability, or activate a DNA damage response (e.g., telomere recombination). The main function of telomeres is the protection of chromosomal integrity during DNA replication; moreover, they themselves are protected by a shelterin protein complex. Telomeres stabilize the ends of linear chromosomes and prevent the ends from being recognized as a double strand break. In human cells, telomeres contain hexameric tandem repeats, 5′TTAGGG 3′, of DNA sequence. To maintain the proliferative ability of cells, the elongation of telomeres is executed by adding telomeric DNA repeats to the 3′chromosomal ends by telomerase. In the absence of telomerase, the telomeres shorten in every cell division. Telomerase as an RNA-dependent DNA polymerase repairs the sequences of telomeres after each cell division; but in humans, this enzyme is active in stem cells, germ cells [1, 2, 3], and cancer cells only.
\nDuring development of an individual, mature oocytes and cleavage stage embryos display low or absent telomerase activity, whereas in the blastocyst stage, its activity is high again. As in cells during early cleavage, the telomeres become remarkably longer, and an alternate lengthening of telomeres may play a role in their elongation. Processes of telomeric DNA recombination between homologous sister chromatids take place in the cleavage stage, and the length of telomeres is then maintained from the blastocyst stage onward by telomerase [4]. Telomeric DNA recombination between telomeres on separate chromosomes such as gene conversion and the elongation of telomeres by DNA polymerase activity by mechanisms like break-induced replication can lengthen telomeres independently of telomerase activity [5].
\nThe mechanism of DNA replication results in progressive shortening of the ends of linear DNA molecule. That shortening limits the life span of individual cells and it is referred to as replication senescence [6]. Recently, it is well known that telomere attrition is observed during normal cellular aging, but telomere dysfunction may also contribute to the onset and progression of age-related diseases like atherosclerosis and myocardial infarction [7]. Telomere attrition is regarded as one of the so-called hallmarks of aging as proposed in [8].
\nMany tissues and organs contain cycling undifferentiated stem cells that provide cells for their renewal. The frequency of their mitotic division is different among tissues; examples of the most active are epidermal cells and cells of the bone marrow. Those cells are characterized by high levels of telomerase expression and disorders of telomere homeostasis cause, or at least take part in, the pathogenesis of serious inherited diseases, for example, dyskeratosis congenita [9], aplastic anemia, other bone marrow syndromes [10, 11, 12] and/or idiopathic pulmonary fibrosis [13]. Moreover, increased incidence of diabetes mellitus was identified in patients suffering from those pathologies [14]. Inherited bone marrow failure syndromes threaten also the prenatal development due to fetal malformations and intrauterine growth retardation accompanied with an abnormally small placenta [15].
\nThe correct function of telomerase-telomere complex depends on both genetic predispositions and external factors (age, reactive oxygen species, and exogenous genotoxic factors). Mutations in the telomerase holoenzyme in either of the two genes,
The prenatal development of an individual is conditioned by placenta, the transient organ that functions exclusively for the time of pregnancy. In order to meet fetal requirements, the placenta holds the functions of still undeveloped fetal organs, for example, lung and kidney. It is the site of transport of oxygen, ions, nutrients, and maternal immunoglobulins from mother to fetus, and carbon dioxide and wastes from fetus to mother. The placenta also maintains pregnancy by production of steroid and protein hormones and other factors. Due to its position between maternal and fetal bloodstreams, the placenta acts as a barrier against infectious agents and regulates the maternal immune tolerance, gas exchange, and fetal nutrition. On the other hand, its structure and function are negatively impacted by maternal and fetal metabolic disturbances in pathological pregnancies.
\nPlacental tissues originate in extraembryonic structures, that is in trophoblast, the outer layer of the blastocyst, which invades maternal tissues and gives rise to the cytotrophoblast and syncytiotrophoblast, and in extraembryonic mesoderm that is requisite for the formation of placental vasculature and supporting connective tissue.
\nThe progress of fetal growth and maturation of fetal organs is essentially accompanied by the growth of placental size. It is performed by continuous cell proliferation till the term of gestation [21] and balanced with differentiation and apoptosis in all tissue compartments. The weight of term placenta is 500–600 g, the estimated surface area of syncytiotrophoblast available for maternofetal transport is 11–13 m2, and the inner fetal capillary surface area is about 12 m2 [22].
\nHuman placenta is formed by chorionic plate and its repeatedly branched projections, chorionic villi, that are immersed in maternal blood circulating in the intervillous space. The growth of villi goes hand in hand with fetal growth. They develop into various types during pregnancy, and their classification depends on size and structural features. Basically, each villus is covered by the layer of trophoblast consisting of continuous cytoplasmic mass with numerous nuclei, that is, syncytiotrophoblast, and cuboidal cells of cytotrophoblast appearing as a continuous layer underneath syncytiotrophoblast in early gestation, but sparsely spread in term placenta. As nuclei in syncytiotrophoblast do not divide, cytotrophoblast cells play the role of stem cells of trophoblast. They undergo mitotic division, and their fusion with syncytiotrophoblast enlarges its mass. As shown by detection of cell cycle markers (e.g., Ki67, PCNA), they display proliferative potential over the duration of pregnancy [23, 24, 25].
\nThe other source of placental tissues is extraembryonic mesoderm. For the placental development, this cell population gives rise to the mesenchyme adjoining villous trophoblast. Mesenchymal derivatives, that is, cells of connective tissue, endothelial cells, pericytes, and smooth muscle cells then form villous stroma and vascular bed. It is obvious that they follow the growth of trophoblast, and their proliferation and subsequent differentiation contribute to the formation of new functionally efficient villi, and thus to the enlargement of the organ and its functional capacity. It is significant particularly in the third trimester when the rapid development of terminal villi accompanies the rapid enlargement of fetal size [22]. Previous studies have demonstrated the proliferative potential of cells in villous vascular bed and stroma in early pregnancy as well as at term [24, 25]. The proliferative potential of cells in terminal villi of normal human term placenta is also demonstrated in Figure 1\n.\n
\nProliferative activity of cytotrophoblast (arrows), stromal cell (arrowhead), and capillary endothelium (asterisk) in terminal villi of normal term placenta demonstrated by Ki-67 immunohistochemistry. Bar = 50 μm.
In order to provide nutrition for the increasing metabolic requirements of growing fetus, the placenta displays continuous cell proliferation during its entire existence. Despite the fact that fetal demands attain their maximal level at term, it is expected that cells in placenta at term decrease their proliferative capacity due to telomere shortening and undergo senescence similar to somatic cells in other organs. It is also supposed that those changes in telomere length might take part in the initiation of parturition [26]. Telomere shortening during pregnancy was found also in the placenta of mice [27]. As shown in another study in mouse, the proportion of representative short telomeres, that is, 3- and 5-kb telomere fragments, significantly increases toward the end of pregnancy. The authors conclude that the quantity of representative short telomeres increases prior to parturition and takes part in the mediation of cellular aging in the placenta, finally leading to parturition [26]. Those findings are consistent with other studies regarding the impact of short telomere rather than average telomere length [28].
\nDue to its location in maternal uterus, the placenta is influenced by any abnormal metabolic conditions in both mother and fetus. The negative influence demonstrates itself in pathological structural features as well as in impaired function. In such organ displaying mitotic activity, altered telomere homeostasis may take part in those adverse changes. Here, we summarize data on telomere length and telomerase activity in placentas from normal pregnancies and pregnancies complicated by metabolic disturbances threatening pregnancy outcome, as are maternal diabetes mellitus, preeclampsia, and intrauterine growth restriction.
\nIn view of the facts mentioned above, telomere length emerged as a promising marker generally in medicine, but the utility of such measurements highly depends on valid methodologies [7]. The average telomere length is highly variable among different cell types and among different individuals. There are also gender differences, which could be detected at birth. Additionally, the average telomere length declines with age [16].
\nTelomeres may be repaired either by the enzyme telomerase using its RNA template or by recombination. The methodologies examining telomere homeostasis in different tissues are therefore based not only on the determination of the length of telomeric DNA sequences, but they examine also the status and expression of the reverse transcriptase
Method | \nReferences | \n
---|---|
TRF | \n[29, 30, 31] | \n
STELA | \n[32, 33, 34] | \n
Q-PCR, T/S ratio | \n[29, 35, 36, 37, 38] | \n
Interphase Q-FISH | \n[36, 39, 40, 41, 42, 43, 44, 45] | \n
hTERT-FISH | \n[36] | \n
hTERC-FISH | \n[36, 39, 41, 46] | \n
Immunohistochemistry | \n[43, 45, 47] | \n
RT-PCR for hTERT | \n[29, 41, 48, 49, 50, 51] | \n
RT-PCR for hTERC | \n[29] | \n
TRAP | \n[33, 38, 48, 52, 53] | \n
TRAP | \n[52, 53] | \n
Illumina methylation array | \n[37] | \n
Experimental methods used in placenta research.
\n
\n
O’Callaghan and Fenech [60] described the modification of qPCR-based technique allowing the determination of an absolute telomere length due to the use of artificially synthesized DNA standard containing the defined number of telomeric repeats.
\nPCR-based techniques are quite popular among researchers because they require lower DNA quantity and usual laboratory equipment. Due to their relatively low costs, they may be employed in high-throughput epidemiologic studies. One shortcoming of PCR-based methodologies is that the resulting values inform only about the average telomere length in the specimens.
\n\n
\n
\n
A method for telomere capture evaluation based on interphase Q-FISH has been established by Amiel et al. [64]. When telomeres shorten to the critical length, repair pathways are activated. In the process of telomere capture, a critically short telomere obtains a new telomeric sequence from another chromosomal end. In the original method, the number of fluorescent signals for a single copy gene, SNRP, which is localized on chromosome 13, was compared with the number of signals for 15qter region of this chromosome [64] to follow not only random aneuploidy but also telomere capture or translocation of telomere. The methodology was also used in placenta research [39, 48].
\nThe
\n
The methodology of
\n
\n
Microdissection followed by qPCR allows selection of cells for analysis using classical histological technique and it is suitable for the studies based on archival material [35]. Microdissected cells may be examined by qPCR methodology, and therefore, its main disadvantage is that it provides information only about the relative average length of telomeres in analyzed samples. The methodology does not result in the determination of the lengths of the longest or the shortest telomeres contained in the sample. Comparison of T/S ratios related to a reference sample allows evaluation of differences between the groups of samples (for instance between healthy controls and patients).
\nWhole genome sequencing (WGS) captures sequence information from the entire genome, including the telomeres, and is increasingly being applied in research and in the clinic. In 2014, Ding et al. [77] demonstrated a novel method, TelSeq, which allows measurement of average telomere length by using whole genome or exome sequencing data. It was the first study that evaluated in detail the relationship between the frequency of telomere repeats and telomere length. With the potential to be a relatively high-throughput method, this may overtake qPCR as the method of choice in future studies. Their study was the first computational method that had been validated against an established experimental method (Southern blot measurements of the mean length of terminal restriction fragments).
\nThe telomere length is closely associated with telomerase (human telomerase reverse transcriptase—hTERT) activity (TA) and the availability of its RNA component (hTERC or TERRA—telomeric repeat-containing RNA) in tissues.
\n\n
The presence of telomerase itself may be detected in tissues by means of
In Table 1, the studies that examined the expression of
The telomerase activity may be measured by a wide panel of methodologies based on addition of telomerase substrate and detection of amplified telomerase products by
\n
\n
\n
Not only the presence of DNA sequences of genes
Wilson et al. [37] used
\n
The assessment of telomere length in normal pregnancy gives important data regarding dynamics of placental cellular proliferation. The study on third trimester placentas using the qPCR has shown decreased telomere length between gestational weeks 28 and 42 (13.98–10.56 kbp) [38]. The application of qPCR and Southern blot-based terminal restriction fragment (TRF) assay confirmed considerably longer telomeres in first trimester villi than in term placentas, telomeres of which were found to be longer than those in cord blood mononuclear cells [29, 84].
\nSome authors took into consideration that the position of villous tissue in the placenta may influence the telomere length, and therefore collected and processed samples of the whole placenta from more locations [29, 37, 84]; nevertheless, no site-specific differences of telomere length were determined except [84] showing that the telomerase activity was detected in term placenta restricted to biopsy sites near umbilical cord only. Moreover, the Southern blot-based TRF assay discovered longer telomere length in placental samples than in cord blood cells [84]. The study by qPCR proved that telomeres in placentas of female fetuses are longer than in placentas of male fetuses at the same gestational week. This finding suggests an influence of hormonal milieu during intrauterine development [37]. On the other hand, the other study performed by single telomere length analysis (STELA) revealed neither influence of fetal sex nor influence of the mode of delivery [32].
\nThe above-mentioned findings in chorionic villi and normal placenta suggest that telomere length is maintained by active telomerase during pregnancy. Nevertheless, the papers dealing with this topic present equivocal results. Using TRAP assay, Wright et al. [33] found no detectable telomerase activity in placenta. To the contrary, telomerase activity studied by TRAP assay and in situ TRAP assay was found in both chorionic villi at 5–14 weeks of gestation and normal placentas at 23–42 weeks of gestation [49]. Expression of telomerase protein was detected by immunohistochemistry in cytotrophoblast of chorionic villi [47, 85]. Decreasing relative telomerase activity was shown in comparison of chorionic villi in first, second and third trimester. In normal villi from 6 to 40 gestational weeks, the presence of telomere RNA component (TERC) was demonstrated, whereas telomerase reverse transcriptase (TERT) was not found in samples from second and third trimesters [86]. Immunohistochemical reaction revealed telomerase expression in trophoblast and stroma of villi in 10th week, but not in term placenta [87]. Using RT-PCR method, the hTERT-RNA expression was found in normal chorionic villi from 6th to 10th gestational week as well as in normal placentas from 12th to 41st gestational week, whereas hTERT protein expression was found in chorionic villi, but only in the fourth part of placental samples [88].
\nIt is evident that normal placental growth and development carried out by cell proliferation is conditioned by appropriate telomere length ensured by homeostasis of telomerase system. For optimal course of those processes, normal metabolic milieu is necessary in mother, placenta, and fetus. The most critical condition of intrauterine development is adequate oxygen supply. The early pregnancy phase, that is, first 10 weeks, runs under low oxygen levels. This relative hypoxia before the constitution of the fetoplacental and uteroplacental blood circulation induces various factors, one being the hypoxia-inducible factor 1, that upregulates hTERT expression (and telomerase activity), and its decrease with gestational age is in correlation with decrease of telomerase activity logically followed by telomere shortening [88]. As the placenta consumes about 40% of the oxygen supplied to fetoplacental unit [89], the hypoxic conditions have negative impact on all processes running there. And hypoxia also represents a key factor in genesis of pregnancy pathologies discussed in the following parts of this chapter.
\nThere are two main forms of maternal diabetes mellitus, the insulin-dependent form with onset before conception, and gestational diabetes diagnosed usually in second half of pregnancy that disappears after birth. In the insulin-dependent type diabetes, an autoimmune process destroys β-cells of the islets of Langerhans completely and the patient is then treated by insulin supplementation.
\nAs shown in experiments with mice, the type 2 diabetes, and similarly gestational diabetes, may involve telomere shortening during pathogenesis. Shorter telomeres are associated with impaired β-cell regeneration, impaired glucose-stimulated insulin secretion by disorders of insulin release leading to impaired glucose tolerance as well as to increased β-cell senescence [14, 90].
\nBoth forms of maternal diabetes are characterized by maternal hyperglycemia and thus higher amount of glucose transported to fetus. Metabolic complications derived from hyperglycemia threaten the mother; manifest themselves in placental structure and function; have negative influence on fetal well-being, perinatal morbidity and mortality; and long-lasting effect on the postnatal life of the individual. In pregnancies complicated by maternal diabetes mellitus, the alterations of placental structure and function as well as the pregnancy outcome depend on the quality of metabolic control. Placentas from poorly controlled diabetes are larger and heavier and microscopic picture shows disturbances of villous maturation [22]. The oxidative stress produced by imbalance of glucose and oxygen supply in fetoplacental unit is compensated by enhanced placental angiogenesis demonstrated by higher villous capillary branching [91]. It is possible to suppose that both, the higher placental weight and enhanced angiogenesis, are a consequence of escalated cell proliferation leading to exhaustion of telomeres available for mitotic division.
\nRegarding the telomere length in placenta from pregnancies complicated by maternal diabetes, the available data are not quite consistent. In the qPCR-based study examining large cohort of placentas, maternal diabetes was found associated with longer telomere length [38]. In another study comparing telomere length in cytotrophoblast of placentas from poorly controlled maternal diabetes and normal pregnancies by FISH method, the result indicated shorter telomeres in the diabetic group [42]. In the same groups of patients, the immunohistochemically identified telomerase expression, the expression of mRNA for hTERT, and the expression of
Preeclampsia is a disease of pregnancy characterized by new-onset maternal hypertension and proteinuria. It may begin in 28–34 gestational weeks (early-onset preeclampsia) or after 34 weeks (late-onset preeclampsia). It is commonly accepted that the preeclampsia originates in deficient placentation, that is, decreased invasion of the maternal tissues by extravillous trophoblast. Under normal conditions, the endothelium and smooth muscle cells of uterine spiral arterioles are replaced with trophoblast and their diameter becomes wide allowing delivery of blood at low pressure to the intervillous space. The decreased trophoblastic invasion produces narrow uteroplacental arteries and the resulting malperfusion of the intervillous space causes oxidative stress of the fetoplacental unit manifested among others by reduced development of the villous tree and placental growth retardation. Increased placental proliferative activity found using detection of PCNA and Ki67 in preeclampsia may be a sign of increased cell turnover [92]. The associated systemic vascular inflammation in maternal organism may cause injury of multiple organs.
\nIn placentas in preeclampsia, the analysis of villous cytotrophoblast based on the quantitative FISH method showed shorter telomeres, more end-to-end telomere aggregates, and abnormal
In intrauterine growth restriction (IUGR), the growth and development of fetus is delayed by 3–4 weeks regarding the gestational age and the birth weight is low, under 10th percentile for gestational age. Fetal growth restriction is associated with restricted placental size caused by arrest mechanisms reducing cell proliferation [45]. There are two types of IUGR, symmetric and asymmetric. The fetus displaying symmetric IUGR has normal body proportion, the fat and muscle tissue are reduced. It is usually associated with genetic factors causing, for example, already mentioned bone marrow syndromes [9, 10, 11, 12] or infections. The asymmetric IUGR is characterized by normal size of head and reduced chest and abdominal circumference due to reduced fat and muscle tissue. It is often associated with placental insufficiency arising, for example, in preeclampsia and may be related to oxidative stress.
\nStudies performed by quantitative FISH method and RT-PCR on placental cytotrophoblast in IUGR gave an evidence of shorter telomeres, lower telomerase activity, decreased hTERT mRNA, and decreased
Lower proliferative potential found in placenta in IUGR [52, 70, 76, 93] seems to be consistent with decreased telomerase activity in cytotrophoblast of IUGR placenta [52, 76]. In placenta associated with asymmetric IUGR, only weak, if any, telomerase activity, hTERT expression, and copy numbers of telomerase reverse transcriptase were found by qPCR and in situ TRAP assay [49, 51, 53]. Shorter telomeres associated with higher expression of cell senescence markers were found in placenta samples in IUGR [31] and shorter telomeres detected by quantitative FISH technique and reduced average telomere length detected by qPCR were shown in [36]. To the contrary, no difference was revealed in average telomere length assessed by qPCR between normal placenta and placenta in IUGR [37].
\nAppropriate fetal growth and development is conditioned by appropriate placental growth and development. It is accomplished by balanced cell proliferation, differentiation, and apoptosis. Cell proliferation is influenced by the length of telomeric sequences of chromosomes and their elongation due to telomerase activity. This review article summarizes available data on telomere length and telomerase activity of placenta in pregnancy-complicating situations, that is, maternal diabetes mellitus, preeclampsia, and intrauterine growth restriction (Table 2) as well as methods used for this research (Table 1).
\nDiagnosis | \nTelomere length | \nTelomerase activity | \n
---|---|---|
Normal placenta | \nTelomere length is reduced in the course of pregnancy; placental telomere length is not site-specific [32, 33, 37, 38, 84] | \nhTERT expression and telomerase activity were found [47, 49, 84, 85]; telomerase activity decreases in the course of pregnancy [86, 87, 88] | \n
Placenta associated with maternal diabetes mellitus | \nMaternal diabetes is associated with longer placental telomeres [38]; there is no difference in placental telomere length in well-controlled diabetes [34, 35]; telomeres are shorter in placentas from poorly controlled diabetes [42] | \nLower expression of hTERT, hTERT-mRNA, lower | \n
Placenta associated with preeclampsia | \nNo differences of telomere length between normal placentas and placentas in preeclampsia [37, 84]; shorter telomeres, more end-to-end telomere aggregates, higher telomere aggregates count [43, 44] | \nLower expression of hTERT [44], abnormal | \n
Placenta associated with IUGR | \nShorter telomeres [31, 36, 45]; no difference in telomere length [37] | \nLower expression of hTERT, hTERT-mRNA, lower | \n
Summarized data on telomere length and telomerase activity in normal placenta and placenta in case of maternal diabetes mellitus, preeclampsia, and IUGR.
In normal placentas, longer telomeres and higher telomerase activity were found in early pregnancy, they gradually decreased till the term. Although the available studies on placentas from pregnancies complicated by maternal diabetes are not numerous, their results corroborated by experimental studies suggest that diabetic metabolic conditions contribute to telomere shortening and that the appropriate metabolic control achieved by adequate treatment may function as a prevention of this adverse process. The results of research on telomere length and telomerase activity in preeclampsia are still equivocal and rather suggest debatable comparability of methods applied in those studies. The telomere length in placenta associated with IUGR was found lower and accompanied with decreased expression and activity of components of telomerase apparatus.
\nMaternal diabetes mellitus, preeclampsia as well as IUGR do not only complicate pregnancy but are also taken as causes of adverse outcomes for individuals later in postnatal period. Further investigation of the effect of factors influencing telomere length and telomerase activity may contribute to better understanding of those links. The placental DNA is identical to the DNA of fetal cells and the period of its existence equal to the prenatal period of the fetus spent in the same maternal environment. As telomeres are susceptible to external conditions of maternal milieu (i.e., oxidative stress, reactive oxygen species, exogenous genotoxic insults), those epigenetic influences may accelerate their shortening [94]. Prospective studies in experimental models and of course in long-time prospective studies in human should elucidate if there is a relation of final telomere length in placentas at term and newborn and if the measurement of placental telomere length could have a predictive potential for individual.
\nRecently, the immunomodulatory role of telomeric sequences was recognized [78, 95]. Telomeric sequences originated from trophoblasts may circulate in the pool of cell-free DNA in maternal plasma and contribute to timing of parturition [26] by stimulation of maternal immune response against placenta. The role of telomeric sequences contained in cell-free DNA in plasma of healthy persons in the regulation of immune system performance was also described [95]. Additionally, the telomeric sequences were found also in cytoplasm where they regulate inflammatory response via their interaction with TLR9 receptor [78].
\nIn view of all these facts, the study of telomeres and their homeostasis in placenta seems to be crucial for the understanding of pathogenesis in the broad spectrum of pregnancy complications.
\nThis work was funded by the grant No. Progres Q25/LF1 of the Ministry of Education, Youth and Sport of the Czech Republic, and by the grant RVO-VFN 64165 of the Ministry of Health of the Czech Republic.
\nThere are no conflicts of interest.
FISH | fluorescence in situ hybridization |
IUGR | intrauterine growth restriction |
HIF | hypoxia induced factor |
hTERT | human telomere reverse transcriptase = catalytic component of telomerase activity |
IUGR | intrauterine growth retardation |
qPCR | quantitative polymerase chain reaction |
RT-PCR | reverse transcriptase polymerase chain reaction |
SFE | signal free ends |
\nTERC\n | telomerase RNA component gene |
\nTERT\n | telomerase catalytic component gene |
TRAP | telomeric repeat amplification protocol |
TRF | terminal restriction fragment |
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.
The Edited Volume, also known as the IntechOpen Book, is an IntechOpen pioneered publishing product. Edited Volumes make up the core of our business - and as pioneers and developers of this Open Access book publishing format, we have helped change the way scholars and scientists publish their scientific papers - as scientific chapters.
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\n\nNot sure if this is the right publishing option for you? Feel free to contact us at book.department@intechopen.com.
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From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. 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Dr. Chen\\'s research interests include bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. He has published more than ninety scientific papers and serves as an editorial board member for Plant Methods, Biomolecules, and International Journal of Molecular Sciences.",institutionString:"National University of Kaohsiung",institution:{name:"National University of Kaohsiung",institutionURL:null,country:{name:"Taiwan"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:45,paginationItems:[{id:"82135",title:"Carotenoids in Cassava (Manihot esculenta Crantz)",doi:"10.5772/intechopen.105210",signatures:"Lovina I. Udoh, Josephine U. Agogbua, Eberechi R. Keyagha and Itorobong I. 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He\nreceived a short-term scholarship to carry out his post-doctoral\nstudies abroad, from Japan International Cooperation Agency\n(JICA), in coordination with the Egyptian government. Dr.\nShalaby speaks fluent English and his native Arabic. He has 77\ninternationally published research papers, has attended 15 international conferences, and has contributed to 18 international books and chapters.\nDr. Shalaby works as a reviewer on over one hundred international journals and is\non the editorial board of more than twenty-five international journals. 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