Complications of IO in patients undergoing HSCT [24]
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",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"abf31c9873fc2d88b8ee05c6adb53a29",bookSignature:"Dr. David Bienvenido-Huertas",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10104.jpg",keywords:"Sustainable Construction, Innovative Construction, Construction Processes, Sustainable Design, Design Optimization, Maintenance Minimization, Energy Efficiency, Energy Conservation Measures, Thermal Comfort, Socio-cultural Integration, Urban Environment, Visual Impact",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 26th 2020",dateEndSecondStepPublish:"September 23rd 2020",dateEndThirdStepPublish:"November 22nd 2020",dateEndFourthStepPublish:"February 10th 2021",dateEndFifthStepPublish:"April 11th 2021",remainingDaysToSecondStep:"5 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"David Bienvenido-Huertas has completed his Ph.D. as an Architect, currently, he is a researcher of the Building Construction II Department at Universidad de Sevilla, Spain",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"320815",title:"Dr.",name:"David",middleName:null,surname:"Bienvenido-Huertas",slug:"david-bienvenido-huertas",fullName:"David Bienvenido-Huertas",profilePictureURL:"https://mts.intechopen.com/storage/users/320815/images/system/320815.jpg",biography:"PhD Architect. Researcher of the Building Construction II Department at Universidad de Sevilla, Spain. Active member of the Research Group TEP970: Technological Innovation, 3d Modeling Systems and Energy Diagnosis in Heritage and Building at the Universidad de Sevilla. His area of expertise covers climate change in the building sector, adaptive thermal comfort, heat transfer, fuel poverty, energy conservation measures, and design of nearly zero energy buildings. 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Although remarkable advances in transplant immunology and supportive care allowed widespread use of HSCT, transplant related morbidity and mortality remain as a problem [1-7]. Early complications including sinusoidal obstruction syndrome (SOS), hemorrhagic cystitis, engraftment syndrome, idiopathic pneumonia syndrome (IPS), infections and graft versus host disease (GVHD) are the major causes of morbidity and non relapse mortality (NRM). High doses of radiotherapy and chemotherapy of the conditioning regimen have adverse effects on all organs and tissues of the recipient, which also triggers several early and late effects of variable intensity [1, 3, 5-8]. Iron overload (IO) is a relatively common condition in patients with hematological malignacies and HSCT recipients. Free iron which accompanies IO might contribute to the already existing prooxidant state in HSCT recipients by inducing the formation of reactive oxygen species (ROS). Tissue peroxidation and organ damage, as a consequence, contribute to the development of some early transplant complications [2, 4, 5, 9]. Increasing number of transplants performed each year and improved transplant techniques result in a rise in the number of long term survivors. The primary goal of HSCT is to cure the primary disease. However long term transplant related morbidity might be very challenging and might significantly impair the quality of life. Late effects might be the consequence of the direct toxicity of chemoradiotherapy and/or the immunologic complications mainly consisting of GVHD. Besides the secondary late effects including osteoporosis and dental caries, very late effects, namely cardiovascular toxicity considered as tertiary late effect may also occur. Among this wide spectrum of complications, IO has a substantial role as a contributor to liver toxicity, infections and SOS and as a predictor of transplant outcome. Hematopoietic SCT recipients have been demonstrated to have a high degree of liver iron content (LIC) almost in the range of hereditary hemochromatosis (HH) and IO was shown to cause liver fibrosis, heart failure, hypogonadism, diabetes and endocrinopathy in HSCT recipients in the long run [4, 6, 7, 10].
Iron is an essential element which plays a key role in several biochemical reactions including oxygen transport and electron transfer. It mediates the conversion of hydrogen peroxyde (H2O2) to highly toxic free radicals leading to tissue damage by oxidation of proteins, peroxidation of membrane lipids and modification of nucleic acids [4]. Under normal circumstances, an appreciable concentration of free iron does not exist outside physiological sinks. Any released ferrous iron (Fe+2) is immediately chelated in cells by compounds such as citrate or adenosine diphosphate. Thus, labile iron could not participate in the Haber–Weiss reaction, which catalyses the formation of ROS. Free iron may directly initiate lipid peroxidation which destroys membrane structure resulting in increased oxidative stress and cellular damage. Excess iron accumulation causes chronic free radical induced tissue damage in multiple organs and leads to progressive organ dysfunction, which results in significant morbidity and mortality. In this respect, IO should be prevented in order to preclude the adverse impact of free iron on natural homeostasis [9, 11].
This chapter will focus on iron balance and the course of excess iron in HSCT recipients. The adverse impact of IO on transplant outcome and the preventive strategies will also be discussed.
Iron is vital for all living organisms and takes part in several metabolic processes, including DNA synthesis, oxygen and electron transport. Although iron is a critical element in cell growth and multiplication, it is potentially toxic in excess amounts by generating ROS [5, 11-13]. Reactive oxygen species have a potential to damage DNA and proteins by lipid peroxidation. Labile iron participates in free radical formation via Fenton reaction which was first recognized in 1894. Namely, trace amounts of iron as Fe+2 could catalyze the oxidation of tartrate by H2O2. Consequently, superoxide anion (O2-) or H2O2 is converted to toxic free radicals such as hydroxyl radical (OH-). This process is mediated by the Fenton reaction catalyzed by iron, where O2- reduces ferric iron (Fe+3) to produce oxygen and Fe+2. This reduced iron becomes reoxidized by H2O2 to produce OH- [5, 11].
a. Fenton reaction; b. Iron catalyzed Haber–Weiss reaction or the superoxide driven Fenton reaction [5].
There are no physiological mechanisms in humans to excrete excess iron and iron homeostasis is primarily regulated at the level of absorbtion [4, 9, 11, 14-16]. The majority of iron absorbtion occurs via enterocytes in the proximal small intestine. The conversion of dietary inorganic non–heme iron to Fe+2 is facilitated by the brush border ferri reductases. Iron is transported across the cellular membrane by the divalent metal transporter 1 (DMT1) which transfers Fe+2 across the apical membrane and into the cell through a proton coupled process [9, 15, 16]. Ferroportin is an iron efflux pump that mediates the export of Fe+3 from the enterocyte. Prior to transport, Fe+2 is converted to Fe+3 by either hephaestin or ceruloplasmin both of which have ferroxidase activity. Subsequently, iron is uploaded to transferrin which is the primary iron transporter in the circulation. Ferric iron bound to transferrin is soluble and non reactive. The majority of iron (60–70%) is incorporated into hemoglobin while the rest is stored in hepatocytes, myoglobin and reticuloendothelial macrophages [9]. Hepcidin, the main regulator of iron absorbtion, inhibits intestinal absorbtion and release of storage iron in iron-overloaded states, whereas its expression is markedly decreased in iron deficiency states. Hepcidin interacts directly with ferroportin, causing its internalization, degradation and blocking iron release from cells to plasma. Hepcidin acts as an acute phase reactant which is responsible for the anemia of inflammation. Its production is upregulated by body iron excess and inflammation whereas downregulated by anemia and hypoxia [9, 14, 16].
Cell survival depends on the balance between the destructive and beneficial effects of iron [9, 12]. Natural iron homeostasis comprises regulation mechanisms to control iron excess. The primary protective pathway is the sequestration of iron in ferritin or transferrin. Ferritin is the chief storage molecule while transferrin is functionary for the transport of iron. Ferritin captures and buffers the intracellular iron pool, thus it makes iron available for critical cellular processes while protecting lipids, DNA and proteins from potentially toxic effects of iron. Iron stored in ferritin is not capable of catalyzing radical reactions and is considered as safe. It is well known that serum ferritin concentration closely parallels body iron reserves. However, as free iron is the main form of iron which can precipitate in oxidative stress, any measure of unbound iron will result in deleterious effects. The balance of free iron to bound iron changes and free iron becomes available to catalyze free radical reactions in iron overloaded states [5, 9]. Large amounts of excess iron in the circulation are likely to exceed the serum iron binding capacity (SIBC) and non transferrin bound iron (NTBI) will emerge eventually. Non transferrin bound iron bypasses the normal regulatory mechanism of receptor mediated iron uptake and is able to stimulate the peroxidation of membrane lipids and the formation of ROS. The intracellular counterpart of NTBI is considered as labile iron pool (LIP) which is bound mainly to low molecular weight compounds. Labile iron pool is catalytically active and capable of initiating free radical reactions. The expansion of the LIP and simultaneously increased NTBI may trigger cell toxicity. Generation of LIP leads to unregulated iron uptake and subsequent intracellular storage either within ferritin molecules or as hemosiderin. The adverse effects of IO can arise from the elevation of NTBI and LIP in plasma and might as well cause organ damage mediated by the accumulation of tissue iron in target organs. The equilibrium between the LIP and iron locked in the ferritin shell is critical to maintain the normal function of cellular iron enzymes. Imbalance in this equilibrium results in the uncontrolled loading of organs, such as the liver, heart and endocrine glands, with free iron which generates free radicals and causes cell damage [12, 17]. Eventually, NTBI and LIP may be more relevant iron markers than serum ferritin and transferrin as a predictor of IO induced tissue damage. Alterations in ferritin levels are seen commonly in clinical practice often reflecting perturbations in iron homeostasis or metabolism. Serum ferritin differs markedly from tissue ferritin in molecular weight, iron and carbonhydrate content, subunit size and amino acid sequence. The extracellular form of ferritin, termed as serum ferritin, is used as a clinical marker of iron status. Tissue ferritin is the more efficient storage form of iron than is serum ferritin and the function of serum ferritin has to be clarified in these circumstances [9, 12]. Serum ferritin is usually correlated with NTBI, whereas inflammation, acute and chronic liver diseases and malignancies may also cause elevated serum ferritin levels regardless of the iron stores [12].
Iron overload is a significant problem in autologous (auto) and allogeneic (allo) HSCT recipients and may adversely affect transplant outcome [4, 18]. The diagnosis of IO has been reported in up to 88% of long term survivors of HSCT on the basis of serum ferritin levels [19]. Iron overloaded state may last for a long time after transplantation. In a cross sectional study by Majhail et al, in which LIC on MRI was used for diagnosis, the prevalence of IO was reported to be 32% in allo-HSCT recipients who had survived 1 year or more following HSCT [20]. In another study by the same group, serum ferritin levels were found to be above 1000 ng/ml in 34% of allo-HSCT and 13% of auto-HSCT recipients. Thus, IO may be less prevalent among recipients of auto-HSCT compared to allo-HSCT as expected [21].
The main causes of IO in HSCT are prolonged dyserythropoiesis, increased intestinal iron absorbtion due to anemia and chemotherapy associated mucositis which leads to increased iron absorbtion, transfusion burden and release of iron from injured tissues [8, 22].
Iron overload is particularly common in HSCT recipients with hemoglobinopathies and hematological malignancies which require frequent transfusions and is associated with ineffective erythropoesis such as acute leukemia and myelodysplastic syndrome (MDS). Transfusion load is considered to be the principal cause of IO in this group, as each unit of packed red blood cells (PRBC) contains approximately 200–250 mg iron. Since there is no physiological mechanism for excreting excess iron, iron accumulation is inevitable after 10–20 transfusions [22-24]. Ineffective erythropoiesis might be a contributing factor leading to excessive iron absorbtion particularly in MDS and thalassemia which is mediated by erythroid regulators of iron metabolism which suppress hepcidin and result in increased iron absorbtion. Elevated growth differentiation factor 15 (GDF–15) levels are considered to be the initiating event in this context. Ineffective erythropoiesis either as a feature of the underlying disease or a consequence of intensive treatment leads to inhibition of hepcidin possibly due to overexpression of GDF–15 and thus increases iron absorbtion and toxicity. Hematopoietic SCT recipients are at risk of IO due to prior transfusion load, increased iron absorbtion related to elevated GDF–15 levels and peri–tansplant transfusions [22, 24, 25].
Bone marrow (BM) and tumor cell destruction which occurs as a consequence of high dose therapy and release of iron from damaged cells as well as underutilization of iron due to the inhibition of erythropoiesis as a result of cytotoxic therapy are important factors in the etiology of IO. Erythropoiesis, which is the main route of iron utilization, is temporarily halted by the conditioning regimen [8, 22, 23, 26]. Conditioning treatment with chemo/radiotherapy during HSCT causes toxicity and immunosuppression leading to organ damage and infectious complications mainly in the first 3 months of the procedure [27]. Free iron, which acts as a free radical catalyser, might increase the toxicity of the conditioning regimen during HSCT. Serum iron parameters were demonstrated to be elevated 2–3 days during conditioning chemotherapy prior to stem cell infusion in a report by Gordon et al [13]. Non transferrin bound iron appears shortly after conditioning regimen and remains detectable in most patients throughout the peri–transplant period. Transferrin saturation (TS) increases during the conditioning regimen, often reaching to levels above 80% with the consequent emergence of NTBI [28]. The ability of ferritin to sequestrate iron and binding of iron to transferrin is exhausted in HSCT recipients receiving conditioning regimen, thus leading to excess NTBI formation. The extent of BM suppression caused by the conditioning regimen is correlated with the elevation of NTBI [27]. A substantial decrease in plasma anti-oxidant defense has also been demonstrated in HSCT recipients, and NTBI levels were found to be inversely correlated with plasma antioxidant capacity in a report by Yegin et al [29]. A derangementof the prooxidative/antioxidative balance was demonstrated as antioxidants only partially recover to baseline values until day 14 after HSCT [30, 31].
Hepatic toxicity due to chemotherapy and radiation might lead to hepatocellular damage with subsequent further release of hepatic iron stores. Liver damage may also disturb transferrin synthesis [28, 30]. A decrease in transferrin due to hepatic toxicity, stored iron leaking from injured liver to blood and a suppression of erythropoietic activity during treatment may causes elevated TS levels. Thus, increasing TS succeeds and contributes to the appearance of potentially toxic NTBI in the circulation. Iron in its NTBI form is a potent catalyst in Fenton’s reaction which produces ROS capable of causing cellular damage through various mechanisms. Tissue damage such as mucositis and liver injury is common after HSCT and may be partly mediated by NTBI during cytotoxic chemoradiotherapy [28, 29, 32]. It is indicated that increased NTBI levels may contribute to organ toxicity and infectious complications in the early post–transplant period [29].
\n\t\t\t\tComplication\n\t\t\t | \n\t\t\t\n\t\t\t\tIncidence\n\t\t\t | \n\t\t\t\n\t\t\t\tMechanism of Injury\n\t\t\t | \n\t\t
Infection | \n\t\t\tVariable | \n\t\t\tImmune dysregulation, mediated in part by IO, iron-rich microbial environment | \n\t\t
Chronic liver disease | \n\t\t\tCommon | \n\t\t\tMultifactorial, including IO | \n\t\t
SOS | \n\t\t\tCommon (up to 54%) | \n\t\t\tConditioning regimen, prior irradiation, possibly IO | \n\t\t
IPS | \n\t\t\tUncommon (2-8%) | \n\t\t\tPro-inflammatory events and increased ROS (mediated by IO) | \n\t\t
Complications of IO in patients undergoing HSCT [24]
\n\t\t\t\tComplication \n\t\t\t | \n\t\t\t\n\t\t\t\tComments\n\t\t\t | \n\t\t
\n\t\t\t\tEarly (<1 year) \n\t\t\t | \n\t\t\t\n\t\t |
\n\t\t\t\tInfections\n\t\t\t | \n\t\t\t\n\t\t\t\tMucormycosis, invasive aspergillosis, listeria monocytogenes and other infections\n\t\t\t | \n\t\t
\n\t\t\t\tAcute GVHD\n\t\t\t | \n\t\t\t\n\t\t\t\tNo clear evidence available, elevated ferritin might increase risk\n\t\t\t | \n\t\t
\n\t\t\t\tSOS\n\t\t\t | \n\t\t\t\n\t\t\t\tIron overload might increase risk\n\t\t\t | \n\t\t
\n\t\t\t\tNRM\n\t\t\t | \n\t\t\t\n\t\t\t\tElevated ferritin associated with increased risk in allo and auto-HSCT recipients\n\t\t\t | \n\t\t
\n\t\t\t\tLate ("/>1 year)\n\t | \n\t\n |
\n\t\tInfections\n\t | \n\t\n\t\tMucormycosis, invasive aspergillosis and other infections\n\t | \n
\n\t\tChronic GVHD\n\t | \n\t\n\t\tNo clear evidence available, decreased risk reported with elevated ferritin\n\t | \n
\n\t\tLiver Function Abnormalities\n\t | \n\t\n\t\tIron overload increases risk\n\t | \n
\n\t\tCardiac Late Effects\n\t | \n\t\n\t\tIron overload might increase risk\n\t | \n
\n\t\tNRM\n\t | \n\t\n\t\tNo clear evidence available\n\t | \n
The Role of IO in Early and Late Complications of HSCT [4]
Iron toxicity may play an important role in the pathogenesis of transplant related complications [Table 1, 2]. In a series of 25 patients who underwent HSCT, very high levels of ferritin (>3000 ng/ml) and TS (>100%) dramatically increased transplant related mortality (TRM) and decreased overall survival (OS) which was particularly attributed to infections [32]. As iron is an essential element for all pathological microorganisms, excess amounts of free iron might increase microbial growth and the probability of severe infections [33]. The coexistence of excess plasma iron with the damage to the mucosal barrier may also predispose to infectious events with bacterial translocation. Hypoferraemia is a normal response to infection and appears to be a part of a natural resistance mechanism whereas hyperferremia can predispose to bacterial and fungal infections. In this context, elevated TS and ferritin levels are proven risk factors for the development of systemic fungal infections in patients with hematological malignancies [1, 33, 34]. Furthermore, an increase in late fungal infections, especially mucormycosis, has been reported in iron loaded patients after HSCT [35]. Elevated pre–transplant ferritin levels seem to effect prognosis adversely in myeloablative HSCT primarily due to increased NRM. On the other hand, elevated iron stores apart from providing a milieu for infection and organ toxicity, may also be in relevance to tumor growth. Thus elevated ferritin levels might be in association with relapse and relapse mortality [36]. Mahindra et al reported that elevated pre–transplant serum ferritin level was an independent adverse risk factor for OS in patients undergoing non myeloablative HSCT. Inferior survival in patients with elevated ferritin was related to both higher rates of treatment related mortality and relapse mortality [37]. On the other hand it should also be noted that ferritin is an acute phase reactant and a marker of inflammation besides its role as a surrogate marker of iron status. Thus, elevated ferritin levels might as well indicate a group of patients with more agressive primary disease biology and a subgroup of patients who are already more likely to experience disease relapse. Thus the association of elevated ferritin levels with relapse might be unrelated to IO.
The adverse impact of IO on transplant outcome has been demonstrated most convincingly in patients with thalassemia where class III patients with extensive liver damage had higher TRM [38]. Besides increased TRM, other complications attributed to IO includes fungal infections, hepatic dysfunction and hepatic SOS/Veno occlusive disease (VOD) [4, 27, 38, 39]. In fact, thalassemia is a benign disorder and ferritin is directly a marker of excess iron and elevated levels could not be attributed to the biology of an underlying malignant pathology. As a result of the above mentioned data, pre–transplant serum ferritin was included in a prognostic scoring system for acute leukemia and MDS patients undergoing allo–HSCT [40]. The late morbidity of IO is primarily due to the involvement of heart and liver. Although iron related liver function test (LFT) abnormalities have been reported, there are no studies that describe the role of IO in late onset cardiomyopathy and hepatic fibrosis/cirrhosis in patients transplanted for diseases other than thalassemia. Post–transplant iron depletion therapy has been shown to reverse hepatic fibrosis and cardiomyopathy in children with thalassemia who have undergone allo–HSCT [4].
Liver disease is a frequent cause of morbidity and mortality following allo–HSCT and affects 90% of recipients and up to 5–10% of toxic deaths are liver related. Liver injury in the early post–transplant period may be secondary to drug toxicity, SOS, acute GVHD, opportunistic infections, total parenteral nutrition, tumor invasion and cholestatic disorders [3, 41]. Long term liver disease is also a common complication of HSCT, as 57, 5% of survivors developed chronic liver disease (CLD) at 2 years after transplantation in a retrospective series of 106 patients reported by Tomas et al. In this retrospective study, the combination of chronic hepatitis C and IO was presented as the most frequent cause of CLD [41]. On the other hand, chronic GVHD also contributes to liver toxicity. The timing and pattern of LFT abnormalities, history of pre or post transplantation hepatitis, presence of GVHD at other sites and transfusion burden might be helpful in determining the etiology of liver disease. Accurate diagnosis of the etiology of liver dysfunction is generally problematic even though the patterns of biochemical, clinical and histological abnormalities can aid diagnosis. Liver biopsy in patients following HSCT is not without risks, particularly due to thrombocytopenia during the early post–transplant period. The most common indication for liver biopsy is to assess the possibility of GVHD in allo–HSCT in the late post–transplant period with persistently abnormal LFTs and no evidence of GVHD on other sites. In this clinical setting, the sensitivity and specifity of serum ferritin as a marker of IO is not well defined due to its concomittant role as an acute phase reactant [3, 5, 8, 24, 41-43]. Liver biopsy may be performed when atypical clinical features are present or multiple disease processes are likely to occur simultaneously or when there is poor response to therapy that has been instituted [44]. The management of liver dysfunction under these conditions may be complicated as overlapping features often complicate the diagnosis and establishing the correct diagnosis is crucial to institute disease specific therapy. Autopsies performed in 10 patients who died early after HSCT showed iron accumulation in a range equivalent to that of patients suffering from HH [26]. A cumulative cirrhosis incidence of 3, 8% by 20 years after HSCT has been reported previously [8]. This rate seems to be an underestimation as the majority of long term survivors have not been subjected to liver biopsy. In a retrospective study by Sucak et al, severe IO was demonstrated in 75% of 24 liver biopsies which were performed with the presumptive diagnosis of hepatic GVHD in 20 patients with persistent elevation of liver enzymes in the post–transplant setting. The initial clinical diagnosis of GVHD was refuted in 43, 5% of the patients. Median number of post–transplant transfusions, TS and ferritin levels were found to be significantly higher in patients who had histologically proven hepatic IO. A significant correlation between serum ferritin levels and histological grade of iron in the hepatocytes was also demonstrated [10]. In another study by Iqbal et al, the diagnosis obtained at laparoscopic liver biopsies altered targeted therapy in 31% of patients. Iron overload was found in 81, 25% of a total of 32 biopsies [45]. A diagnosis of IO after HSCT was demonstrated based on histological evidence of siderosis found in 52, 4% of liver biopsies performed at 15–110 days post-transplant in another study. Liver biopsies were performed for diagnostic purposes in patients with chronic liver dysfunction. An improvement in LFT was observed in 21 of the 23 patients (91%) with IO who underwent phlebotomy [41]. Namely, IO seems to be underestimated as a cause of liver dysfunction in HSCT setting and liver biopsy which allows disease specific therapy could be life saving.
Hepatic IO may also worsen the natural course of chronic viral hepatitis and the response to antiviral therapy. Fujita et al demonstrated that liver iron deposition was more common in chronic hepatitis C compared to hepatitis B and was associated with liver disease progression. Increased hepatic iron stores in chronic hepatitis C were related to resistance to Interferon/Ribavirin treatment [46]. Thalassemic patients with liver fibrosis and hepatomegaly who undergo HSCT, have a markedly reduced OS and event free survival compared to patients without evidence of liver disease. The liver disease in these patients is due to a combination of severe IO and chronic viral hepatitis both of which improve with effective iron chelation therapy [19, 26, 47]. Iron is also deposited in other tissues such as myocardium or BM. Slow and spontaneous decrease in iron stores has been reported in thalassemic children in the years following HSCT. This natural iron depletion could normalize iron stores in individuals with mild siderosis. However, in patients with moderate to severe IO this slow depletion could not prevent the development of liver dysfunction. For this reason, iron depletion protocols have been developed for patients with severe IO [19, 23, 26, 47].
Sinosoidal obstruction syndrome is a treatment related toxicity associated with auto and allo–HSCT which is seen in 6–54 % of the recipients. The severity of SOS ranges from a mild reversible to a progressive course with a mortality rate close to 100% [5, 24].
The role of pre–transplant hyperferritinemia in the development of SOS was first demonstrated by Morado et al in a cohort of 180 auto–HSCT recipients. In this prospective study, SOS was defined in 12, 2% of patients based on McDonald criteria. Patients with pre–transplant ferritin levels above 300 mg/dl were shown to have a higher risk of developing SOS [48]. In a recent report by Maradei et al, a pre–transplant serum ferritin level above 1000 ng/dl was identified as an independent risk factor for the development of SOS [39]. A retrospective study of 250 HSCT recipients by Sucak et al, in which SOS incidence was reported to be 29, 7%, demonstrated significantly higher pre–transplant serum ferritin levels in patients with SOS [49]. In another study reported by Sucak et al, pre–transplant ferritin levels were found to be higher in HSCT recipients who developed SOS in the post–transplant setting [50]. Serum ferritin may be increased in conditions other than IO in this particular group of patients, including chronic inflammation and infection. Nevertheless, values higher than 1000 ng/ml were rarely reported in these inflammatory conditions [1, 25, 29, 39, 48-51].
Iron induced hepatotoxicity is multifactorial which involves oxidative stress and modulation of gene expression of Kuppfer cells. Cellular injury is induced by iron generated ROS and peroxidation of lipid membranes [39]. Risk factors associated with the development of SOS are defined as preexisting liver dysfunction, previous abdominal irradiation, high dose total body irradiation, high dose preperative regimens, advanced disease and HLA mismatch or unrelated HSCT. The typical hepatocellular lesion of SOS mainly occurs in zone 3 of hepatic acines including a characteristic endothelial lesion which is shown to be associated with hypercoagulability. The oxidant effect of iron on endothelial and and hepatocyte membranes mediated by ROS contributes to the development of these typical lesions of SOS [48, 50]. The risk of SOS is higher in carriers of at least one allele of the hemochromatosis gene, HFE, which predisposes to iron deposition in the liver [24].
Patients with HH and other diseases with IO are considered to be more susceptible to infections, as iron adversely affects the phagocytic, chemotactic and bactericidal capacity of granulocytes and monocytes and inhibits the activity of natural killer cells and macrophages [35, 52]. A number of studies have demonstrated the adverse impact of IO on the development infections in HSCT recipients. Tachibana et al observed an association between IO and blood stream infections (BSI) in 114 patients who underwent allo–HSCT. They found that pre–transplant serum ferritin levels significantly predicted BSI within the 100–day period after allo–HSCT [1]. A direct correlation between hepatic IO and BSI was demonstrated in a retrospective cohort of 154 allo – HSCT recipients, as patients with hepatic IO tended to experience more frequent and prolonged episodes of lethal BSI [53]. Altes et al reported a ferritin level above 1500 μg/l was associated with the occurence of bacteremia and febrile days in first 3 months after auto–HSCT [27]. A prospective study investigated the risk factors for 140 early infection episodes which occured in 367 multiple myeloma (MM) patients undergoing auto–HSCT. Bone marrow iron stores were identified as significant risk factors for early severe infections [54]. Pre–transplant serum ferritin levels were demonstrated to be associated with fungal infections after allo–HSCT in several studies [33-35, 49, 55, 56]. Tunçcan et al identified the predictive role of pre–transplant serum ferritin level in the development of hepatosplenic candidiasis among 255 HSCT recipients. Hepatosplenic candidiasis was diagnosed in 6 (2, 3%) patients. Pre–transplant serum ferritin levels were significantly higher in patients with hepatosplenic candidiasis [55]. Özyilmaz et al studied the relationship between serum ferritin level and pulmonary fungal infections in 148 allo – HSCT recipients. In this study, the sensitivity and specifity of ferritin > 1000 ng/ml for the prediction of fungal pulmonary infections were found to be 67% and 70%, respectively [56].
Idiopathic pneumonia syndrome comprises a group of disorders that result in interstitial pneumonitis and/or widespread alveolar injury with an incidence of 2–8 % and a mortality of up to 70% in the HSCT setting. There is increasing evidence implicating ROS and pro–inflammatory events as major contributing factors to IPS [5, 24]. The mechanism of iron induced IPS probably involves endothelial injury by catalytically active iron released from heme groups, which can trigger a cascade of events leading to acute lung injury and pulmonary fibrosis [24]. Currently, there are no studies regarding the direct association of IO and IPS, except the oxidative milieu, which is partly a consequence of IO.
The role of IO in the pathogenesis of GVHD has been evaluated in a number of studies. There are conflicting results regarding the relationship between IO and GVHD in HSCT recipients. In a prospective cohort of 190 allo – HSCT recipients reported by Pullarkat et al, the effect of elevated pre–transplant ferritin on acute GVHD was assessed. Grade 2 or above acute GVHD was diagnosed in 48% of patients. Acute GVHD was more frequent in patients with high ferritin levels (≥1000 ng/ml). This was attributed to the increased ROS mediated injury on exposure to the conditioning regimen in iron overloaded patients, as antigen exposition following tissue injury was indicated to be the initiating event in the pathogenesis of GVHD [38]. Similarly in a report by Platzbecker et al, which was performed in 172 patients with MDS, transfusion burden reflected by ferritin levels, was found to be correlated with a higher probability of acute GVHD [57]. On the other hand, Mahindra et al investigated 222 patients who underwent myeloablative allo–HSCT and demonstrated that pre–transplant ferritin level >1910 μg/l was associated with decreased incidence of chronic GVHD [58]. Furthermore, in a study of 264 patients who underwent allo–HSCT for various hematological malignancies, no significant difference in the cumulative incidence of acute and chronic GVHD was demonstrated in high (≥599 ng/ml) and low (<599 ng/ml) ferritin groups [59]. Alessandrino et al reported that transfusion dependency was an independent risk factor for the development of acute GVHD, but not for chronic GVHD [60]. On the other hand, IO might as well mimic GVHD resulting in unnecessary continuation or intensification of immunosuppressive therapy for GVHD [18]. Apart from hepatocellular, cardiac and other organ dysfunction, IO may worsen the natural course of liver GVHD, similar to the status with chronic hepatitis and its response to therapy [3, 18, 23, 51, 57]. It is speculated that intestinal iron absorbtion is increased as a result of epithelial injury related to chemotherapy or GVHD. Suggesting that IO might be the consequence rather than being the cause of intestinal GVHD [23]. The liver and the intestinal mucosa, which express essential iron regulatory genes including hepatic antimicrobial protein (HAMP), the gene that encodes hepcidin and ferroportin 1, are targets of conditioning related toxicity as well as GVHD, initiated by donor derived T lymphocytes. The ensuing release of cytokines including IL-6, might directly affect the expression of hepcidin as IL-6 is a potent inducer of hepcidin via STAT3 [61]. Graft versus host disease also involves the interaction of Fas ligand expressed on activated donor T lymphocytes with host tissue including enterocytes and hepatocytes. T lymphocyte induced tissue damage disrupts iron homeostasis leading to uncontrolled iron accumulation which may aggravate tissue damage related to the development of GVHD and infections [15]. The pattern of the relationship between IO and GVHD remains to be confirmed in future studies.
Several recent reports demonstrated that IO is an adverse prognostic factor for patients undergoing allo–HSCT [1, 17, 22, 36, 59, 62-66]. In a retrospective cohort of 114 AML and MDS patients, the OS rate at 5 years was found to be significantly better in patients with ferritin levels < 1000 ng/ml [1]. Tanaka et al evaluated the outcome of 47 patients with acute leukemia or MDS who underwent reduced intensity HSCT. High ferritin level which was defined as >1000 ng/ml was associated with worse 2 year OS on multivariate analysis [62]. Another study by the same group demonstrated the adverse impact of elevated ferritin levels on 5 year OS in a cohort of 143 patients with acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) who received allo–HSCT with myeloablative and non myeloablative conditioning regimens [63]. Transfusion dependency, predicted by serum ferritin levels, was found to be independently associated with reduced OS and increased NRM in a retrospective cohort of 357 MDS patients undergoing allo–HSCT [60]. The transplant iron score which included serum ferritin level above 1000 ng/ml was tested in 78 patients who received allo or auto–HSCT. The independent impact of IO on transplant survival was indicated with the most pronounced predictive power of the iron score restricted to allo–HSCT recipients. A high iron score (≥2) was associated with 50% absolute decrease in OS at 1 year [67]. Lim et al reported the adverse impact of elevated serum ferritin on OS in 99 MDS patients who underwent reduced intensity HSCT [64]. Altes et al demonstrated that serum ferritin levels ≥3000 μg/l and TS ≥100% were associated with a decreased OS and increased TRM, which was attributed to a high infectious mortality [32]. On the other hand Pullarkat et al analyzed 190 patients and demonstrated that elevated pre–transplant ferritin levels were associated with increased risk of death and day 100 mortality, mainly due to acute GVHD and infections [38]. Mahindra et al demonstrated a pre–transplant serum ferritin > 685 ng/ml was associated with lower OS and relapse free survival in 315 patients with Hodgkin and non Hodgkin lymphoma who received auto–HSCT, whereas same ferritin level exhibited a higher incidence of relapse and relapse mortality. They identified the baseline ferritin level was best correlated with poor survival. They concluded that elevated iron stores may also increase tumor growth, as tumor cells require more iron for DNA synthesis due to rapid proliferation [36]. Same group confirmed their results in a study of 222 allo–HSCT recipients with a serum ferritin level >1910 μg/l associated with lower OS, lower relapse free survival and higher NRM rates [58]. Furthermore they demonstrated inferior survival rates related to higher rates of TRM and relapse mortality in patients with elevated ferritin levels who received non myeloablative conditioning [37]. In a large retrospective study by Armand et al, an elevated pre–transplant serum ferritin level was significantly associated with lower OS and disease free survival. This association was particularly restricted to patients with acute leukemia and MDS which was particularly attributed to transfusion load. They suggested a possible role of iron chelation therapy in the pre and post – transplant setting, as they showed an absolute difference of 37% in 5–year OS for patients with MDS between the highest and lowest ferritin quartiles [66]. Sucak et al demonstrated an adverse impact of a pre–transplant serum ferritin level >500 ng/ml on OS and TRM in 250 patients who received auto and allo–HSCT, underscoring the prognostic effect of IO in auto transplants [49]. The same group confirmed their results with a more toxic form of iron, NTBI, in a retrospective cohort of 149 patients. In concordance with the previous report, a significant impact of NTBI on day 30 and day 100 survival was shown in auto–transplanted patients for the first time in iron and transplant connection [29]. Notwithstanding, in a prospective study by Armand et al, pre–transplant IO predicted by LIC which is considered to be the gold standard indicator of IO, was not found to be associated with increased mortality, relapse, SOS or GVHD [68]. Therefore, they assumed that the adverse prognostic impact of pre–transplant hyperferritinemia may be related to factors independent of IO. Taken together, it is speculated that ferritin may be prognostic not because it reflects iron stores but because it is an acute phase reactant [68, 69].
Liver remains to be the most accessible parenchymal organ that can be used to estimate tissue iron load after HSCT. Iron overload is not uncommonly seen in various other primary liver diseases such as alcoholic liver disease, chronic viral hepatitis, non alcoholic steatohepatitis, liver cirrhosis and HH. Histological evaluation of liver specimens is essential in the management of these disorders. The reported incidence of significant liver fibrosis in HSCT recipients varies from 5% to 80% and LIC has been demonstrated to have a particular role in the progression of fibrosis [26, 41, 70]. Though ferritin continues to be the mainstay for the initial clinical evaluation of IO, liver biopsy is still the gold standard for quantifying iron. Measurement of hepatic iron stores provides the most reliable estimate of body iron burden. Liver iron content exceeding 80 mcmol/g of liver dry weight was found to be consistent with IO with a hepatic index greater than 1, 9 mmol/kg/year. However, the need for a relatively large volume of tissue as well as its invasive nature has made this procedure less appealing to most clinicians and patients [4, 9, 53]. Although liver biopsy is an invasive procedure and can not be safely administered in patients with very low platelet counts, a liver biopsy can be advantageous in some HSCT recipients as it can also exclude alternative causes of hepatic dysfunction, such as infections and GVHD. In high risk patients, liver biopsy using a transjuguler approach may be a feasible alternative to percutaneous biopsy [4, 17].
Superconducting quantum interference device (SQUID) assesses total body iron by using biomagnetic susceptometry. Ferritin and hemosiderin are the only paramagnetic materials in the human body, thus the magnitude of these parameters is directly related to the amount of iron in a certain volume of tissue. The device utilizes the magnetic property of iron in ferritin and hemosiderin to estimate hepatic iron stores. Furthermore, it is considered to be the non invasive reference standard for estimation of LIC as it has an excellent correlation with liver biopsy. However, widespread clinical use is limited by its cost, complexity and very limited availability [4, 9, 17].
Liver iron content measurement has limited predictive value for extrahepatic iron deposition. The liver is the dominant iron reservoir for the body, accounting for more than 80% of the total body iron and has high capacity mechanisms for clearing both transferrin and NTBI species from the circulation. The heart and endocrine tissues have tightly regulated transferrin uptake and develop IO only when there is circulating NTBI. High liver iron (15-20 mg/g dry weight) damages liver parenchyma and increases circulating NTBI levels dramatically. As no liver iron can be considered safe from a cardiac and endocrinological perspective, extrahepatic monitoring by magnetic resonance imaging (MRI) is essential [71]. Magnetic resonance imaging becomes increasingly important in the evaluation of iron status as it is non invasive, more rapidly and widely available. Designating liver iron by older MRI techniques and equipment showed variable correlation with the biopsy estimates of LIC. More recent MRI techniques T2* and R2* MRI are reproducible methods for non invasive estimation of LIC with reported sensitivity and specifity of 89% and 80%, respectively [4, 17, 72-74]. It has the additional benefit of identifying relatively early IO within organs prior to the onset of dysfunction. Magnetic resonance imaging can be used to co-measure iron deposition within the heart, liver and pituitary gland as it does not appear that a single organ gives the full picture of total body IO. In fact, patients can accumulate cardiac iron, despite apparently normal hepatic iron levels and thus be at risk for arrhythmia or congestive heart failure. The discordance of values in two tissues can be resolved with the use of MRI to detect cardiac iron. Cardiovascular MRI could potentially be used not only to determine myocardial iron content but also cardiac function and therefore could be used to investigate the effects of iron mediated organ damage. Non invasive measurement of LIC has also been achieved using an MRI technique based on the proton transverse relaxation rates within the liver. The technique can be implemented on, most clinical 1, 5–T MRI measurements, making it readily available to the clinical community. This technique resulted in a high specifity and sensitivity over a greater range of LIC than any other MRI–based method of LIC assessment [9].
High prevalence of IO in long term survivors of HSCT emphasizes the need for routine screening for IO in this population. Ferritin is a cellular iron storage protein that buffers iron in a soluble and non toxic form. Under normal conditions ferritin levels in the serum are low but steadily increase in conditions of IO. Therefore, assessment of serum ferritin levels serves as a simple and widely used surrogate marker for IO. Serum ferritin levels are however subject to natural fluctuation and can also be greatly affected by a range of inflammatory conditions that are particularly relevant in HSCT recipients. Although being a useful test for initial screening of IO in HSCT recipients, serum ferritin is not a reliable indicator of total body iron burden particularly in patients who have ongoing acute infections or inflammatory diseases [2, 4, 17, 20, 22, 23, 38, 75, 76]. Serial serum ferritin measurements can compensate the potential fluctuations and help to establish a general picture of IO over time. Nevertheless, at 1 year after–transplantation when inflammatory stress has largely subsided, most patients have a serum ferritin of <1000 ng/ml and no clinical evidence of IO; serum ferritin in these patients decline slowly with time [23]. Unlike tissue ferritin a substantial proportion of serum ferritin is glycosylated which suggests that plasma ferritin is actively secreted from reticuloendothelial system or parencymal cells. Serum ferritin in contrast to tissue ferritin was claimed to have a low iron content even in iron loaded patients in some earlier studies. It is therefore claimed that serum ferritin does not provide a major source of hepatic iron either in normal individuals or in patients with IO diseases [4, 20, 22, 23, 75]. On the contrary a direct correlation between serum ferritin levels and transfusion burden has been observed with a level of 1000 ng/ml after a median of 21 PRBC transfusions. Thus repeated measurement of serum ferritin levels seems to be a valid method to monitor secondary IO in patients with transfusion dependent anemias and MDS [17]. Majhail et al studied the prevalence of IO in 56 allo–HSCT recipients and demonstrated the poor predictive value of ferritin for estimating LIC. The overall prevalence of IO was 32%. Clinically significant IO (LIC>7 mg/g) was uncommon in patients with serum ferritin levels less than 1000 ng/ml. However, the LIC on MRI was moderately correlated with serum ferritin. As a result, they indicated ferritin to be a good screening test but a poor predictor of tissue IO and recommended estimation of LIC before initiating chelation therapy. They considered that this lack of association between ferritin and LIC might be related to the variability in ferritin levels because of ineffective erythropoiesis or underlying inflammation or infection [20]. Whereas in a study by Bazuave et al, serum ferritin, transferrin, TS, iron, soluble transferrin receptor (sTfR) and C reactive protein levels in 230 HSCT recipients were measured. All iron parameters were found to be significantly associated with survival. A combination of ferritin and TS was shown to have the highest prognostic power. They concluded that the predictive power of ferritin was derived from its association with IO rather than inflammation. Inferior survival in patients with IO was related to both TRM and relapse. As sTfR and TS were found to have superior prognostic value when compared to ferritin, they suggested to combine serum ferritin with TS for prediction of IO [2].
Recent evidence suggests that the determination of iron status before HSCT has important prognostic implications. There is a gap between the time that patients are identified for HSCT and the time that actual transplant takes place. During this period, most patients stay transfusion dependent. After patients are exposed to conditioning regimen and stem cell infusion, serum ferritin levels are prone to a false elevation due to its role as an acute phase reactant. Thus, accurate evaluation and diagnosis of iron toxicity after HSCT remains as a challenge [53, 67] [Table 3].
\n\t\t\tDiagnostic Test\n\t\t | \n\t\t\n\t\t\tAdvantages \n\t\t | \n\t\t\n\t\t\tDisadvantages\n\t\t | \n\t
Liver Biopsy | \n\t\tReference method, can assess degree of hepatic fibrosis, can evaluate other causes of hepatic dysfunction (GVHD) | \n\t\tInvasive procedure, not feasible in patients with thrombocytopenia or coagulopathy | \n\t
SQUID | \n\t\tGood correlation with liver biopsy, noninvasive | \n\t\tVery limited availability | \n\t
MRI | \n\t\tGood correlation with liver biopsy (T2 or R2 MRI), noninvasive, widely available | \n\t\tVariety of MRI techniqueshave not been validated with liver biopsy, contraindications (metal implants, claustrophobia) | \n\t
Serum ferritin and TS | \n\t\tNoninvasive, widely available | \n\t\tSensitive but not specific for IO, poor correlation with liver biopsy | \n\t
Diagnostic Tests for Assessment of Body Iron Stores in HSCT Recipients [4]
Non transferrin bound iron is toxic to living systems because it can act as a catalyst in the formation of ROS which in turn stimulate lipid peroxidation in membranes. In iron-overloaded states when SIBC becomes fully saturated, NTBI complexes appear in the serum. In a study by Harrison et al, serum ferritin was raised in 21 of 28 patients following treatment for hematological malignancy, whereas only 16% of them had LFT abnormalities. However, NTBI was detected in 4 of 6 patients with an unexplained elevated LFTs. Therefore, they considered that NTBI might be a more specific indicator of IO than the serum ferritin concentrations [77]. Assessment of NTBI is a potentially useful approach that allows the estimation of toxic iron levels. However, the methods for determining this free fraction of body iron and its precise prognostic significance require fine tuning [17].
The current paradigm of managing post–transplant IO is based on extensive experience in children with transfusion dependent anemias [4]. Post–transplant iron depletion therapy has been shown to reverse hepatic fibrosis and cardiomyopathy in patients with thalassemia [4, 78]. However, there is no published data indicating the benefit of iron removal therapy on long term morbidity and mortality in HSCT recipients, especially for diseases other than thalassemia [4].
Decisions regarding the management of IO should be individualized and based on a review of several factors including the need for ongoing PRBC transfusion therapy, time since transplantation, ability to tolerate iron depleting therapy and urgency to reduce body iron stores [Table 4]. For instance, coexisting anemia can preclude the use of phlebotomy whereas renal impairment might increase the risk of toxicity from iron chelating drugs. Also depletion of iron stores would be more imperative in patients with IO related liver test abnormalities or cardiac dysfunction compared to those without end organ toxicites [4].
\n\t\t\tModality\n\t\t | \n\t\t\n\t\t\tAdvantages\n\t\t | \n\t\t\n\t\t\tDisadvantages\n\t\t | \n\t
Phlebotomy | \n\t\tExtensive experience with proven efficacy, no significant side effects | \n\t\tNot feasible in patients with anemia or poor venous access | \n\t
Deferoxamine | \n\t\tExtensive experience with proven efficacy | \n\t\tInconvenient administration route and schedule, side effects (ototoxicity, growth retardation) | \n\t
Deferiprone | \n\t\tOral iron chelator | \n\t\tUnproven efficacy, side effects (neutropenia, hepatic fibrosis) | \n\t
Deferasirox | \n\t\tOral iron chelator, efficacy similar to deferoxamine | \n\t\tLong term toxicity profile not established, side effects (nephrotoxicity) | \n\t
Treatment Options for Iron Overload after HSCT [4]
Iron overload may be a cause of persistent hepatic dysfunction after HSCT. Patients with LIC>15 mg/g dry weight should be treated aggresively with both phlebotomy and chelation; when LIC is 7–15 mg/g dry weight, phlebotomy is indicated; when LIC is under 7 mg/g dry weight treatment is indicated only if there is evidence of liver disease. Mobilization of iron from heavily overloaded patients improves cardiac function, normalizes serum alanine transaminase levels and results in improved liver histology [24, 79].
In patients with extreme IO, effective pre–transplant chelation therapy is suggested to improve post–transplant survival, as IO is clearly related to treatment related morbidity and mortality after HSCT [4, 24, 67, 79]. In the pre–transplant period vigorous iron chelation may be important but prospective studies are required to prove a survival benefit after HSCT. In the post–transplant period phlebotomy sometimes combined with erythropoiesis stimulating agents (ESA) may be successfully applied in thalassemia. For those patients who can not be phlebotomized iron chelation can be considered. Prospective studies of the impact of iron chelation therapy before and after HSCT on post–transplant morbidity and mortality are mandatory [4, 24].
The American Society for Blood and Marrow Transplantation (ASBMT) 2012 guidelines recommend annual serum ferritin measurement in patients who received PRBC transfusions pre or post–transplantation. Subsequent monitoring with serum ferritin should be considered among patients with elevated levels, especially in the presence of abnormal LFTs, PRBC transfusions or HCV infection. Additional diagnosting testing including liver biopsy, MRI or SQUID may be indicated if therapy is intended for presumptive IO. Current prescribing guidelines recommend continuation of iron reduction till ferritin levels are below 500 ng/ml [3, 9, 51, 60, 72].
Phlebotomy is a feasible option for the treatment of IO following HSCT. Many studies have documented its efficacy in early and late post–transplant setting. It has been shown that subclinical left ventricular diastolic dysfunction and impaired left ventricular contractility in patients with thalassemia may be reversed by phlebotomy initiated after HSCT [51]. Iron overload should be treated by means of phlebotomy and/or chelation therapy especially when IO coexists with chronic viral hepatitis. Phlebotomy has the advantage over chelation of better compliance, fewer side effects and lower costs. The use of ESA may facilitate the success of this strategy in patients with low hemoglobin levels [4, 19, 22, 26, 70].
After normalization of transaminases and serum ferritin with aggressive phlebotomy, maintenance phlebotomy is required every 3-6 months to prevent iron reaccumulation and keep serum ferritin in a low normal range. The gradual rise in ferritin after successful iron depletion suggests that there is a signal for increased iron absorbtion and the signal persists well beyond the peri–transplant period. It may be that post–transplant immunosuppressants reduce the level of cytokines that normally stimulate hepcidin production and allow increased absorbtion of dietary iron. In addition hepatic GVHD may result in disordered hepcidin regulation, as it likely does in chronic viral hepatitis and might explain increased risk of IO and the need for maintenance phlebotomy after successful iron depletion [23].
Treatment with phlebotomy is not possible in patients who are transfusion dependent. Chelation may be preferred for iron depletion [9]. There are limited data on the pharmacological chelation of iron during the post–transplant period including the safety, optimal dose, time for initiation of treatment and duration of therapy [51, 80, 81].
Deferoxamine, the first available iron chelator, has a proven efficacy and safety with decades of experience and has also been studied in HSCT recipients. Recommended treatment schedule is at least 5 nights per week subcutaneous delivered via a pump for 8-12 hours [4, 9]. It is effective in lowering serum ferritin levels and LIC and prevents endocrinological complications. Long term treatment is also associated with a reduction in cardiac complications and improved survival. Redness and induration at the infusion site are the most common side effects. Audiological, ophthalmological, growth and bone toxicities may be minimized by avoiding overchelation. Deferoxamine treatment in the HSCT setting is complicated by the short half life and the ability to release iron to bacteria and fungi. Deferoxamine supports the growth of zygomycetes because it acts as xenosidephore delivering iron to iron uptaking molecules of the species [22, 51, 81]. The greatest challenge with DFO is patient adherence with therapy because the need for parenteral administration is cumbersome, uncomfortable, inconvenient and time consuming [51]. Cardiac morbidity and mortality continue to occur in patients treated with DFO, likely related to difficulties with adherence [4, 9, 22, 51, 81].
Deferiprone is an oral iron chelator which was first identified in 1980s and subsequently approved for clinical use in Canada and Europe especially when DFO is contraindicated. Deferiprone is not commercially available in all countries and has not been investigated in HSCT recipients. It has a short half life of only 1, 5 hours and thus requires 3 times daily dosing. Unfortunately, it does not control liver iron as effective as DFO even after years of continued treatment. In contrast, a recent study in patients with thalassemia showed better myocardial function in those receiving Deferiprone. Retrospective studies have also demonstrated reduced cardiac morbidity and mortality and lower myocardial iron deposition among patients treated with Deferiprone compared with DFO and Deferasirox (DFX). A reduction or stabilization of serum ferritin levels and LIC in most patients with transfusional IO was demonstrated. The high risk of agranulocytosis necessitates weekly blood monitoring. Thus, toxicity profile of the drug may be inappropriate for transplant recipients [4, 9, 81].
A novel oral iron chelator, DFX was approved by the US Food and Drug Administration in 2005 and represents a significant advancement in the treatment of IO. It is a tridentate oral iron chelator which is lipid soluble but highly protein bound. It has a plasma half life about 12 hours and thus is ideal for once daily dosing. It binds iron in a 2/1 ratio. It is excreted by the hepatobiliary system and the chelated iron is excreted via the feces. The effective dose is between 20-40 mg/kg. It is generally well tolerated by patients although some dose modifications may be necessary for diarrhea. Phase III trials demonstrated that DFX at 20-30 mg/kg/day led to the maintenance or reduction of iron burden as measured by LIC in chronically transfused patients. Reductions in LIC and serum ferritin are similar to those found in the subcutaneous use of DFO. Commonly reported side effects include skin rash, nausea, vomiting and diarrhea and elevations in serum creatinine levels, which may be important in patients treated with calcineurin inhibitors. Gastrointestinal disturbances often improve with continued administration of the drug. Elevations in serum creatinine occur in approximately 1/3 of subjects. Side effects associated with DFX therapy may overlap or exacerbate early complications such as calcineurin induced renal injury seen after allo–HSCT, which Mkes it complicated to use early after HSCT. The availability of an oral iron chelator has simplified the treatment of IO, but more experience with its use in HSCT recipients is needed [4, 9, 22, 80, 81].
The role of IO in HSCT recipients and guidelines for screening strategies warrants further studies. The value of routine screening for IO, the method of determining it, whether it should be with serum ferritin, by determining LIC with non invasive MRI or biopsy and identifying a subgroup of patients who might benefit from phlebotomy and/or iron chelating agents requires future prospective studies. The possibility of IO should be considered in patients who are candidates for HSCT. Red blood cell transfusion should be limited whenever possible and chelation and/or phlebothomy should be considered in the course of documented IO. pre–transplant preventive measures should also be adopted to avoid IO and improve survival in these patients.
The Israeli-Palestinian is a classic case of intractable conflict where ordinary citizens are at the middle of the struggle. It is a lengthy fight where generation after generation is born into the reality of violence, despair, and suffering. The conflict seems to operate as a destructive evolutionary system that has a life of its own. Almost any substantial attempt to generate the conditions for a positive change in the Israeli-Palestinian case, so far, has failed and complicated the situation beyond imagination. The main argument of this essay is that a revolutionary peace process is required in order to break the evolutionary progression of violence and despair.
A revolutionary change-building program requires applying peacemaking, peacebuilding, and peacekeeping measures simultaneously.1 However, peacemaking, peacebuilding, and peacekeeping are controversial concepts that should have different interpretations in different situations. For example, following the Second World War, the UN was established as a major peacekeeping institution. The aim was to create an institution that would be able to manage, stop, and prevent clashes between armies.2 The Israeli-Palestinian case—an intractable conflict where ordinary civilians are at the center of the confrontation—is a different type of conflict. It requires the establishment of different mechanisms to build, keep, and maintain order and stability.
The struggle to build a peaceful social order has to cope with different types of conflicts and crises. The three elements of a peace revolution—peacemaking, peacebuilding, and peacekeeping—should be formulated according to the logic of the situation.3 This paper suggests a multidimensional process, which might be appropriate for crises similar to the Israeli-Palestinian case. Peacemaking is a consensus-building process that involves different societal elements (leaders, political elites, and ordinary citizens) in efforts to conclude a negotiated peace deal.4 Peacebuilding means constructing international, bilateral, and domestic frameworks for a peaceful social order that copes with the needs and concerns of the conflicting parties.5 Peacekeeping suggests creating political, civilian, and militaristic means to maintain order and stability (Table 1).6
Category | Meaning | Means |
---|---|---|
Peacemaking | Consensus building | Diplomacy in three dimensions: political-elite diplomacy, public diplomacy, and people-to-people diplomacy |
Peacebuilding | Building a framework for a peaceful social order | International support, peaceful relationship-building between the parties and domestic reforms within each one of them |
Peacekeeping | Building mechanisms to keep law, order, and stability | Political, civilian, and militaristic mechanisms to cope with tensions, disputes, and crises |
Peace revolution as a three-dimensional process.
The structure of the paper follows the logic of the central argument—peace needs to be made, built, and kept. It is divided into sections: peacemaking, peacebuilding, and peacekeeping. Each section focuses on different aspects of the challenge of change in the Israeli-Palestinian situation. However, each of the sections concretizes that the distinction between peacemaking, peacebuilding, and peacekeeping is more of a theoretical outline that helps us to understand the complexity of the situation, shed light on the challenge of peace, and assist in developing new creative ideas.7
The paper combines theoretical research, comparative case studies, and experimental practice. It grows out of the literature on peacemaking, peacebuilding, and peacekeeping. It draws lessons from peace processes in different situations of intractable conflict, such as the struggle for change in Northern Ireland during the “troubles” and the struggle to dismantle the Apartheid system in South Africa. It offers practical insights from the Minds of Peace Experiment (MOPE)—a short-term Israeli-Palestinian public negotiating assembly—which has been taking place in different forms, variations, and places. This multifaceted methodology intends to tackle the study of peace revolution from different points of view.
There is an agreement among peace researchers that peacemaking means negotiating a peace contract that can put an end to a conflict. This paper suggests a revolutionary peacemaking approach that attacks the challenge of reaching a negotiated contract from different angles and viewpoints. It offers a look at a peacemaking revolution as a consensus-building process, which involves key elements of the conflicting parties—leaders, elites, and people—in a multidimensional negotiating process. It is a more conclusive strategy than the dominant peacemaking experience in the Middle East, which, often enough, involves only leaders and elites.8
A revolutionary peacemaking approach, according to this paper, is a consensus-building process that operates on three levels: political elite, “ordinary” people, and the interactions between the two. It suggests a three-level structure of peacemaking diplomacy: political-elite diplomacy, public diplomacy, and people-to-people diplomacy (Table 2).
Level of operation | Mechanisms | Description |
---|---|---|
Top | Political-elite diplomacy | Peacemaking engagement between political elites |
Middle | Public diplomacy | Interactions between political elites and ordinary people |
Bottom | People-to-people diplomacy | Peacemaking engagement between ordinary people |
Peacemaking diplomacy in three dimensions.
Political-elite diplomacyoffers various channels of communication between official and unofficial elites of the opposing sides, who are interested in reaching a peaceful settlement to the conflict. In general, political-elite diplomacy comprises three main channels of interaction: track II diplomacy (unofficial dialog between elites who do not have official positions in the government), secret diplomacy (secret negotiations between officials), and track I diplomacy (formal negotiations between officials).9
Classical examples, such as the Oslo Accords of the 1990s, demonstrate that political-elite diplomacy offers efficient operative channels for helping leaders and elites reach innovative agreements in stalemate situations. Its main disadvantage is that it does not offer effective methods to involve the publics in the peacemaking efforts, prepare the people for a change, and help them deal with ongoing crises along the peace road. As a result, political-elite diplomacy is vulnerable to violent acts of spoilers, radicals, and extremists, who are determined to use aggressive means to crush any effort to reach a negotiated peace contract. Indeed, violent events made a major contribution to the collapse of the Oslo Accords of the 1990s. The cumulative effect of the ongoing violence has led to a loss of public belief in the possibility of creating a constructive change. The decrease of public support of the peacemaking gives the momentum to the opposition of the peace process, who makes sure that the conflict will continue.10
People-to-people diplomacy offers various modes of interaction linking the opposing sides at the grassroots level, such as different dialog groups, multinational workshops, educational projects, scientific collaborations, and partnership in peacemaking grassroots organizations. More focused on peace dialog than other collaborative projects, classical examples such as The Parents Circle-Families Forum11 and Seeds of Peace12 indicate that people-to-people diplomacy can be effective in building peace coalitions, showing that there are peace supporters on both sides,13 and preparing ordinary citizens for change. The main disadvantage of people-to-people diplomacy is that it, often enough, is disconnected from the leadership level. It hardly involves political leaders in the grassroots peacemaking channels and can barely motivate and influence them to reach innovative negotiating agreements. The result is that people-to-people diplomacy, which usually does not operate on a mass scale, faces many difficulties in transferring the spirit of change to the operational political level.14
Public diplomacy, in our multidimensional configuration, is designed to close the gaps of the two previous diplomatic modes (political-elite and people-to-people) by using different methods of marketing, public relations, and social protest. It operates in two opposite directions. In one direction, public diplomacy provides instruments for leaders to prepare the public for a substantial peacemaking process, get their feedback on new ideas, receive their input on the limits of possible compromises, and generate public support in negotiating groundbreaking agreements (top-down). In the other direction, public diplomacy offers tools for people to motivate political leaders to initiate a peacemaking process (bottom-up).15
This paper suggests creating a (peacemaking) public diplomacy institution—an Israeli-Palestinian Public Negotiating Congress. A public negotiating congress (PNC) is a democratic peacemaking institution that invites representatives of the conflicting people to negotiate different solutions to their conflict. All congress participants, who reflect the political spectrum in the conflicting societies, would have to commit to principles of non-violent discourse.16
The congress is built to involve the conflicting publics in the peacemaking efforts, prepare the people for change, and motivate the leaderships to reach agreements. The idea to establish an Israeli-Palestinian Public Negotiating Congress is inspired by the multiparty negotiations that enabled a revolutionary change in the struggle against Apartheid in South Africa and in Northern Ireland during the “troubles.”17
In South Africa and Northern Ireland, leaders came to the conclusion that they need a public diplomacy device to involve the public in the peace process. These leaders used diplomatic interactions to create the multiparty congresses. In the Israeli-Palestinian situation, so far, leaders do not even consider creating a similar public diplomacy device. They mainly focus on political-elite diplomacy in the effort to stabilize the situation. As an alternative choice, it is worth examining the possibility that an Israeli-Palestinian Public Negotiating Congress—which can be regarded as an Israeli-Palestinian version of the multiparty negotiations in South Africa and Northern Ireland—will emerge from people-to-people interactions. One people-to-people project that is designed to reach this goal is the Minds of Peace Experiment.
The Minds of Peace Experiment (MOPE) is a short-term Israeli-Palestinian public negotiating assembly. The MOPE invites teams of Israelis and Palestinians to negotiate a peace deal, generally over a 2-day period of five sessions. The assembly is co-moderated by Israelis and Palestinians, who lead the interaction in a framework of general rules. The dialog is open to the public and invites its participation.
The Minds of Peace Experiment was conducted in various sizes and formats and in different locations. It has been demonstrated as a powerful instrument for people-to-people diplomacy. The various rounds of the MOPE indicate that the initiative is effective in involving ordinary people in the struggle for peace, preparing them for painful compromises, and creating peacemaking coalitions. However, without extensive use of public diplomacy, the influence of the MOPE is doomed to remain marginal. There is a necessity to create domestic and international pressure to institutionalize the initiative. The MOPE needs to grow, develop, and transform into a major revolutionary institution—an Israeli-Palestinian Public Negotiating Congress with substantial political influence.18
This paper suggests looking at a peacemaking revolution as a consensus-building development that involves the different societal elements—leaders, elite, and people—in the struggle for peace and stability. To reach this goal, it is necessary to create a balance between political-elite diplomacy and public diplomacy. Political-elite diplomacy provides diplomatic channels for leaders to reach agreements. Public diplomacy intends to involve the public in the peacemaking efforts, prepare the people for a change, and motivate the leaderships to accomplish a settlement. A major public negotiating congress is a public diplomacy instrument that has the potential to create the equilibrium.19 On the one hand, it can serve as a political tool for leaders to create public support in a negotiating process that can produce a peace contract (top-down). On the other hand, it can serve as political instrument for people to influence leaders and demand that they initiate an effective peacemaking policy (bottom-up).20 Moreover, a public negotiating congress can be discovered as a revolutionary device that could invite new political groups and leaders to the political arena.21
The multiparty negotiations in Northern Ireland and South Africa taught us that an Israeli-Palestinian Public Negotiating Congress can be an effective peacemaking institution that could open new political opportunities and push the train of change in unimagined directions. In both cases, political leaders established the multiparty talks in order to generate public support in the peacemaking. In the Israeli-Palestinian case, political-elite diplomacy is the main peacemaking setting. There are no signs of leadership interest and motivation to establish a public diplomacy device for involving the publics in the change-making efforts. As a desperate choice, this paper suggests considering the option of a public negotiating congress growing from people-to-people interactions.
The Minds of Peace Experiment is a grassroots initiative that intends to demonstrate the peacemaking potential of a major public negotiating congress, to help evaluate its possible outcomes, and to generate support for its creation. However, I did not find any example where a major public negotiating congress emerged of people-to-people activities.22 Perhaps, the Minds of Peace initiative is doomed to fail like almost all other peacemaking initiatives so far. Nevertheless, it is impossible to predict the future.23
Peacebuilding, in this paper, means building the conditions for a peaceful social order that can cope with the fears, needs, and concerns of the opposing factions. It is a multidimensional configuration, which needs to cope with challenges in three main dimensions: international, generating international support for a peaceful social order and marginalizing the impact of international spoilers; interparty, building peaceful relationships between the conflicting parties; and intraparty, domestic reforms within the opposing parties in order to cope with internal obstacles for peace and stability (Table 3).
Level of operation | Goal | Means |
---|---|---|
International | Generating international support for peace and stability | Diplomacy |
Interparty | Building peaceful relationships between adversaries | Sociopolitical initiatives, such as economic collaboration, education for peace, and reconciliation projects |
Intraparty | Building the foundations for order and stability in the opposing parties | Domestic reforms within the opposing parties |
Peacebuilding as a three-dimensional configuration.
International. In this paper, we suggest looking at the Israeli-Palestinian struggle as a communal conflict. It is a struggle between two communities—Israeli and Palestinian—who were destined to live side by side. We believe that this approach has the best chances to cope with the conflict constructively and help the conflicting parties to reach a negotiated resolution. Any attempt at “globalizing” the conflict—for example, analyzing it in Huntington’s terms of clash of civilizations—marginalizes the ability to resolve the conflict or, even, to transform it.24 However, there are certain problems that Israelis and Palestinians cannot solve by themselves. They need international assistance in coping with essential problems standing in the way of peace and stability.
Coping with the problem of the Palestinian refugees, which will, probably, need to relocate in different locations,25 and the urgent need to marginalize the impact of an international spoiler, such as Iran, are two examples of major problems for which Israelis and Palestinians will need international assistance and intervention. This means that any realistic peace initiative needs to establish working relationships with the international community in order to guarantee its commitment and support.
Diplomacy, as a key instrument of foreign affairs, is the tool to reach international support. Naturally, there are major disagreements between Israelis and Palestinians upon the very essence of the desired international intervention in the peace process. For example, who are the international players that should take part in the peace process? What will be their role? Where is the line between legitimate and illegitimate intervention?26
According to the methodology suggested in this paper, Israelis and Palestinians need to reach a peace agreement in bilateral negotiations (peacemaking), while the international community should support it, marginalize the influence of spoilers, and assist in implementing the agreements. The boundaries of international intervention should be negotiated and determined early in the peacemaking stage.
Interparty. There is a broad consensus that the only feasible settlement to the Israeli-Palestinian conflict is a “two-state solution”—the establishment of a Palestinian state beside Israel. Nevertheless, it seems impossible to completely separate between the two national units. Interaction between Israelis and Palestinians is inevitable. For example, there is no continuity of land between the West Bank and Gaza. It looks that the holy places in Jerusalem require a special arrangement in a framework of two-state solution. Arab residents of Israel are relatives of Palestinians in the West Bank and Gaza.27
Israelis and Palestinians will need to create mechanisms for building peaceful relationships, which are critical for maintaining peace, order, and stability. The challenge necessitates multidimensional peacebuilding measures, including joint economic projects, education for peace and tolerance, and reconciliation. Let me demonstrate the challenge by focusing on certain aspects of these three dimensions:
Economic cooperation: Ordinary Palestinians and Israelis are struggling in their daily life. Palestinians are struggling to make a decent living and support their families in a difficult situation of developing their society, while Israelis are struggling under the burden of the high cost of living in Israel. Economic cooperation can benefit the two sides. For example, Israelis are interested in buying quality low-price goods, which Palestinians know how to manufacture and sell.
Creating Israeli-Palestinian free-trade zones can benefit the two sides.28 Israelis, who are interested in buying quality goods at reasonable prices, can create a market for Palestinians who can manufacture quality goods at a low cost. The economic interests of the two sides can be a vehicle for peaceful relation building. For example, it can demonstrate to the people the interdependence of the two societies; it can assist in developing friendly relationships between adversaries (or more precisely former adversaries); and it has the potential of reducing hostility and the impact of prejudice on the attitude of people of the opposing sides toward each other.
Education: Hostile relationships between neighbors, which are destined to live side by side, are a proven recipe for clash. To live in a peaceful social order, the two sides—Israelis and Palestinians—will need to overcome classical symptoms of intractable conflict, such as chronic mistrust, prejudice, and dehumanization of the other. Education, in general, and peace education, in particular, can play an important role in coping with the challenge.
Education has a critical influence on worldview and the sociopolitical attitude of human beings, especially of the young generation. Israelis and Palestinians will need to do major reforms in their educational curriculum—such as stopping the incitement, teaching the very essence of tolerance and pluralism, and even teaching the other’s culture and traditions. However, changing educational programs is not easy. The old system has its own dynamic evolution and protective mechanisms.
Observations show that in transition periods, between war and peace, educational systems, often enough, are transformed or more precisely revolutionized, by force. For example, after the Second World War, the Allied Forces forced major domestic reforms in the educational systems of Japan and Germany. They insisted that the new educational system be based on liberal values.29 These paradoxical cases, where peace and liberal education were forced by coercive means, have a general lesson. They demonstrate that building the conditions for peace and stability, by establishing a new framework of rules and institutions, cannot be free from elements of force, power, and manipulation.30 Good intentions are not enough.
Reconciliation: In the middle of the twentieth century, after the Second World War, it was almost impossible to imagine peace and reconciliation in Europe. About 50 years later, former entrenched enemies, such as Germany and France, established a confederation, the European Union. Today, it is almost impossible to imagine a violent conflict between members of the EU. It looks that there is a reconciliation in Europe. Is reconciliation possible in the Middle East? Is reconciliation possible between two national communities, Israelis and Palestinians, whose ethnic, religious, and cultural identities seem to be so different? Is reconciliation possible after about 120 years of intractable conflict that seems to have a life, dynamic, and evolution of its own?
Analyzing the situation in the light of Huntington’s theory—the clash of civilization—leads to pessimism.31 In this framework, the Israeli-Palestinian conflict is a point of clash between different cultural units (civilizations). Therefore, it is impossible to solve the conflict and reconcile between the parties. The old city of Jerusalem, which is extremely important to believers of different religions, demonstrates the problem.
In contrast to Huntington’s theory, this paper suggests analyzing the situation from a different perspective. Huntington’s theory globalizes the problem and calls it a symptom of “clash of civilizations,” while our approach examines the conflict as a communal struggle—a conflict between two national communities. Our approach holds better chances of coping with a difficult situation. Huntington’s theory offers despair in advance. Israelis and Palestinians cannot afford to be engaged in a cold peace. For peace and stability, it is mandatory to develop tools for reconciliation.
From a practical perspective, there are good reasons for optimism in this direction. Palestinians, who believe that the Arab states have part of the blame in their situation, see the deteriorating situation of the Arab world in contrast to the prosperity of the West and Israel. It is reasonable to assume that they have a desire (or, at least, a secret desire) to be part of the success. Israelis have aspired, for a long time, to become part of the new Middle East and stop being a fortified isolated castle. Peace and reconciliation between Israelis and Palestinians may open a gate to fulfill these aspirations.
There are grassroots initiatives that focus on reconciliation between the two parties.33 These successful programs operate on a very minor scale. They need to expand, integrate into educational systems, and operate on a mass-scale level.
Intraparty. The focus on the internal situation within the opposing parties adds another important dimension to the struggle for building a momentum for a peace revolution. It suggests domestic reforms within the opposing societies, within the Israeli and the Palestinian societies, in order to create opportunities to resolve the struggle and to form a framework for a long-lasting stable peace. The idea of suggesting domestic reforms within each party draws on insights of constitutional economists, like James Buchanan [33], and political scientists, like Samuel Huntington [26]. These thinkers emphasized that an adequate framework of rules and institutions is a necessary condition for the evolutionary transition from social chaos to a peaceful social order.
In our context, domestic reforms that improve the internal cohesion of each society, the rule of law, and the accountability of political leaders may help the opposing populations to discover the value of peace, to start believing that it can be achieved, and to explore possibilities for reaching it. These necessary measures could potentially create an effective framework for a substantial peace process and reduce the impact of radicals, extremists, and spoilers. The “paradox of violence” can demonstrate the importance of reforming major elements within each of the opposing societies.34
A classical characteristic of intractable conflict is the paradox of violence—almost any progression toward a positive change is likely to cause a growth in the level of violence. It is possible to identify two main reasons for this observation. The first is spoilers—radical elements increase efforts to sabotage almost any kind of peace process by violent means. The second is internal tensions—any progress toward peace between opposing societies tends to increase tensions within each one of them. This symptom characterizes developing societies that lack sufficient instruments to cope with domestic tensions and disagreements by peaceful means. Let me elaborate on the second reason, which is more related to the focus of this section (domestic reforms in the conflicting societies).
A society is built of various elements, such as individuals, ethnic groups, economic corporations, religious congregations, and political associations. These different social elements do not necessarily hold similar priorities, preferences, and sociopolitical agenda. Intractable conflict is a unifying force. Opponents may collaborate in order to fight a joint enemy. However, as soon as there is progress toward peace, tensions within each of the conflicting parties appear and become a dominant factor. For example, the struggle against the Apartheid system in South Africa had unified the nonwhite people. This “unification” made the impression that the struggle is between the “black” population and the “white” one. However, the progress toward a new governmental system exposed the diversity within the “black” people and led to violent clashes within the nonwhite camp.35
Israeli academics have emphasized that the Palestinian authority is a developing entity.36 It lacks instruments to cope with social crises that can follow transition from one sociopolitical order to another. The unilateral withdrawal of the Israeli forces from the Gaza Strip, led by the former Israeli Prime Minister Ariel Sharon in 2005, demonstrates the difficulties and the obstacles.
Sharon’s plan to withdraw Israeli troops, and about 8000 Jewish settlers, from Gaza and 4 small areas in the West Bank had a dramatic effect on the situation. Following the unilateral withdrawal, Israel—a modern country with established democratic institutions—survived the shock, but the Palestinian authority collapsed. The events that followed were a coup by Hamas in Gaza and a bloody civil war within the Palestinian society. Since then the Palestinian society is politically divided. The radical Islamic movement, Hamas, which is committed to radical Islamism, controls Gaza, while the secular nationalist movement Fatah, whose official agenda is building an independent Palestinian civil society based on the 1967 cease-fire line (two-state solution), administers the major parts of the West Bank.
Israeli scholars point out that the tragic situation in the Gaza case enfolds a general lesson—any intention to divide the land endangers the security of Israel. The Palestinian authority in the West Bank is a developing entity that lacks instruments to cope with social crises that can follow a transition from one sociopolitical order to another. There is a grave danger that any Israeli withdrawal from the West bank will lead to a repeat of the Gaza scenario—collapse of the Palestinian authority, radical elements, such as Hamas and the Islamic State of Iraq and Syria (ISIS), taking control and launching missiles at the center of Israel.37
In any framework of partition of the land between the two peoples, domestic reforms in the Palestinian society are a precondition to a successful peace process. For the sake of peace and stability, it is necessary for the Palestinians to establish the foundations of a modern independent state: building public institutions; creating a stable, efficient, and transparent administration; disarming violent groups; and developing all other mechanisms of a decent civil society.
The difficult task of creating the conditions for peace and stability requires preparing the opposing societies, Palestinians and Israelis, for coexistence in any possible framework. This means that domestic reforms in the Palestinian society are not enough to create a long-lasting change. There is a need for domestic reforms within the state of Israel, especially, in regard to the sensitive issue of “national identity” and its practical implications.
Israel is a multicultural society. The Israeli population includes a majority of Jewish citizens who came from different parts of the world and a large minority of non-Jewish citizens (about 20% Arabs). Nevertheless, Israel is considered a Jewish state. It is true that a major part of Arab-Israelis’ integration in the Israeli society is expressed through participation of the Arab population in the democratic processes of Israel.38 Nevertheless, the fact that a non-Jewish population belongs to a Jewish state holds many elements of exclusion. The politics of exclusion is expressed in many dimensions of Israeli social life. For example, in the psychological dimension, many Arab-Israelis see themselves as second-class citizens, and in the symbolic sphere, the national symbols of the country are taken from Jewish tradition.
According to pluralist perception, having a national home is a basic need. Human beings need a place that will accept them simply because they belong.39 The non-Jewish citizens of Israel have a problem seeing the Jewish state as their national home. As Professor Joseph Agassi [38] noted, this problem has direct and indirect implications on the Israeli-Palestinian conflict.
According to Agassi, establishing a stable decent Palestinian state will necessarily lead to tensions within Israel. The reason is that Arab-Israelis, who live in different parts of the country and have difficulties seeing the Jewish state as their national home, can see the new Palestinian state as their natural national homeland. The inevitable result, according to Agassi, is that they will aspire to live (on their land in Israel) under a Palestinian rule. Jewish Israelis are likely to object and reject such a drastic political motivation. The different motivations can lead to a dangerous clash.
Due to the situation of the Arab world, in general, and the Palestinian society in particular, the establishment of a decent and stable Palestinian state looks like a dream at this stage. However, Agassi’s analysis enfolds a lesson—Israelis will have to think seriously about how to better integrate ethnic minorities in Israel. The existence of Arab citizens of Israel has many important effects upon the conduct of the country in general and its relations with Palestinians in the territories in particular.40 Improved relationships between the Arab minority and the Jewish majority in Israel might pave the way for better relations with a future Palestinian polity and create direct and indirect opportunities for peacemaking. It can help the Jewish population in Israel to overcome the obsessive fear of losing the Jewish character of the state. The implications can be substantial and dramatic. For example, the people in Israel might overcome prejudice against Arabs, be more receptive to examine seriously creative solutions to the conflict, and even consider including Arab representatives in Israeli delegations for future negotiations.
Transition from one social order to another is difficult for almost any society. A transitional period for developing entities, which have hardly developed political and social mechanisms to cope with new challenges, can end in disaster. Huntington [26] pointed out that the lack of an effective framework of rules and institutions in changing societies can be used and abused by a new sociopolitical force to take control. The new political player who comes to power is not necessarily able to, interested to, or knowledgeable about how to establish a new sociopolitical order that can benefit the members of society.
The collapse of Gaza to the hand of the radical movement Hamas demonstrates the danger of drastic unilateral moves in the West Bank situation. Moreover, it shows that the three elements of peacebuilding (international support, relationship building, and domestic reforms) are intertwined. For example, it is quite clear that Palestinian domestic difficulties are not the only internal Palestinian problems. They are also an Israeli problem and a regional problem. It is in the best interests of Israelis, Egyptians, and Jordanians to help the Palestinians establish a viable stable polity that could fight the expansion of religious fanaticism.
The analysis of the peacebuilding challenge in the Israeli-Palestinian situation also demonstrates that peace revolution is a composite of peacemaking, peacebuilding, and peacekeeping. These elements are intertwined and need to be applied simultaneously. Peacebuilding measures (international support, relationship building, and domestic reforms) can help in providing a safety net for stability during a peacemaking process. It helps to guarantee that if the negotiation fails, the outcomes will not be disastrous as they have been in the past.
After the Second World War, peacekeeping was understood as division between entrenched enemies.41 The guiding principle was “Good fences create good neighbors.” The end of the Cold War and the growing numbers of intrastate struggles have led to alteration in this view of peacekeeping. The concept of peacekeeping was extended to cases where it is impossible to hermetically separate enemies.42
The unavoidable contact between Israelis and Palestinians shows that it is mandatory to design and implement a nontraditional peacekeeping strategy. A nontraditional strategy involves different societal elements—such as citizens, political leaders, and special security forces—in the efforts to maintain peace, order, and stability.
The challenge of peacekeeping is multidimensional. To simplify and demonstrate the need to design a multidimensional strategy to keep peace and stability, the paper suggests focusing on three levels of peacekeeping: political, military, and civilian: An Israeli-Palestinian Congress for Peace and Security can be a political institution for monitoring joint activities and coping with tensions, disputes, and ad hoc sociopolitical problems between the two sides. A joint border security force can be established to protect the east border of a new Palestinian state in the West Bank (the border between the new Palestine and Jordan in a framework of two-state solution). A joint civil guard can be established to help in keeping order and stability in places where Israeli and Palestinian civilians are in direct contact (Table 4).
Level of operation | Goals | Mechanisms |
---|---|---|
Political | Coping with sociopolitical problems, coordinating joint activities, and monitoring shared mechanisms | Israeli-Palestinian Congress for Peace and Security |
Military | Protecting the border between a new Palestinian state and Jordan | A joint border guard |
Civilian and police | Coping with civilian problems and keeping law and order in friction points | Security cooperation and a joint civil guard |
Peacekeeping in three dimensions.
Let me elaborate.
Politics. Peace revolution is a dynamic process, which has an evolutionary dynamic. Political instruments that were created to lead a change in the peacemaking phase need to be modified and changed in the peacekeeping stage. This evolutionary progression needs to be considered at the beginning of the process.
The peacemaking section of this paper proposes establishing a powerful instrument for the peacemaking part of a peace revolution—a major Israeli-Palestinian Public Negotiating Congress. The congress is a consensus-building institution that is planned to involve different societal elements of the conflicting societies (leaders, elites, and people) in the peace efforts. Its main tasks are to offer political alternatives to the violent struggle, prepare the publics for a change, and motivate the leaderships to reach agreements. However, once a peace agreement has been achieved, this peacemaking institution needs to be transformed, or it will become useless. The logic of the evolutionary progression of a peacemaking revolution proposes that a pubic negotiating congress—a major peacemaking institution—should be transformed into a major peacekeeping institution, which could be labeled as congress for peace and security.44
The inevitable friction between Israelis and Palestinians will require political instruments to cope with inevitable tensions, disagreements, and joint problems. In the post-conflict phase, a joint peacekeeping congress could deal with tensions, disputes, and ad hoc problems, initiate and coordinate joint projects in various fields (such as education, economics, and politics), and establish mechanisms for reconciliation.
Similar to the UN, which is the global peacekeeping institution, the main actual power of the peacekeeping congress (Israeli-Palestinian Congress for Peace and Security) is its very existence. In the peacemaking stage, a public negotiating congress involves the publics in the struggle for peace and generates public pressure to reach a settlement. In the post-conflict phase, the peacekeeping congress should remind everyone of the high cost of conflict and the precious value of peace.
A difficult question is how to start and build this institutional evolution (from peacemaking congress to a peacekeeping congress), which is so necessary for a peace revolution. Unfortunately, this critical discussion is not in scope of this paper.45
Military. In a framework of a “two-state solution,” Israel demands that the new Palestinian state will be demilitarized. However, it is a joint interest of Israelis and Palestinians that the eastern border—the border between the new state of Palestine and Jordan—be protected from invasion of hostile forces (such as ISIS). Who will protect the border between Palestine and Jordan after Israel pulls back its military forces from the area?
In different rounds of the Minds of Peace Experiment (MOPE)—a small-scale Israeli-Palestinian public negotiating assembly, which was conducted in different locations with different delegations of Israelis and Palestinians—the delegations agreed on the creation of a joint Israeli-Palestinian security force that will operate in a security zone near the border.46 This idea has different versions with different implications. For example, in some of the assemblies, the delegations agreed that the joint security force would become part of the IDF. In other assemblies, Palestinians were concerned that soldiers, with IDF uniforms, in Palestinian areas would remind the people of the occupation and the consequences could be harmful. To prevent such complications, the delegations in these assemblies agreed that the border guard unit would have their own special uniforms. In addition, it is worth considering that the border guard unit will be linked to Israel, Palestine, and the Israeli-Palestinian Congress for Peace and Security (which was, previously, proposed as a political peacekeeping institution). Of course, the details need to be discussed and negotiated by the two sides.
Another option which was raised by some scholars is that, eventually, the Palestinians will need to be in charge of protecting their border. They propose a two-stage process. In the first stage, an international force will protect the border and train a Palestinian border guard unit. In the second stage, the international force will leave, and the Palestinian force will take responsibility.47
It seems that the first proposal has better chances of being accepted by Israelis and Palestinians. It is hard to imagine Israelis and Palestinians agreeing that an international force, and later a new Palestinian security unit, will be in charge of their security. A joint Israeli-Palestinian border guard unit, as in the first proposal, can indirectly serve also as a peacebuilding instrument. Its cooperative feature can help to explore possibilities of improving the relations between Israelis and Palestinians.
Civilian and police. The security challenges in the making of a new social order are multidimensional. The interdependence between Israelis and Palestinians, which makes the security problem so difficult to handle, nevertheless holds peacebuilding opportunities. Let me demonstrate by focusing on the three main problems: order and stability within Palestinian territories, settlements, and holy places.
Order and stability within Palestine: As already mentioned, the Palestinian society is suffering from symptoms of a developing entity. Israelis, who object to the “two-state solution,” claim that any attempt to implement this type of solution is doomed to fail and would endanger the security of Israel.48 The fear is that a new Palestinian state in the West Bank will collapse into civil war similar to the Gaza crisis in 2008. Since civil wars usually end in the victory of one party and not power sharing,49 the results can be a hostile regime (such as Hamas and ISIS) in the West Bank. That would be a serious security threat near Israeli towns.
Building a strong and efficient Palestinian police force is necessary to prevent this dangerous scenario. Israel can help in training the Palestinian police. The cooperation between security forces of the two sides, which works quite well in the West Bank, could be modified, tailored, and expanded for the new situation. In addition, a joint civil guard can be established in order to help in stabilizing a new social order.
Jewish settlements in the West Bank: Any form of solution, which is based on the establishment of a Palestinian state, has to cope with the presence of Jewish settlements (about 400,000 settlers) in the West Bank. The “optimal” solution to the problem is probably a mix of three options: (1) border modifications and land exchange: annexation of Jewish settlements to Israel and compensation to Palestinians in return; (2) evacuation of Jewish settlements; and (3) Jewish settlements in the West Bank will remain under Palestinian sovereignty.50
The settlements in the West Bank that cannot be annexed to Israel (option 1) and cannot be evacuated (option 2) will need to remain under Palestinian sovereignty (option 3). This will create major security problems. For example, who will solve disputes between Jewish neighbors? Should religious Jewish settlers call Palestinian police in such matters? Can a Palestinian police officer serve as a moderator in a dispute between religious Jews?
A joint Israeli-Palestinian civil guard can be helpful in such situations. It could assist in coping with such sensitive problems that are beyond the capacity of a regular police force. Of course, the two sides will need to discuss and negotiate the very essence of any joint civil guard. This project—the creation of a joint civil guard—has also peacebuilding implications. It can contribute to the transformation of hostile relationships between entrenched enemies who fight one another into cooperative relationships between neighbors who are trying to cope with joint problems.
The holy places in Jerusalem: The holy city of Jerusalem, the walled area, which is so important to believers of different religions, needs to be administered with much care, sophistication, and creativity. A joint civil guard, which will be subject to a joint municipality, can take into consideration the needs of those who care about the city. It can become a symbol of pluralism, tolerance, and peace.
This section suggests three peacekeeping mechanisms that operate in three intertwined dimensions: congress for peace and security (politics), a joint border guard (military), and a joint civil guard (civilian). It would be important, efficient, and beneficial that Israelis and Palestinians discuss and negotiate the structure, authority, and operation of any peacekeeping mechanism beginning as early as the peacemaking step. It could help avoid future complications when implementing any negotiated peace contract. Moreover, it could be a trust-building move that demonstrates to the people that any peace agreement would be signed and implemented only when mechanisms to keep security, order, and stability are established.51
Intractable conflict is a severe crisis. It is a longtime struggle where generations in turn are born into the reality of aggression, despair, and violence. The conflict seems to have a life of its own. It is like a disease that controls the body. A revolutionary process is needed to create a sustainable change.
Revolution is an “overthrow of an established social order” Friedrich ([41], 5). Peace revolution is a conclusive attack on the foundations and structure of the conflict and the sociopolitical destructive mechanisms that constantly feed it. Peace revolution is planned to involve, at least, three key elements of the opposing parties (leaders, elites, and people) in a change-building process that tackles the conflict from different levels, sides, and directions.
A revolutionary peace process needs to take into consideration that peace needs to be made, built, and kept. Peacemaking suggests diplomatic instruments to involve key social elements of the conflicting parties (leaders, elites, and people) in a multidimensional negotiation of a peace contract. Peacebuilding offers a program to construct a negotiated framework for a new social order, which copes with the needs, fears, and concerns of the conflicting factions. Peacekeeping advocates the creation of a multidimensional system of different operating mechanisms (political, militaristic. and civilian) to maintain law and order.
Distinguishing between the three elements of a peace revolution (peacemaking, peacebuilding and peacekeeping) is not always clear. Moreover, as this paper shows, these elements are intertwined. It will be a mistake to concentrate on one element of the challenge of peace (such as peacemaking) without taking into account the others. It can lead to the same old familiar failures.
Intractable conflict, similar to almost all phenomena in the social sciences, is a complex phenomenon.52 It is a composite of components, factors, and variables of different dimensions, such as psychology, economics, and religion. Peace revolutionaries need to take into account, as much as possible, the complexity of the situation and, accordingly, construct an innovative multidimensional approach to change. This is the main message of this paper.
Sapir Handelman is the co-laureate of the 2010 Peter Becker Award for Peace and Conflict Research. He is an associate professor (senior lecturer) and the head of the conflict studies division at Achva Academic College, Israel. Dr. Handelman founded and leads the Minds of Peace NGO, which is based on his concepts of conflict resolution in intractable conflicts.
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
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\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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