Iron overload and iron chelation therapy in patients with myelodysplastic syndrome treated by allogeneic stem‐cell transplantation: Report from the working conference on iron chelation of the Gruppo Italiano Trapianto di Midollo Osseo
Authors: Emilio Paolo Alessandrino, Emanuele Angelucci, Mario Cazzola, Matteo Giovanni Della Porta, Paolo Di Bartolomeo, Antonella Gozzini, Luca Malcovati, Pietro Pioltelli, Simona Sica, Alberto Bosi
Journal: American Journal of Hematology (2011)

Many myelodysplastic syndrome (MDS) patients have a long history of transfusion before eventually undergoing transplantation and therefore are at high risk of developing parenchymal iron overload. Recently, retrospective studies suggested that iron overload has some prognostic impact in MDS patients treated by allogeneic stem-cell transplantation (allo-SCT) as previously observed in thalassemia. However, the optimal strategy to assess iron overload and to reduce iron burden during and after transplant procedure remains to be determined. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) promoted a consensus process aimed at providing clinical practice recommendations that can support the appropriate choice for iron overload assessment and for iron chelation therapy in MDS patients undergoing allo-SCT. A systematic review of the published literature (1990–2010) was performed. An Expert Panel was selected according to the framework elements of the NIH Consensus Development Program, comprising 10 physicians with different areas of expertise (iron metabolism, SCT, and MDS patient management/treatment). Based on the available scientific evidence and consensus among experts, clinical recommendations were formulated on appropriate assessment of iron body stores, selection of candidates to iron chelation therapy before and after allo-SCT, and treatment modalities. Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders clinically characterized by peripheral cytopenia and an increasing risk of evolution into acute myeloid leukemia [1-3]. The natural history of MDS, ranging from indolent conditions over years to forms that rapidly progress to leukemia, complicates clinical decision-making regarding therapeutic modalities and timing of intervention [4, 5]. The only curative treatment in MDS patients is allogeneic stem-cell transplantation (allo-SCT) [6-8]. Long-term survival rates of between 25 and 70% were reported after transplantation [9, 10]. However, despite advances in transplantation technology, there is still considerable morbidity and mortality associated with this approach. Nonrelapse mortality in adult MDS ranges from 37 to 68%, whereas the relapse rate ranges from 24 to 58% [7, 8, 11]. Given the high risk associated with allo-SCT, an accurate selection of candidate patients is needed [12, 13]. Iron-related tissue damage is an important adverse prognostic factor in transfusion-dependent thalassemia patients treated by allo-SCT [14, 15]. In these recipients, iron overload may increase the risk of nonrelapse mortality, and this complication may be prevented by iron chelation therapy [16]. Many MDS patients have a long history of transfusion before eventually undergoing transplantation and therefore are at high risk of developing parenchymal iron overload [1, 4, 17, 18]. In addition, iron overload may persist long after transplantation [19, 20]. In these patients, the optimal strategy to evaluate iron overload and to reduce iron burden during and after transplant procedure has not been determined. Therefore, the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) promoted a consensus process aimed at addressing the open issues on this clinical setting. Within the GITMO study group, two chairmen of the Project were designated (EPA and AB). An Expert Panel was then selected according to the framework elements of the NIH Consensus Development Program, [21] comprising 10 physicians with different areas of expertise (iron metabolism, SCT, and MDS patients management/treatment). The Panel met three times in Pavia at the Department of Hematology and Oncology, Fondazione IRCCS Policlinico S. Matteo, University of Pavia. A systematic review of the literature was performed including indexed original papers, indexed reviews, and educationals, abstracts of conference proceedings (ASH, EHA, and EBMT). Indexed papers and reviews were searched in PubMed and limited to English language publications edited between 1990 and 2010. Full papers were ranked according to the Scottish Intercollegiate Guideline Network criteria [22]. During the first Panel meeting, the Expert Panel agreed on the goal of the project to provide clinical practice recommendations that can support the appropriate choice for iron overload assessment and for iron chelation therapy in patients with MDS treated by allo-SCT. A list of key clinical questions was identified based on the major issues emerged from the first Panel meeting: (1) is there any evidence that iron overload may impact the posttransplantation outcome in MDS patients? (2) How should be determined iron body status in MDS transplant recipients? (3) Which MDS patients undergoing allo-SCT could benefit from treatment of iron overload? (4) Which is the most appropriate iron chelation treatment for MDS patients before and after allo-SCT? The experts were invited to formulate in an independent manner proper evidence-based statements for each clinical question. Based on these statements and after Panel discussion, clinical recommendations were formulated. To date, there is limited evidence on the role of iron in organ damage in patients with MDS. In an autopsy study of 135 subjects with chronic acquired anemia, ∼60% of patients who had received more than 75 units of red blood cells had cardiac iron deposits [23]. In 1981, Schafer et al. [24] reported the clinical consequences of acquired transfusional iron-overload in adult patients with refractory anemia or aplastic anemia who had received a mean of 120 units of red blood cells. In this study, 10 out of 15 liver biopsy specimens contained between 7 and 26 times the normal levels of iron and typically showed portal fibrosis. Cardiac left ventricular function was impaired in only the most heavily transfused patients, or in those with coexisting coronary artery disease; all 15 patients had glucose intolerance associated with a significantly reduced insulin output. The authors concluded that widespread subclinical organ dysfunction can result from transfusional iron overload developing in adulthood [24]. Secondary iron overload, assessed as serum ferritin level, is associated with reduced survival in transfusion-dependent patients with MDS [1]. The worst affected patients were those in WHO criteria subgroups RA, RARS, and isolated 5q-syndrome, which have the longest median survival and are therefore more prone to develop the toxic effects of iron overload [4]. More recently, it has been shown that iron overload has some prognostic impact in MDS patients undergoing allo-SCT [25]. Scientific evidence mainly derives from retrospective investigations, while no data are currently available examining the impact of iron chelation therapy on survival of MDS treated with allo-SCT. Armand et al. [26] reviewed 590 patients who underwent myeloablative allo-SCT at the Dana-Farber/Brigham and Women's Hospital transplantation program between 1997 and 2005. An elevated pretransplantation serum ferritin level was found to be strongly associated with lower overall and disease-free survival (5-year overall survival 54% and 27%, 5-year disease-free survival 43% and 27% in patients with low [0–231 ng/ml] vs. high [>2,034 ng/mL] pretransplantation ferritin level, respectively). Subgroup multivariable analyses demonstrated that this association was restricted to patients with acute leukemia or MDS and that, in the latter group, the inferior survival was attributable to a significant increase in nonrelapse mortality (hazard ratio for mortality associated with a high-pretransplantation ferritin level [>2,515 ng/ml] = 2.6) [26]. Ferritin determination as a marker of iron overload should be considered with some caution due to its concomitant role as acute-phase reactant [27, 28]. In this context, it should be noted that this and other above-mentioned studies are potentially biased by the fact that they did not take into account transfusion history before transplantation [26, 29]. It is very important to clarify whether high ferritin levels at the time of transplantation were due to transfusions or inflammation. The GITMO group evaluated the prognostic impact of pretransplantation transfusion history in MDS patients undergoing allo-SCT in a retrospective analysis on 357 subjects reported to Italian transplantation registry between 1997 and 2007 [30]. A regular transfusion need before transplantation was reported in 223 subjects, with a median number of packed red blood cell units received of 20 (range, 5–151) corresponding to a median iron intake of 4 g (range, 1–30 g). In multivariate analysis, transfusion-dependency was independently associated with reduced overall survival and increased nonrelapse mortality. This effect was noticeable only in subjects receiving myeloablative conditioning, in which the cumulative incidence of nonrelapse mortality in transfusion-independent and in transfusion-dependent patients was 33 and 45%, respectively. There was an inverse relationship between transfusion burden (which is a direct objective and quantitative estimation of body iron load), and overall survival after transplantation, the outcome significantly worsening in subjects who received more than 20 red cell units. Among transfusion-dependent patients undergoing myeloablative allo-SCT, pretransplantation serum ferritin level had a significant effect on overall survival and nonrelapse mortality (hazard ratio 1.40 and 1.42, respectively). This effect was maintained after adjusting for transfusion burden and duration, suggesting that the negative effect of transfusion history on outcome might be determined at least in part by iron overload [30]. The reason of the association between iron overload and increased nonrelapse mortality in MDS remains to be clarified: in the Boston series, a trend toward an increased risk of veno-occlusive disease in patients with high ferritin level was noticed; [26, 31] other results suggest that the presence of pretransplantation iron overload might be a risk factor for acute graft versus host disease (GVHD) (in the GITMO cohort, the occurrence of acute GVHD in transfusion-independent and in transfusion-dependent patients was 57 and 67%, respectively); [30] finally, an increased incidence of infectious complication after allo-SCT in subjects with iron overload was reported in patient series including subjects affected with MDS (in a cohort of 264 subjects undergoing allo-SCT causes of nonrelapse mortality were related to infection in 5% and 14% of patients with low and high pretransplantation ferritin, respectively) [32]. Limited data are available on the effect of secondary iron overload in patients receiving reduced intensity conditioning [30, 33]. However, some evidence suggests that iron overload has a limited effect on these subjects, who are less exposed to the risk of transplant-tissue damage and related mortality with respect to those receiving a standard conditioning regimen [30]. The Expert Panel agrees that transfusion iron overload may increase the risk of nonrelapse mortality in MDS patients receiving allo-SCT. A comprehensive assessment of body iron is recommended in all MDS patients undergoing allo-SCT. Although prolonged (years) anemia and ineffective erythropoiesis could lead to increased intestinal iron absorption and increased iron stores, transfusional iron is responsible for the large part of the iron overload in MDS [34]. The human body has not evolved a mechanism to clear excess iron, and therefore patients receiving regular red blood cell transfusions invariably develop iron overload [35]. Red blood cells contain about 1.16 mg iron/ml; thus, 1 unit of blood contains 200–250 mg of iron, and an iron overload can occur after 10–20 transfusions [36]. During conditions of normal iron balance, iron is bound and transported by transferrin, which is about 30% saturated. Frequent blood transfusions produce a gradual increase in transferrin saturation and in the appearance of nontransferrin-bound iron (NTBI). This ultimately might result in the uncontrolled loading of organs, such as the liver, heart, and endocrine glands, with free iron that generates free radicals and causes cell damage [23]. The diagnostic tools currently available for the evaluation of body iron status in patients with MDS are reported in Table I. In the absence of massive bleeding or regular chelation, a very simple calculation of the transfusion history provides direct, quantitative, and accurate evaluation of the body iron burden [36]. The most easy and useful serological tests to evaluate iron overload are serum ferritin and serum transferrin saturation [27, 28, 34]. Both are easy and inexpensive to be performed. Serum ferritin is an acute phase reactant, fluctuating in response to inflammation, liver function, and ascorbate deficiency. A single elevated serum ferritin value is not able to adequately predict amount of body iron burden; however, if serial measures are available, ferritin provides a good parameter of body iron status [1]. In MDS patients with transfusion-dependent anemia, a transfusion burden of more than 20 packed red blood cell units and/or a serum ferritin level >1000 ng/ml without signs of inflammation or liver disease are generally used to define the presence of body iron overload [37-39]. Transferrin saturation is a useful test to determine patients at risk of iron overload, as a high value for transferrin saturation suggests parenchymal iron loading [40]. The liver iron concentration (LIC) is a reliable indicator of total body iron stores in patients with thalassemia major [41], and liver iron biopsy with iron measurement by atomic absorption spectroscopy remains the gold standard for the assessment of iron overload in these patients. However, liver biopsy is invasive and cannot be used in many patients with MDS, especially for serial assessments. Noninvasive techniques such as superconducting quantum interference device (SQUID) [42] and magnetic resonance imaging (MRI) [43] are now available for evaluation of liver iron. SQUID is available in only few centers in the world and has not been validated with respect to gold standard determination of LIC by liver biopsy. MRI is ubiquitous and offers great potential for widely accessible noninvasive estimate of liver and cardiac iron concentration. During last few years, remarkable advances have been made in the use of T1, T2, and T2* MRI relaxation time techniques to quantify tissue iron. The reciprocal of T1 and T2*, known as R2 and R2*, is directly proportional to iron concentration and demonstrated the most promising results. Both R2 and T2* showed a strong correlation with liver iron content determined by biopsy and good reproducibility [43, 44], and MRI R2 technique has been registered in the United States and EU for determination of liver iron content. Estimation of myocardial iron by MRI has become increasingly available but requires expertise in use and standardization [45]. The T2* value in cardiac tissue shorten as the iron concentration increases, and, in thalassemia, a T2* value <20 ms (implying myocardial iron overload) has been associated with a higher risk of decreased left ventricular ejection fraction [46]. MRI T2* has been used to study both liver and myocardial iron loading in patients with MDS. Di Tucci et al. [47] studied 27 transfusion-dependent patients, most of whom did not receive iron chelation therapy. All patients who had received at least 24 red blood cell units showed MRI T2* detectable hepatic iron, while only patients with long-term transfusion history and evidence of severe hepatic iron overload (T2* < 1.4 ms) showed pathological cardiac T2* values. Armand et al. [48] reported a prospective investigation of 48 patients with acute leukemia or MDS undergoing myeloablative allo-SCT, using MRI to estimate LIC and cardiac iron. Forty-one patients had hepatic iron overload, which was significant (LIC ≥5.0 mg/gdw) in 20 cases, while cardiac iron overload was documented in 1 patient. In this study, a strong correlation between pretransplantation serum ferritin and estimated LIC was reported. Plasma non-transferrin bound iron (NTBI) has been detected in patients with thalassemia major and in individuals with low-risk MDS, but its clinical utility is unclear [49]. A few assays are now available for the determination of serum hepcidin [50]. They represent research tools at present, clinical applications are likely in the future. In fact, inappropriately low hepcidin levels in patients receiving blood transfusions might indicate a high risk of parenchymal iron loading [34]. Several methods are available to evaluate iron target tissues (in particular, liver, cardiac, and endocrine pancreas). Advanced liver fibrosis has been associated with an increased risk of long-term liver complication following chemotherapy and allo-SCT [20]. Liver fibrosis can be studied by liver biopsy if feasible. Recently, transient elastography has been proposed for noninvasive liver fibrosis and cirrhosis liver study. If available, the transient elastography could be a reasonable first option, but a negative result does not exclude the presence of an important fibrosis [51]. In the presence of iron overload, cardiac left ventricular function can be quantified using MRI, multiple gated acquisition scan, or echocardiography. The first two methods are not affected by interoperator variability and more easily adapted to longitudinal observations. Endocrine pancreas is a selected site of iron accumulation and subclinical endocrine function can be present in all iron overload conditions. Glucose tolerance can easily deteriorate during and following transplantation and can be detected by oral glucose tolerance test [52]. All patients candidate to allo-SCT should be evaluated for iron overload taking in account transfusion history, previous iron chelation, and the following biochemical iron parameters: serum iron level, total iron binding capacity, serum ferritin, and percentage of transferrin saturation (see Fig. 1). In patients showing clinical signs of liver and/or heart damage, the Expert Panel suggests to perform MRI T2* for cardiac study and MRI R2 for liver iron study. Liver biopsy is not routinely advisable in this setting of patients. Patients who underwent allo-SCT should be also evaluated for the presence of iron overload after achievement of stable engraftment and withdrawal of immunosuppressive therapy. Flow chart for the study of iron status in MDS patients candidate to allo-SCT. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Available evidence on safety and efficacy of chelation therapy in MDS patients during and after allo-SCT is scanty. Thus, data form thalassemic patients were considered by the Panel as translated evidence to address the question whether iron chelation therapy may prevent or reduce the harmful effect of iron overload in MDS patients undergoing allo-SCT. In addition, indirect evidence from studies evaluating the effect of iron overload on posttransplantation outcome in MDS was considered to identify the most appropriate candidates to iron chelation. Iron-related tissue damage is a recognized adverse prognostic factor in transfusion-dependent thalassemia patients with undergoing allo-SCT [14, 16], and an effective iron chelation therapy may prevent the impact of iron overload on nonrelapse mortality [15]. For MDS patients eligible for a transplant procedure, the available evidence and consensus-based therapeutic guidelines recommend that iron chelation therapy should be early considered [37-39] (characteristics of currently available iron chelators for MDS patients are reported in Table II). This is particularly relevant for patients with low-risk disease at diagnosis, which have a long history of transfusion if they eventually undergo transplantation and are therefore at high risk of iron overload and of iron-related tissue damage [1, 34]. The additional risks of disease complications and comorbidity that might preclude these patients from transplantation and/or worse posttransplantation outcome are to be considered when implementing delayed transplant strategies in these patients [12, 53]. Optimizing supportive care (including chelation therapy) is mandatory to this purpose. In clinical practice, the observation of iron overload due to red-cell transfusion is rather common in MDS patients undergoing allo-SCT [30] in reason of no or short term of chelation therapy or poor response/compliance to treatment. As reported earlier, retrospective investigations suggest that iron overload (as defined by increased serum ferritin level and transfusional burden) has a negative prognostic impact in MDS patients undergoing allo-SCT by increasing the risk of nonrelapse mortality [26, 30]. In the GITMO experience [30] when considering patients receiving myeloablative conditioning, the cumulative incidence of nonrelapse mortality was 45% in subjects with transfusional history and 33% in those without transfusion history. On the other hand, among patients receiving nonmyeloablative conditioning, the cumulative incidence of nonrelapse mortality was 22% and 21% in the two groups, respectively. When evaluating the prognostic impact of secondary iron overload by a multivariable analysis, in both Boston [26] and GITMO [30] studies, pretransplantation ferritin level maintained a significant effect on nonrelapse mortality only in patients treated with myeloablative allo-SCT (HR 3.2, P = 0.02 and HR = 1.42, P = 0.03, respectively). Overall, these data suggest that the effect of pretransplantation iron overload is restricted to MDS patients who received a myeloablative conditioning regimen and are, therefore, at higher risk of developing transplant-related toxicity. In transplant survivors, iron overload may persist long after the procedure because of the limited iron excretion capability of human body [19]. In the thalassemia experience, serum ferritin and the transferrin saturation slowly return to normal only in patients with a very low iron burden before transplantation [15]. Persistence of tissue iron overload after allo-SCT can cause significant morbidity and mortality, as observed in thalassemia patients [46, 54]. To remove excess iron appears to be particularly relevant in patients affected by HCV infection because of the well-known synergic effect of these two conditions [16]. The Expert Panel agrees that all MDS patients who are transfusion-dependent and are potential candidate to allo-SCT should receive iron chelation therapy to prevent iron accumulation. If iron overload has occurred in patients for whom a myeloablative allo-SCT has been planned, the Expert Panel agrees that an attempt should be performed to reduce body iron stores. However, the Expert Panel also recommends that the accomplishment of the reduction of iron overload should not cause a delay in transplantation. Transplant survivors in whom iron overload persists after the procedure should also be considered for treatments aimed at reducing body iron excess once engraftment is stable and immunosuppressive therapy discontinued. As discussed earlier, the available evidence on safety and efficacy of chelation therapy in MDS patients during and after allo-SCT is scanty; thus, data from thalassemia were considered by the Panel as translated evidence to identify the most appropriate iron chelation treatment for MDS patients during and after allo-SCT. In a study by Gaziev et al. [55], 15 thalassemic patients undergoing allo-SCT received deferoxamine at a dose of 40 mg/kg/day as a 24-hr intravenous infusion administered before and early-posttransplant (until day +60). Intravenous deferoxamine therapy did not affect the engraftment parameters or the incidence of infections or acute GVHD in this clinical trial, and no adverse effects were observed during chelation therapy. Moreover, deferoxamine therapy resulted in a significant decrease of serum ferritin at 6 months after transplantation with respect to untreated control group [55]. These results suggest that the administration of deferoxamine during and early-post-allo-SCT is safe and effective. The Expert Panel recommendation for peritransplant iron chelation therapy in MDS patients with iron overload is to offer intravenous deferoxamine infusion (40 mg/kg/day as a 24-hr intravenous infusion). After allo-SCT, patients have normal erythropoiesis capable of producing a hyperplastic response to phlebotomy, so that this procedure can be contemplated as a method for mobilizing iron from overloaded tissues. Angelucci et al. [54] treated with a phlebotomy program (6 ml/kg blood withdrawal at 14-day interval) 41 thalassemic patients with prolonged follow-up after allo-SCT (range, 2–7 years). After a mean period of treatment of 35 months, a significant decrease of serum ferritin (from 2,587 ng/ml to 417 ng/ml), of transferrin saturation (from 90% to 50%), of LIC evaluated on liver biopsy specimens (from 20.8 to 4.2 mg/g dry weight) and of aspartate/alanine transaminases was observed with respect to baseline evaluation. Moreover, an improvement on hepatic fibrosis was documented in 7 patients. No cases of graft failure, prolonged anemia, or protein depletion were seen, and adherence to phlebotomy protocol was 72% [54]. According to joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation, phlebotomy is the treatment of choice in long-term SCT survivors with iron overload documented by liver iron content greater than 7 mg/g dry weight [56]. In the setting of MDS, only anecdotical experience on the use of phlebotomy in the posttransplantation period are reported. Busca et al. [57] retrospectively analyzed for the presence of iron overload a series of 102 consecutive patients who underwent allo-SCT (including 17 subjects affected with MDS). Nineteen of the 24 eligible patients (defined by the absence of disease recurrence and/or poor performance status) for iron-depletion therapy underwent regular phlebotomy (at 7–14-day interval until a serum ferritin level <500 ng/ml) and 13 completed the program in a median of 287 days, reaching the target of a ferritin level <500 ng/ml. LIC was significantly reduced in 8 of the 9 patients who were revaluated by SQUID at the end of the phlebotomy program [57]. In patients with MDS and iron overload after transplant, iron removal through phlebotomy is the first choice therapy (6 ml/kg blood withdrawal at 14-day interval). For those patients who cannot be phlebotomized due to low hemoglobin level or cardiac impairment, deferoxamine or deferasirox should be considered. The optimal strategy, however, remains to be defined. In patients receiving phlebotomy, target iron status is serum ferritin inside the normal laboratory range and transferrin saturation <45%. In patients receiving iron-chelating agents therapy should be continued until ferritin has reached levels below 500 ng/ml; periodic biochemical evaluation of body iron status should be performed in order to avoid toxicity by overchelation. All authors provided substantial contributions to conception and design, acquisition of evidence and analysis and interpretation of data, in particular during panel meetings. All authors also participated in drafting the article and revising it critically, and gave, final approval of the manuscript. EPA and AB were responsible for the project's design and analysis of results. We are greatly indebted to Amici dell'Ematologia di Pavia (AEP) ONLUS for the helpful support in the organization and conduct of the Consensus Conferences and in the whole project.