Management of High Ferritin in Long-Term Survivors After Hematopoietic Stem Cell Transplantation

Management of High Ferritin in Long-Term Survivors After Hematopoietic Stem Cell Transplantation Eolia Brissot,a,b Bipin N. Savani,c and Mohamad Mohtya,b,d,e Management of high serum ferritin levels after allogeneic hematopoietic stem cell transplantation (allo-HSCT) should, from the diagnostic standpoint, be based on the pathophysiological mechanisms underlying the development of hyperferritinemia. This knowledge is essential for differentiating increased serum ferritin due to iron overload from “non–iron overload” situations such as inflammation, metabolic syndrome, or hepatitis. Once body iron overload has been proven, especially by quantifying tissue iron excess with the noninvasive magnetic resonance imaging (MRI) method, it is important, considering the damaging effects of chronic iron overload in these patients, to start iron depletive therapy by oral chelation or phlebotomy. At present, more data are needed to assess the long-term deleterious effects of iron excess in the HSCT population, and to define the most appropriate therapeutic strategy for removing iron burden. Also, preventing iron overload prior to HSCT might prove essential for improving patient prognosis through decreasing HSCT-related mortality. Semin Hematol 49:35– 42. © 2012 Elsevier Inc. All rights reserved.

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llogeneic hematopoietic stem cell transplantation (allo-HSCT) is being increasingly used as curative therapy for severe disorders of the hematopoietic and immune systems. Over time, the focus has moved from immediate recipient survival to longterm follow-up. Advances in HSCT practice and supportive care have led to improved outcomes and increasing number of long-term HSCT survivors. For long-term survivors (⬎2 years post-HSCT), the prospect for long-term survival is excellent (85% at 10 years after HSCT). However, life expectancy remains lower than expected.1 Therefore, a regular and long-lasting monitoring is useful not only to follow-up the initial disease but also to investigate the different transplant-related complications.2 Elevated serum ferritin concentrations aCentre

Hospitalier et Universitaire (CHU) de Nantes, Service d’Hématologie Clinique, Nantes, France. bUniversité de Nantes, Faculté de Médecine, Nantes, France. cHematology and Stem Cell Transplantation Section, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, TN. dCentre d’Investigation Clinique en Cancérologie (CHU) CHU de Nantes, Nantes, France. eINSERM CRNCA UMR 892, Nantes, France. Address correspondence to Professor Mohamad Mohty, Hématologie Clinique, CHU de Nantes, Place A. Ricordeau, F-44093 Nantes Cedex, France. E-mail: [email protected] 0037-1963/$ - see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2011.10.003

Seminars in Hematology, Vol 49, No 1, January 2012, pp 35– 42

are common in allograft recipients. Ferritin measurement is recommended as part of the long-term follow-up guidelines recommendations at 1 year post-HSCT.3 This concise review will discuss the significance and management of high serum ferritin levels in long-term survivors after allo-HSCT.

DEFINITION AND MECHANISMS Reference concentrations of serum ferritin may vary across laboratories due to differences in analytical techniques and reference populations; age and gender are also important determinants.2,4 It is usually admitted that serum ferritin concentrations greater than 300 ␮g/L in men and greater than 200 ␮g/L in women correspond to elevated values. The mechanisms accounting for elevated serum ferritin concentrations are usually increased ferritin synthesis (including acquired/genetic conditions with or without iron overload) and increased release of ferritin from damaged cells.5

DIAGNOSIS AND MANAGEMENT When determining the cause(s) of ferritin elevation, it should be kept in mind that high serum ferritin does not systematically reflect iron overload and that the diagnostic approach in HSCT patients can be complex because of multiple potential causes (Figure 1). 35

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E. Brissot, B.N. Savani, and M. Mohty

Figure 1. Main causes of hyperferritinemia in allograft recipients.

The first diagnostic key is to evaluate plasma transferrin saturation, which corresponds to the ratio of plasma iron concentration over transferrin concentration. Transferrin is the protein that ensures the transport of circulating iron and normal transferrin saturation is less than 45%. Also, one should bear in mind that the clinical setting often provides accompanying clues to the diagnosis. Diagnosis of hyperferritinemia with normal or low transferrin saturation levels (⬍45%) can be related to: ●

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Inflammation: Inflammation, either acute or chronic and whatever its cause, is likely to increase serum ferritin sometimes up to 1,000 ␮g/L. The pro-inflammatory cytokines increase serum ferritin by a double mechanism, a direct one via induction of ferritin synthesis and an indirect one via hepcidin increase. Hepcidin is the iron-regulating hormone that acts especially by blocking the iron egress from duodenal enterocytes and (splenic) macrophages iron into the plasma. Hyperhepcidinemia explains that, in case of inflammatory syndrome, increased serum ferritin is associated with low serum iron levels and even on the long term by anemia (corresponding to the so called “anemia of chronic disease”). Therefore, testing for serum c-reactive protein (CRP) is a further biochemical key for interpreting hyperferritinemia. HSCT patients due to immunological and/or infectious factors are at high risk for inflammatory syndrome. Metabolic syndrome: The metabolic syndrome is a constellation of risk factors for cardiovascular disease characterized by abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and insulin resistance.6 –9 Besides, individuals with the metabolic syndrome are at increased risk for atherosclerotic cardiovascular diseases in the near future.10 The metabolic syndrome represents today one of the most frequent causes of hyperferritinemia.11 Considering HSCT survivors, these patients do have a higher risk of diabetes and hypertension, potentially leading to a higher risk of cardiovascular complications.12 Several studies have shown

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that HSCT patients are prone to develop premature arterial vascular disease.13,14 In this setting, hyperferritinemia is often comprised between 500 and 1,200 ␮g/L and body iron excess is mild, usually less than three times the upper normal limit of hepatic iron concentration as noninvasively judged by magnetic resonance imaging. Therefore, in this syndrome, the relatively high degree of hyperferritinemia is in deep contrast with the moderate tissue overload burden. Alcoholism: Enhanced plasma ferritin levels can be a consequence of the inducing role of alcohol on ferritin synthesis.15 Hyperferritinemia usually reverts to normal after 3 months of abstinence. Therefore, possible coexisting excessive chronic alcohol consumption must be searched in HSCT patients, and verifying the presence of macrocytosis and hyper gamma glutamyl transpeptidase (hyperGGT) is necessary for correct interpretation of hyperferritinemia. A good clinical indication is provided by significant fluctuations of serum ferritin in line with the variations of alcohol intake over time. Other rare causes of hyperferritiniemia without increased transferrin saturation should also be ruled out. Some of them are associated with marked iron overload such as non–HFE-related hemochromatosis due to mutations of the ferroportin gene or hereditary aceruloplasminemia.16 Other causes are not associated with iron excess. It is especially the case of the ferritincataract syndrome, Gaucher’s disease, or macrophage activation syndrome. The latter is mainly seen in Epstein-Barr virus infection or various hematologic conditions.

Diagnosis of hyperferritinemia with increased transferrin saturation (⬎45% but most often ⬎60%) can be related to: ●

Acute and chronic hepatitis: Whenever hepatic cytolysis is present, intracellular ferritin can be released into the bloodstream due either to real membrane damage or to solely altered membrane

High ferritin after allo-HSCT

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permeability. The same holds true for intracellular iron, which is released in excess into the plasma, contributing to increased transferrin saturation. Moreover, in case of hepatocellular failure, transferrin synthesis is decreased, contributing to accentuate the increase of transferrin saturation. In order to lead to significant hyperferritinemia, cytolysis must be severe. Transaminase determination (ALT, AST) is therefore an important diagnostic parameter to explore elevated serum ferritin values in this context. Applied to the HSCT situation, various hepatic disorders can account for hyperferritinemia: major elevations of serum ALT can be observed in an otherwise stable HSCT survivor, due to varicella zoster or herpes simplex virus infection, or to drug-induced liver injury,17 as well as hepatitis presentation of chronic graft-versus-host disease (GVHD) and flares of chronic hepatitis B or C following tapering or discontinuation of immune-suppressive drugs.18,19 Iron overload: Iron excess occurs in 30% to 60% of allo-HSCT recipients.20 There are several reasons why iron status is elevated post-transplantation. Red blood cells (RBCs) transfusion therapy as supportive care for chronic anemia is the principal cause of iron overload in these patients. One unit of RBCs contains approximately 200 mg of heme iron, which represents more than 100 times the iron quantity, which, every day, is absorbed from a normal diet.21 Clinical evidence has shown that iron burden can occur after as few as 20 units of transfused blood, given that human body has no efficient physiologic mechanisms for clearing iron in excess. Chemotherapy and chemo/radiotherapy can also change iron status. The underlying disease may itself be associated with disturbed iron metabolism, such as beta-thalassemia major and refractory anemia with ringed sideroblasts of myelodysplastic (MDS) syndromes. It has been shown in beta-thalassemia and MDS patients that ineffective erythropoiesis, which can also be a consequence of the intensive treatment, leads to inhibition of hepcidin, likely due to overexpression of growth factor 15,22 therefore contributing to increased iron absorption and macrophagic iron release. In transfusional-related iron overload, iron coming from erythrophagocytosis of transfused RBCs first accumulates within macrophages. It is subsequently released into the plasma, oversaturating transferring, and inducing a special circulating iron species, called non–transferring-bound iron (NTBI). NTBI is especially important for two reasons: (1) it is very quickly deposited in parenchymal cells of the liver, heart, pancreas, and endocrine tissues; and (2) it is potentially toxic through its component called labile plasma iron (LPI), which leads to the formation of reactive oxygen

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species. LPI is usually present when transferrin saturation is ⱖ75%.4,23 Therefore the adverse consequences of iron overload are due to accumulation of tissue iron in target organs and also to elevation of NTBI and LPI in plasma. The differential distribution of iron between parenchymal and macrophagic (or reticuloendothelial) cells indicates different pathogenetic mechanisms of iron accumulation and different organ targets. Indeed, liver parenchymal iron overload is usually the result of excessive iron absorption by enteral route, such as observed in anemias with ineffective erythopoiesis, but may also reflect enhanced internal redistribution of transfused erythrocyte iron recycled from the macrophagic cells, as observed in the more advanced stage of transfusion iron overload.24 Thus far, only few studies have investigated the effects of persistent iron overload on long-term morbidity of HSCT in non-thalassemic recipients. These late effects may differ between thalassemic and nonthalassemic patients, notably due to the different tissue iron distribution (parenchymal cells versus macrophages). In a prospective study of 133 survivors with childhood leukemia after HSCT, Chotsampancharoen and al25 described that hyperferritinemia was frequent (93%) and associated with low cardiac fractional shortening and elevated total bilirubin and ALT. Patients with hypothyroidism and growth hormone deficiency had higher level of iron overload. In another study, Rose et al found that the high ferritin group differed significantly from normal ferritin group in terms of RBCs transfused, and levels of AST and ALT. No patients had clinical cardiopathy.26 Iron overload can mimic hepatic GVHD exacerbation, thus resulting in unnecessary continuation or intensification of immunosuppressive therapy for GVHD, and treatment by phlebotomy resulted in normalization of liver function.27 In post-HSCT patients who had elevated liver enzymes, 75% had a histologic diagnosis of iron overload, and iron excess was the sole histopathologic abnormality in 33% of cases.28 Data on the role of iron in organ damage in MDS are still limited.29 It was recently shown that all MDS patients who had received 20 or more RBC units had iron accumulation in the liver, as detected by MRI,30 and serum ferritin was found to have a significant impact on survival of patients with refractory anemia.31,32 In transplanted thalassemia patients, iron overload has been associated with potentially dramatic late complications, including liver disease fibrosis33 and heart disease.34 Coexisting genetic iron overload, in particular HFE-related (type 1) hemochromatosis, must be evaluated every time hyperferritinemia with ele-

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vated transferrin saturation is due neither to hepatic cytolysis nor to transfusional iron overload.35

PRACTICAL ASSESSMENT OF BODY IRON STORES As mentioned above, it is of paramount importance, when facing hyperferritinemia, to evaluate the level on tissue iron. Several methods are available for this purpose and have, over time, been dominated by noninvasive techniques. ●

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The hepatic iron concentration that detects increases in both hepatocytes and macrophages (Kupffer cells) is a reliable indicator of total body iron stores in patients with thalassemia major.36 Liver biopsy remains the most accurate test and is considered as the gold standard for measuring liver iron concentration (LIC) either by semiquantitative histological method (based on Perls staining) or biochemical determination of hepatic iron concentration. It also allows the evaluation of concomitant liver disease such as steatohepatitis, alcoholic liver disease, or viral hepatitis, and therefore to diagnose liver diseases that could not be identified with noninvasive methods.5,37 However, liver biopsy remains an invasive procedure justifying why noninvasive techniques, such as MRI, are increasingly used.38 – 40 Indeed, T2 hyposignal is specific of iron excess and the degree of hyposignal correlates with the increase of hepatic iron. MRI is also useful for the evaluation of splenic iron (using the T2* technique). Cardiac biopsy enables the histologic assessment of myocardial iron deposition in patients with iron overload. However, it is an invasive approach that can result in serious complications so that it is now rarely performed. Noninvasive MRI T2*correlates closely with the results of cardiac biopsy in patients with high or low levels of iron heart deposition.41,42 Cardiac T2* magnetic resonance can also identify patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major and is superior to serum ferritin and liver iron.43 Therefore eliminating excess iron from the heart becomes the dominant therapeutic objective. It should be noticed that iron removal from the heart is much slower than from the liver and that liver iron can reach an optimal range despite severe cardiac overload. Nonetheless, sustained severe iron overload with high hepatic iron prospectively predicts cardiac iron loading.44 However, there are little MRI imaging data on iron overload in non-thalassemic HSCT recipients. The results could be different from those in thalassemia major patients since the clinical context of iron loading is different. Au et al. performed a study of

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MRI assessment of iron overload in the heart, liver, pancreas, and pituitary gland in 20 HSCT recipients with a median peak ferritin level of 7,715 ␮gl/L.45 Unlike thalassemia major patients, HSCT recipients did not show significant cardiac iron deposits or heart failure. Besides, they found a high incidence of T2*liver abnormality with abnormal ferritin levels. No conclusion could be made with MRI measurements of iron in the pancreas and pituitary gland. In a study on allo-HSCT survivors conducted by Rose et al,26 there was a significant correlation between the numbers of RBCs transfused and ferritin values, between the numbers of RBCs and the LIC estimated by MRI, and also between the ferritin values and LIC as estimated by MRI. Majhail et al reported that 19 of 56 allo-HCST survivors had a ferritin level greater than 1,000 ␮g/L (of whom 18 had elevated LIC on R2 MRI).46 Nevertheless, they found that serum ferritin was moderately correlated with LIC. Similarly, a moderate correlation was observed between transferrin saturation and LIC. In the Busca et al study, on 42 allo-HSCT recipients who had ferritin levels greater than 1,000 ␮g/L (median follow-up, 578 days), iron overload was quantified by SQUID (superconducting quantum interference device). Twenty patients had moderate iron overload (LIC 1,000 –2,000 ␮g Fe/g wet weight [ww]), nine had severe iron excess (LIC ⬎2,000 ␮g Fe/g ww), and five had normal LIC value (⬍400 ␮g Fe/g ww). In these five patients, four had GVHD or infection. Overall, although serum ferritin is a useful test for initial screening of iron overload in transplant recipients, it should not be considered as a highly reliable indicator of total body iron burden. Infection, inflammation, and GVHD frequently occur in HSCT recipients, therefore decreasing both sensitivity and specificity of ferritin for measuring iron overload.47

Therapeutics Options Therapeutic management of hyperferritinemia in long HSCT survivors depends on the cause. In the scope of the present review, we will focus on the treatment of iron overload which is the main cause of hyperferritinemia in post-HSCT patients. The natural history of established iron overload and its impact in adult allogeneic HSCT survivors remains poorly documented. In patients cured of thalassemia by HSCT, a spontaneous, but slow decrease, in serum ferritin and liver iron concentrations at 1 year following HSCT48,49 were reported. However, the rate of unloading was not sufficient to reduce tissue iron excess very late after transplantation in patients treated for hematologic malignancies.26 Based on experience in children with hemoglobinopathies, persistent iron overload may be a

High ferritin after allo-HSCT

risk for developing organ damage and dysfunction. In patients with MDS or acute leukemia undergoing myeloabalative allogeneic HSCT, pretransplantation transfusion history and high serum ferritin have a significant unfavorable prognostic value, inducing a significant decrease on overall survival and increase of non-relapse mortality.50,51 In all, although prospective studies of the impact of iron overload after HSCT on post-transplantation morbidity and mortality are needed, removal of iron excess does constitute an important goal. ●

Phlebotomy treatment is a simple and effective approach to remove excess iron from tissues. Compliance is usually good and the procedure is relatively straightforward and inexpensive. It has been reported in adult HSCT survivors with iron overload, both with or without the use of erythrocyte-stimulating agents.26,27,52–54 However, caution should be the rule in the use of erythropoiesisstimulating agents because of the lack of studies on their impact on hematopoiesis in HSCT recipients. It has been shown in the HSCT population that phlebotomies can reduce serum ferritin levels and liver iron concentrations.26,27,35,53,55 Whether the repeated venesection procedure might also have a putative unfavorable stimulating effect on hemopoiesis in this subset of patients remains an opened question.

Nevertheless, a proportion of HSCT recipients may not be eligible for phlebotomy because of coexisting anemia. ●

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Deferoxamine (Desferal, Novartis, Switzerland) has been available for many years and considered as the standard of care in this setting. A few studies of deferoxamine use in HSCT recipients confirmed its effectiveness in the management of iron overload.56,57 However, this compound has several limitations, especially absence of oral absorption and that, when administered parenterally, it has a very brief half-life. The latter explains the need for subcutaneous administration, through a portative pump device, 12 hours per day, 5 days a week, which can lead to serious problems of compliance, especially in younger individuals. Furthermore, deferoxamine could promote anticancer activities against solid tumors and leukemia cells.58 – 60 Kaloyannidis et al have shown that deferoxamine administration in 143 patients transplanted for hematologic malignancies may improve disease-free survival (DFS) by reducing relapse.57 However, the exact role of the decrease in iron overload on relapse needs to be explored. Therefore, these patients should be treated with orally absorbed iron-chelating agent. Deferiprone (Ferriprox, Suedish Orphan Biovitrum, Sweden) was significantly more effective than

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deferoxamine for improving asymptomatic myocardial siderosis in beta-thalassemia major.61,62 However, it has not been investigated in HSCT recipients. Moreover, some cases of neutropenia have been reported, making it difficult to use in allograft patients. Deferasirox (Exjade, Novartis, Switzerland) is another recent oral iron chelator, which has been used in post-HSCT patients.35,53 However, given the small number of cases, a meaningful conclusion regarding the efficacy of deferasirox in the setting of iron overload cannot yet be drawn. The most common adverse events of deferasirox therapy are gastrointestinal events and mild increase in serum creatinine levels. Considering that toxic renal drugs, such as calcineurin inhibitors, are frequently used in HSCT recipients, deferasirox administration in this setting has to be evaluated by further studies. One protocol of deferasirox therapy after HSCT is currently recruiting (NCT01159067). This pilot clinical trial is assessing safety and tolerability of deferasirox in hematopoietic stem cell transplant recipients who have iron overload and is also evaluating the effect of this drug on labile plasma iron. Three others studies are ongoing or have just been completed (for details, see: www.clinicaltrials.gov).

Evaluation of the patient before the initiation of iron-chelating therapy should include a detailed characterization of the underlying disorder, documentation of transfusion, and determination of body iron load by measurement of serum ferritin levels and liver iron concentration, estimation of the rate of transfusional iron loading and assessment of cardiac iron deposition.

CONCLUSION In conclusion, the appropriate management of high serum ferritin levels in HSCT patients requires a proper knowledge of the pathophysiological mechanisms underlying the development of hyperferritinemia in order to establish, in the clinical setting, whether increased serum ferritin is due to iron overload or to non–ironoverloaded situations such as inflammation, metabolic syndrome, hepatitis, or associated alcoholism. Once iron overload has been proven, especially using the noninvasive (MRI) method for quantifying tissue iron excess, it is logical, considering the likely damaging effects of chronic iron overload in these patients, to start an iron-depleting treatment (Figure 2). More data are, however, required in order both to assess the long-term deleterious effect of iron excess in this patient population, and to define the best therapeutic strategy. Preventing iron overload before performing

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E. Brissot, B.N. Savani, and M. Mohty

Figure 2. Schematic organigram of hyperferritinemia management. TS, transferrin saturation; ALT, alanine aminotransferase; AST, aspartate aminotranferase; CRP, c-reactive protein. *Until ferritin reaches normal range values; **ongoing clinical trials; ***if non anemia; ⫹/- relates to the invasive nature of liver biopsy.

allogeneic stem cell transplantation is an essential therapeutic approach.50,51,63– 65

Acknowledgments M. Mohty would like to thank the Région Pays de Loire, the Association pour la Recherche sur le Cancer (ARC), the Fondation de France, the Fondation contre la Leucémie, the Agence de Biomédecine, the Association Cent pour Sang la Vie, the Association Laurette Fuguain, and the IRGHET for their generous and continuous support for our clinical and basic research work. The Nantes group is supported by several grants from the French National Cancer Institute (PHRC, INCa).

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