Pediatric Hematology and Oncology, 27:374–379, 2010Copyright C© Informa UK Ltd.ISSN: 0888-0018 print / 1521-0669 onlineDOI: 10.3109/08880011003739463

POSTTRANSPLANT ORAL IRON-CHELATING THERAPY IN PATIENTS

WITH β-THALASSEMIA MAJOR

M. Akif Yesilipek, MD, Gulsun Karasu, MD, Mediha Kazik, MD,

Vedat Uygun, MD, and Zeynep Ozturk � Department of PediatricHematology-Oncology, Akdeniz University School of Medicine, Antalya, Turkey

� Allogeneic hematopoetic stem cell transplantation (HSCT) is the only radical cure of β-thalassemia. However, iron overload remains a cause of morbidity and mortality in posttransplantperiod. The authors present 7 patients as a preliminary report who underwent bone marrow trans-plant (BMT) and received oral chelating therapy (deferasirox) because of poor compliance to phle-botomy and desferrioxamine. The patients investigated mainly for possible side effects of deferasirox.No negative effect was seen in aspartate aminotransferase (AST), alanine aminotransferase (ALT),hemoglobin (Hb), and donor chimerism of the patients while serum ferritin levels significantly re-duced (P = .018). Although serum creatinin significantly increased (P = .034), it was in normallimits in all patients. The authors believe that this report shows promising findings to plan furtherstudies to clarify clinical safety and efficacy of deferasirox in posttransplant period.

Keywords bone marrow transplantation, iron overload, thalassemia

Hematopoetic stem cell transplantation (HSCT) is the only curative treat-ment modality in patients with hemoglobinopathies. Thalassemia-free sur-vival has been reported as more than 80% in some papers [1]. However,in thalassemia patients iron overload persist in many years and it is a rela-tively common problem even in posttransplant period. It may cause severemorbidity and also mortality in patients even though full donor chimerismis achieved [2]. Although successful iron removal was reported either withdesferrioxamine or phlebotomy in posttransplant period, there is no reportwith new oral chelation agents [3, 4].

In this paper, we report 7 β-thalassemia patients who received deferasiroxto reduce excessive body iron in posttransplant period as a preliminaryreport.

Received 26 October 2009; accepted 26 February 2010.Address correspondence to M. Akif Yesilipek, MD, Department of Pediatric Hematology-Oncology,

Akdeniz University School of Medicine, Antalya, Turkey. E-mail: yesilipek@akdeniz.edu.tr

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Posttransplant Iron Chelating in β-Thalassemia 375

PATIENTS AND METHODS

Seven thalassemia major patients who underwent HSCT in Akdeniz Uni-versity School of Medicine Department of Pediatric Hematology-Oncologywere enrolled to this study. The characteristics of the patients are shown inTable 1. All patients’ diagnosis as being thalassemia major was confirmedwith molecular tests. Risk classification prior to HSCT was made accordingto Pesaro classification [5]. Liver biopsy was performed in all patients beforetransplantation to evaluate hemosiderosis and fibrosis. Chimerism analyseswere performed at the end of 1st, 3rd, 6th, and 12th month of posttransplantperiod. Chimerism was evaluated by fluorescent in situ hybridization (FISH)in patients with sex-mismatched HSCT and by short tandem repeats (STRs)in others. Chelating therapy was started 6 to 12 months after HSCT. All pa-tients received deferasirox (Exjade, Novartis) with the dosage of 30 mg/kg,everday, orally. Chelating therapy is planned to be stopped when ferritinlevel is <500 µ/g/L. Serum blood urea nitrogen and creatinin levels werechecked weekly during the 1st month and then 2 times in a month. Serum ala-nine aminotransferase (ALT) and aspartate aminotransferase (AST) levelsand also complete blood counts were also checked periodically. Ferritin lev-els were measured once a month. The patients’ parents provided informedconsent at the beginning of the therapy. Wilcoxon signed test was used forstatistical evaluation of ALT, AST, serum creatinin, and ferritin levels beforeand after therapy.

RESULTS

Three of 7 patients were classified as Class II and 4 were Class III be-fore HSCT. Two of them had Grade II and 5 of them had Grade III–IVhemosiderosis and median hepatic fibrosis score was II (Ishak system) attime of HSCT. In pretransplant period, all patients were transfusion depen-dent and received chelating therapy. Median number of received transfu-sion was 96 (range: 45–228 transfusions). In all patients, deferasirox therapyachieved reduction in serum ferritin levels (Figure 1). None of the patientshad serum creatinin abnormality during the treatment. We also did not ob-serve any negative effect on ALT, AST, and hemoglobin (Hb) levels andchimerism status of the patients (Table 1).

DISCUSSION

Iron stores remain elevated after HSCT in thalassemic patients whohad significantly increased iron load (Class II and III patients) [1]. It hasbeen shown that it is necessary to reduce iron overload to prevent somecomplications such as cardiac and liver dysfunction [6, 7]. Mariotti et al.[8] suggested that transplanted thalassemia patients with subclinical left

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Posttransplant Iron Chelating in β-Thalassemia 377

FIGURE 1 Decrease in serum ferritin levels during therapy period.

ventricular diastolic dysfunction and impaired left ventricular contractil-ity may reverse with an effective regimen of iron reduction. Furthermore,Muretto et al. [9] reported that cirrhosis may be reversible after iron removaltreatment. Iron depletion after HSCT by desferrioxamine (DFO) or phle-botomy has been shown to effectively deplete body iron [3, 9]. However,DFO treatment is usually cumbersome for these patients, leading to lowcompliance to treatment program. Although, phlebotomy is considered astreatment of choice for treating iron overload following HSCT, it is difficultto perform in younger or anemic children. Recently, the new oral chelatingagents such as deferiprone and deferasirox have preferably been used dueto improved compliance. However, there is no experience with these drugsin transplanted thalassemic patients in respect to safety and efficacy. Thisis the restricting factor for usage of oral chelation in posttransplantationperiod. In our center by the end of August 2009, 114 β-thalassemia patientshad underwent HSCT, some of whom had experienced liver and cardiaccomplications in posttransplant period. We even lost a case with full donorchimerism because of liver cirrhosis. We believe that iron reduction is oneof the most important measures in posttransplant period to improve qualityof life and survival of the patients. Although DFO has been preferred by theclinicians because of experiences in application and also safety profile in thisgroup of thalassemia patients, some patients refused DFO using because ofsubcutaneous (SC) administration. Here in this paper, we report 7 patientswho underwent HSCT and received deferasirox instead of DFO to reduceserum ferritin levels after transplantation. It is well known that serum ferritinis not a good indicator for body iron overload. On the other hand, it has

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378 M. A. Yesilipek et al.

TABLE 2 Pretreatment and Posttreatment Comparison of the Laboratory Test Results

Pretreatment (Median) Posttreatment (Median) P value

Ferritin 4137 945 .018ALT 57 34 .028AST 41 26 .018Creatinin 0.34 0.46 .034

been widely use as a noninvasive and simple method particularly in develop-ing countries. Furthermore, Telfer et al. [10] reported that quantification ofliver iron from a single liver biopsy has little value in long-term monitoringof iron stores and most complications can be avoided if ferritin levels canbe brought down to <1500 µg/L. Also, Shalitin et al. [11] pointed out thatserum ferritin levels may be a predictor of impaired growth and puberty inthalassemia major patients.

Deferasirox (Exjade, ICL670) is an oral chelator with high iron-bindingpotency and selectivity. It has proven efficacy in reducing organ and plasmairon burden across a broad range of transfusion-dependent adult and pedi-atric patients [12–14]. However, long-term safety profile has not been estab-lished yet. Increasing in serum creatinin and elevations of liver transaminasesare the major side effects of deferasirox therapy published so far [14]. Safetyof a drug is very important in transplanted thalassemia patients with a higherrisk of previous organ damage related with either transfusional iron over-load or toxicities of the medications used during transplantation. Becauseof neutropenia risk of deferiprone, the other oral chelator available to use,deferasirox was preferred to be used in this study. The patients were in-vestigated closely for possible side effects during the treatment. Althoughtransient elevations in ALT and AST were observed, both were in normalrange at last evaluation. No negative effect was seen in Hb levels or chimerismstatus of the patients (Tables 1, 2). We noticed prominent decline in serumferritin levels as well as in ALT and AST values of the study group (P < .05).Although increase in creatinin levels were significant at last evaluation com-pared to initial value, all were kept within normal limits (P = .034) (Table 2).No other side effect that is attributed to deferasirox (such as dermatologicand gastrointestinal) was seen in our patients.

We think that this preliminary report with limited cases presents a promis-ing result to plan prospective and detailed multicenter studies with largerpopulation. The decline in ferritin levels seems acceptable, although only3 patients were being able to receive the drug longer than 12 months.

In conclusion, deferasirox may provide safety iron removal in posttrans-plant period in circumstances in which venous access is prohibitive or thepatient is anemic. However, close monitorization of the serum creatininlevel is essential. Further studies with more patients and longer follow up arerequired to define its clinical efficacy and safety.

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Posttransplant Iron Chelating in β-Thalassemia 379

Declaration of Interests: The authors report no conflicts of interest. Theauthors alone are responsible for the content and writing of the paper.

REFERENCES

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[2] Lucarelli G, Angelucci E, Giardini C, et al. Fate of iron stores in thalassemia after bone marrowtransplantation. Lancet. 1993;342:417–421.

[3] Angelucci E, Muretto P, Lucarelli G, et al. Phlebotomy to reduce iron overload in patients cured ofthalassemia by bone marrow transplantation. Blood. 1997;90:994–998.

[4] Giardini C, Galimberti M, Lucarelli G, et al. Desferrioxamine therapy accelerates clearance of irondeposits after bone marrow transplantation for thalassemia. Br J Haematol. 1995;89:868–873.

[5] Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in patients with thalassemia.N Engl J Med. 1990;322:417–421.

[6] Majhail NS, Lazarus HM, Burns LJ. Iron overload in hematopetic cell transplantation. Bone MarrowTransplant. 2008;41:997–1003.

[7] Jastaniah W, Harmatz P, Pakbaz Z, et al. Transfusional iron burden and liver toxicity after bonemarrow transplantation for acute myelogenous leukemia and hemoglobinopathies. Pediatr BloodCancer. 2008;50:319–324.

[8] Mariotti E, Angelucci E, Agostini A, et al. Evaluation of cardiac status in iron-loaded thalassemiapatients following bone marrow transplantation: improvement in cardiac function during reductionin body iron burden. Br J Haematol. 1998;103:916–921.

[9] Muretto P, Angelucci E, Lucarelli G. Reversibility of cirrhosis in patients cured of thalassemia bybone marrow transplantation. Ann Intern Med. 2002;136:667–672.

[10] Telfer PT, Prescott E, Holden S, et al. Hepatic iron concentration combined with long-term moni-toring of serum ferritin to predict complications of iron overload in thalassemia major. Br J Haematol.2000;110; 971–977.

[11] Shalitin S, Carmi D, Weintrob N, et al. Serum ferritin level as a predictor of impaired growth andpuberty in thalassemia major patients. Eur J Haematol. 2005;74:93–100.

[12] Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oraliron chelator, in patients with beta-thalassemia. Blood. 2006;107:3455–3462.

[13] Vichinsky E, Onyekwere O, Porter J, et al. A randomized comparison of deferasirox versus de-ferroxamine for the treatment of transfusional iron overload in sickle cell anemia. Br J Haematol.2007;136:501–508.

[14] Vichinsky E. Clinical application of deferasirox: practical patient management. Am J Hematol.2008;83:398–402.

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