Iron chelation therapy for patients with sickle cell disease and iron overload

A 21-year-old male with sickle cell disease (SCD) presented with severe pallor. He had received a total of 100 red blood cell (RBC) units in his lifetime, had a mean serum ferritin level of 3133 ng/ml, and liver iron concentration (LIC) of 12 mg Fe/g dry weight (dw). He was started on subcutaneous deferoxamine (DFO) infusions at a dose of 56 mg/kg/d, five days a week (equivalent to 40 mg/kg/d, seven days a week) and continued to receive 8–10 RBC units/year as treatment for pain. During the first six months of chelation therapy, his serum ferritin levels fell by around 50% of the pretreatment value, but then started to increase back up to the baseline values. The patient was noncompliant with DFO therapy. He experienced pain at the site of injection, could not sleep and was concerned about carrying a pump and not being accepted by his peers. He dropped out of college and abstained from all social activities. He was referred to a psychologist; however, this failed to improve compliance and he opted to stop DFO therapy altogether. The role of iron chelation therapy has long been acknowledged in the management of iron overload in patients receiving blood transfusion therapy; however, data specific to the treatment of patients with SCD are limited. DFO (Desferal®; Novartis Pharma AG, Basel, Switzerland) was the first iron chelator to be licensed, more than 40 years ago, for chronic iron overload as a result of transfusion-dependent anemia and remains the current reference standard iron chelator. The efficacy and safety of DFO is well established in patients with β-thalassemia major [1-3]; however, clinical evaluation in SCD-specific populations is limited. Early small-scale studies of transfused patients with SCD showed that DFO was able to increase urinary iron excretion [4, 5] and intensive chelation regimens in heavily iron-overloaded patients with SCD showed acceptable efficacy and safety [6-8]. In these small-scale studies, there were no reported incidences of impaired hearing or visual acuity, toxicities that have been noted in patients with β-thalassemia major and other rare anemias when doses are inappropriately high for the level of iron overload [9]. However, careful regulation of dosage and regular audio-visual monitoring is still advised. Increased zinc excretion demonstrated at very high DFO doses (180 mg/kg) [8] may lead to extreme zinc deficiency in patients with SCD who may already have decreased plasma zinc levels [10]. The verification of possible adverse events specific to patients with SCD most certainly requires further study. The major limitation of DFO is the requirement for frequent, slow parenteral administration, which can be painful and inconvenient. Compliance has a noticeable impact on a patient's response to therapy and can have serious consequences, as described in this case. In patients with β-thalassemia major, the demands of DFO therapy have been shown to have a negative impact on quality of life and mental health [11]. The impact of infusions may be greatest for adolescents and young adults, when being able to socialize with peers and forming intimate relationships is especially important [12]. Many patients and their families find the treatment regimen challenging [13] and, therefore, alternative oral therapies have been developed with the potential to facilitate compliance. Deferiprone (Ferriprox®; Apotex Inc., Toronto, ON, Canada) was the first orally active iron chelator to undergo evaluation in patients with transfusion-dependent iron overload. It is currently only available, however, in selected countries and indicated for the second-line treatment of iron overload in adult patients with thalassemia major only in whom DFO therapy is inadequate, intolerable, or unacceptable, and it is not currently available in the US for any indication [14]. The efficacy of deferiprone in controlling iron burden in patients with β-thalassemia major has been controversial [15, 16]. In addition, deferiprone has not been extensively evaluated in patients with SCD [17-20] and is not currently licensed for this indication. The approach of combining deferiprone with DFO has also been reported in a single male patient with SCD [21]; however, this regimen still requires compliance with DFO. Clinical trials in patients with β-thalassemia major have identified major complications including agranulocytosis, nausea, arthritis, and persistent liver dysfunction [22], and therefore patients treated with deferiprone require close monitoring. A 10-year-old boy with SCD developed serum ferritin levels of 2450 ng/ml after receiving more than 20 units of RBCs and was started on deferasirox at 20 mg/kg/d to reduce his serum ferritin levels. After three months of iron chelation therapy, the boy presented with severe gastrointestinal symptoms including diarrhea, nausea, and occasional vomiting, and was reluctant to continue taking deferasirox. As the diarrhea was severe, deferasirox therapy was interrupted until the diarrhea had resolved and then deferasirox was reintroduced at a lower dose of 10 mg/kg/d. The patient was also advised to take deferasirox at night rather than in the morning. He was also shown to be lactose intolerant, which may have contributed to the symptoms and therefore lactase capsules (Lactaid®; McNeil Nutritionals, Ft. Washington, PA) were taken in addition to the evening deferasirox dose. Increased fluid intake and adequate hydration were also emphasized. The gastrointestinal symptoms resolved and the patient was compliant with therapy and after three months of continuous deferasirox therapy, his serum ferritin had reduced to 1800 ng/ml. The patient continued on deferasirox 20 mg/kg/d with good tolerance, achieving a mean serum ferritin level of 1,500 ng/ml. Deferasirox (Exjade®; Novartis Pharma AG, Basel, Switzerland) is a once-daily oral iron chelator that has been extensively evaluated in patients with a wide range of transfusion-dependent anemia, including SCD, in both adult and pediatric patients [23, 24]. In a 1-year, multicenter, open-label, Phase II trial investigating the safety and efficacy of deferasirox versus DFO in patients with SCD [23], deferasirox treatment resulted in statistically significant and similar reductions in LIC as compared to DFO (−3.0 ± 6.2 [P < 0.001] vs. −2.8 ± 10.4 [P = 0.022] mg Fe/g dw for deferasirox vs. DFO, respectively). Deferasirox doses of 20 or 30 mg/kg/d were comparable with the reference standard therapy, DFO (40–60 mg/kg/d) (see Fig. 1). The most notable adverse events, irrespective of the relationship to study medication, were transient gastrointestinal symptoms and skin rash, consistent with clinical studies of deferasirox in patients with thalassemia major [23, 24]. There are a number of options available to manage gastrointestinal events, including dose interruption in severe cases, although counseling and supportive care is sufficient in the majority of patients with mild symptoms [25]. Management of gastrointestinal symptoms is a common situation faced by treating physicians, and a practical approach with the use of dose interruption is often suitable. Mean ± SD change in liver iron concentration (LIC) according to dose for deferasirox (solid squares) and deferoxamine (DFO, open squares) [23]. Reproduced with permission. Vichinsky E et al. Br J Hematol 2007;136:501–508. © John Wiley & Sons. The 21-year-old male with SCD (previously referred to in Case 1) was started on deferasirox 20 mg/kg/d; however, over the first six months, his serum ferritin levels continued to increase (see Fig. 2). Deferasirox was escalated to 30 mg/kg/d and serum ferritin levels started to decline steadily. However, after three months at this dose, serum creatinine levels increased >33% above the pretreatment level on two consecutive occasions. Glomerular filtration rate remained normal and there was no evidence of proteinuria or microalbuminuria. Alanine aminotransferase (ALT) also remained within normal levels. Deferasirox dose was therefore reduced to 20 mg/kg/d. Serum creatinine levels returned to normal and remained so throughout treatment. Even though deferasirox was decreased to 20 mg/kg/d, serum ferritin levels also continued to decline and by 21 months, serum ferritin levels dropped to below 500 ng/ml (see Fig. 2). As a result, the deferasirox dose was decreased to 10 mg/kg/d and later stopped completely. The patient continues to be monitored and will recommence therapy if serum ferritin levels reach 1000 ng/ml. Serum ferritin and serum creatinine trends over time and deferasirox dose adjustments. As patients with SCD often have abnormal renal function, patients receiving deferasirox should be monitored for increases in renal biochemical markers which can be readily managed with dose adjustments and interruptions if necessary. A recently pooled analysis of patients with a variety of anemias concluded that deferasirox may be used in patients with baseline creatinine clearance of 40–<60 ml/min with close monitoring, and should not be used in patients with baseline creatinine clearance of <40 ml/min [26]. The patients included in the 1-year deferasirox comparative trial had relatively normal renal and hepatic function [23]. During the study, 2.3% of patients receiving deferasirox experienced serum creatinine increases exceeding the upper limit of normal (ULN), compared with 3.2% of patients receiving DFO. Two consecutive increases in ALT levels >5 × ULN were observed in five patients treated with deferasirox, three of whom had at least one ALT level measurement >5 × ULN during the screening period. Elevations in ALT levels were transient in four patients and drug administration was continued as normal. One patient with persistently elevated ALT permanently discontinued treatment [23]. A dose reduction algorithm for the management of renal complications as specified in the deferasirox Summary of Product Characteristics has been used successfully to treat patients in our clinic as summarized in this example case. Although these data imply that deferasirox is well tolerated in patients with SCD, further studies are required in patients with abnormal baseline serum creatinine levels. Preliminary results from an extension to the 1-year comparative study have demonstrated continued reduction in body iron burden without increases in the incidence of adverse events for up to 3.5 years [27]; therefore, deferasirox has the potential to prevent complications of iron overload in patients with SCD who require ongoing blood transfusions. The body of evidence highlighting the benefits of deferasirox treatment in patients with SCD is growing, and longer-term data highlighting differences between the treatment of patients with SCD compared with other anemias are keenly awaited [28, 29]. Evidence has been accumulating to support the value of RBC transfusion therapy as an effective treatment for many complications associated with SCD, including reduction of the risk of stroke in children [30-33]. The landmark stroke prevention trial (STOP) demonstrated that the probability of remaining stroke-free was increased by 92% with long-term transfusion therapy in children with SCD. The follow-up study (STOPII) where patients were randomized to continue or stop receiving red cell transfusions was subsequently terminated and concluded that it was unsafe to stop transfusions in patients who were at high risk of stroke. Chronic or intermittent RBC transfusion therapy increases hemoglobin content and can decrease the proportion of sickle hemoglobin in the circulation to <30% of total hemoglobin [34]. However, repeated transfusions can lead to rapid iron loading and, as excess iron cannot be normally excreted, it accumulates over time in parenchymal tissue cells and is associated with organ damage, and ultimately, death [35]. There is a choice of transfusion method, depending on the specific requirements of the patient, including top-up, manual exchange, and automated exchange approaches. Top-up transfusions will inevitably lead to a greater positive iron balance, whereas exchange transfusion offers an alternative approach without the risk of increasing whole blood viscosity or contributing to iron burden, but it requires specialized equipment and skilled technicians. In contrast to patients with β-thalassemia major who require regular, lifelong blood-transfusion therapy, patients with SCD tend to receive transfusions on a more intermittent basis and iron accumulation may not be as routinely monitored and treated. Since patients with SCD now have improved life expectancy, transfusion therapy may be administered over considerably longer periods of time, increasing the potential for both allo-immunization and iron accumulation. Body iron overload has been shown to be associated with morbidity and mortality in patients with SCD [36, 37] and a positive correlation has been observed between the severity of iron overload and frequency of hospitalization [38]. There is also growing evidence to suggest a role for iron overload in the development of other SCD comorbidities such as pulmonary hypertension and cirrhosis [39, 40]. The clinical sequelae of iron overload have been widely reported in patients with β-thalassemia major, but data in patients with SCD have been more limited. The distribution and consequences of iron overload in patients with SCD have been shown to differ compared with patients with β-thalassemia major. Although the liver is the primary site of excess iron storage in both patients with SCD and β-thalassemia major, with LIC correlating significantly with the duration of transfusions, there are some disparities in the occurrence of organ injury [41, 42]. Furthermore, extensive studies in regularly transfused patients with β-thalassemia major have identified heart failure as the leading cause of death due to iron accumulation in the myocardium [43, 44]. While cardiac decompensation and cardiomyopathy are known clinical manifestations in patients with SCD, magnetic resonance imaging (MRI) T2* evaluation of cardiac iron load in patients with SCD has indicated lower levels of iron accumulation despite similar transfusion burdens [42, 45, 46]. A similar situation is seen with iron overload-associated endocrinopathy, which has been shown to be common in patients with β-thalassemia major but rarely reported in the population of patients with SCD [42, 47]. There are several hypotheses to explain these distinct differences in iron loading and organ toxicity, including differences in the rate and duration of transfusions as well as the possibility that the chronic inflammatory state associated with SCD is protective against tissue damage [48]. Another possible reason may be lower gastrointestinal absorption of iron in patients with SCD due to high hepcidin levels. Lower levels of nontransferrin-bound iron (NTBI) in patients with SCD, relative to those seen in patients with thalassemia major, also indicate that there may be intrinsic differences in iron transport and storage between these two populations [45, 49, 50]. As NTBI readily enters cardiac myocytes, this may account for the relative lack of cardiac iron in patients with SCD. Long-term studies are still required to address disease-specific consequences of iron overload in patients with SCD. While our understanding of iron overload-related organ damage in patients with SCD is still developing, the necessity for routine monitoring of iron is evident. Regular monitoring of iron overload is currently recommended in all patients who have been previously transfused with multiple RBC units over a protracted period of time or are currently undergoing regular transfusions [51, 52]. Serial measurement of steady-state serum ferritin levels is a relatively robust, convenient, and inexpensive marker of body iron burden, shown in certain studies to correlate very roughly with LIC across various transfusion-dependent anemias [53-55]. However, SCD is well recognized as a chronic inflammatory disease, with high cytokine levels (including tumor necrosis factor, IL-1 and IL-8) that are further elevated during episodes of crisis and which can affect the evaluation of serum ferritin levels [23, 52, 56, 57]. Therefore, a number of studies have failed to demonstrate a positive correlation of serum ferritin with LIC in patients with SCD [41, 58-62]. Other methods of monitoring body iron burden, such as measurement of LIC by biopsy or MRI techniques, may therefore be a more reliable approach [63], although these methods are not necessarily available in all clinics. The volume of transfused blood, or better, transfusion rate (total life transfusion units received/years receiving transfusions), may also be useful indicators of iron accumulation in patients with SCD [61, 64]. Labile plasma iron (LPI) is a directly chelatable form of NTBI, produced under conditions of iron overload and taken up by tissues through unregulated pathways. A correlation between NTBI and transfusion burden has been demonstrated, although NTBI measurements offered poor predictability of LIC as compared with serum ferritin levels [65]. Furthermore, LPI levels have also been shown to be low and within the normal range (<0.4 μmol/l [66]) in patients with SCD despite high serum ferritin [67]. Transfusion burden assessed by total life transfusion and transfusion rate, serial serum ferritin measurements in steady state, and MRI techniques remain good tools for iron overload assessment in patients with SCD. Iron overload is an inevitable consequence of long-term transfusion therapy, for which iron chelation therapy is indicated and recommended (Table I). All patients who receive RBC transfusions and iron chelation therapy should be regularly monitored and given practical and educational support in order to improve compliance with therapy. Although oral iron chelators are now available, compliance still remains a critical issue for patients and their health care team. It is important to educate families, especially parents, and encourage them to report possible adverse events associated with therapy that could affect compliance, particularly since earlier reporting of symptoms often results in improved outcomes for the patient. If a patient is not responding well to therapy, the factors affecting compliance should be considered as a possible cause and dealt with appropriately. Further studies are still required with longer-term follow-up, as life expectancy continues to increase in patients with SCD; therefore, a longer duration of iron chelation therapy will be required. Such data will help to instruct physicians and patients about the benefits of iron chelation therapy, hopefully leading to further reductions in the morbidity and mortality currently associated with SCD. The authors thank Professor David G. Nathan—Farber Cancer Institute, Boston, MA, USA—for providing valuable advice to the construction of this manuscript. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We would like to thank Dr Rebecca Helson for medical editorial assistance with this manuscript. The authors are fully responsible for the content and editorial decisions for this manuscript.

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