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Recent advances in improving the management of sickle cell disease
Blood Reviews 23 Suppl. 1 (2009) S9–S13
Contents lists available at ScienceDirect
Blood Reviews journal homepage: www.elsevier.com/locate/blre
REVIEW
Recent advances in improving the management of sickle cell disease Adlette Inati* Rafik Hariri University Hospital, Beirut, Lebanon
article info
abstract
Keywords: Sickle cell disease Iron overload Stroke Iron chelation therapy Deferasirox
Appropriate blood transfusions can both prevent and treat serious complications related to sickle cell disease (SCD), but inevitably lead to iron overload and its complications in terms of morbidity and mortality. Transfusion history and serial serum ferritin level assessments are convenient and cost-effective measures for monitoring iron overload in SCD. Monitoring and treatment of patients with SCD-related iron overload lags behind the standards of care for b-thalassaemia. Data from the EPIC trial suggest suboptimal iron chelation in SCD, highlighting the need to carefully monitor iron levels and initiate iron chelation therapy to avoid serious clinical sequelae. Deferasirox is effective and well tolerated in patients with SCD, including paediatric patients. Patient compliance is, however, important for effectiveness of iron chelation therapy. © 2009 Elsevier Ltd. All rights reserved.
Introduction The pathophysiology of sickle cell disease (SCD) was elucidated more than 50 years ago. A single base-pair change in the b-globin gene causes a single amino-acid substitution in the b-globin chain, resulting in the formation of aberrant haemoglobin S (HbS). Upon deoxygenation, HbS polymerizes to the sickle form and presents as two distinct clinical phenotypes characterized by either haemolysis or vaso-occlusion.1 Phenotype severity varies widely among patients with SCD, ranging from completely asymptomatic cases to very severe forms, although most patients (about 70%) have a moderate phenotype. During the first 6 years of life, SCD manifests primarily as bacteraemia, pain, acute splenic sequestration, acute coronary syndrome (ACS), and stroke.2–4 Chronic organ damage appears in the early teens. During adulthood, additional symptoms can arise. Acute symptoms include worsening of anaemia and priapism. Chronic symptoms include avascular necrosis, pulmonary hypertension, leg ulcers, microalbuminuria that can lead to renal failure, retinopathy, cholelithiasis, and iron overload. Awareness of the importance of managing iron overload in SCD patients is increasing gradually. Survival rates have improved remarkably in recent years, owing to interventional measures such as neonatal screening, penicillin prophylaxis, and disease-modifying therapies such as hydroxyurea, blood transfusions, and stem cell transplantation.5–7 As survival improves, more patients with SCD are expected to receive blood transfusions and for longer periods. The risk of iron overload, however, also increases as the number of * Correspondence: Dr. Adlette Inati. Head, Division of Pediatric Hematology-Oncology, Medical Director, Children’s Center for Cancer and Blood Diseases, Rafik Hariri University Hospital, Beirut, Lebanon. Research Associate, Balamand University, Consultant Hematologist, Chronic Care Center, Beirut, Beirut, Lebanon. E-mail address: [email protected] (A. Inati). 0268-960X /$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
transfusions increases. The following review summarizes the role of blood transfusions in patients with SCD, the clinical consequences of transfusion-related iron overload, and recent advances in the management of iron overload specifically in SCD. Blood transfusions in SCD Blood transfusions are administered in SCD to increase oxygencarrying capacity, replace rigid, sickle-shaped red blood cells with normal, deformable cells, and restore blood flow.8,9 Transfusions may be indicated for a variety of reasons in patients with SCD, including acute or episodic symptoms or long-term management. For medical emergencies, top-up or simple transfusions are usually indicated for severe anaemia due to parvovirus-induced transient red cell aplasia and for acute splenic sequestration. Exchange transfusions, on the other hand, are recommended for acute chest syndrome, severe sepsis, acute hepatic sequestration, acute multiorgan failure and, most importantly, stroke. Stroke is a leading cause of morbidity and mortality in children with SCD and is particularly associated with sickle cell anaemia. By the age of 20 years, 11% of SCD patients will have had a stroke, and over 50% of patients who have suffered one stroke will experience a recurrence.10,11 Blood transfusions reduce the risk of stroke. A randomized multicentre stroke prevention trial (STOP I) showed that the probability of high-risk children remaining stroke-free is significantly increased with chronic blood transfusions.8 Based on data from the STOP I trial, transcranial Doppler (TCD) screening has been recommended for all children with SCD aged 2–16 years. The STOP II trial, which randomized patients with normalized TCD following transfusions to either continue or discontinue transfusion therapy, was stopped early due to the high rate of events in patients who stopped receiving regular transfusions. The study found that 34% of patients
S10
A. Inati / Blood Reviews 23 (2009) S9–S13 y = 10.069x + 475.12 R 2 = 0.2527 p < 0.001 5000 4000 3000 2000 1000
y = 10.069x + 475.12 R 2 = 0.2527
6000
LIC (mg Fe/g dry wt)
Serum ferritin (μg/L)
6000
p < 0.001
5000 4000 3000 2000 1000
0
100
200
300
400
Total number of lifetime transfusions
0
100
200
300
400
Total number of lifetime transfusions
Fig. 1. MRI R2 mapping accurately estimates iron overload in patients with SCD. Sample size: 52. Data from Inati A et al.19 . LIC = liver iron concentration; MRI = magnetic resonance imaging; SCD = sickle cell disease.
who discontinued transfusions reverted to a high-risk state for stroke according to TCD, thereby emphasizing the need to continue transfusions in this category of patients.12 Iron overload in SCD Chronic blood transfusions can result in iron overload. Under normal conditions, iron in the plasma binds with transferrin for safe and effective processing. Transfusions can increase iron levels to a point where transferrin becomes saturated, and levels of toxic non-transferrin bound iron (NTBI) increase. The presence of NTBI in plasma due to frequent blood transfusions eventually leads to uncontrolled iron loading in organs.13 If not treated effectively, iron overload results in significant morbidity and mortality. Iron overload is often underestimated in SCD. A review of causes of death in two studies involving more than 500 adult patients with SCD revealed that between 7% and 45% of deaths could be attributed to iron overload.14,15 Nevertheless, monitoring and treatment of iron overload tends to be suboptimal in SCD patients, compared with other anaemias associated with transfusional iron overload, such as b-thalassaemia major. A recent cross-sectional study in transfused patients with SCD and b-thalassaemia major in 31 clinics in the USA, Canada, and the UK revealed disparities in the monitoring and management of iron overload between these two diseases.16 The likelihood of performing a liver biopsy for routine iron monitoring was significantly higher in b-thalassaemia major than SCD. Patients with b-thalassaemia major were also more likely to undergo screening for iron-related organ injury. Furthermore, in the EPIC trial, 24% of the 80 iron-overloaded patients with SCD were chelation-naive prior to study entry, despite having a median serum ferritin level of 3163 ng/mL.17 These observations highlight the need for better monitoring and intervention for iron overload in SCD patients. Various tools have been defined for assessment of iron overload. Measuring serum ferritin (SF) levels is a non-invasive, inexpensive, and widely available method. Its accuracy, however, is confounded by multiple factors such as inflammatory processes which can increase serum ferritin levels. It is advisable to obtain serial serum ferritin values in steady state to assess trends rather than to rely on a single value. Transferrin saturation is another readily available cost-effective indicator; however, it is significantly decreased during pain crises. Liver iron concentration (LIC) by biopsy is the “gold standard” and has been shown to accurately predict total body iron stores. However, it is invasive and requires experience and expertise. Magnetic resonance imaging (MRI) has been validated to measure iron levels in multiple organs including the heart, liver, pancreas, and spleen. It is sensitive and noninvasive, but also expensive. Superconducting quantum interference device (SQUID) is also non-invasive, quantitative, and accurate but
its availability is limited and it can only measure iron in the liver. NTBI, the toxic form of iron, is a novel indicator of iron overload which is still being investigated. Recent studies have shown that NTBI seems to encompass forms of iron that are readily chelated.18 In a recent cross-sectional study enrolling 52 randomly selected chelation-naive Lebanese SCD patients, LIC as assessed by R2 magnetic resonance imaging (MRI) significantly correlated with steady-state serum ferritin.19 This highlights the value of using serum ferritin to monitor iron overload. Both serum ferritin levels and LIC were significantly correlated with the total number of lifetime transfusions (TLT).19 However, transfusion rate (TR) calculated according to the following formula [TLT (units)/years receiving transfusion] was a much stronger predictor of serum ferritin (R2 = 0.959; p < 0.001) and LIC (R2 = 0.978; p < 0.001) than TLT (Fig. 1). No patient with a TR less than 10 units/year had a serum ferritin >1000 ng/mL or LIC >3 mg Fe/g dw; once this threshold was exceeded, serum ferritin and LIC rose linearly with TR.20 In a subset of 23 patients, cardiac T2* MRI was normal in all subjects, and no correlation was found between T2* MRI and either serum ferritin or LIC, confirming earlier observations that liver iron overload may occur in SCD patients in the absence of cardiac iron overload (Fig. 2).21,22 Management of iron overload One way to minimize iron overload in SCD patients is to use red-cell exchange transfusions. This approach is effective but underutilized in the treatment of acute and chronic disease manifestations.8,9 It increases oxygen-carrying capacity while reducing blood viscosity and is associated with minimal-to-no iron overload. However, redcell exchange transfusions are expensive and require expertise and two venous access points. They are also associated with a higher risk of infection and allo-immunization.23 Red-cell exchange transfusions are not indicated for pain, but are useful in acute infarctive stroke, ACS, multi-organ failure, and some hepatic syndromes.23,24 The most common way to manage transfusional iron overload is with iron chelation therapy. Guidelines have recently been established for the use of iron chelation therapy in patients with SCD (Table 1).23,24 The largest study of iron chelation therapy conducted to date specifically in SCD patients is Study 109.25 In this study, a total of 195 patients with SCD, half of whom were children, were randomized to receive either deferasirox or deferoxamine. Patients who finished the 1-year core study were eligible to either continue deferasirox or to crossover from deferoxamine to deferasirox therapy in the extension study period which has now reached 3.5 years. Data from the 1-year core study demonstrated that changes in iron levels (LIC and serum
A. Inati / Blood Reviews 23 (2009) S9–S13
45
45
40
40
35
35
Cardiac T2* (ms)
Cardiac T2* (ms)
50
p = NS
50
30 25 Normal T2*
20 15
S11 p = NS
30 25 Normal T2*
20 15 10
10 High serum ferritin
5
5
Mild LIC Moderate LIC
Severe LIC
3
15
0
0 0
1000
2000
3000
4000
Serum ferritin (ng/mL)
0
6
9
12
18
21
24
LIC (mg Fe/g dw)
Fig. 2. Absence of cardiac siderosis in sickle cell disease. N = 23 (17 sickle cell anaemia, 6 sickle thalassaemia). Data from Inati A et al.21 . LIC = liver iron concentration; NS = non-significant.
Table 1 Guidelines for treatment of iron overload in patients with SCD. Data from the Division of Blood Diseases (DBDR) at the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of health (NIH)2,24 and Sickle Cell Society, UK.23
overload in patients with SCD Data from the Division of Blood Diseases (DBDR) at the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of health (NIH)2,24 and Sickle Cell Society, UK. 23 NIH guidelines on “The management of sickle cell disease” (2002)24 recommend that chelation therapy (with deferoxamine) is considered when: Patients have received cumulative transfusions of 120 cc pRBC/kg Steady-st ate serum ferritin level > 1,000 μg/L LIC ≥7 mg Fe/g dry w t UK guidelines on “Standards for the clinical care of adults with sickle cell disease” (2008)23 recommend that iron chelation therapy (with DFO or deferasirox) is considered when: Patients have received at least 20 top-up transfusions LIC ≥7 mg Fe/g dry w t DFO = deferoxamine; LIC = liver iron concentration; pRBC = packed red blood cells; SCD = sickle cell disease.
2. Castro O, Brambilla DJ, Thorington B et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 1994; 84:643-649. 23. Sickle Cell Society, UK, 2008. Available at: www.sicklecellsociety.org/CareBook.pdf. 24. National Institutes of Health, National Heart, Lung, and Blood Institute, and Division of Blood Diseases and Resources, The management of sickle cell disease. Bethesda, MD: NIH. (NIH Publication No 02-2117).
ferritin) were achieved in a dose-dependent manner (Fig. 3).25 Iron balance was achieved with 10 and 20 mg/kg/day deferasirox, and negative iron balance with 30 mg/kg/day. Similar iron balances were achieved with deferoxamine at comparable doses (35 to 50 mg/kg/day).25 Furthermore, at weeks 2, 12, and 24, and at the end of the study, significantly more patients in the deferasirox group reported that the treatment was “very convenient” or “convenient”, compared with those taking deferoxamine (Fig. 4).26 Over a median of 3.1 years of treatment, deferasirox continued to provide dosedependent maintenance or reduction in serum ferritin.27 The adverse event profile in the extension study was similar to that observed in the 1-year core study, with the annual frequency of investigator-reported adverse events decreasing from year to year. Serum creatinine levels did not change substantially from baseline over 3.5 years of deferasirox treatment. In the extension
study, nine patients (6.8%) had two consecutive increases in serum creatinine that were both >33% above baseline and above the ULN; progressive increases in serum creatinine, however, were not observed.27 Similar results have been reported based on real-world experience with deferasirox outside of the clinical trial setting. Raphael et al.28 assessed the efficacy and safety of treatment with deferasirox in a retrospective review of 59 paediatric patients (48 had SCD) with significant iron overload. The mean serum ferritin level at baseline was 2117 ng/mL, despite the fact that 53% had received prior deferoxamine. Adherence to treatment with oral deferasirox in these patients was relatively high (76%). Thirty-four patients received at least 12 months treatment with deferasirox. Among these patients, a reduction in serum ferritin levels was seen in 30% of patients overall and 44% of patients with good compliance.
A. Inati / Blood Reviews 23 (2009) S9–S13 Corrected LIC
Change in serum ferritin (μg/L)
Change in iron burden (μg/L) (mg Fe/g dry weight)
S12
4 2 0 –2 –4 –6 –8 –10 –12 –14
3000
Serum ferritin levels
2000 1000 0 –1000 –2000 –3000 –4000 –5000
Deferasirox (n = 113)
Deferasirox (n = 83)
Deferoxamine (n = 54)
Deferoxamine (n = 33)
–16 –18
5 < 25
10 25 – < 35
20 35 – < 50
30 50
Deferasirox Deferoxamine
5 < 25
10 25 – < 35
20 35 – < 50
30 50
Planned starting dose (mg/kg/day)
Planned starting dose (mg/kg/day)
Fig. 3. Dose-dependent changes in iron burden. In patients with sickle cell disease, iron balance was achieved with 10 and 20 mg/kg/day deferasirox, and negative iron balance with 30 mg/kg/day. Data from Vichinsky E et al.25 . LIC = liver iron concentration.
Deferasirox Deferoxamine
90
methods, such as liver biopsy and MRI, can provide a more accurate assessment of body iron, but are also invasive (biopsy) and expensive (MRI). • The oral iron chelator deferasirox is effective and well tolerated in patients with SCD, including paediatric patients.
80
Patients (%)
70 60 50 40
Disclosure
30 20 10 0 Baseline
Week 2
Week 12
Week 24
End of study
Fig. 4. Convenience of iron chelation therapy. At weeks 2, 12, 24 and end of study, significantly more patients in the deferasirox group reported that treatment was “very convenient” or “convenient” compared to those patients on deferoxamine (p < 0.0001). Data from Vichinsky E et al.26 . Reproduced with permission from S. Karger AG, Basel.
Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. The author is fully responsible for the content and editorial decisions for this manuscript. Ryan Blanchard is thanked for medical editorial assistance with this manuscript. Conflict of interest and funding Dr Inati has received speaker’s honoraria and research funding from Novartis.
Conclusions
References
Despite being a monogenic disease, SCD is characterized by phenotypic heterogeneity and varying degrees of severity. Blood transfusions remain an important component of the management of SCD, and have been shown to effectively reduce the risk of stroke in these patients. Chronic transfusions, however, can lead to iron overload, which is associated with substantial morbidity and mortality. Evidence suggests that iron overload is underappreciated in SCD, leading to suboptimal monitoring and intervention. Several methods are available to asses iron levels in the body; tracking the patient’s transfusion history and serum ferritin levels over time is a relatively easy and cost-effective way to monitor trends in iron levels. Iron chelation therapy is an effective way to maintain or reduce iron levels in SCD patients with transfusional iron overload. Studies have demonstrated that the oral iron chelator deferasirox is safe and effective in adult and paediatric patients (aged 2 years or more) with SCD, with relatively good rates of treatment compliance.
1. Inati A, Koussa S, Taher A, et al. Sickle cell disease: new insights into pathophysiology and treatment. Pediatr Ann 2008;37:311–25. 2. Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 1994;84:643–9. 3. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood 1995; 86:776–83. 4. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998;91:288–94. 5. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med 1986;314:1593–9. 6. Vichinsky E, Hurst D, Earles A, et al. Newborn screening for sickle cell disease: effect on mortality. Pediatrics 1988;81:749–55. 7. Vichinsky EP. Comprehensive care in sickle cell disease: its impact on morbidity and mortality. Semin Hematol 1991;28:220–6. 8. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5–11. 9. Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. N Engl J Med 1995;333:206–13. 10. Ohene-Frempong K. Indications for red cell transfusion in sickle cell disease. Semin Hematol 2001;38(1 Suppl 1):5–13. 11. Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in patients with sickle cell disease treated with erythrocyte transfusions. J Pediatr 1995;126:896– 899. 12. Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med 2005;353:2769–78. 13. Al-Refaie FN, Wickens DG, Wonke B, et al. Serum non-transferrin bound iron in beta-thalassaemia major patients treated with desferrioxamine and L1. Br J Haematol 1992;82:431–6.
Practice points • Patients with SCD who receive blood transfusions may be at risk of developing iron overload, which can contribute to morbidity and mortality. • Monitoring and treatment of iron overload in SCD is currently inadequate, compared with the standard of care in patients with other transfusion-dependent anaemias. • The most cost-effective way to assess body iron levels is by using the transfusion history and serum ferritin levels; other
A. Inati / Blood Reviews 23 (2009) S9–S13 14. Darbari DS, Kple-Faget P, Kwagyan J, et al. Circumstances of death in adult sickle cell disease patients. Am J Haematol 2006;81:858–63. 15. Aduloju SO, Palmer S, Eckman JR. Mortality in sickle cell patient transitioning from pediatric to adult program: 10 years grady comprehensive sickle cell center experience. Blood 2008;112: abstract 1426. 16. Fung EB, Harmatz PR, Milet M, et al. Disparity in the management of iron overload between patients with sickle cell disease and thalassemia who received transfusions. Transfusion 2008;48:1971–80. 17. Cappellini MD, Porter J, El-Beshlawy A, et al. Tailoring iron chelation by iron intake and serum ferritin: prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Haematologica 2009 [Epub ahead of print]. 18. Breuer W, Hershko C, Cabantchik ZI. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci 2000;23:185–92. 19. Inati A, Taha M, Musallam KM, et al. Magnetic resonance imaging R2 mapping accurately estimates iron overload in sickle cell disease patients. EHA 2009: abstract 1285. 20. Inati A, Musallam KM, Wood JC, et al. Iron overload indices rise linearly with transfusion rate in patients with sickle cell disease. Blood; in press. 21. Inati A, Musallam KM, Wood JC, et al. Absence of cardiac siderosis by MRI T2* despite transfusion burden, hepatic and serum iron overload in Lebanese patients with sickle cell disease. Eur J Haematol 2009;83:565–71.
S13
22. Inati A, Musallam KM, Taha M, et al. Magnetic resonance imaging T2* in the evaluation of cardiac iron overload in patients with sickle cell disease. EHA 2009: abstract 1286. 23. Sickle Cell Society, UK, 2008. Available at: www.sicklecellsociety.org/CareBook.pdf. 24. National Institutes of Health, National Heart, Lung, and Blood Institute, and Division of Blood Diseases and Resources. The management of sickle cell disease (NIH Publication No 02-2117). Bethesda, MD: NIH; 2002. 25. Vichinsky E, Onyekwere O, Porter J, et al. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007;136:501–8. 26. Vichinsky E, Pakbaz Z, Onyekwere O, et al. Patient-reported outcomes of deferasirox (Exjade, ICL670) versus deferoxamine in sickle cell disease patients with transfusional hemosiderosis. Substudy of a randomized open-label phase II trial. Acta Haematol 2008;119:133–41. 27. Vichinsky E. Coates T, Thompson AA, et al. Deferasirox (Exjade® ), the once-daily oral iron chelator, demonstrates safety and efficacy in patient with sickle cell disease (CD: 3.5-year follow-up. ASH 2008: abstract 1420. 28. Raphael JL, Bernhardt MB, Mahoney DH, et al. Oral iron chelation and the treatment of iron overload in a pediatric hematology center. Pediatr Blood Cancer 2009;52:616–20.
Contents lists available at ScienceDirect
Blood Reviews journal homepage: www.elsevier.com/locate/blre
REVIEW
Recent advances in improving the management of sickle cell disease Adlette Inati* Rafik Hariri University Hospital, Beirut, Lebanon
article info
abstract
Keywords: Sickle cell disease Iron overload Stroke Iron chelation therapy Deferasirox
Appropriate blood transfusions can both prevent and treat serious complications related to sickle cell disease (SCD), but inevitably lead to iron overload and its complications in terms of morbidity and mortality. Transfusion history and serial serum ferritin level assessments are convenient and cost-effective measures for monitoring iron overload in SCD. Monitoring and treatment of patients with SCD-related iron overload lags behind the standards of care for b-thalassaemia. Data from the EPIC trial suggest suboptimal iron chelation in SCD, highlighting the need to carefully monitor iron levels and initiate iron chelation therapy to avoid serious clinical sequelae. Deferasirox is effective and well tolerated in patients with SCD, including paediatric patients. Patient compliance is, however, important for effectiveness of iron chelation therapy. © 2009 Elsevier Ltd. All rights reserved.
Introduction The pathophysiology of sickle cell disease (SCD) was elucidated more than 50 years ago. A single base-pair change in the b-globin gene causes a single amino-acid substitution in the b-globin chain, resulting in the formation of aberrant haemoglobin S (HbS). Upon deoxygenation, HbS polymerizes to the sickle form and presents as two distinct clinical phenotypes characterized by either haemolysis or vaso-occlusion.1 Phenotype severity varies widely among patients with SCD, ranging from completely asymptomatic cases to very severe forms, although most patients (about 70%) have a moderate phenotype. During the first 6 years of life, SCD manifests primarily as bacteraemia, pain, acute splenic sequestration, acute coronary syndrome (ACS), and stroke.2–4 Chronic organ damage appears in the early teens. During adulthood, additional symptoms can arise. Acute symptoms include worsening of anaemia and priapism. Chronic symptoms include avascular necrosis, pulmonary hypertension, leg ulcers, microalbuminuria that can lead to renal failure, retinopathy, cholelithiasis, and iron overload. Awareness of the importance of managing iron overload in SCD patients is increasing gradually. Survival rates have improved remarkably in recent years, owing to interventional measures such as neonatal screening, penicillin prophylaxis, and disease-modifying therapies such as hydroxyurea, blood transfusions, and stem cell transplantation.5–7 As survival improves, more patients with SCD are expected to receive blood transfusions and for longer periods. The risk of iron overload, however, also increases as the number of * Correspondence: Dr. Adlette Inati. Head, Division of Pediatric Hematology-Oncology, Medical Director, Children’s Center for Cancer and Blood Diseases, Rafik Hariri University Hospital, Beirut, Lebanon. Research Associate, Balamand University, Consultant Hematologist, Chronic Care Center, Beirut, Beirut, Lebanon. E-mail address: [email protected] (A. Inati). 0268-960X /$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
transfusions increases. The following review summarizes the role of blood transfusions in patients with SCD, the clinical consequences of transfusion-related iron overload, and recent advances in the management of iron overload specifically in SCD. Blood transfusions in SCD Blood transfusions are administered in SCD to increase oxygencarrying capacity, replace rigid, sickle-shaped red blood cells with normal, deformable cells, and restore blood flow.8,9 Transfusions may be indicated for a variety of reasons in patients with SCD, including acute or episodic symptoms or long-term management. For medical emergencies, top-up or simple transfusions are usually indicated for severe anaemia due to parvovirus-induced transient red cell aplasia and for acute splenic sequestration. Exchange transfusions, on the other hand, are recommended for acute chest syndrome, severe sepsis, acute hepatic sequestration, acute multiorgan failure and, most importantly, stroke. Stroke is a leading cause of morbidity and mortality in children with SCD and is particularly associated with sickle cell anaemia. By the age of 20 years, 11% of SCD patients will have had a stroke, and over 50% of patients who have suffered one stroke will experience a recurrence.10,11 Blood transfusions reduce the risk of stroke. A randomized multicentre stroke prevention trial (STOP I) showed that the probability of high-risk children remaining stroke-free is significantly increased with chronic blood transfusions.8 Based on data from the STOP I trial, transcranial Doppler (TCD) screening has been recommended for all children with SCD aged 2–16 years. The STOP II trial, which randomized patients with normalized TCD following transfusions to either continue or discontinue transfusion therapy, was stopped early due to the high rate of events in patients who stopped receiving regular transfusions. The study found that 34% of patients
S10
A. Inati / Blood Reviews 23 (2009) S9–S13 y = 10.069x + 475.12 R 2 = 0.2527 p < 0.001 5000 4000 3000 2000 1000
y = 10.069x + 475.12 R 2 = 0.2527
6000
LIC (mg Fe/g dry wt)
Serum ferritin (μg/L)
6000
p < 0.001
5000 4000 3000 2000 1000
0
100
200
300
400
Total number of lifetime transfusions
0
100
200
300
400
Total number of lifetime transfusions
Fig. 1. MRI R2 mapping accurately estimates iron overload in patients with SCD. Sample size: 52. Data from Inati A et al.19 . LIC = liver iron concentration; MRI = magnetic resonance imaging; SCD = sickle cell disease.
who discontinued transfusions reverted to a high-risk state for stroke according to TCD, thereby emphasizing the need to continue transfusions in this category of patients.12 Iron overload in SCD Chronic blood transfusions can result in iron overload. Under normal conditions, iron in the plasma binds with transferrin for safe and effective processing. Transfusions can increase iron levels to a point where transferrin becomes saturated, and levels of toxic non-transferrin bound iron (NTBI) increase. The presence of NTBI in plasma due to frequent blood transfusions eventually leads to uncontrolled iron loading in organs.13 If not treated effectively, iron overload results in significant morbidity and mortality. Iron overload is often underestimated in SCD. A review of causes of death in two studies involving more than 500 adult patients with SCD revealed that between 7% and 45% of deaths could be attributed to iron overload.14,15 Nevertheless, monitoring and treatment of iron overload tends to be suboptimal in SCD patients, compared with other anaemias associated with transfusional iron overload, such as b-thalassaemia major. A recent cross-sectional study in transfused patients with SCD and b-thalassaemia major in 31 clinics in the USA, Canada, and the UK revealed disparities in the monitoring and management of iron overload between these two diseases.16 The likelihood of performing a liver biopsy for routine iron monitoring was significantly higher in b-thalassaemia major than SCD. Patients with b-thalassaemia major were also more likely to undergo screening for iron-related organ injury. Furthermore, in the EPIC trial, 24% of the 80 iron-overloaded patients with SCD were chelation-naive prior to study entry, despite having a median serum ferritin level of 3163 ng/mL.17 These observations highlight the need for better monitoring and intervention for iron overload in SCD patients. Various tools have been defined for assessment of iron overload. Measuring serum ferritin (SF) levels is a non-invasive, inexpensive, and widely available method. Its accuracy, however, is confounded by multiple factors such as inflammatory processes which can increase serum ferritin levels. It is advisable to obtain serial serum ferritin values in steady state to assess trends rather than to rely on a single value. Transferrin saturation is another readily available cost-effective indicator; however, it is significantly decreased during pain crises. Liver iron concentration (LIC) by biopsy is the “gold standard” and has been shown to accurately predict total body iron stores. However, it is invasive and requires experience and expertise. Magnetic resonance imaging (MRI) has been validated to measure iron levels in multiple organs including the heart, liver, pancreas, and spleen. It is sensitive and noninvasive, but also expensive. Superconducting quantum interference device (SQUID) is also non-invasive, quantitative, and accurate but
its availability is limited and it can only measure iron in the liver. NTBI, the toxic form of iron, is a novel indicator of iron overload which is still being investigated. Recent studies have shown that NTBI seems to encompass forms of iron that are readily chelated.18 In a recent cross-sectional study enrolling 52 randomly selected chelation-naive Lebanese SCD patients, LIC as assessed by R2 magnetic resonance imaging (MRI) significantly correlated with steady-state serum ferritin.19 This highlights the value of using serum ferritin to monitor iron overload. Both serum ferritin levels and LIC were significantly correlated with the total number of lifetime transfusions (TLT).19 However, transfusion rate (TR) calculated according to the following formula [TLT (units)/years receiving transfusion] was a much stronger predictor of serum ferritin (R2 = 0.959; p < 0.001) and LIC (R2 = 0.978; p < 0.001) than TLT (Fig. 1). No patient with a TR less than 10 units/year had a serum ferritin >1000 ng/mL or LIC >3 mg Fe/g dw; once this threshold was exceeded, serum ferritin and LIC rose linearly with TR.20 In a subset of 23 patients, cardiac T2* MRI was normal in all subjects, and no correlation was found between T2* MRI and either serum ferritin or LIC, confirming earlier observations that liver iron overload may occur in SCD patients in the absence of cardiac iron overload (Fig. 2).21,22 Management of iron overload One way to minimize iron overload in SCD patients is to use red-cell exchange transfusions. This approach is effective but underutilized in the treatment of acute and chronic disease manifestations.8,9 It increases oxygen-carrying capacity while reducing blood viscosity and is associated with minimal-to-no iron overload. However, redcell exchange transfusions are expensive and require expertise and two venous access points. They are also associated with a higher risk of infection and allo-immunization.23 Red-cell exchange transfusions are not indicated for pain, but are useful in acute infarctive stroke, ACS, multi-organ failure, and some hepatic syndromes.23,24 The most common way to manage transfusional iron overload is with iron chelation therapy. Guidelines have recently been established for the use of iron chelation therapy in patients with SCD (Table 1).23,24 The largest study of iron chelation therapy conducted to date specifically in SCD patients is Study 109.25 In this study, a total of 195 patients with SCD, half of whom were children, were randomized to receive either deferasirox or deferoxamine. Patients who finished the 1-year core study were eligible to either continue deferasirox or to crossover from deferoxamine to deferasirox therapy in the extension study period which has now reached 3.5 years. Data from the 1-year core study demonstrated that changes in iron levels (LIC and serum
A. Inati / Blood Reviews 23 (2009) S9–S13
45
45
40
40
35
35
Cardiac T2* (ms)
Cardiac T2* (ms)
50
p = NS
50
30 25 Normal T2*
20 15
S11 p = NS
30 25 Normal T2*
20 15 10
10 High serum ferritin
5
5
Mild LIC Moderate LIC
Severe LIC
3
15
0
0 0
1000
2000
3000
4000
Serum ferritin (ng/mL)
0
6
9
12
18
21
24
LIC (mg Fe/g dw)
Fig. 2. Absence of cardiac siderosis in sickle cell disease. N = 23 (17 sickle cell anaemia, 6 sickle thalassaemia). Data from Inati A et al.21 . LIC = liver iron concentration; NS = non-significant.
Table 1 Guidelines for treatment of iron overload in patients with SCD. Data from the Division of Blood Diseases (DBDR) at the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of health (NIH)2,24 and Sickle Cell Society, UK.23
overload in patients with SCD Data from the Division of Blood Diseases (DBDR) at the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of health (NIH)2,24 and Sickle Cell Society, UK. 23 NIH guidelines on “The management of sickle cell disease” (2002)24 recommend that chelation therapy (with deferoxamine) is considered when: Patients have received cumulative transfusions of 120 cc pRBC/kg Steady-st ate serum ferritin level > 1,000 μg/L LIC ≥7 mg Fe/g dry w t UK guidelines on “Standards for the clinical care of adults with sickle cell disease” (2008)23 recommend that iron chelation therapy (with DFO or deferasirox) is considered when: Patients have received at least 20 top-up transfusions LIC ≥7 mg Fe/g dry w t DFO = deferoxamine; LIC = liver iron concentration; pRBC = packed red blood cells; SCD = sickle cell disease.
2. Castro O, Brambilla DJ, Thorington B et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 1994; 84:643-649. 23. Sickle Cell Society, UK, 2008. Available at: www.sicklecellsociety.org/CareBook.pdf. 24. National Institutes of Health, National Heart, Lung, and Blood Institute, and Division of Blood Diseases and Resources, The management of sickle cell disease. Bethesda, MD: NIH. (NIH Publication No 02-2117).
ferritin) were achieved in a dose-dependent manner (Fig. 3).25 Iron balance was achieved with 10 and 20 mg/kg/day deferasirox, and negative iron balance with 30 mg/kg/day. Similar iron balances were achieved with deferoxamine at comparable doses (35 to 50 mg/kg/day).25 Furthermore, at weeks 2, 12, and 24, and at the end of the study, significantly more patients in the deferasirox group reported that the treatment was “very convenient” or “convenient”, compared with those taking deferoxamine (Fig. 4).26 Over a median of 3.1 years of treatment, deferasirox continued to provide dosedependent maintenance or reduction in serum ferritin.27 The adverse event profile in the extension study was similar to that observed in the 1-year core study, with the annual frequency of investigator-reported adverse events decreasing from year to year. Serum creatinine levels did not change substantially from baseline over 3.5 years of deferasirox treatment. In the extension
study, nine patients (6.8%) had two consecutive increases in serum creatinine that were both >33% above baseline and above the ULN; progressive increases in serum creatinine, however, were not observed.27 Similar results have been reported based on real-world experience with deferasirox outside of the clinical trial setting. Raphael et al.28 assessed the efficacy and safety of treatment with deferasirox in a retrospective review of 59 paediatric patients (48 had SCD) with significant iron overload. The mean serum ferritin level at baseline was 2117 ng/mL, despite the fact that 53% had received prior deferoxamine. Adherence to treatment with oral deferasirox in these patients was relatively high (76%). Thirty-four patients received at least 12 months treatment with deferasirox. Among these patients, a reduction in serum ferritin levels was seen in 30% of patients overall and 44% of patients with good compliance.
A. Inati / Blood Reviews 23 (2009) S9–S13 Corrected LIC
Change in serum ferritin (μg/L)
Change in iron burden (μg/L) (mg Fe/g dry weight)
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4 2 0 –2 –4 –6 –8 –10 –12 –14
3000
Serum ferritin levels
2000 1000 0 –1000 –2000 –3000 –4000 –5000
Deferasirox (n = 113)
Deferasirox (n = 83)
Deferoxamine (n = 54)
Deferoxamine (n = 33)
–16 –18
5 < 25
10 25 – < 35
20 35 – < 50
30 50
Deferasirox Deferoxamine
5 < 25
10 25 – < 35
20 35 – < 50
30 50
Planned starting dose (mg/kg/day)
Planned starting dose (mg/kg/day)
Fig. 3. Dose-dependent changes in iron burden. In patients with sickle cell disease, iron balance was achieved with 10 and 20 mg/kg/day deferasirox, and negative iron balance with 30 mg/kg/day. Data from Vichinsky E et al.25 . LIC = liver iron concentration.
Deferasirox Deferoxamine
90
methods, such as liver biopsy and MRI, can provide a more accurate assessment of body iron, but are also invasive (biopsy) and expensive (MRI). • The oral iron chelator deferasirox is effective and well tolerated in patients with SCD, including paediatric patients.
80
Patients (%)
70 60 50 40
Disclosure
30 20 10 0 Baseline
Week 2
Week 12
Week 24
End of study
Fig. 4. Convenience of iron chelation therapy. At weeks 2, 12, 24 and end of study, significantly more patients in the deferasirox group reported that treatment was “very convenient” or “convenient” compared to those patients on deferoxamine (p < 0.0001). Data from Vichinsky E et al.26 . Reproduced with permission from S. Karger AG, Basel.
Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. The author is fully responsible for the content and editorial decisions for this manuscript. Ryan Blanchard is thanked for medical editorial assistance with this manuscript. Conflict of interest and funding Dr Inati has received speaker’s honoraria and research funding from Novartis.
Conclusions
References
Despite being a monogenic disease, SCD is characterized by phenotypic heterogeneity and varying degrees of severity. Blood transfusions remain an important component of the management of SCD, and have been shown to effectively reduce the risk of stroke in these patients. Chronic transfusions, however, can lead to iron overload, which is associated with substantial morbidity and mortality. Evidence suggests that iron overload is underappreciated in SCD, leading to suboptimal monitoring and intervention. Several methods are available to asses iron levels in the body; tracking the patient’s transfusion history and serum ferritin levels over time is a relatively easy and cost-effective way to monitor trends in iron levels. Iron chelation therapy is an effective way to maintain or reduce iron levels in SCD patients with transfusional iron overload. Studies have demonstrated that the oral iron chelator deferasirox is safe and effective in adult and paediatric patients (aged 2 years or more) with SCD, with relatively good rates of treatment compliance.
1. Inati A, Koussa S, Taher A, et al. Sickle cell disease: new insights into pathophysiology and treatment. Pediatr Ann 2008;37:311–25. 2. Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 1994;84:643–9. 3. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood 1995; 86:776–83. 4. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998;91:288–94. 5. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med 1986;314:1593–9. 6. Vichinsky E, Hurst D, Earles A, et al. Newborn screening for sickle cell disease: effect on mortality. Pediatrics 1988;81:749–55. 7. Vichinsky EP. Comprehensive care in sickle cell disease: its impact on morbidity and mortality. Semin Hematol 1991;28:220–6. 8. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5–11. 9. Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. N Engl J Med 1995;333:206–13. 10. Ohene-Frempong K. Indications for red cell transfusion in sickle cell disease. Semin Hematol 2001;38(1 Suppl 1):5–13. 11. Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in patients with sickle cell disease treated with erythrocyte transfusions. J Pediatr 1995;126:896– 899. 12. Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med 2005;353:2769–78. 13. Al-Refaie FN, Wickens DG, Wonke B, et al. Serum non-transferrin bound iron in beta-thalassaemia major patients treated with desferrioxamine and L1. Br J Haematol 1992;82:431–6.
Practice points • Patients with SCD who receive blood transfusions may be at risk of developing iron overload, which can contribute to morbidity and mortality. • Monitoring and treatment of iron overload in SCD is currently inadequate, compared with the standard of care in patients with other transfusion-dependent anaemias. • The most cost-effective way to assess body iron levels is by using the transfusion history and serum ferritin levels; other
A. Inati / Blood Reviews 23 (2009) S9–S13 14. Darbari DS, Kple-Faget P, Kwagyan J, et al. Circumstances of death in adult sickle cell disease patients. Am J Haematol 2006;81:858–63. 15. Aduloju SO, Palmer S, Eckman JR. Mortality in sickle cell patient transitioning from pediatric to adult program: 10 years grady comprehensive sickle cell center experience. Blood 2008;112: abstract 1426. 16. Fung EB, Harmatz PR, Milet M, et al. Disparity in the management of iron overload between patients with sickle cell disease and thalassemia who received transfusions. Transfusion 2008;48:1971–80. 17. Cappellini MD, Porter J, El-Beshlawy A, et al. Tailoring iron chelation by iron intake and serum ferritin: prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Haematologica 2009 [Epub ahead of print]. 18. Breuer W, Hershko C, Cabantchik ZI. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci 2000;23:185–92. 19. Inati A, Taha M, Musallam KM, et al. Magnetic resonance imaging R2 mapping accurately estimates iron overload in sickle cell disease patients. EHA 2009: abstract 1285. 20. Inati A, Musallam KM, Wood JC, et al. Iron overload indices rise linearly with transfusion rate in patients with sickle cell disease. Blood; in press. 21. Inati A, Musallam KM, Wood JC, et al. Absence of cardiac siderosis by MRI T2* despite transfusion burden, hepatic and serum iron overload in Lebanese patients with sickle cell disease. Eur J Haematol 2009;83:565–71.
S13
22. Inati A, Musallam KM, Taha M, et al. Magnetic resonance imaging T2* in the evaluation of cardiac iron overload in patients with sickle cell disease. EHA 2009: abstract 1286. 23. Sickle Cell Society, UK, 2008. Available at: www.sicklecellsociety.org/CareBook.pdf. 24. National Institutes of Health, National Heart, Lung, and Blood Institute, and Division of Blood Diseases and Resources. The management of sickle cell disease (NIH Publication No 02-2117). Bethesda, MD: NIH; 2002. 25. Vichinsky E, Onyekwere O, Porter J, et al. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007;136:501–8. 26. Vichinsky E, Pakbaz Z, Onyekwere O, et al. Patient-reported outcomes of deferasirox (Exjade, ICL670) versus deferoxamine in sickle cell disease patients with transfusional hemosiderosis. Substudy of a randomized open-label phase II trial. Acta Haematol 2008;119:133–41. 27. Vichinsky E. Coates T, Thompson AA, et al. Deferasirox (Exjade® ), the once-daily oral iron chelator, demonstrates safety and efficacy in patient with sickle cell disease (CD: 3.5-year follow-up. ASH 2008: abstract 1420. 28. Raphael JL, Bernhardt MB, Mahoney DH, et al. Oral iron chelation and the treatment of iron overload in a pediatric hematology center. Pediatr Blood Cancer 2009;52:616–20.