1. Clinical Focus: Management of Transfusional Iron Overload in Patients With Sickle Cell Anemia, Thalassemia, and Myelodysplastic Syndromes
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2. Faculty
Rami Komrokji, MD Associate Professor of Oncologic Services Department of Oncologic Services University of South Florida Clinical Director Malignant Hematology H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida
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3. Disclosure of Conflicts of Interest
Postgraduate Institute for Medicine (PIM) assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.
The faculty and CCO staff reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity.
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4. Disclosures
Rami Komrokji, MD, has no significant financial relationships to disclose. The following PIM clinical content reviewers, Linda Graham, RN, BSN, BA; Jan Hixon, RN, BSN, MA; Trace Hutchison, PharmD; Julia Kirkwood, RN, BSN; and Jan Schultz, RN, MSN, CCMEP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.
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5. Overview: Transfusional Iron Overload
Red blood cell transfusions are commonly used to relieve anemia due to thalassemia, sickle cell disease, myelodysplastic syndromes, and other congenital and acquired refractory anemias
Lack of iron excretion mechanisms leads to accumulation of iron in liver, heart and endocrine organs (anterior pituitary, pancreatic β cells)
Increases iron-induced liver disease, endocrine disorders, cardiomyopathy, liver cirrhosis
Techniques to monitor for iron overload
Serum ferritin, liver biopsy, MRI, number of transfusions
Iron overload, as a result of blood transfusion, is a significant concern in patients with sickle cell anemia, thalassemia, and myelodysplastic syndromes (MDS). As reviewed by Brittenham, red blood cell (RBC) transfusion for symptomatic anemia is the backbone of supportive care treatment for patients with these hematologic diseases, as well as other congenital and acquired refractory anemias.[1]
Transfusions are potentially lifesaving and provide symptom relief for the patient. However, they have short-term complications, including transfusion reactions and fluid overload. In the long run, because the body does not have a mechanism to excrete iron, multiple frequent transfusions results in the accumulation of iron in the liver, heart, and endocrine organs. Iron deposition in these tissues can lead to cirrhosis, cardiomyopathy, diabetes, and other complications.
Typically, units of blood is the threshold where patients start developing iron overload. It is estimated that each unit of blood has approximately 250 mg of iron.
Each of the tests to monitor iron overload has advantages and disadvantages. The most commonly used test is serum ferritin analysis because it is easy to obtain and is not invasive. However, it also can be an acute-phase reactant and, thus, may provide false results. The gold standard for assessing iron overload is through a liver biopsy, but this is an invasive procedure and patients with MDS are at particular risk of bleeding. Finally, new methods that use magnetic resonance imaging to evaluate iron overload are emerging but are not yet widely used in the clinic.
1. Brittenham GM. N Engl J Med. 2011;364:

6. Transfusion Dependency in MDS
Good IPSS Risk*
Intermediate IPSS Risk
Transfusion independent
Transfusion independent
1.0
Transfusion dependent
1.0
Transfusion dependent
0.9
0.9
0.8
0.8
0.7
0.7
Cumulative Proportion Surviving
0.6
0.6
Cumulative Proportion Surviving
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
HR, hazard ratio; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndromes; OS, overall survival.
Iron overload in patients with MDS is common, since these patients are often dependent on blood transfusion supportive care. As expected from excess iron deposition, patients with MDS experience poorer outcomes and increased incidences of iron-induced cardiomyopathy, diabetes, liver cirrhosis, and other complications.
Key lessons about transfusion dependency in MDS came from a study by Malcovati and colleagues[2] that looked at the burden of transfusion dependency and its effect on outcome in lower-risk patients. Patients who were RBC transfusion dependent had significantly shorter overall survival than patients who were transfusion independent (hazard ratio: 2.16). This was seen in patients with good-risk IPSS as well as intermediate-risk IPSS.
Certainly this could reflect the underlying disease biology, in that patients who are transfusion dependent have worse disease, but it also reflects the iron overload sequelae of blood transfusions. 20 40 60 80
100
120
140 20 40 60 80
100
120
140
Survival Time (Mos)
Survival Time (Mos)
*Excludes isolated 5q-.
Transfusion-dependent patients had a significantly shorter OS than transfusion-independent patients (HR: 2.16; P < .001)
2. Malcovati L, et. al. J Clin Oncol. 2005;23:

7. Survival and Risk of AML in MDS Patients Stratified by Serum Ferritin LevelsOS
Time Without AML
1.0
1.0
Ferritin < 1000 μg/L
Ferritin ≥ 1000 μg/L
0.8
0.8
0.6
0.6
Probability
Probability
0.4
0.4
0.2
0.2
P < .0001
P < .0001
AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; OS, overall survival.
Further evidence that iron overload is associated with poorer outcomes can be seen in the data from Sanz and colleagues,[3] which were presented at the 2008 annual meeting of the American Society of Hematology (ASH). Here, they used serum ferritin as a surrogate marker for iron overload in patients with MDS and evaluated overall survival and risk for acute myeloid leukemia (AML) transformation in patients stratified by serum ferritin level (> or < 1000 ng/mL). A high serum ferritin level correlated with poor outcome and, interestingly, time to AML transformation as well.
Another study in patients with lower-risk MDS showed an association between the serum ferritin level and survival.[4] In this study, a 36% reduction in survival for every incremental increase of 500 ng/mL in serum ferritin > 1000 ng/mL was noted. 5 10 15 20 5 10 15 20
Yrs From Diagnosis
Yrs From Diagnosis
Development of transfusional iron overload is a significant independent prognostic factor for overall survival and evolution to AML
3. Sanz G, et al ASH. Abstract 640.

8. Risk of Cardiac Events in MDS Patients With Multiple Transfusions
513 new cases of MDS from January - March 2003 in the US Medicare SAF5% claims database
SAF5%, standard analytic file comprised of randomly selected, 5% sample of all Medicare beneficiaries
During a 3-yr follow-up, cardiac events were more common in transfused vs nontransfused MDS patients (P < .001) and in MDS patients vs individuals without MDS (P < .001)
100
82.4 80
67.1 60
Cardiac Events (%)
MDS, myelodysplastic syndromes; SAF5%, Medicare Standard Analytic File 5%.
Additional studies have examined the incidence of iron-induced complications such as cardiac event risk in MDS patients.
A study by Goldberg and colleagues[5] evaluated 513 new cases of MDS in a random sampling of Medicare patients and showed that those who received transfusion were more likely to have cardiac events compared to nontransfused patients and the overall Medicare population. The percentage of cardiac events in the non-MDS population was 54.5% whereas the highest rate of cardiac events was observed in patients with MDS who were RBC transfusion dependent.
54.5 40 20
MDS Transfused (n = 205)
MDS Nontransfused (n = 307)
Overall Medicare
SAF5% population
(N = 1,379,185)
5. Goldberg SL, et al. J Clin Oncol. 2010;28:

9. Risk of Diabetes in MDS Patients With Multiple Transfusions
Development of diabetes was more common in transfused than in nontransfused MDS patients and overall SAF5% Medicare population during a 3-yr follow-up
P = .02* 50
P < .0001 50
44.4
40.0
37.1 40 40
33.1
33.1 30 30
Developed Diabetes (%)
Developed Diabetes (%) 20 20 10 10
MDS, myelodysplastic syndromes; SAF5%, Medicare Standard Analytic File 5%.
Similar findings were observed regarding the effect of transfusions on the development of diabetes.[6] Patients with MDS and transfusion dependence generally had a higher risk of developing diabetes than the overall Medicare population (44.4% of patients with MDS who were RBC transfusion dependent developed diabetes compared with 37.0% of those with MDS without transfusion dependence and 33.0% in the overall Medicare population).
These findings indicate that RBC transfusion dependency and iron overload affect survival partly because of the underlying biology of the disease but also because of the sequelae of iron overload, including cardiomyopathy, cardiac events, liver disease, and the development of diabetes.
MDS Patients (n = 513)
Overall Medicare
SAF5% population
(N = 1,379,185)
MDS Transfused (n = 205)
MDS Non- transfused (n = 307)
Overall Medicare SAF5% population
(N = 1,379,185)
*For comparison of transfused and nontransfused MDS patients.
6. Goldberg SL, et al. J Clin Oncol. 2010;28:

10. Retrospective Analysis of Survival in MDS Patients Receiving Iron Chelation Therapy
For patients with low and intermediate-1 MDS, ICT was associated with a significant improvement in OS
P < .03
ICT +
(Not reached at 160 mos)
No ICT
40.1 mos ( )
ICT, iron chelation therapy; MDS, myelodysplastic syndromes.
No prospective randomized clinical trial has answered the question of whether patients with iron overload and MDS benefit from iron chelation therapy. However, several retrospective and observational prospective studies have attempted to address it.
Data from a retrospective analysis evaluated a small number of patients who did or did not receive iron chelation therapy, predominantly through the use of subcutaneous iron chelators.[7] Median overall survival was not reached in patients receiving regular iron chelation vs 40 months in patients with no iron chelation. 50
100
150
200
Median Survival (Mos)
7. Leitch HA. Leuk Res. 2007;31(suppl 3):S7-S9.

11. Iron Chelation Therapy and Survival in MDS
Survey of 170 patients with MDS referred for RBC transfusion at 18 French treatment centers during 1-mo period
Assessments: hematologic data, RBC transfusion requirement, iron chelation therapy, and iron overload
Cohort survival prospectively followed
Standard iron chelation therapy
Deferoxamine 40 mg/kg/day SC for 3-5 days/wk: n = 41
Deferiprone mg/kg/day: n = 5
Deferoxamine SC + deferiprone: n = 5
Deferasirox mg/kg/day: n = 6
Low-dose iron chelation therapy
Deferoxamine bolus 2-3 g/wk SC: n = 12
Deferoxamine mg/kg IV once after RBC transfusion: n = 7
IV, intravenous; MDS, myelodysplastic syndromes; RBC, red blood cells; SC, subcutaneous.
A separate prospective observational study was reported from France, which surveyed 170 patients with MDS referred for RBC transfusion at 18 treatment centers during a 1-month period.[8] The patients, who were receiving standard iron chelation, were assessed and followed prospectively for survival. Some patients received subcutaneous deferoxamine, deferiprone, or subcutaneous deferoxamine plus deferiprone, whereas a small number of patients received deferasirox. Of note, a group of patients received low-dose iron chelation with subcutaneous deferoxamine bolus or intravenous deferoxamine after RBC transfusion.
8. Rose C, et al. ASH Abstract 249.

12. Iron Chelation Therapy and Survival in MDS
OS significantly improved for patients who received iron chelation therapy
Results consistent across all subgroups analyzed (IPSS low and intermediate-1, sex, age)
1.00
Median survival:
115 mos iron chelation therapy
51 mos no iron chelation therapy
P < .0001
0.75
Survival Distribution Function
0.50
IPSS, International Prognostic Staging System; MDS, myelodysplastic syndromes; OS, overall survival.
Results showed that overall survival was significantly improved in patients who received iron chelation.[9] The median survival was more than doubled at 115 months in patients who received iron chelation vs 51 months in patients who did not receive iron chelation. Moreover, outcomes were better for patients who received standard iron chelation rather than low-dose iron chelation.
ICT
0.25
No CT 50
100
150
200
250
Diagnosis to Death Time (Mos)
9. Rose C, et al. ASH Abstract 249.

13. Deferasirox in MDS: EPIC and US03 Studies
US03[10,11] results
HI by IWG criteria: 8/176 (5%)
Erythroid response: 5
Major platelet response: 1
Combined platelet + neutrophil response: 1
Both EPIC[12,13] and US03[11] studies required
Baseline serum ferritin ≥ 1000 ng/mL
> 20 units red blood cell transfusions
Treatment: deferasirox mg/kg daily Mo
Serum Ferritin, ng/mL
EPIC
(N = 341)
US03
(N = 176)
2730
3397 3
2358
3057 6
2210
2802 9
2076
2635 12
1904
2501
HI, hematologic improvements; IWG, International Working Group; MDS, myelodysplastic syndromes.
Two prospective studies have examined the use of the oral iron chelation agent deferasirox in MDS for the purpose of lowering serum ferritin levels: the US03 study in the United States[10,11] and the EPIC study in Europe.[12,13] In both studies, the primary endpoint was reduction in serum ferritin in patients with MDS who are transfusion dependent; overall survival was not a primary endpoint.
Both studies showed that deferasirox effectively reduced serum ferritin in those patients by Month 12. In addition, labile plasma iron was lowered in those patients, which is an accurate measurement of iron overload.
10. List AF, et al. ASH Abstract List AF, et al. J Clin Oncol. 2012;30:
12. Gattermann N, et al. ASH Abstract Cappellini MD, et al. Haematologica. 2010;95:

14. Iron Chelation Therapy in Patients With Low-Risk MDS
Retrospective analysis of patients with lower-risk MDS (low- and int-1 risk)
Serum ferritin ≥1000 ng/mL
N = 97: n = 45 (ICT), n = 52 (BSC)
ICT included n = 10 (deferoxamine) and n = 35 (deferasirox)
Median follow-up: 86 mos
ICT in lower risk MDS patients with elevated serum ferritin ≥ 1000 ng/mL was associated with improved OS and a trend to lower AML transformation)
ICT
BSC
Patients, n 45 52
OS, mos 59 34
 HR (95% CI; P value)
0.52 ( ; .013)
Progression to AML, %
15.6
21.2
P value
.33
AML, acute myeloid leukemia; BSC, best supportive care; ICT, iron chelation therapy; int-1, intermediate-1; MDS, myelodysplastic syndromes; OS, overall survival.
Other groups have reported retrospective studies on outcomes with iron chelation in MDS. For example, at 2011 ASH annual meeting, our group reported our experience in 97 patients with lower-risk MDS and serum ferritin > 1000 ng/mL.[14] Forty-six percent of patients received iron chelation, including deferasirox in 35 patients and deferoxamine in 10 patients. Outcomes were similar to those previously reported: The median overall survival for patients with iron chelation was 59 months compared with 34 months without chelation (P = .013). Of importance, the rate of AML transformation was higher in patients who did not receive iron chelation: 21% of the patients receiving no chelation progressed to AML compared with 16% who did receive chelation.
14. Komrokji RS, et al. ASH Abstract 2776.

15. TELESTO Study IA IA IA: at 50% of primary composite events (~ 3 yrs)
Deferasirox N = 420
10 mg/kg/day (1st 2 wks)
20 mg/kg/day (Wks 2-12)
Up to 40 mg/kg/day (after 12 wks)
Screening
1 mo
1 yr
2 yrs
3 yrs
4 yrs
5 yrs
Low or int-1 risk MDS
Serum ferritin > 1000 mcg/L and < 2500 mcg/L
Placebo N = 210
10 mg/kg/day (1st 2 weeks)
20 mg/kg/day (weeks 2-12)
Up to 40 mg/kg/day (after 12 weeks) IA IA
Expected
end of study
IA, interim analysis; int-1, intermediate-1; MDS, myelodysplastic syndromes.
The ongoing randomized TELESTO clinical trial is comparing deferasirox with placebo,[15] and, hopefully, will confirm these findings in a prospective fashion. We encourage clinicians to enroll patients on this study.
54% chance to stop the trial
depending on IA results
Randomized 2:1 (Deferasirox:Placebo)
IA: at 50% of primary composite events (~ 3 yrs)
at 75% of primary composite events (~ 4 yrs) 15 15

16. MDS Patients Who Are Likely to Benefit Most From Management of Iron Overload
Characteristic
NCCN[16]
MDS Foundation[17]
Transfusion status
Received packed RBC units
Continuing transfusions
Transfusion dependent, requiring 2 units/mo for > 1 yr
Serum ferritin level
> 2500 ng/mL
1000 ng/mL
MDS risk
IPSS: low- or int-1
WHO: RA, RARS, and 5q-
Patient profile
Candidates for allografts
Life expectancy > 1 yr and no comorbidities that limit progress
A need to preserve organ function
Int-1, intermediate-1; IPSS, International Prognostic Staging System; MDS, myelodysplastic syndromes; NCCN, National Comprehensive Cancer Network; RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; RBC, red blood cells; WHO, World Health Organization.
Current guidelines for patients with MDS, including those from the National Comprehensive Cancer Network (NCCN)[16] and the MDS Foundation,[17] identify patients who are likely to benefit from management of iron overload. The NCCN guidelines recommend considering iron chelation therapy in patients who have received units of packed RBCs, have an ongoing transfusion need, have a serum ferritin level > 2500 ng/mL, and have lower-risk MDS. The NCCN guidelines also recommend considering iron chelation for patients who are candidates for allogeneic stem cell transplantation.
The MDS Foundation guidelines are somewhat different: While also recommending chelation therapy in the same group of transfusion-dependent patients with lower-risk IPSS MDS, these guidelines use a serum ferritin cutoff of 1000 ng/mL to consider starting iron chelation.
The bottom line is that iron chelation therapy is now well accepted for patients with lower-risk MDS and a serum ferritin level of ≥ 2500 ng/mL, which is thought to be secondary to iron overload. In our practice, we consider iron chelation therapy for lower-risk patients with MDS if their serum ferritin exceeds 1000 ng/mL.
16. NCCN. Clinical practice guidelines in oncology: MDS. v Bennett JM. Am J Hematol. 2008;83: 16

17. Pretransplantation Iron Overload in Adult Patients Undergoing HSCT
10,000
8000
6000
4000
2000
Median Pretransplant Serum Ferritin (ng/mL)
CML, chronic myeloid leukemia; HSCT, hematopoietic stem cell transplantation; MPD, myeloproliferative disorder.
Current guidelines (eg, NCCN[18]) endorse considering iron chelation therapy in patients with MDS who are candidates for allogeneic hematopoietic stem cell transplantation, as iron overload is common in these patients. Approximately 18% of patients with lymphoma or myeloma will have ferritin > 1000 ng/mL compared with 52% of patients with acute leukemia or another myeloid malignancy.[19]
Lymphoma Acute Myelo- Aplastic CML or Other Myeloma Leukemia dysplasia Anemia MPD
19. Pullarkat V, et al. Bone Marrow Transplant. 2008;42: 17

18. Secondary Iron Overload Effects Post-transplantation Outcome in MDS Patients
Probability of overall survival
Probability of non-relapse mortality
1.0
1.0
Ferritin <1000 ng/mL
Ferritin 1000–1999 ng/mL
Ferritin 2000–3000 ng/mL
Ferritin >3000 ng/mL
HR: 1.40
(P = .01)
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
Cumulative Proportion Surviving
0.5
Nonrelapse Mortality (Probability)
0.5
0.4
0.4
0.3
0.3
Ferritin < 1000 ng/mL
Ferritin ng/mL
Ferritin ng/mL
Ferritin > 3000 ng/mL
0.2
0.2
HR: 1.42
(P = .03)
HR, hazard ratio; MDS, myelodysplastic syndromes.
Several studies have suggested that in patients with higher serum ferritin levels, the 100-day posttransplantation mortality was worse, overall survival was inferior, and the rate of acute graft vs host disease was higher. In a study by Alessandrino and colleagues,[20] 357 patients undergoing allogeneic stem cell transplantation for primary MDS between 1997 and 2007 were evaluated, of which 135 were transfusion dependent. Pretransplantation serum ferritin levels were available for 129 of those 135 patients and a significant correlation was observed between the number of units of packed RBCs received and serum ferritin. Pretransplantation serum ferritin level also had a significant effect on overall survival (hazard ratio: 1.4) and on nonrelapse mortality (hazard ratio: 1.42). This effect was maintained after adjusting for transfusion burden and duration, suggesting that the negative influence of transfusion history on outcome might be related to iron overload.
0.1
0.1 20 40 60 80
100
120
140
160 20 40 60 80
100
120
140
160
Mos
Mos
Posttransplantation outcome of transfusion-dependent patients receiving standard conditioning according to serum ferritin level
20. Alessandrino EP, et al. Haematologica. 2010;95: 18

19. Iron Chelation Prior to HSCT: Survival Outcomes
1.0
1.0
0.8
0.8
0.6
0.6
OS Rate
Event-Free Survival
0.4
0.4
P = .001
P < .001
0.2
SF > 1000 ng/mL
SF < 1000 ng/mL
ICT
0.2
SF > 1000 ng/mL
SF < 1000 ng/mL
ICT
ICT, iron chelation therapy; HSCT, hematopoietic stem cell transplantation; SF, serum ferritin.
In a smaller retrospective study, results suggested that iron chelation therapy prior to stem cell transplantation can improve outcome. Lee and colleagues[21] reviewed 101 patients who had received stem cell transplantation, comparing outcomes in 3 subgroups: patients who had serum ferritin > 1000 ng/mL at transplantation, those who maintained ferritin < 1000 ng/mL before transplantation without chelation therapy, and patients whose ferritin level decreased to < 1000 ng/mL with chelation therapy. Overall survival and event-free survival rates were better in patients who received iron chelation therapy prior to transplantation. This study showed that iron depletion after transplantation, where historically phlebotomy was used, was an effective strategy; however, it may take several months to reach the target goal.
Very limited data are available on the combination of phlebotomy plus deferasirox as a method to reach more quickly the goal of serum ferritin levels < 1000 ng/mL in posttransplantation patients. However, the available data suggest that this may be a feasible approach.[22]
The sum of these results clearly support the use of iron chelation therapy before and after hematopoietic stem cell transplantation. Chelation therapy can lead to reduced serum ferritin in patients who require it and may improve overall survival in patients with MDS after stem cell transplantation. 12 24 36 48 60 12 24 36 48 60
Mos From Transplantation
Mos From Transplantation
21. Lee JW, et al. Bone Marrow Transplant. 2009;44: 19

20. Deferasirox Therapy in Patients With Sickle Cell Disease20 30 15
Serum ferritin
Deferasirox dose 10 25 5 20 -5
Median Relative Change in Serum Ferritin (%)
Mean Deferasirox Dose (mg/kg/day)
-10 15
-15
-20 10
-25
-30 5
-35
-40 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Mos
LIC, liver iron concentration; SD, standard deviation.
Iron overload is also a common complication of transfusions in patients with sickle cell disease. The safety and efficacy of deferasirox in patients with sickle cell disease has been examined.[23] Results from a multicenter, randomized trial showed that the median serum ferritin level was reduced by 35% by Year 4 with deferasirox. However, few patients were compliant, even given the use of oral medication; only 21% of patients remained on study at the end of 5 years. Although the oral and subcutaneous iron chelators are effective, compliance is a very important issue that needs to be addressed.
Patients, n 95 88 81 65 61 50 40 38 29 25 20
Dose was based on baseline LIC
Median serum ferritin reduce by 35% by Yr 4
Only 21% of patients remained on study at end of 5 yrs
23. Vichinsky E, et al. Br J Haematol. 2011;154:

21. Chelator Properties That Affect Compliance
 Table[24]
Deferoxamine
Deferasirox
Deferiprone
Advantages
Long-term safety record
Highly effective
Strongest chelator
Oral administration
Daily dosing
Better cardiac protection compared to deferoxamine
Allows aggressive iron chelation when iron stores are low with minimal excess toxicity
Disadvantages
Parenteral administration
Local skin reactions
May be inferior to deferiprone for cardiac protection
Challenging patient compliance
GI disturbance limits tolerability
Many patients have inadequate response at MTD
Not yet demonstrated to reduce cardiac siderosis
GI disturbances and joint pain limit tolerability
Rare agranulocytosis and neutropenia
In a study comparing patient preferences, patients were more willing to continue taking deferasirox than deferoxamine by end-of-study (84% vs 11%, respectively; P < .001)[25]
Reducing the number of IV infusions of deferoxamine, by using high-dose deferoxamine administered over 48 hrs every 2-4 wks, was shown to be safe and effective for reduction of iron overload in sickle cell disease[26]
GI, gastrointestinal; IV, intravenous; MTD, maximum tolerated dose.
There are several options to improve compliance with chelation therapy, chief among these is the use of oral administration.[24] In a study comparing patient preferences, patients were more likely to continue taking oral iron chelation than subcutaneous deferoxamine by the end of the study.[25]
There are currently 3 approved options in the United States for iron chelation. Deferoxamine has been in use the longest and effectively reduces iron overload. It can be administered subcutaneously or parenterally. Its disadvantages include local skin reaction and challenging compliance because patients need to use a subcutaneous pump or parenteral administration overnight several nights per week. Another approach to make deferoxamine treatment less intrusive is to reduce the number of intravenous infusions by using higher-dose deferoxamine. This was shown, in the experience of a single center, to be safe and effective at reducing iron overload in sickle cell disease.[26]
24. Neufeld EJ. Hematology Am Soc Hematol Educ Program. 2010;2010: Vichinsky E, et al. Acta Haematol. 2008;119: Kalpatthi R, et al. Pediatr Blood Cancer. 2010;55:

22. Chelator Properties That Affect Compliance
 Table[1]
Deferoxamine
Deferasirox
Deferiprone
Administration
SC or IV, continuous infusion 5-7 days/wk
Oral suspension
Oral tablet
Common AEs
Local skin reaction, hearing loss, late bone problems
Rash, GI disturbances, diarrhea, mild changes in creatinine, proteinuria, transaminases
GI disturbances, joint pain, arthritis
Severe AEs
Retinopathy, acute pulmonary distress
Peptic ulcers, liver or renal dysfunction leading to failure, cytopenias
Agranulocytosis, neutropenia
Cost $$
$$$$
$-$$
Box warnings
Noted more often when administered in excess of iron burden
Deferoxamine: ocular and auditory disturbances, acute renal failure, hepatic dysfunction, adult respiratory distress syndrome, growth retardation in children
Deferasirox: renal failure, hepatic failure, gastrointestinal hemorrhage
Deferiprone: agranulocytosis, infection (leading to death)
AE, adverse events; GI, gastrointestinal; IV, intravenous; SC, subcutaneous.
The other 2 available iron chelators are deferasirox and deferiprone, which as oral agents may be more appealing in terms of compliance. Like deferoxamine, these are also effective in reducing iron overload. Deferasirox efficacy has been shown to be equivalent to, or possibly better than, deferoxamine in MDS.[28]
Deferasirox is a reasonable alternative to deferoxamine but has a toxicity profile including gastrointestinal symptoms like diarrhea as well as discomfort, rash, increased creatinine (especially in elderly patients), proteinuria, and elevation in liver functions. Thus, baseline evaluation of the serum ferritin, creatinine, and urine protein are indicated.
Deferiprone, the other orally available iron chelator, has shown the best long-term cardiac outcome compared with deferoxamine. The major adverse effects of deferiprone, in addition to gastrointestinal symptoms, include the possibility of diarrhea and cytopenia with agranulocytosis, which requires close monitoring of blood counts.
In addition, for many patients receiving deferoxamine or deferasirox, the guidelines recommend annual ocular and auditory monitoring because of the rare, but important, risk of deafness, especially with deferoxamine.
28. Neufeld EJ. Hematology Am Soc Hematol Educ Program. 2010;2010:

23. Comparison Study of Deferasirox vs Deferoxamine in β-Thalassemia Patients
Phase III trial in β-thalassemia patients aged 2 yrs or older[29]
Patients randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline LIC
2000 10
1000
Mean Serum Ferritin Change From Baseline (μg/L ± SD)
Mean LIC Change From Baseline (Fe/g ± SD)
-1000
-10
DFO, deferoxamine; DFX, deferasirox; LIC, liver iron concentration; SD, standard deviation.
Iron chelation therapy is effective at reducing serum ferritin levels in patients with β-thalassemia. The efficacy of deferasirox and deferoxamine were compared in a study of patients with β-thalassemia aged 2 years or older.[29] Patients were randomized to receive treatment with oral deferasirox or subcutaneous deferoxamine, with dosing of each according to the patients’ baseline liver iron concentration. Both agents showed equivalency, lowering the serum ferritin from baseline.
-2000
-3000
-20
DFO
DFX
DFO
DFX
DFO
DFX
DFO
DFX
DFO
DFX
DFO
DFX
DFO
DFX
DFO
DFX
Baseline LIC:
< 3 mg Fe
< 3-7 mg Fe
> mg Fe
> 14 mg Fe
Baseline LIC:
< 3 mg Fe
< 3-7 mg Fe
> mg Fe
> 14 mg Fe
Deferasirox < 20 mg/kg/day failed to consistently lower LIC and serum ferritin
29. Cappellini MD, et al. Blood. 2006;107:

24. Iron Overload Summary
Iron chelation therapy is effective at reducing serum ferritin levels, cardiac events and diabetes in patients with blood transfusion–related iron overload
Iron chelation therapy can improve survival after HSCT and in lower-risk MDS
Compliance is a major issue in successful treatment
Advent of orally available chelators, it is hoped, will increase compliance
Each chelator has its own unique safety profile
HSCT, hematopoietic stem cell transplantation.
In summary, in patients with hereditary diseases like sickle cell disease or thalassemia, the importance of iron chelation is well established with data revealing decreased complications such as cardiomyopathy or liver disease. For patients with MDS, the data also indicate the utility of iron chelation therapy, but prospective randomized studies will be very important to address the optimal therapy for iron chelation therapy.
Compliance remains a significant issue. Oral iron chelators are more appealing but do not alone guarantee compliance, especially for patients faced with a lifetime of therapy. Patients should be encouraged to comply with their prescribed regimen and monitored closely. Clinicians should consider the use of oral iron chelation, which has minimal adverse effects, to keep patients on treatment.

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