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G.E. Linder and S.T. Chou
Regular assessment of iron overload is recommended for patients with SCD receiving chronic transfusion therapy.2 While serum ferritin levels are widely available, relatively inexpensive, and can be easily serially monitored, ferritin is an acute phase reactant and its levels do not always corre- late with total body iron stores. Magnetic resonance imag- ing is currently the recommended technique for quantifying liver iron.101,102 Both R2 and R2* magnetic resonance imaging data show strong correlation with iron levels on liver biop- sy but are not interchangeable, so the same method should be used to monitor a patient longitudinally.102 Regular assessment of liver iron concentration by liver magnetic res- onance imaging every 1-2 years is recommended for chron- ically transfused patients with SCD or those with sustained serum ferritin levels ≥1000 ng/mL.2 Given the rarity of car- diac iron overload in SCD, routine screening for cardiac iron levels by T2* magnetic resonance imaging is recommended only for patients with evidence of cardiac dysfunction or a severe iron overload (liver iron content >15-20 mg/g).2
Iron chelation is recommended for patients on chronic transfusion therapy who have sustained serum ferritin lev- els >1000 ng/mL or liver iron content >3-7 mg/g liver dry weight (normal range 0.8-1.5 mg/g liver dry weight).102 There are currently three iron chelators licensed and approved for use in Europe and the USA, all of which have been shown to be effective in mitigating iron overload in patients with hemoglobinopathies (Table 3).102-104 Successful chelation therapy is dependent upon the patients’ adher- ence and the tolerability and toxicities of the drugs used.
Chronic transfusion modality and transfusion parameters can be modulated to reduce iron loading. In erythrocyta- pheresis, post-procedure hematocrit can be targeted to a value equal to or lower than the pre-procedure hematocrit to maintain a neutral or net negative iron balance. For patients who transition from simple transfusion to RCE due to iron overload, targeting a slightly lower hematocrit at the end of the procedure than the pre-transfusion hematocrit will reduce total body iron stores over time. Chelation ther- apy can be combined with RCE for greater reduction in liver iron content for iron-overloaded patients requiring chronic transfusions.105
Global challenges in transfusion support for sickle cell disease
The worldwide incidence of SCD is highest in sub- Saharan Africa, accounting for approximately 75% of the global burden of SCD.106,107 Although red cell transfusion significantly reduces morbidity and mortality associated
Table 3. Characteristics of iron chelators.
Deferasirox (Exjade, Jadenu)
with SCD, transfusion support in sub-Saharan Africa is limited by the availability and safety of blood products. While 13% of the global population resides in sub- Saharan Africa, only 4% of blood donations occur in this region.108 Blood donations in Africa have increased over the past decade, but widespread blood shortages remain.108 The high cost of blood products in these regions poses a further challenge.109 Red cell and whole blood transfusions in patients with SCD in sub-Saharan Africa are often restricted to patients with acute complications. Transcranial Doppler screening is not widely available, and chronic transfusion therapy is often unattainable.
Several studies have supported higher rates of transfu- sion reactions in regions of Africa compared to those in higher-resource regions, attributable to factors including limited implementation of leukoreduction, challenges in maintaining temperature control during storage of blood products, and need for effective quality and transfusion education systems.109,110 While most countries in Africa routinely screen blood products for human immunodefi- ciency virus, hepatitis B, and hepatitis C, the residual risk of transfusion-transmitted viral infection is relatively high, particularly in countries with higher percentages of paid or family/replacement blood donors.108,111 Transfusion-transmitted malaria and emerging infectious diseases pose additional burdens.
Pre-transfusion testing in sub-Saharan Africa typically comprises ABO and D typing and saline crossmatching. Antiglobulin reagents are in limited supply, and antibody screening is not consistently performed in most set- tings.109,112 Although pre-transfusion antigen typing and prophylactic antigen matching are not routinely available in low-income countries, rates of alloimmunization among patients with SCD in sub-Saharan Africa may be equivalent to or lower than those in higher or middle income countires.112 It is hypothesized that reduced transfusion rates and greater antigenic similarity between donor and recipient populations contribute to these findings, although further studies are required.
Efforts to improve transfusion support for patients with SCD living in lower-resource countries are para- mount and, along with other measures, such as increas- ing availability of hydroxyurea, would undoubtedly improve care and quality of life for the majority of patients with SCD.
Future directions
Transfusion therapy is a cornerstone of treatment in SCD. Clinical trials have proven that transfusions are
Dose
Route of administration
Route of excretion
Toxicities
14-28 mg/kg/day (Jadenu) 20-40 mg/kg/day (Exjade)
Oral
[Jadenu: coated tablet or sprinkles] [Exjade: dispersible tablet]
Fecal
Gastrointestinal upset, proteinuria, renal dysfunction, raised transaminases, gastrointestinal bleeding (rare)
Deferoxamine (Desferal)
40-50 mg/kg/day
Parenteral (intravenous or subcutaneous)
Urine and fecal
Injection site reactions, anaphylaxis (rare), infection, renal and auditory impairment (rare)
Deferiprone (Ferriprox)
75-100 mg/kg/day
Oral
Urine
Gastrointestinal upset, raised transaminases, arthropathy, rash, neutropenia, agranulocytosis
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haematologica | 2021; 106(7)