A phase 1-2 study was carried out byHsieh et al (2014) determining the efficacy of nonmyeloablative allogeneichematopoietic stem-cell transplantation for adults with severe sickle celldisease. Data showed improvement in respective mean hemoglobin levels forfemales and males as 8.8±0.3 and 9.3±0.5 g per deciliter before transplantationand 12.6±0.
6 and 12.7±1.1 Nine patients developed long-term, stable donorlymphohematopoietic engraftment at levels that sufficed to reverse the sicklecell disease phenotype whereas all patients were alive at a median follow-up of30 months after transplantation.
Several studies of allogeneic transplantationin individuals have presented a high overall survival rate of over 90% andtransplant related mortality of less than 15% as well as a risk for seriouscomplications (i.e. graft failure, grade III–IV acute GVHD and extensivechronic GVHD) ranging from 0-20% (See Table 1). Alternative sources of haemopoietic stemcells include the Umbilical cord blood (UCB) and hematopoietic cells fromvolunteer donors and have been successful in HSCT (Pinto et al, 2008). UCBpossibly produces less GYHD than does standard bone marrow transplantation(level III evidence). A disadvantage of UCB transplantation is slower haematopoieticengraftment and perhaps a higher rate of graft rejection. Although SCA modifying therapies such asHydroxyurea and chronic transfusion are available that have substiantiallydecreased the symptoms, these therapies do not prevent or reverse any futurecomplications. To date, allogeneic HSCT remains the only curative form oftreatment for SCA.
SCAhas been identified as a global public health problem by the World HealthOrganisation (WHO) and the united nations (UN) with over 5 million affectedpeople worldwide and more than a quarter million live births every year (Pielet al, 2013). The sickle cellgene is prevalent throughout sub-Saharan Africa, the Middle East and regions ofthe Indian sub-continent with haemoglobin S carrier frequencies ranging from 5%to 40% or more of the population. The WHO has reported around 85% of SCA disorders andover 70% of all affected births occur in Africa. Due to the severity of the symptoms of SCA, it isimportant to diagnose the disorder as early as possible.
SCA issuggested by the typical clinical presentation of chronic hemolytic anemia andvaso-occlusive crisis. Screening is usually performed in a newborn bloodspot test and the diagnosis is confirmed when electrophoresisdemonstrates the presence of homozygous HbS. When the blood vessels are obstructedby the rigid, sickle cells, vaso-occlusion can occur. The resulting lack ofblood in the bones causes symptoms such as dactylitis and infarction if otherRBC’s cannot pass through to deliver oxygen to the tissues. Other complicationsinclude liver damage due to a blockage of oxygen delivery to the liver tissue andsplenic infarction because of an accumulation of trapped sickle cells leadingto autosplenectomy.
In SCA, the nucleotidebases generate the abnormal HbS due to a substitution of the glutamine aminoacid usually present on the sixth position in normal DNA with Valine. Underhypoxic conditions, insoluble HbSobtains the capacity to polymerise into a long rope-like fiber which alignswith other fibres forming a fascicle that distorts the red blood cell (RBC)into a sickle shape. Repeated sickling of RBC’s occur due to episodes ofpolymerisation and depolymerisation in response to oxygen tension duringcirculation which causes early RBC destruction and thus haemolytic anaemia. Thefirst successful haematopoietic stem cell transplantation (HSCT) was conductedin 1984. Significant advances have been made since and approximately 1,200patients have undergone transplantation (Center forInternational Blood and Marrow Transplant Research, European Society for Bloodand Marrow Transplantation personal communication, 2014).
SCA is an inherited blood disorder caused by a qualitative mutation inthe haemoglobin beta gene (HBB) resulting in an abnormalversion known as haemoglobin S (HbS). Typically, normal haemoglobin(HbA) consists of four protein subunits, two alpha-globin and two beta-globin.Replacement of only one beta-globin subunit with HbS results in an asymptomaticheterozygous carrier of the sickle cell trait however the replacement of bothbeta-globin subunits leads to homozygous SCA (Blann & Ahmed, 2014).