The substitution of the glutamine amino acid usually

The first successful haematopoietic stem cell transplantation (HSCT) was conducted in 1984. Signi?cant advances have been made over the past 10–20 years and an increasing number of patients with debilitating sickle cell anaemia (SCA) have undergone the treatment. SCA is a blood disorder caused by an inherited qualitative mutation in the haemoglobin beta gene (HBB) resulting in an abnormal version known as haemoglobin S (HbS). Typically, normal haemoglobin (HbA) consists of two alpha-globin and two beta-globin protein sub units. Replacement of only one beta-globin subunit with HbS results in an asymptomatic heterozygous carrier of the sickle cell trait, however the replacement of both beta-globin subunits leads to homozygous SCA (Blann & Ahmed, 2014). The sickle cell gene is prevalent throughout sub-Saharan Africa, the Middle East and regions of the Indian sub-continent with HbS carrier frequencies ranging from 5% to 40% or more of the population. SCA has been identified as a global public health problem by the World Health Organisation (WHO) and the united nations (UN) with over 5 million affected people worldwide and more than a quarter million live births every year (Piel et al, 2013). The WHO has also reported around 85% of SCA disorders and over 70% of all affected births occur in Africa.

 

In SCA, nucleotide bases generate the abnormal HbS due to a substitution of the glutamine amino acid usually present on the sixth position in normal DNA with Valine. Under hypoxic conditions, HbS is much less soluble than normal HbA and obtains the capacity to polymerise causing formation of fibrous aggregates of Hb that distort the red blood cell (RBC) into a sickle shape (See figure 1). These cells can become physically entrapped in the microcirculation, a process that is enhanced by inflammation and integrin molecule expression, resulting in red cell and leukocyte adhesion to endothelium. Initially, the oxygen-dependent sickling process is reversible, however repeated membrane damage causes irreversible change which leads to intravascular haemolysis (IH). Thus, chronic anaemia is the primary clinical manifestation of SCA (Steinberg et al, 2009).

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Figure 1: Pathophysiological mechanism of Sickle Cell Anaemia. (ET-1 denotes endothelin 1, NO – Nitric Oxide, NOS nitric oxide synthase, O2 ? superoxide, VCAM-1 vascular-cell adhesion molecule 1, and XO – xanthine oxidase)

Theoretically, the pathogenesis of Sickle Cell complications have been described as 2 sub-phenotypes with distinct, underlying mechanisms. Vasculopathic complications such as priapism, leg ulcers, pulmonary hypertension and stroke are linked to a high rate of IH and low steady-state Hb levels. These manifestations result from dysfunction of the vascular endothelium caused by NO deficiency due to NO scavenging by vascular reactive oxygen species and the heme of the free sickle Hb in the plasma as well as arginine catabolism by plasma arginase. Accordingly, Gladwin et al (2004) described patients with pulmonary hypertension had a related increase in markers of hemolysis such as elevated serum LDH and deduced that NO depletion by increased levels of plasma Hb is implicated in pathogenesis. The “viscosity-vaso-occlusion” sub-phenotype is responsible for erythrocyte sickling complications such as vaso-occlusive pain crisis, acute chest syndrome and avascular necrosis which are related to high steady-state Hb levels, raised leukocyte counts and low fetal Hb (inhibits HbS polymerisation). These conditions are likely to result from obstruction of blood vessels by the sickle cells and leukocytes; consequently, chronic organ damage in areas such as the liver can occur due to a blockage of oxygen delivery to the liver tissue (Gladwin and Sachdev, 2012). Acute splenic sequestration is observed as early as 5 weeks after birth in SCA patients (Airede, 1992).

 

Figure 2: Chronic and acute complications in Sickle Cell Anaemia.

Due to the severity of these complications in SCA, early diagnosis and treatment is important in infants before the development of functional hyposplenism and deadly infections. Since 2006, Newborn blood spot screening is available to all infants in the UK at 5-8 days of age (Streetly et al, 2017). The diagnosis is confirmed when electrophoresis demonstrates the presence of homozygous HbS and examination of the peripheral blood film may reveal sickle cells, or an elevated reticulocyte count compared to the Hb concentration.

 

Development of SCA modifying therapies such as hydroxyurea which induces protective HbF and chronic transfusion have been beneficial in prolonging survival with reports of a reduction in disease-related mortality during childhood to 1 to 2 percent (Quinn et al, 2010). With increased longevity, severe complications such as cardiovascular and organ damage continue to be an critical cause of mortality in SCA.

 

At present, HSCT remains the only curative form of treatment for SCA. Haemopoietic stem cells (HSCs) are immature cells found in the bone marrow or peripheral blood that can develop into any of the three blood cell types (red cells, white cells or platelets). CD34The aim of the therapy is to replace the sickle cell and its cellular progenitors with donor HSCs to produce RBCs expressing total or at least partial correction of the abnormal haemoglobin phenotype in a process known as engraftment (Walters, 2001). In SCA, transplantation is usually allogeneic where stem cells are obtained from a related or unrelated donor, however it is ideal that the recommended donor is a sibling with an identical human leukocyte antigen (HLA) type (LHSC 2003).

 

Before transplantation, the patient undergoes conditioning and receives preparative regimens which provide both myeloablation and effective immunosuppression. Myeloblative conditioning (MC) consist of high doses of busulfan (BU), cyclophosphamide (CY), anti-thymocyte globulin (ATG) or total lymphoid irradiation (Adamkiewicz 2004; Bernaudin 1993; Locatelli 2003; Vermylen 1998; Walters 2001).

 

The potential for a successful outcome of allogeneic BMT was illustrated in a report for the Center for International Blood and Marrow Transplant Research (CIMBR) that described 67 patients who received the treatment with MC from 1989-2002. BU and CY based regimens were used in patients with a median age of 10 years at transplantation. 64/67 patients had 5-year event-free survival (EFS) and overall survival (OS) of 85% and 97%. Similar results were obtained in a multicenter study by Maheshwari et al (2014) of myeloablative BMT from HLA-identical sibling donors. All 16 child and adolescent patients had a 100% event-free survival (EFS) rate and successful long-term engraftment (median 100%, range 80-100) after 3 years.

 

Following allogeneic HSCT, there are many, limiting risk factors contributing to increased morbidity and mortality such as Graft-versus-host disease (GVHD), an immunological reaction where the donor cells are rejected. Graft failure is another damaging complication defined as >95% recipient CD3+ or CD34+ cells at any single time after engraftment. Maheshwari et al reported only 2 out of the 16 patients developing Grade II acute GVHD with zero cases of GF. In contrast, Panepinto et al (2007) reported 9 patients had GF with signs of sickle erythropoiesis and 8 patients had recurrence of SCA.

 

On the other hand, non-myeloabative conditioning (NMC) has produced more advantages than MC in patients with SCA. Adult patients with SCA have generally been excluded from myeloablative BMT trials because of the risk of morbidity and mortality resulting from accumulated end-organ damage. Non-myeloablation could be the preferred type of conditioning due to the reduced toxicity meaning children and adults with mild to moderate end organ toxicity would still be eligible for BMT.

 

A phase 1-2 study carried out by Hsieh et al (2014) determined the efficacy of a nonmyeloablative allogeneic BMT for 23 adults with severe SCA. A single total body irradiation dose of alemtuzumab and oral sirolimus were administered. Data showed improvement in mean Hb levels for females and males. Nine patients developed long-term, stable donor engraftment. After a median follow up of 30 months, all patients were alive (See figure 4).

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Summary of non myeloabalative and non. Talk about importance of other approaches.

 

 

As shown in table 1, several studies of allogeneic transplantation in individuals have presented a high overall survival rate of over 90% and transplant related mortality of less than 15% as well as a risk for serious complications (i.e. graft failure, grade III–IV acute GVHD and extensive chronic GVHD) ranging from 0-20%.

 

 

References

N

Median Age (Years)

Regimen

OS

Rejection

DFS

cGvHD

TRM

Panepinto et al (2007)

67

 

Myeloablative
 
Bu-Cy, CsA, MTX

85%

13%

82% @ 6 years

13.5%

2%

Mcpherson et al (2011)

27

8.6

Myeloablative
Bu-Cy-ATG

96%

0%

96% @ 5 years