In conclusion, AlloHCT has shown
success in eradicating the symptoms and complications related to SCA IN
PAEDIATRIC PATIENTS however more prospective
controlled trials comparing HSCT and standard of care are needed to determine
the long-term influence on QOL in adult patients (Yawn et al, 2014). However,
development of more therapies targeting GVHD is currently most critical in those
with the disorder.
Figure 4: Overall
survival in children with SCA who had an unrelated donor transplant facilitated
by NMDP/Be The Match.
Although substantial evidence exists supporting
the use of MSD HSCT, only 18% of SCA patients have a HLA MSD (Angelucci et al,
2014). Recent data from a matched unrelated donor (MUD) clinical trial of 29 children with
severe SCA showed 1- and 2-year EFS of 76% and 69%, and OS rates of 86% and 79%
after a median follow-up of 26 months. The incidence rate
of cGVHD was reported at 62%
with 38% extensive cGVHD and an associated mortality of seven deaths. In future, the focus of MURD transplantation for SCA should be to decrease
occurrence of GVHD prophylaxis. Additionally, an OS rate of 72% was documented for children
with a MUD and CB units at 5 years Figure 4.
the other hand, CB transplantation poses a risk of infection because of slower neutrophil engraftment as well as higher risks of graft failure and rejection. To counteract
this, a conditioning regimen with increased intensity is needed but this poses
it’s own risk of further toxicities such as organ damage etc.
Subsequently, Locatelli et al (2013) conducted
a study assessing outcomes of HSCT using either BM or CB to establish whether CB decreased
HSCT complications. With
a median follow-up of 70 months, 6- year OS was high at 97% whereas 6-year EFS rates
were 92% and 90%. Patients with SCA had excellent outcomes after HLA identical
sibling CBT with less GVHD and none had cGVHD.
An alternative source of HSCs to consider
in transplantation is Umbilical cord blood (CB) which in comparison to BMT provides
reduced incidence and
severity of GvHD as well as the ease and safety of hematopoietic collection (Pinto et al, 2008).
summary, NMC could be the preferred conditioning
regimen in adult patients usually excluded from BMT trials. Despite the promising survival outcomes, routine
application of this method is not possible for children because of the probable,
long-term toxicity of TBI.
In 2014, a phase 1-2 study carried out
by Hsieh et al (2014) determined the
possibility of decreasing the toxicity of HSCT via nonmyeloablative allogeneic BMT.
A single total body irradiation (TBI)
dose of alemtuzumab and oral sirolimus were given to 23 adults with
severe SCA. 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 with no acute or chronic GVHD (See figure 4).
A better outcome of transplantation
was experienced in children with HLA matched donors however MC is generally too
toxic for adult patients with SCA who have accumulated organ damage, therefore
causing a risk of morbidity and
mortality. Some of the toxicities
observed are infertility and gonadal failure and graft versus host disease
(GVHD) (an immunological reaction where the donor
cells reject recipient tissues).
Chronic GVHD (cGVHD) seems to be an important issue affecting
the quality of life of patients in most studies with high rates of >20%. Graft failure (GF) is another damaging complication defined as
>95% recipient CD3+ or CD34+ cells at any single time after engraftment. Panepinto et al (2007) reported
6/54 patients given
the bone marrow graft type developed aGVHD and 11 had cGVHD whereas 9 patients had GF with signs of sickle erythropoiesis.
Median Age (Years)
Panepinto et al (2007)
Bu-Cy, CsA, MTX
85% @ 5 years
Bernaudin et al (2010)
93% @ 3 years
Mcpherson et al (2011)
96% @ 5 years
Lucarelli et al (2014)
@ 9 years
Dedeken et al
86% @ 8 years
Table 1: Outcomes
of myeloablative HSCT in patients with SCA with matched sibling donors (MSD).
in table 1, several studies of myeloablative transplantation in individuals
have presented a high overall survival rate of over 90% and transplant related
mortality (TRM) of less than 15%.
potential for successful allogeneic BMT with
MC was illustrated in a report for the Center for International Blood and Marrow
Transplant Research (CIMBR) that described 67 patients who received treatment
from 1989-2002. 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% EFS rate and
successful long-term engraftment (median 100%, range 80-100) after 3 years.
Indications for Allogeneic
BMT require myeloablative (MC) or non-myeloablative conditioning (NMC) to enable successful
engraftment. MC consists of high doses of busulfan (BU), cyclophosphamide (CY),
anti-thymocyte globulin (ATG) or total lymphoid irradiation (Adamkiewicz
2001) however, some individuals experience mixed donor chimerism after transplantation
where both donor and recipient cells co-exist.
At present, HSCT remains the only curative form of treatment for SCA. The
procedure utilizes haemopoietic stem cells (HSCs), the 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). The 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 termed 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 donor
is a sibling with an identical human leukocyte
antigen (HLA) type (LHSC 2003).
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).
However, these therapies only ameliorate some SCA manifestations resulting in accumulated organ
damage in adulthood.
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). Examination of the peripheral blood film may reveal sickle cells,
or an elevated reticulocyte count compared to the Hb concentration. The diagnosis is confirmed when
electrophoresis demonstrates the presence of homozygous HbS.
Figure 2: Chronic and
acute complications in Sickle Cell Anaemia over the lifespan.
The pathogenesis of Sickle
Cell complications have been hypothesised 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) found 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 associated with high steady-state Hb levels, raised
leukocyte counts and low fetal Hb (inhibits HbS
polymerisation). These conditions are likely to result from blood vessel
obstruction 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
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)
abnormal HbS is generated when a single nucleotide mutation causes an amino
acid substitution of glutamine to Valine at the sixth
position in the
beta-globin chain. 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. These cells can
become entrapped in the microcirculation, a process enhanced by inflammation
and integrin molecule expression, resulting in red cell and leukocyte adhesion
to endothelium (See figure 1). Initially, the oxygen-dependent sickling process
is reversible, however repeated membrane damage causes irreversible change
which leads to intravascular haemolysis (IH) and chronic anaemia (Steinberg et
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. 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. Natural selection
has enabled resistance to malaria in certain populations due to retention of the
HbS mutation in those with heterozygous Hb allelles (Blann & Ahmed, 2014). The WHO has reported around 85% of SCA disorders and over 70% of
all affected births occur in Africa.
cell anaemia (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 a mortality rate of >80% by age 18 in Africa (Piel
et al, 2013). SCA is a blood disorder caused by an inherited qualitative
mutation in the haemoglobin beta gene (HBB) resulting in the
Sickle haemoglobin (HbS). The ?rst curative treatment for SCA was
reported in 1984 after haematopoietic stem cell transplantation (HSCT) of a patient with both SCA and acute myeloid Leukemia. Significant
advances have been made since and many children have undergone the procedure.