Hematopoietic Stem Cell Transplant in Treating Sickle-Cell Disease

Hematopoietic Stem Cell Transplant in Treating Sickle-Cell Disease

Introduction

Sickle-cell disease (SCD) is a life-threatening condition that affects the blood and several body organs. The illness was first reported in 1910 by Herrick (Inusa et al., 2019). It is defined as a disorder that is genetically inherited and occurs when the single amino acid glutamic acid is substituted to valine in the sixth position of the β-chain of hemoglobin, which is known as hemoglobin S (HBS) (Aljuburi, 2014). The disorder modifies the standard shape of red blood cells (RBC). The change in the shape of the RBCs is known as sickling because they attain a sickle-shape, and their ability to carry oxygen is limited. The modified RBCs often stick within blood vessels and reduce blood flow to various body parts (Kato, Steinberg& Gladwin, 2017). They have a short lifespan, and this may lead to anaemia. Sickle-cell anaemia affects multiple organs and systems in the body, and it has both acute and chronic complications, which can be fatal. The complexity of the disorder poses challenges to patients, their families, and medical professionals.  There are various methods of managing and treating SCD. However, its treatment and management can be costly, intensive, and time-consuming (Neumayr, Hoppe & Brown, 2019).  The methods of treatment include Hydroxyurea therapy, RBC transfusion therapy, and Hematopoietic Stem Cell Transplant (Neumayr, Hoppe & Brown, 2019). Hematopoietic Stem Cell Transplant (HSCT) is an effective method of treating SCD that is available for patients today.

Etiology

SCD is inherited through an autosomal recessive pattern.  The substituted and defective gene that causes the disorder can be passed to children by either the mother or the father.  If only one of the parents has the defective gene and passes it to the child, the offspring will have the sickle-cell trait. They will have one normal and one defective hemoglobin gene.  He/ she can manufacture both the defective and normal sickle-cell hemoglobin; they are carriers, and they can pass the condition to their children. In case two people who are carriers have a baby, there is a 25%  chance that their child will have the disease, 50% probability of the child being a carrier, and 25% probability that the child will neither have the disorder nor be a carrier.

Epidemiology

SCD predominantly affects people from developing countries or continents such as Africa, India, and Arab (Inusa et al., 2019).  Nevertheless, in the United States, SCD is among the most prevalent genetic disorders, and approximately 100,000 people have the disease (Neumayr, Hoppe & Brown, 2019). The statistics include one person in every 365 African-Americans, and one in16, 300 Hispanic Americans (Neumayr, Hoppe & Brown, 2019).  It is associated with decreased life expectancies of about fifty years in America (Wastnedge et al., 2018).  It also leads to increased spending in health care and vital quality-of-life impairments. Globally, about 306, 000 people are born annually with SCD; 80% of the people are from Sub-Saharan Africa; this represents over 300,000 births (Inusa et al., 2019). The highest number of patients comes from Nigeria and the Democratic Republic of Congo (Inusa et al., 2019).  However, the prevalence of the disorder is increasing in developed countries, primarily due to increased rates of migration from the countries where the condition is highly prevalent.  Approximately 14,000 people with SCD in the United Kingdom and France (Inusa et al., 2019). Equally, Italy and Germany are experiencing the same changes due to the increased number of immigrants from Africa (Inusa et al., 2019).

Despite the progress that has been made to improve the clinical outcomes for SCD, people with homozygous SCD have a shortened lifespan. A study conducted in the US from 1979 to 2014 revealed that the average increase in mortality age between 28 to 43 years (Neumayr, Hoppe & Brown, 2019). The leading cause of these deaths is chronic cardiac complications that result from SCD. In Sub-Saharan Africa, 50% -90% of the people born with the condition die before they attain five years (Inusa et al., 2019). Five hundred children from low income and middle-income countries die every day due to SCD (Wastnedge et al., 2018). The deaths can be prevented or reduced by implementing strategies that will ensure early diagnosis of the genetic disorder.

Pathology

SCD is a clinical condition that includes various hemolytic anaemias that are heritable with variable impacts on life expectancy.  The pathophysiology of SCD is directly related to deoxygenated hemoglobin polymerization that causes a cascade of pathological events. These events include the sickling of erythrocytes and vaso-occlusion (Neumayr, Hoppe & Brown, 2019).  However, its pathophysiology does not follow a specific pattern because some patients may experience mild symptoms, while others their symptoms are severe (Sundd, Gladwin & Novelli, 2019). There are two main pathological processes for SCD, which are hemolysis and vaso-occlusion. Hemolysis results in several clinical events that affect the quality-of-life for patients.   These events include dysfunctioning of the endothelial, consumption of nitric oxide, and dysregulation (Sundd, Gladwin & Novelli, 2019).   Endothelial dysfunction results in other complications such as stroke, leg ulceration, and pulmonary hypertension.

Vaso-occlusion occurs when blood vessels are blocked by sickling RBCs that stick together (Liu et al., 2018). The blockage can take place anywhere and cause a painful crisis or vaso-occlusive crisis (Liu et al., 2018). The acute pain crisis can happen anywhere or where the blockage took place. Acute pain events affect about 60% of the people who have SCD (Newmar, Hoppe & Brown, 2019).  The painful episodes can commence at six months of age and continue throughout the whole life of a patient. Acute pain is the cause of three-quarters of hospital admissions among SCD patients (Lanzkron et al., 2015). They are considered as the most disabling and discouraging consequence of the illness.

Diagnosis

Blood tests are the standard methods of diagnosing SCD.  They are used to check if there is any defective form of hemoglobin. In America, the blood test is a must for newborns so that treatment can begin early (Neumayr, Hoppe & Novelli, 2019). The sample of blood is derived from a vein found in the arm in adults, while in children, the sample is derived from the heel or a finger. The samples are then taken to the laboratory for further screening. If one is suffering from SCD, additional tests can be conducted to check if there are any complications.

Parents who have SCD can request their unborn child to be screened to determine if they could be having the condition.  The child can be diagnosed by taking a sample of the amniotic fluid that surrounds the child in the womb. The correct diagnoses will help medical care professionals to determine the best method of treatment to use.

Treatment of Sickle-Cell Disease

Historically, treatment approaches for SCD have been limited.  However, a better understanding of the molecular components of the illness and encouragement from regulatory bodies has led to the emergence of new methods of treatment (King & Sheroy, 2014).  Most of the therapies aim to address the disorder as a whole clinical entity from the proximal polymerization of deoxygenated hemoglobin to distal pathological events such as vaso-occlusion (Neumayr, Hoppe & Novelli, 2019). However, most methods of treatment have succeeded in relieving painful crises and preventing or reducing complications.

The methods of treatment include hydroxyurea, which was approved in 1998 by the FDA (Neumayr, Hoppe & Novelli, 2019). The drug was initiated to lower the frequency of acute pain events and decrease the need for blood transfusions in patients who have homozygous SCD, especially adults.  Another method of treatment is long-term RBC transfusion therapy, whose aim is to manage both acute and chronic complications. L-glutamine is another drug that was approved in 2017 to lessen the complications of homozygous SCD in patients whose age is ≥ five and adults (Neumayr, Hoppe & Novelli, 2019).  Currently, the only practical and reliable curative therapy for people with SCD is HSCT (Kassim & Sharma, 2014).

Hematopoietic Stem Cell Transplantation (HSCT) in Treating SCD

HSCT is the only curative therapy that is available today for treating SCD patients.  Previously, it was only offered in severe cases of SCD; however, people have accepted it as a method of treating SCD due to the many benefits related to it.  HSCT involves the infusion of body parts that have CD3⁺ and CD4⁺ cells, such as the bone marrow and cord blood (Kassim & Sharma, 2017).  This technique aims to restore immunity and hematopoiesis in patients who have SCD.

The first clinical trials for the efficiency of HSCT were from transplants conducted on children who had β-thalassemia major (Bhatia & Sheth, 2015). The clinical development of this gene is more predictable and consistent. Thus, the only barrier to using HSCT is the availability of a donor. Successful HSCT results in either partial or complete erythropoiesis. It is also significant in stabilizing and restoring the functions of organs that are affected, such as the lungs and the central nervous system. The curative impacts of HSCT have led to its increased use in different medical care settings. Approximately, 1,200 SCD patients have used HSCT since it was successfully applied to treat patients with acute leukemia and SCD in 1984 (Bhatia & Sheth, 2015). The increased use of this treatment technique is associated with reduced rates of infection. The main focus areas for improvement are graft versus host disease (GVHD), long-term organ toxicities, availability of donors, and graft rejection (GR) (Hulbert & Shenoy, 2018). The technique is related to an overall survival rate of 93%, and its mortality rates are at 7%, and infections mainly cause them (Bhatia & Sheth, 2015). However, the main challenge of using HSCT is the lack of donors (Hulbert & Shenoy, 2018), and thus alternative sources are being established.

Expanding Donor Sources

In the past, patients who had severe SCD were the only ones allowed to undergo transplantation if they had a matched sibling donor (MSD). Although human leukocyte antigen (HLA) matched sibling donor (MSD) has high reliability, less than 14% of the patients are lucky to enjoy it (King & Shenoy, 2014). To optimize positive results, these small percentages of patients should consider undergoing the treatment when the disorder is in its early stages.  Patients who have sufficient sibling cord products should also consider undergoing the treatment at an early stage. If the cord products have a low amount of CD4+ cells, engraftment can be optimized by combining the marrow cells with the cord products from the same donor (King & Shenoy, 2014). Most SCD patients are not lucky to have MSD.

Several options are available to be used in the absence of MSD. The options include umbilical cord blood (UCB) and mismatched or matched unrelated donor (m-MUD) or a haploidentical donor. These options have specific complications that are associated with the source of graft and approach used for transplantation (Hulbert & Shenoy, 2018). The complications include graft rejection (GR), graft versus host disease (GVHD), and delays in the reconstitution of the immunity system. Complications can cause unacceptable or adverse clinical outcomes.

Umbilical Cord Blood (UCB)

UCB has been alternatively used as an allergenic donor to treat genetic disorders in children. Its use has been successful because it is rich in progenitor cells and hematopoietic stem cells. Cord blood has the same success as bone marrow in the treatment SCD.  The overall survival rate for UCB is 100%, while the event-free survival is 90% (Bhatia & Sheth, 2015).  Besides, the probability of experiencing both acute and chronic GVHD is low.  The success rate associated with using UCB to treat SCD has led to professionals advocating for banking of cord blood.

However, professionals are against the use of unrelated cord blood because their overall survival rate is at 62.5%, and the event-free survival is 50% (Bhatia & Sheth, 2015). The statistics prove that using this regime to treat SCD can be detrimental to the patient.  Despite the higher rate of donor engraftment associated with it, the use of unrelated cord blood is also related to a slower rate of immune reconstitution and higher mortality rates that are related to transplantation (Abraham et al., 2017). To reduce these negative impacts specific strategies are being implemented. The strategies include the use of ex vivo expansion of cord blood and double cord blood units (Abraham et al., 2017).

MUD (Matched Unrelated Blood)

They are used as alternative sources of stem cells for HSCT. Nevertheless, the safety and feasibility of this regimen are still under investigation. They can be used in symptomatic SCD patients who are not lucky to have MSD (Joseph, Abraham & Fitzhugh, 2018).  Although the approach may be safe for those who have no possibility of MSD, it may be limited by the need for an 8/8 HLA-MUD. The probability of finding MUD varies across different races and ethnic groups. The likelihood of finding an 8/8 HLA-MUD is highest among the Europeans and the Caucasians (75%) while it is lowest among the black Central and South Americans (16%) (Bhatia & Sheth, 2015). The probability of African-Americans getting an 8/8 HLA-MUD is at 18% (Bhatia & Sheth, 2015). The results are disappointing because the prevalence of SCD is high in Africa; thus, the low probability of finding unrelated donors will limit the availability of this treatment approach.

Haploidentical Donor Transplant

It is a treatment approach that involves matching the tissue of the patient, especially the HLA tissue type, with that of a related or unrelated donor (Wiebking et al., 2017). It uses blood-forming cells from a half-matched donor to replace the defective ones in SCD patients. In most cases, the donor is usually a family member (Fuchs, 2015). Although the approach has a chance of expanding donor availability, its safety is still under investigation.  A study conducted to determine the safety of haploidentical HSCT revealed that it has a free survival of 38% and an overall survival rate of 75%.   This approach is advantageous as it increases the probability of every SCD patient finding a donor because almost everyone has at least one haploidentical relative (Fuchs, 2015).  However, the approach is new, and it is still under investigation; hence, it is not available in all treatment centers.

Selection of Patients for HSCT

Medical care professionals can use particular selection criteria to determine if a patient can undergo HSCT.  Patients who have homozygous SCD are the main people who are allowed to undergo HSCT. The patients have severe and recurrent complications, and they require therapy that can relieve their pain and suffering (Bhati & Sheth, 2015). It is also advisable to pick patients who have an HLA-MSD.

Moreover, patients who experience a cascade of pathological events such as severe and frequent vaso-occlusive episodes and acute pain episodes can be allowed to use HSCT. Patients whose lungs and the central nervous system have been damaged by the SCD can use the treatment approach (Bhatia & Sheth, 2015). Children are also preferred over adults because their body organs and systems are not likely to be severely damaged. They have a lower risk of getting morbidities that are transplant-related. The family members of the homozygous SCD patient should be HLA-tested to determine if they can be donors. Subsequently, the family members should be informed about the risks of using the treatment approach.

Optimal Timing for HSCT

Superior outcomes have been observed among younger patients who use HSCT and have MSD-HCSTs. A study conducted in Belgian revealed that there are lower mortality rates among patients who are younger than ten years (Hulbert & Shenoy, 2018). MSD-HCSTs performed between 1986 tom2013 revealed that patients who are younger than 16 years had an event-free survival of 93% while the older patients had an event-free survival of 81% (Gluckman et al., 2017). Death ratio increased by 10% once the patient got a year older (Gluckman et al., 2017) Equally, GVHD free survival is at 86% for patients who are five years and 77% for older patients (Gluckmann et al., 2017). The functioning of the spleen is likely to be stabilized and restored after HSCT (Nickel et al., 2016). The positive outcomes suggest that HSCT is preferable for patients who are younger and have MSD because, during this time, organ function can be improved or stabilized.

Performing HSCT on young patients also has particular financial benefits. An evaluation conducted on 161 children discovered that inpatient medical care expenditures were $467, 747 that year; however, they significantly dropped to $33, 112 in the preceding year (Arnold et al., 2017). Besides, in children, there is a balance between the risks of HCST and its benefits.

Long-term Impacts of HSCT

A lot of debate surrounds the long-term toxicities that result from using HSCT to treat SCD. There has been a significant reduction in the impacts of severe complications, such as GVHD and rejection. Their decreased effects have been proved by the high overall survival rate and event-free survival of HSCT, as shown in table 1. However, most patients, the effects of the approach on fertility have remained a significant concern for most patients and their families. The risk of infertility associated with HSCT has prevented many patients from seeking medical help. Many factors increase the risk of infertility after using HSCT. The factors include gonadotoxic chemotherapeutic agents, use of radiation in the conditioning regimen, and the stage of puberty during the time of HSCT (Bhatia & Sheth, 2015). Long-term monitoring of patients who had HSCT with myeloablative conditioning revealed that nine out of thirteen males had normal levels of follicle-stimulating hormone, and only three had normal levels of testosterone hormone (Bhatia & Sheth. Besides, eight out of fourteen suffered from primary ovarian failure (Bhatia & Sheth, 2015). Several fertility preservation strategies such as cryopreservation of sperms and preservation of ovarian tissue and oocytes are being implemented to solve this problem (Pecker et al., 2018).   Although these strategies give SCD patients the hope of getting expectant, they are expensive and may not be covered by insurance.  Therefore, more research should be conducted to offer a solution to this problem.

Critique and Conclusion

The increased morbidity and mortality rates related to homozygous SCD makes me support the use of HSCT. The use of this approach has reduced the death rates of young children, with most of them celebrating their 18^th birthday. SCD causes severe damage to the organs of young patients and those that are asymptomatic. Therefore, proper patient monitoring should be conducted before recommending HSCT. I would suggest that all children who can be treated with HSCT should be part of prospective clinical studies. More research should also be conducted on how to reduce the complications related to HSCT use, especially among older patients. I also feel that the eligibility criteria for HSCT should be changed. The treatment approach should be used on all homozygous SCD patients who have MSD despite their age or severity of the complications. Affordable strategies on how to reduce the risks of infertility should also be implemented. Despite the progress in using HSCT to treat SCD, systematic research should continue. The research should focus on how to improve the financial, social, physical, and emotional well-being of the affected patients.

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