Hematopoietic Stem Cell Transplantation: An Approach in the Treatment of Sickle Cell Disease

Introduction

Hematopoietic Stem Cell Transplantation (HSCT), sometimes called Bone Marrow Transplantation (BMT), is a treatment indicated for several types of hematological neoplasms, such as leukemia, lymphoma, multiple myeloma, and other autoimmune hematological diseases and immunodeficiencies [1].

During the last two decades, the use of this therapy has expanded throughout the world and its technology has evolved. Nowadays, it is used for new indications, such as autoimmune and hereditary metabolic disorders [2, 3].

Pediatric HSCT presents unique challenges, such as the need to adjust doses of chemotherapy and radiotherapy according to the child’s age and size. Furthermore, emotional and psychological support for both the child and the family is essential throughout the process, as the transplant and the recovery period can be intense and challenging [4].

Sickle cell disease (SCD) is an inherited blood disorder that shortens the survival of red blood cells, causing anemia. According to the World Health Organization (WHO), approximately 5% of the world’s population carries trait genes for hemoglobin disorders, mainly sickle cell disease and thalassemia. Annually, more than 300,000 babies are born with serious hemoglobin disorders. Worldwide, 120 million people are affected by the disease, and of these, 66% live in Africa [5].

Considered as the only treatment capable of curing sickle cell anemia, hematopoietic stem cell transplantation (HSCT) is effective in curative therapy for the disease. In this sense, this research sought to address advances and new perspectives in hematopoietic stem cell transplantation (HSCT) in the treatment of sickle cell disease.

Pathophysiology and clinical manifestations of sickle cell disease

Sickle cell disease (SCD) is an umbrella terminology that represents a group of autosomal recessive diseases. There are variable genotypes of SCD, but the most common is sickle cell anemia (HbS), which results from the inheritance of two copies of the HbS mutation (homozygous) and accounts for 65% to 70% of all cases of SCD [6].

Sickle cell disease (SCD) is hereditary resulting from an autosomal recessive genetic mutation of red blood cells, which results from the inheritance of two sickle cell genes, with one gene from each parent. When both parents carry a gene for hemoglobin S (HbS), known as sickle cell trait, there is a 25% chance of their children inheriting the disease, a 25% chance of their children being unaffected, and a 50% chance of carrying the genetic mutation as an asymptomatic carrier [7].

The disease is characterized by a mutation in the DNA of chromosome 11, caused by the specific replacement of the nitrogenous base thymine (T) with adenine (A), which changes from GAG to GTG [8]. The exchange of nitrogenous bases in DNA (Figure 1), instead of encoding the production (transcription) of the amino acid glutamic acid, will, from then on, determine the production of the amino acid valine, which will enter position 6 in the sequence of amino acids that make up the beta chain of hemoglobin, modifying its molecular structure [9].

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The pathophysiology of sickle cell disease is related to the ability of hemoglobin S to crystallize under conditions of low oxygen concentration. This crystallization leads to deformation of the red blood cells, which take on a sickle or crescent shape instead of their normal disc shape. Sickle red blood cells are less flexible and have a shorter lifespan, which results in chronic anemia [4].

In sickle cell disease (SCD), sickle hemoglobin (HbS) tends to polymerize under conditions of low oxygen saturation. Red blood cells containing HbS polymers tend to convert the normal biconcave disc shape of red blood cells into a rigid and irregular sickle shape that can block blood vessels in the microcirculation, thus impairing the supply of oxygen to tissues [10].

Hematopoietic Stem Cell Transplantation in Sickle Cell Disease

HSCT is the replacement of diseased or suppressed bone marrow with another healthy bone marrow from a histocompatible donor [11]. Currently, hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with sickle cell disease and aims to restore normal hematopoiesis and, thus, prevent damage from successive episodes of sickling [12].

Hematopoietic stem cell transplantation (HSCT) is equivalent to a treatment modality seen as a highly invasive and highly complex procedure, which involves the use of medications chemotherapy, radiotherapy sessions, blood transfusions and other methods that can cause numerous risks to the patient’s life [13]. The treatment consists of providing the patient with progenitor cells that can be taken from the patient himself (autologous transplant), from a donor (allogeneic transplant) or even from umbilical cord cells [1].

The new transplanted cells are intended to reconstitute the patient’s hematopoietic and immune systems. Thus, the production of blood cells and cytotoxic destruction of remaining diseased cells of the recipient are expected to occur. With the success of the transplant, hematopoiesis becomes subordinate to the new graft and no longer to the diseased bone marrow [14].

Allogeneic hematopoietic stem cell transplantation has become an increasingly acceptable treatment option for sickle cell disease. An analysis of 1,000 human leukocyte antigen (HLA)-matched identical sibling donor transplants performed between 1986 and 2013, at 106 centers in 23 countries worldwide. Patients were mainly children (n = 846; <16 years), with a median age of 9 years. The excellent outcome over 3 decades confirms the role of HLA-identical sibling transplantation for children with SCD [15].

Currently, even with advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care for this disease is unequal. With recent advances in medical treatment, the natural history of sickle cell disease (SCD) continues to evolve as morbidity and mortality decline [16].

Since 1990, 4 large randomized trials to prevent central nervous system (CNS) injury have been completed, presenting evidence-based guidelines for the primary and secondary prevention of stroke in children with SCD [17, 18]. However, in sub-Saharan African countries and India, where more than 90% of children are born with SCD [19] evidence- based primary and secondary stroke prevention strategies are not presented. Thus, ∼50% of children with SCD will have a cerebral infarction before they are 18 years of age.

Allogeneic HSCT, graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality in pediatric patients. This disease develops due to a “protection” that the recipient’s immune system carries out against the donor’s cells and, depending on the intensity, can result in rejection of the transplanted graft, which can be acute (most common), occurring in up to 6 weeks after transplantation, or chronic, occurring after 6 weeks of transplantation [20, 21, 22].

In the study by Hsieh, et al. [23], the findings indicate that patients who underwent hematopoietic stem cell transplantation (HSCT) mostly presented a reversal of the sickle cell disease phenotype, in addition, those grafted continued to be disease-free and without the manifestation of sickle cell disease. graft versus host, that is, tolerance to the donor cells occurred, which brings greater survival and quality of life to patients.

In a more recent study, de Costa, et al. [24], identified better disease-free survival results after HSCT in children with sickle cell disease, especially with hematopoietic progenitor cells. The findings agree with previous studies [25]. which state that patients undergoing transplantation can have average survival and disease-free survival rates above 90% and 73%, respectively.

Allogeneic HSCT procedure from siblings remains the type of treatment considered the gold standard for the disease, as it has high success rates. However, it is still a therapeutic modality that has the disadvantage of low availability of compatible donors and the risk of developing graft-versus-host disease [26].

Marques, et al. [27] state that, even though hematopoietic stem cell transplantation is the hope of many patients, representing, in most cases, the only form of treatment for cases of SCD, it still has serious implications such as the occurrence of SCD. Acute graft versus host, causing impacts on the quality of life of these patients, in their psychological, social, biological aspects and cognitive impairment in children and adolescents, according to Castro, et al. [28].

The quality of life of transplanted children with sickle cell disease can also be harmed by the appearance of early and late complications, such as the evolution of insulin resistance, systemic arterial hypertension and/or dyslipidemia and, consequently, the development of metabolic syndrome after HSCT [29].

Hematopoietic stem cell transplantation (HSCT) can cure children and adults with sickle cell disease. Outcomes have historically been poor for the vast majority of patients who do not have a matching sibling donor. However, the development of haploidentical HCT (haplo-HCT) with high doses of post-transplant cyclophosphamide (PTCy) has allowed long-term curative potential with favorable transplant-related outcomes, although this has not prevented the potential for graft rejection of the human leukocyte antigen incompatibility and repeated red blood cell transfusions [26].

Conclusions

The present study sought to investigate the current perspectives on hematopoietic stem cell transplantation in the treatment of sickle cell disease. In this research it can be observed that sickle cell disease is a highly prevalent pathology in children and adults, however, in recent years, there have been advances in diagnosis and treatment, however, it is not a reality in poor countries such as Africa and Asia, where the number of patients tends to grow. In this sense, it is important to apply and expand neonatal screening programs, and the need for investment in health policies, especially in those countries where the disease is more severe.