Introduction
Sickle cell disease (SCD) stands as the predominant inherited hemoglobinopathy on a global scale. It stems from a genetic alteration involving a single nucleotide, causing hemoglobin to polymerize more readily, resulting in the deformation of red blood cells into a sickle shape. The disease manifests with symptoms including anemia, continuous breakdown of red blood cells, and recurring blockages in blood vessels, leading to acute and chronic complications impacting various organs. SCD affects a significant number of individuals in the United States, with estimates surpassing 100,000, and it occurs in approximately one out of every 500 African-American births and one out of every 1000–1400 Hispanic-American births.
Since the initial bone marrow transplantation (BMT) report in in 1982, over 1,500 patients globally have undergone hematopoietic stem cell transplantation (HSCT) for β-thalassemia major. Major studies identified three risk factors: the presence of hepatomegaly (over 2 cm), liver fibrosis, or irregular iron chelation therapy before transplantation, which correlated with patient outcomes. In some studies, Class I patients, without any risk factor, exhibited the highest thalassemia-free survival rate at 91 %.
Class II patients with one or two risk factors showed an 84 % disease-free survival rate. However, poor-risk patients with iron overload and liver disease due to insufficient chelation therapy had a disease-free survival rate of approximately 50 %. These findings strongly advocate for early HSCT timing, particularly for patients with an HLA (human leukocyte antigen) identical sibling donor. This article covers details about stem cell transplantation for hemoglobinopathies.
What Are Hemoglobinopathies?
Hemoglobin disorders are prevalent across the Mediterranean, Middle Eastern, and Asian regions, representing the most common genetic ailments globally. The Mediterranean area alone harbors over 200,000 β-thalassemia patients. The World Health Organization estimates that approximately 180 million individuals carry one genetic hemoglobin synthesis disorder. Inadequate production of β-globin results in an overabundance of α-globin chains, leading to ineffective erythropoiesis and reduced red blood cell longevity in β-thalassemia patients.
While lifelong red blood cell transfusions and chelation therapy have enhanced patient survival, they fail to eradicate the disease and its associated complications, such as endocrine dysfunctions, progressive liver fibrosis, cardiac ailments, and post-transfusion viral infections, significantly impairing quality of life and raising mortality rates. Drugs like hydroxyurea offer some benefits for sickle cell disease patients but do not prevent organ damage, only modifying the disease's natural progression. Allogeneic hematopoietic stem cell transplantation (HSCT) is the sole curative treatment for these hemoglobin disorders.
What Is Stem Cell Transplantation for Hemoglobinopathies?
Over the past three decades, recent advancements, including early penicillin prophylaxis, pneumococcal vaccination, improved blood transfusion protocols, and hydroxyurea have extended the survival of children with sickle cell anemia (SCA) into young adulthood. Despite this progress in developed nations, the average lifespan for adult patients remains 45 years.
While pneumococcal sepsis is the primary cause of death in children, adults with SCA typically succumb to strokes, multiorgan failure, acute chest syndrome, and recurrent pain crises. Currently, allogeneic blood or bone marrow transplantation stands as the sole known cure for SCD. Although the first bone marrow transplantation (BMT) for SCD was performed in 1984, the number of affected patients receiving transplants remains relatively low, approximately 175, significantly fewer compared to thalassemia during the same timeframe. Patients classified as Class III who underwent this conditioning regimen exhibited a diminished thalassemia-free survival rate.
Consequently, a reduced dosage of cyclophosphamide was administered to mitigate transplant-related toxicity and mortality. Specifically, employing a reduced-intensity dose of the conditioning regimen in younger Class III patients (aged under 17 years) correlated with enhanced overall survival (79%), albeit with a higher rejection rate (30%). The primary issue encountered in these patients was the elevated incidence of rejection.
Regarding stem cell origins for transplantation in thalassemia, most centers opt for bone marrow over peripheral blood stem cells. While certain studies show no discernible variance in chronic graft-versus-host disease rates, others indicate a notably higher complication with blood stem cell transplants. Until it is determined whether blood stem cells offer equal or superior efficacy compared to bone marrow in thalassemia major patients, bone marrow utilization should remain the preferred option.
What Are Indications For Stem Cell Transplantation for Hemoglobinopathies?
The decision to pursue hematopoietic stem cell transplantation (HSCT) for "less severe patients" before significant organ damage sets in remains a topic of debate. On the one hand, there is an argument for early transplantation to forestall organ damage due to sickle cell disease (SCD), mitigate childhood complications, and improve HSCT outcomes by minimizing pre-transplant organ damage and immune reactions.
On the other hand, some advocate for delaying HSCT until new supportive treatments for SCD (sickle cell disease), such as alternative medications beyond hydroxyurea, promising curative therapies like gene therapy, and advancements in HSCT technology, become available. Nonetheless, studies indicate that patients undergoing transplantation at a young age exhibit better three-year overall survival (OS) and event-free survival (EFS), with reduced incidences of acute and chronic graft-versus-host disease (GvHD). These findings underscore the importance of promptly referring SCD patients for HSCT.
The following are the indications for hematopoietic stem cell transplantation:
-
Vasoocclusive complications such as stroke, recurrent episodes of acute chest syndrome (ACS), painful crisis, and sickle nephropathy.
-
There are severe hemoglobinopathies such as β-thalassemia major and sickle cell disease.
-
Low or poor response or intolerance to conventional treatments such as blood transfusions and chelation therapy.
-
Presence of significant disease-related complications, including but not limited to endocrine dysfunctions, progressive liver fibrosis, and cardiac diseases.
-
Failure to maintain adequate quality of life despite standard therapies.
-
Identify a suitable HLA-matched donor, preferably a sibling, for allogeneic hematopoietic stem cell transplantation (HSCT).
-
Early intervention in pediatric patients is needed before the onset of irreversible organ damage.
-
Consideration of HSCT in patients with moderate disease severity but with high-risk features such as poor compliance with treatment or progressive organ damage despite therapy.
-
In cases where the potential benefits of HSCT outweigh the risks associated with the procedure and post-transplant complications.
Conclusion
In summary, HSCT presents a potential cure for individuals with hemoglobinopathies. It is crucial to conduct hematopoietic stem cell transplantation early in childhood to prevent the onset of iron overload and associated complications. Multicenter trials are required to determine optimal conditions to minimize graft rejection and enhance disease-free survival rates, particularly for high-risk patients. Addressing iron overload post-successful HSCT is essential for ameliorating multi-organ dysfunctions.
Currently, stem cell transplantation (SCT) stands as the sole therapy capable of curing β-thalassemia major and sickle cell anemia. SCT demonstrates an 84 % to 91 % likelihood of disease-free survival for young patients with β-thalassemia major and an 84 % probability of disease-free survival for sickle cell disease (SCD) patients. Performing transplantation at a younger age, before the development of disease and treatment-related complications, is imperative. Considering that adult patients face a higher risk of transplant-related mortality with myeloablative regimens, they may be better suited for modern, fludarabine-based, reduced-intensity conditioning regimens, which could potentially enhance transplant outcomes.
