Treatment of sickle cell disease - options and perspective.

Am J Blood Res 2023;13(2):61-70 www.AJBlood.us /ISSN:2160-1992/AJBR0148676 Review Article Treatment of sickle cell disease - options and perspective Loubna Abdel-Hadi, Yendry Ventura Carmenate, Yandy Marx Castillo-Aleman, Samira Sheikh, Aya Zakaria, John Phillips Abu Dhabi Stem Cells Center, Abu Dhabi, UAE Received December 21, 2022; Accepted March 28, 2023; Epub April 15, 2023; Published April 30, 2023 Abstract: Sickle Cell Disease (SCD) is one of the most inherited hematologic diseases affecting humans. Clinically, there is a progressive multiorgan failure and increased mortality in severe cases. The highest prevalence is in West Africa, India, the Mediterranean region, and Middle East countries. Hydroxyurea was the primary drug available for SCD and remains first-line therapy for patients with SCD. Three additional drug therapies, L-glutamine, Voxelotor, and Crizanlizumab, have been approved as adjunctive agents. However, none of these treatments are curative. Effective cell-based therapies are available, such as red blood cell (RBC) exchange and the only curative therapy is hematopoietic stem cell transplantation (HSCT). Gene-editing now shows promise in treating SCD and the β-thalassemias. Recent clinical trials have proven that this therapeutic strategy is effective, however costly. Despite the availability of safe and effective drug treatments, questions focusing on the overall value of these drugs exist in light of rising healthcare costs including hospitalizations and medical interventions. Herein, we report a cost-effective evaluation that can guide future efforts in making decisions towards HSCT as cell therapy treatment in SCD patients. Keywords: Sickle cell disease, fetal hemoglobin, hematopoietic stem cell transplant Introduction Sickle Cell Disease (SCD) was identified by Herrick in 1910 [1] and then characterized biochemically and molecularly by Ingram in 1958 [2]. SCD arises as a result of a single missense mutation, leading to a replacement of glutamic acid by valine in the sixth position of the β-globin chain of hemoglobin. This swap on the protein level, converts HbA into the so-called sickle hemoglobin (HbS). In hypoxic conditions, HbS normally polymerizes resulting in the formation of deoxygenated hemoglobin fibrils, due to hydrophobic interactions between the valines in the adjacent HbS molecules, which in turn interact with the cytoskeleton and distort the natural biconcave disc shape of the red blood cell (RBC) creating the irreversible characteristic sickle or sliver moon-shaped cell. Studies on examining DNA variants within the β-globin gene have confirmed that the HbS mutation occurred independently in several different populations in Central Africa, Central West Africa, African West coast, Arabian Peninsula and India and the presence of falciparum malaria has served as a selective factor in increasing its prevalence [3]. This would suggest that there is genetic pressure or genomic architecture that supports the single base change. Over the generations, the HbS gene has been reached high frequencies in regions with past or present history of malaria endemicity. However, population migration has played a major role in distributing HbS gene even to nonmalaria endemic regions. Worldwide, between 300,000-400,000 individuals are born annually with SCD [4]. The extent of HbS polymerization is the primary determinant of the severity of SCD [5]. Clinically, SCD is characterized by two main pathologic events: hemolysis and recurrent acute vasoocclusive crises (VOC). Over time, individuals with this condition experience numerous other life-threatening comorbidities throughout their lifetimes. Acute comorbidities, which can occur at any age, include VOC, stroke, acute chest Treatment of sickle cell disease syndrome (ACS), acute renal failure, priapism, splenic sequestration and retinopathy. Chronic comorbidities such as skin ulcers, pulmonary hypertension, diastolic heart dysfunction, kidney disease, and osteonecrosis increase with age [6]. Painful VOC crisis are the most common manifestation of SCD and remain the most common reason for presenting to the emergency department and hospitalization. VOC has previously been described to evolve along four distinct phases starting from a low-intensity pain and exacerbating with the development of worsening symptoms such as chronic disabling arthritis due to osteonecrosis affecting the joints, progressive retinopathy, chronic renal failure, increased risks for strokes, and shortened lifespan [7]. Chronic inflammatory processes associated with SCD and originated from a combination of membrane damage of erythrocytes carrying HbS and increased intestinal permeability are the main triggers of VOC development and aggression [8]. Stroke is the main neurological comorbidity in SCD and unfortunately, is one of the few complications seen more often in children than in adults [9]. In children with a severe phenotype of SCD, ~10% have documented stroke, and approximately 20 to 35% have silent cerebral infarcts. Parallel studies established that approximately 11% of patients with SCD will go on to develop a clinically apparent stroke by the age of 20 years, and 24% by the age of 45 years [10]. Strokes may be complicated by impaired cognition and an overall decrease in mental acuity. Silent infarcts, which do not manifest overtly but can accumulate over time, have been shown to cause neurocognitive deficits including severe headache, altered mental status, slurred speech, seizures, and partial paralysis in cases of overt stroke, in school-aged children and adults [10]. Some important ways that SCD manifests in the respiratory system are ACS, caused by infections and/or a blockage of blood flow to the chest and resulting in lung injury, breathing difficulty, low oxygen to the rest of the body. Repeated episodes can cause pulmonary arterial hypertension from the increased pulmonary vascular resistance and diastolic heart dysfunction. ACS is one of the most common causes of hospitalization for children and adults with SCD and is the root cause for more than 25% of premature deaths in sickle cell disease [11]. Multiple studies have 62 estimated the mortality of the disease and found that 50% of patients died before the fifth decade, and most of those who died did not have overt chronic organ failure but during an episode of acute pain, ACS, or stroke [12]. Prospective follow-up made it possible to determine the incidence (approximately 13 per 100 patient-years), risk factors, presentation, and prognosis of the ACS [13]. Patients with SCD are at high risk for developing chronic kidney disease during their lifetime. It is possible that this progressive loss of kidney function is triggered by anemia, hemolysis, inflammation, infections and nonsteroidal pain medications. Acute kidney injury accounts for between 4% and 10% of hospitalized individuals with SCD [14]. Acute renal injury frequently co-occurs more in patients ex (...truncated)