scholarly journals Drug Therapies for the Management of Sickle Cell Disease

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 592
Author(s):  
Parul Rai ◽  
Kenneth I. Ataga
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Organ Damage ◽  
The United States ◽  
Cell Disease ◽  
Multiple Agents ◽  
Middle Income ◽  
Hematopoietic Stem ◽  
Rich Countries ◽  
Low And Middle Income

Sickle cell disease (SCD) afflicts millions of people worldwide but is referred to as an orphan disease in the United States. Over the past several decades, there has been an increasing understanding of the pathophysiology of SCD and its complications. While most individuals with SCD in resource-rich countries survive into adulthood, the life expectancy of patients with SCD remains substantially shorter than for the general African-American population. SCD can be cured using hematopoietic stem cell transplantation and possibly gene therapy, but these treatment approaches are not available to most patients, the majority of whom reside in low- and middle-income countries. Until relatively recently, only one drug, hydroxyurea, was approved by the US Food and Drug Administration to ameliorate disease severity. Multiple other drugs (L-glutamine, crizanlizumab, and voxelotor) have recently been approved for the treatment of SCD, with several others at various stages of clinical testing. The availability of multiple agents to treat SCD raises questions related to the choice of appropriate drug therapy, combination of multiple agents, and affordability of recently approved products. The enthusiasm for new drug development provides opportunities to involve patients in low- and middle-income nations in the testing of potentially disease-modifying therapies and has the potential to contribute to capacity building in these environments. Demonstration that these agents, alone or in combination, can prevent or decrease end-organ damage would provide additional evidence for the role of drug therapies in improving outcomes in SCD.

scholarly journals Potential role of LSD1 inhibitors in the treatment of sickle cell disease: a review of preclinical animal model data

2018 ◽  
Vol 315 (4) ◽  
pp. R840-R847 ◽  
Author(s):  
Angela Rivers ◽  
Ramasamy Jagadeeswaran ◽  
Donald Lavelle
Keyword(s):  
Reactive Oxygen Species ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Reactive Oxygen ◽  
Organ Damage ◽  
The United States ◽  
Oxygen Species ◽  
Cell Disease ◽  
Hematopoietic Stem

Sickle cell disease (SCD) is caused by a mutation of the β-globin gene (Ingram VM. Nature 180: 326–328, 1957), which triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the United States and millions worldwide (Piel FB, et al. PLoS Med 10: e1001484, 2013) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy (Rees DC, et al. Lancet 376: 2018–2031, 2010; Serjeant GR. Cold Spring Harb Perspect Med 3: a011783, 2013). Hematopoietic stem cell transplantation can be curative, but the majority of patients do not have a suitable donor (Talano JA, Cairo MS. Eur J Haematol 94: 391–399, 2015). Advanced gene-editing technologies also offer the possibility of a cure (Goodman MA, Malik P. Ther Adv Hematol 7: 302–315, 2016; Lettre G, Bauer DE. Lancet 387: 2554–2564, 2016), but the likelihood that these strategies can be mobilized to treat the large numbers of patients residing in developing countries is remote. A pharmacological treatment to increase fetal hemoglobin (HbF) as a therapy for SCD has been a long-sought goal, because increased levels of HbF (α2γ2) inhibit the polymerization of HbS (Poillin WN, et al. Proc Natl Acad Sci USA 90: 5039–5043, 1993; Sunshine HR, et al. J Mol Biol 133: 435–467, 1979) and are associated with reduced symptoms and increased lifespan of SCD patients (Platt OS, et al. N Engl J Med 330: 1639–1644, 1994; Platt OS, et al. N Engl J Med 325: 11–16, 1991). Only two drugs, hydroxyurea and l-glutamine, are approved by the US Food and Drug Administration for treatment of SCD. Hydroxyurea is ineffective at HbF induction in ~50% of patients (Charache S, et al. N Engl J Med 332: 1317–1322, 1995). While polymerization of HbS has been traditionally considered the driving force in the hemolysis of SCD, the excessive reactive oxygen species generated from red blood cells, with further amplification by intravascular hemolysis, also are a major contributor to SCD pathology. This review highlights a new class of drugs, lysine-specific demethylase (LSD1) inhibitors, that induce HbF and reduce reactive oxygen species.

scholarly journals The Role of Hematopoietic Stem Cell Transplantation in the treatment of Sickle Cell Disease

2020 ◽  
Vol 7 (09) ◽  
pp. 5024-5032
Author(s):  
Carolina Wishner ◽  
Colleen Taylor ◽  
Monica Williams ◽  
Derian Kuneman
Keyword(s):  
Stem Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell ◽  
Sickle Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Organ Damage ◽  
Cell Transplant ◽  
Cell Disease ◽  
Hematopoietic Stem

Abstract   Sickle cell disease (SCD) affects millions of people around the world and is associated with significant morbidity and premature mortality. It is a chronic, life-long illness that affects virtually every tissue in the body, worsens over time, with varying degrees of morbidity in everyone with the disease.  Before hematopoietic stem cell transplant (HCST), the mainstay of the management of SCD included early identification of the disease through newborn screening, infection prophylaxis with vaccinations and antibiotics, management of pain crises, blood transfusions, and hydroxyurea.   These treatments although beneficial, do not cure SCD, stop the progressive end-organ damage associated with this disease, and are lifelong.   Hematopoietic stem cell transplant is one of two treatment options that offer a cure for SCD and stops the progressive end-organ damage. The purpose of this article is to examine traditional treatments (best medical practice) and HCST for SCD and their associated complications.  The role of HCST in the treatment of sickle cell disease, as well as recent research on HSCT as a cure for SCD, risk factors, patient selection, limitations, and future use of this treatment option, are also reviewed.  Major issues surrounding the use of HCST for treating SCD include the optimal age for transplantation, disease severity, donor source, and the conditioning regimen before transplantation. The future of HCST including gene therapy is also discussed.

scholarly journals Optimal disease management and health monitoring in adults with sickle cell disease

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 505-512 ◽  
Author(s):  
Jo Howard ◽  
Swee Lay Thein
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Multidisciplinary Care ◽  
Organ Damage ◽  
Cell Transplant ◽  
Cell Disease ◽  
Adult Care ◽  
Pharmacological Agents ◽  
Hematopoietic Stem ◽  
Age Related

Abstract In countries with access to organized health care, survival of children with sickle cell disease (SCD) has greatly improved, resulting in a growing population of adults with SCD. Transition from pediatric to adult care presents many challenges for the patient, who now faces the reality of emerging complications in many organs that are cumulative, adding to other age-related nonsickle conditions that interact and add to the disease morbidity. We recommend regular comprehensive annual assessments, monitoring for early signs of organ damage and joint clinics with relevant specialists, if applicable. While maintaining a low threshold for intervention with disease-modifying therapies, we should always keep in mind that there is no single complication that is pathognomonic of SCD, and nonsickle comorbidities should always be excluded and treated if present. We need to reevaluate our approach to managing adults with SCD by putting a greater emphasis on multidisciplinary care while proactively considering curative options (hematopoietic stem cell transplant and gene therapy) and experimental pharmacological agents for adults with SCD of all ages before complications render the patients ineligible for these treatments.

scholarly journals Hematopoietic Stem Cell Transplantation for Sickle Cell Disease: Current Practice and Emerging Trends

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 273-279 ◽  
Author(s):  
Shalini Shenoy
Keyword(s):  
Stem Cell ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Severe Disease ◽  
Organ Damage ◽  
Pulmonary Complications ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Stem Cell Source

AbstractAllogeneic HSCT controls sickle cell disease (SCD)–related organ damage and is currently the only curative therapy available. Over the last 2 decades, HSCT has been limited largely to myeloablative matched sibling donor (MSD) procedures that are feasible only in a minority of patients. As the natural history of the disease has evolved, it is clear that subsets of patients with severe disease are at risk for sudden death, devastating CNS and pulmonary complications, and debilitating vasoocclusive crises. For these patients, the benefits of transplantation can outweigh the risks if HSCT can be safely and successfully performed with low early and late toxicities. This review describes advances and ongoing investigation of HSCT for SCD from the perspectives of recipient age and presentation, donor stem cell source, intensity of conditioning, family and medical perspectives, and other variables that influence outcome. Ultimately, HSCT should be viewed as a viable treatment option for SCD on par with other therapies for select patients who can benefit from the procedure.

Hematopoietic stem cell transplantation and gene therapy are the sole treatments for sickle cell disease and other hemoglobinopathies

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Sickle Cell ◽  
The United States ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Hbf Induction

Linus Pauling and colleagues originally discovered sickle cell disease (SCD) as a molecular genetic abnormality in 1949, and after more than five decades of study, the FDA authorized hydroxyurea as the first HbF-inducing drug for the treatment of VOC in SCD patients in 1998. L-glutamine, crizanlizumab, and voxelotor were authorized by the FDA for the treatment of SCD in adults 20 years ago. There are several FDA-approved medications for treating SCDs in the United States, but the HU is the only EMA-approved medication in Europe.Hematopoietic stem cell transplantation (HSCT) and gene therapy are the sole treatments for SCD and other hemoglobinopathies. Furthermore, miRNAs contribute to the development of novel therapeutics by delineating the molecular mechanisms and signaling networks involved in HbF induction. The transcription factors BCL11A, MYB, KLF-3, and SP1 regulate miRNAs, which have a variety of consequences on target expression. HbF induction is now an important aspect of minimizing hospitalizations and improving survival. A comprehensive perspective on miRNA regulation mechanisms and comprehensive study on miRNAs as a possible SCD treatment are relevant, based on the rising number of detailed miRNA functional investigations. As a biomarker, it might be used to quantify VOCs and discriminate between acute and chronic pain. This is the first study we've seen that suggests miRNAs may be used to treat SCD.

Hydroxyurea Use Among Infants with Sickle Cell Disease: A Survey of Pediatric Hematologists-Oncologists In the United States

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1640-1640 ◽  
Author(s):  
Arun L Singh ◽  
Carlos Lastra ◽  
Kris M. Mahadeo
Keyword(s):  
United States ◽  
Clinical Trial ◽  
Sickle Cell Disease ◽  
Disease Severity ◽  
Sickle Cell ◽  
Response Rate ◽  
Organ Damage ◽  
The United States ◽  
Controlled Clinical Trial ◽  
Cell Disease

Abstract Abstract 1640 A National Institutes of Health expert panel concluded that barriers to hydroxyurea (HU) therapy for patients with sickle cell disease (SCD) exist at multiple levels, including that of healthcare providers.1 Despite calls for more widespread use of HU among infants with SCD, only a small fraction of those who meet currently accepted criteria for HU administration are actually prescribed therapy.1 To address this disparity, we assessed barriers to HU therapy as perceived by Pediatric Hematologists-Oncologists in the United States. This study was approved by the institutional review board. We surveyed 400 Pediatric Hematologists/Oncologists from varying regions in the United States. Prospective participants were emailed a link to an anonymous online survey. To ensure an optimal response rate, two-follow up emails were sent at two week intervals to those who did not initially respond. Our survey instrument was evaluated for content validity by 5 Pediatric subspecialists from geographically diverse areas of the country and included both public and private settings. Response rate was equal to (complete responses+ partial responses)/(complete responses + partial responses + nonresponse + implicit refusals). In this study, a complete response was defined as 80% or more of questions answered and a partial response as less than 80% of questions answered. The response rate for this survey was 25% (n=99). Respondents’ primary areas of practice included pediatric hematology (27.5%; n=22), general pediatric hematology oncology (57.5%, n=46) and pediatric oncology (15%, n=12). Respondents’ practices ranged in the size of their sickle cell populations from 3 to 1600 (median=300). The vast majority of respondents agreed or strongly agreed that HU was an effective treatment for children with SCD (98%, n= 83). Most respondents (55%, n=45) reported the age range of 1–5 years as the youngest age at which they initiated HU therapy among their patients, 17% (n=14) had initiated therapy in a patient between 6months and 1 year of age. Common independent criteria for HU initiation included recurrent acute chest syndromes (94%, n=78), vaso-occlusive crises (93%, n=77), other pulmonary disease (including increased tricuspid regurgitation velocities) (66%, n=55) and priapism (58%, n=48). Interestingly, 30% (n=25) of respondents used patient/family request as an independent criterion for HU therapy. Compliance/adherence (89%, n=72), need for frequent monitoring (78%, n=68) and family concerns regarding toxicity (76%, n= 63) were the most commonly reported barriers to the effective use of HU therapy among patients with SCD. While, 57.8% (n=48) of respondents agreed/strongly agreed that HU is an effective drug for the prevention of organ damage among infants with SCD, only 32% (n= 26) supported the prophylactic use of HU for infants (>6 months) with severe sickle genotypes (SS, SB0), regardless of disease severity. Respondents were most concerned about cytopenias (68%, n=55), fertility (46%, n=37), risk of malignancy (27%, n=22), gastrointestinal disturbances (26%, n=21) and avascular necrosis (17%, n=14). The majority of respondents agreed/strongly agreed that a prospective randomized controlled clinical trial is needed to establish the long-term safety and efficacy profile of HU treatment before prophylactic therapy is offered to infants with severe sickle cell genotypes, irrespective of their disease severity (78%, n=63), or to infants with SCD regardless of genotype and disease severity (82%, n=67). Respondents identified lack of funding for (71%, n=73) and family/patient mistrust towards a clinical trial (45%, n=46) as the major barriers to conducting a prospective study. The majority of respondents (94%, n=78) supported the establishment of a registry for all patients with SCD who are on HU therapy. While most respondents believe HU to be an effective drug for the treatment of patients with SCD and for prevention of associated organ damage, there is concern for potential toxicities of therapy. Most respondents support a prospective randomized controlled clinical trial and/or establishment of a registry for the use of prophylactic HU therapy among infants with SCD. 1. Brawley OW, Conrelius LJ, Edwards LR, et al. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Internal Med. 2008; 148:932-938. Disclosures: Off Label Use: off-label use of hydroxyurea in children.

scholarly journals Cost analysis of acute care resource utilization among individuals with sickle cell disease in a middle-income country

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Clarisse Lobo ◽  
Patricia Moura ◽  
Delaine Fidlarczyk ◽  
Jane Duran ◽  
Roberto Barbosa ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Medication Possession Ratio ◽  
Cost Savings ◽  
Organ Damage ◽  
Cell Disease ◽  
Potential Cost ◽  
Middle Income ◽  
Ed Visits ◽  
The Cost

Abstract Background The costs associated with the treatment of sickle cell disease (SCD) are understudied in low and middle-income countries (LMIC). We evaluated the cost of treating SCD-related acute complications and the potential cost-savings of hydroxyurea in a specialized hematology center in Brazil. Methods The costs (US dollars) of emergency department (ED) and hospitalizations from SCD-related complications between 01.01.2018 and 06.30.2018 were ascertained using absorption and micro-costing approaches. The reasons for acute hospital visits were grouped as: 1) vaso-occlusive (VOC) pain, 2) infection, 3) anemia exacerbation, and 4) chronic organ damage complications. Hydroxyurea adherence was estimated by medication possession ratio (MPR) during the study period. Results In total, 1144 patients, median age 17 years (range 0–70), 903 (78.9%) with HbSS/HbSβ0-thalassemia, 441 (38.5%) prescribed hydroxyurea, visited the ED, of whom 381 (33%) were admitted. VOC accounted for 64% of all ED visits and 60% of all admissions. Anemia exacerbation was the most expensive reason for ED visit ($321.87/visit), while chronic organ damage carried the highest admission cost ($2176.40/visit). Compared with other genotypes, individuals with HbSS/HbSβ0-thalassemia were admitted more often (79% versus 21%, p < 0.0001), and their admission costs were higher ($1677.18 versus $1224.47/visit, p = 0.0001). Antibiotics and analgesics accounted for 43% and 42% of the total ED costs, respectively, while housing accounted for 46% of the total admission costs. Costs of ED visits not resulting in admissions were lower among HbSS/HbSβ0-thalassemia individuals with hydroxyurea MPR ≥65% compared with visits by patients with MPR <65% ($98.16/visit versus $182.46/visit, p = 0.0007). No difference in admission costs were observed relative to hydroxyurea use. Discussion In a LMIC hematology-specialized center, VOCs accounted for most acute visits from patients with SCD, but costs were highest due to anemia exacerbation. Analgesics, antibiotics, and housing drove most expenses. Hydroxyurea may reduce ED costs among individuals with HbSS/HbSβ0-thalassemia but is dependent on adherence level.

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