Option For Sickle Cell Disease Research Articles

Parent and Guardian Knowledge of Hematopoietic Cell Transplantation As a Treatment Option for Sickle Cell Disease

Introduction: Beginning early in childhood, patients with sickle cell disease (SCD) are at risk of life-threatening and debilitating health events. Despite the high morbidity and mortality of this disease, hematopoietic cell transplantation (HCT), the only curative therapy for SCD, remains underutilized. Between 2008 and 2012, an average of 76 HCTs per year were performed on patients with SCD in the United States (US), a remarkably low rate considering that nearly 100,000 people in the US are living with this disease and approximately 1,000 infants are born with SCD in the US each year. Multiple factors may contribute to the low rates of HCT in this population. However, there is a paucity of data concerning the level of awareness of HCT among parents and guardians of children with SCD, an important factor to consider in the assessment of HCT utilization rates.Objectives: To identify the proportion of parents and guardians of children with SCD who are aware of HCT as a treatment option, and to evaluate the relationship between patient demographics and parental/guardian awareness of this treatment option.Methods: A 25-item paper-based survey was developed to assess parent/guardian awareness of HCT, based upon feedback from leaders in SCD community health organizations and pediatric hematologists. The survey was administered to parents/guardians of pediatric patients with SCD during routine outpatient appointments with their child’s hematologist and at SCD community events sponsored by participating clinical sites. The survey was anonymous, and a $5.00 gift card was provided to all participants who completed the survey. Participants were recruited from four clinical centers across three cities in the Midwestern United States. All parents/legal guardians of children (<18 years of age) with SCD, who have not undergone HCT, were eligible to participate. Multivariable logistic regressions were performed to assess the relationship between the following variables and parent/guardian awareness of HCT as a treatment option for SCD: accrual site, patient age, number of full siblings, parent/guardian education level, parent/guardian relationship to patient, duration of custody, and SCD genotype.Results: 229 respondents (95% biological parent, 1% adoptive parent, 4% legal guardian) have participated in the study to date. 95% of all eligible parents/guardians agreed to participate. 82% of study respondents indicated that they have heard of HCT as a treatment option for SCD (N=187). 53% indicated that their child's physician has talked to them about HCT at some point in the past (N=120). On average, patients were 2.84 years old when the parent/guardian first heard about HCT (N=178, 95% CI: 2.31-3.37); patients were 3.08 years old on average when the child's physician first mentioned HCT (N=113, 95% CI: 2.42-3.75). 76% of respondents indicated that they are aware that HCT can potentially cure SCD (N=172). Higher parent/guardian education level and SS genotype were associated with having heard about HCT as a treatment option. SS genotype was associated with having been informed about HCT by their child's physician. Having been informed about HCT by their child's physician was associated with parent/guardian awareness that HCT is a potentially curative treatment.Conclusions: The majority of parents/guardians of children with SCD enrolled in this study have heard of HCT and are aware that HCT is a potentially curative treatment. In this population, non-physician sources of information and parent/guardian education level play an important role in awareness of this treatment modality. Physician-family discussion about HCT plays an important role specifically in parent/guardian awareness of the curative potential of this treatment. These data underscore the importance of physicians discussing HCT with families, particularly those who have limited resources to research treatment options on their own. DisclosuresQuinn:Amgen: Research Funding; Eli Lilly: Research Funding; Silver Lake Research Corporation: Consultancy. Hsu:Centers for Medicare and Medicaid Innovation: Research Funding; Mast Therapeutics: Research Funding; Pfizer: Consultancy, Research Funding; Purdue Pharma: Research Funding; Sancilio: Research Funding; Gerson Lehman Group: Consultancy; Eli Lilly: Research Funding; EMMI Solutions: Consultancy; Astra Zeneca: Consultancy, Research Funding; Hilton Publishing: Consultancy, Research Funding. Piccone:Novartis: Other: Speaker.

Hematopoietic stem-cell transplantation for sickle cell disease: current evidence and opinions

With rapidly expanding evidence of benefit reported by several groups, allogeneic hematopoietic stem-cell transplantation has become an acceptable treatment option for sickle cell disease. It is currently the only curative therapy available. Hematopoietic stem-cell transplantation was offered primarily as a therapeutic option for severe sickle cell disease in the context of myeloablative matched sibling donor transplants over the last two decades and helped to establish the benefits of transplantation for this disorder. While this approach provided proof of principle, the disadvantages and limitations of transplantation became evident along the way. It has been recognized that transplantation for sickle cell disease does not need to adhere strictly to the principles of transplantation for malignant disorders, such as achievement of full donor cell chimerism. As reviewed here, in recent years the transplant community has set out to explore ways to make stem-cell transplantation more available to patients with the disease, define indications and better timing, and offset toxicities with novel approaches to conditioning and better supportive care.

Bone Marrow Transplantation Arrests Cerebrovascular Disease Progression and Improves Psychometric Outcomes in Children with Sickle Cell Disease

Abstract 11Stem cell transplantation (SCT) is currently the only curative option for sickle cell disease. Cerebrovascular disease (CVD) is one of the main indications to undertake this procedure as even with best conventional approaches there is a significant risk of recurrence or progression and there is evidence that SCT arrests disease progression, though more detailed study of outcomes is awaited. Early studies of SCT in sickle cell disease showed a high rate of neurological complications that led to the optimization of protocols.We conducted a retrospective analysis of related SCT in children with severe SCD between 2001 and 2010 at our institution to study the effect of transplantation. 20 patients (11 male, 9 female) received a BMT for sickle CVD (n=11) or recurrent vaso-occlusive crises (n=9). One patient with CVD was a second procedure following primary graft failure in a previous sibling transplant. CVD was investigated with clinical history and examination, transcranial Doppler ultrasound, magnetic resonance imaging/magnetic resonance angiography and psychometric testing using WISC-IV: 7 patients had no evidence of CVD, 5 had silent infarcts, 6 ischaemic stroke and 2 Moya-Moya disease. The median age at transplantation was 136 months (range 34 – 210 months). Donor source was HLA-matched siblings in 18 patients, one 9/10 mismatched sibling and HLA-matched relative in another. Bone marrow was used in all (n=19) but one patient who received combined bone marrow and umbilical cord. All patients (n=18) but two received conditioning with oral busulfan 14 mg/kg, cyclophosphamide 200 mg/kg and alemtuzumab 0.3 mg/kg; 1 patient received fludarabine 160 mg/m2, treosulfan 42 mg/m2, thiotepa 10mg/kg and ATG (Thymoglobulin) 11.25 mg/kg and 1 patient received oral busulfan 16mg/kg, cyclophosphamide 200 mg/kg and antilymphocyte globulin (45 mg/kg). GvHD prophylaxis was provided with ciclosporin and short course methotrexate (n=18), ciclosporin and MMF (n=1) and ciclosporin alone (n=1). Mean cell dose was 3.70 × 108 TNC/kg (range 1.45 – 6.16 × 108 TNC/kg). Neutrophil engrafment (>0.5 × 109/L) occurred at a median of 19.5 days (range 12 – 28 days) and platelet engrafment (>50 × 109/L) at median of 26 days (range 21 – 52 days). The median follow up is 974 days (range 270 – 3622 days). 18 patients achieved stable donor haemopoiesis, one patient suffered secondary graft failure due to Parvovirus B19 infection and one patient died on day +21 post-transplant due to sepsis and multi-organ failure.No significant sickle related neurological events occurred during these transplants. All 18 patients with long-term engraftment achieved radiological stabilization of the underlying CVD. Imaging performed at least 12 months post SCT showed no further changes from pre-transplant images. There were no clinical neurological events after SCT. Psychometric testing demonstrated improvements in all areas in patients transplanted for silent infarcts, particularly those affecting processing speed. In summary, SCT appears safe even in patients with severe CVD, arrests further progression and shows functional improvement. Disclosures:No relevant conflicts of interest to declare.

Stem-cell transplantation in children and adults with sickle cell disease: an update

Sickle cell disease (SCD) is associated with significant morbidity, a decreased lifespan and a poor quality of life. While there is increasing evidence that hydroxyurea can improve the course of severe SCD, hematopoeitic stem-cell transplantation (HSCT) remains the only curative option for SCD. Multicenter trials have shown that HSCT after myeloablative conditioning has excellent outcomes in children with SCD, with an overall survival ranging from 93 to 97% and an event-free survival between 82 and 86%. With better understanding of the course of SCD in adulthood, there has been increasing interest in making HSCT a viable intervention in adults. Nonetheless, older patients with severe disease have not been considered suitable candidates because of the higher risks associated with myeloablative conditioning. Recently, reduced-intensity regimens have been used in adults with good results, albeit in a small number of patients. The main limitation of HSCT in both adults and children with SCD remains the lack of availability of fully matched HLA sibling donors for patients meeting transplant criteria.

Pain site frequency and location in sickle cell disease: The PiSCES project

Treatment options for sickle cell disease (SCD) pain could be tailored to pain locations. But few epidemiologic descriptions of SCD pain location exist; these are based on few subjects over short time periods. We examined whether SCD pain locations vary by disease genotype, gender, age, frequency of pain, depression, pain crisis or healthcare utilization. We enrolled 308 adults with SCD in 2002–2004. Subjects kept daily pain diaries for up to 6months, including a body chart. Mixed model and generalized estimating equations were employed for analyses. Two hundred and sixty subjects completed at least one body chart. An average of 3.3/16 sites (25%) were painful. The number of pain sites varied by age, depression, frequent pain days, crisis and unplanned hospital/ED utilization. Lower back, knee/shin and hip, hurt on average more than a third of pain days, while jaw and pelvis hurt on fewer than 10% of days. Odds of a crisis were increased substantially when pain was in the arm, shoulder, upper back, sternum, clavicle, chest or pelvis (OR>1.5) while the odds of unplanned utilization were substantially increased for the sternum, clavicle and chest (OR>2.0). Pain in SCD varies considerably both within and between subjects, although it occurs most commonly in the lower back and lower extremities. The number and location of pain sites vary significantly by age, frequent pain, crisis and utilization. Identification and understanding of combinations of pain location and intensity may help to understand the etiology of SCD and improve SCD management.

In Vitro Antisickling Effects of Novel Pyridyl Derivatives with Enhanced Potency.

Chemical modification of sickle hemoglobin (Hb S) to form stable high affinity Schiff-base adducts has been an attractive approach towards finding a potential therapeutic option for sickle cell disease (SCD). An ideal candidate drug should rapidly enter the bloodstream, permeate red blood cell membrane, bind specifically with intracellular Hb S and inhibit cell sickling with minimal adverse effect. In an effort to find drugs that satisfy these criteria, we recently designed, synthesized and studied three novel benzaldehydes (INN-296, INN-298 and INN-312) with enhanced potency. The compounds are pyridyl derivatives of benzaldehyde, and hence, combine structural features of two previously determined antisickling agents: vanillin and pyridoxal. All three compounds shifted the allosteric equilibrium of Hb S toward the oxy- or R-state by destabilizing the deoxy- or T-state. The results of in vitro studies of the antisickling effects of a representative compound (INN-312) are reported. Upon incubation of suspensions of sickle erythrocytes (SS cells) with 0.5, 1 or 2 mM of INN-312 under hypoxia (4% O2 :96% N2) at 37°C, sickling of SS cells was inhibited in a dose-dependent manner (15 ± 2, 44 ± 10 and 81 ± 8% inhibition, respectively). Cation-exchange HPLC analysis of lysates from the pre-incubated SS cells revealed a new peak in addition to the original Hb S peak, indicative of formation of Schiff-base adducts of Hb. Oxygen equilibrium curves (OECs) of SS-cell suspensions and lysates were shifted toward the left in a dose-dependent manner. X-ray crystal structures of these derivatives revealed their symmetric binding to the two N-terminal αVal1 of Hb S, and seem to indicate that their superior antisickling activity may arise from effector-induced interference with Hb S polymerization, as well as shifting the OEC to the high affinity state. In vitro studies on INN-296 and INN-298 showed similar results.Studies in vivo were performed using transgenic sickle mice (3 mice per group). The mice were treated intraperitoneally with single doses of 50, 100 or 150 mg/kg of INN-312. To study pharmacokinetic profiles of INN-312 in treated mice, blood samples (~20 μl each) were collected under anesthesia via retro-orbital venipuncture into EDTA tubes at 30 min, 1 h and every hour afterwards for 5 hours. Plasma from each sample was de-proteinized and analyzed by reversed-phase HPLC for quantification of INN-312 present in the blood. A non-compartmental pharmacokinetic model with first-order elimination rate was used to determine the plasma concentration-time data using PK Solutions 2.0 software (SUMMIT Research Services, Montrose, CO, USA). The area under the plasma concentration curve (AUC) increased in a dose-dependent manner (314 ± 22 μg/ml/min, 648 ± 33 μg/ml/min and 1044 ± 63 μg/ml/min in mice treated with 50, 100 and 150 mg/kg, respectively). The terminal half-life (T1/2= 0.75 ± 0.15 h), peak concentration time (Tmax= 0.5 h), and mean resident time (MRT= 1.2 ± 0.2 h) values were consistent for all three dosage groups. The observed maximum plasma concentration (Cmax)was also increased in a dose-dependent manner. These novel pyridyl derivatives of benzaldehyde shifted the position of Hb OEC toward the left most strongly among various compounds reported to date. Further detailed studies are necessary to validate this approach to developing better antisickling agents.

Sickle cell disease: current therapeutic approaches

Sickle cell disease (SCD) is an inherited blood disorder characterised by polymerisation of deoxygenated intracellular sickle haemoglobin (HbS), leading to the deformation of red blood cells (RBC) and the assumption of various sickled shapes. These rigid sickled cells trigger a cascade of vaso-occlusive events, including local inflammation and endothelial injury, leading to painful episodes, chronic haemolytic anaemia and possible end-organ damage and premature mortality. As the first disease whose genetic aetiology was defined more than half century ago, SCD has attracted a great deal of attention from many scientists and researchers worldwide. This has led to major insights into the natural history of SCD, the pathophysiological importance of polymerisation of deoxygenated HbS, and approaches directed towards the prophylaxis or treatment of the complications associated with the disease. Despite such advances, medical management still remains suboptimal and SCD continues to be a significant cause of mortality, morbidity and health disparities worldwide. Hydroxyurea (HU), a potent inducer of fetal haemoglobin (HbF) that inhibits HbS polymerisation, is currently the only approved therapeutic agent for SCD therapy, but its long-term benefits and toxicities are controversial and are still being investigated. Over the past few decades, other novel mechanisms of SCD pathophysiology have been identified in addition to HbS polymerisation. Several of these mechanisms present appropriate targets for drug development and novel therapy for SCD. This article presents a review of potential candidate drugs that have been recently studied and patented as possible pharmacological treatment/management options for SCD.

New concepts in assessing sickle cell disease severity.

Vasoocclusion leads to pain, chronic organ damage, and a decreased life expectancy in patients with sickle cell disease. Therapeutic options for sickle cell disease have usually been evaluated according to their capacity for reducing the frequency of vasoocclusive crises requiring clinical attention. However, the frequency of vasoocclusive crises is not representative for the rate of accumulating organ damage in most sickle cell patients. This implies that the frequency of vasoocclusive crises needn't correlate with disease severity and, although being of importance, cannot solely serve as a parameter of treatment efficacy. Therefore, additional new objective parameters are needed to effectively study the vasoocclusive process in sickle cell disease. Several studies show that intricate adhesive interactions between (red) blood cells, plasma components, and endothelium play a crucial role in the pathophysiology of sickle cell vasoocclusion, offering new potential parameters to effectively assess disease severity as well as new therapeutical targets in the near future. Whether these adhesive mechanisms involve the causes or the effects of vasoocclusion will be determined if their inhibition, by interventive measures, results in therapeutic benefits.