Gene therapy for sickle cell disease passes key preclinical test- Decades-old discovery about fetal hemoglobin is on track for clinical trial in the coming year
A precision-engineered gene therapy virus, inserted into blood stem cells that are then transplanted, markedly reduced sickle-induced red-cell damage in mice with sickle cell disease, researchers from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center report today in the Journal of Clinical Investigation.
The work sets the stage for bringing a decades-old discovery about sickle cell disease to the bedside. A clinical gene therapy trial, using a virus rendered harmless in the laboratory, is expected to launch in the coming year. http://news.harvard.edu/gazette/story/2015/09/achilles-heel-of-sickle-cell-disease/
St. Jude gets $4.4M from NIH for app to improve medication adherence in sickle cell anemia patients
St. Jude’s Children’s Research Hospital has been awarded a six-year, $4.4. million grant from the National Heart, Lung and Blood Institute (part of the National Institutes of Health) to use a mobile app to improve medication adherence by adolescent patients with sickle cell anemia.
A new team comprised of healthcare professionals from St. Jude, the University of Memphis, Methodist University Hospital, Baptist Memorial Hospital, Vanderbilt University and the Sickle Cell Foundation of Tenessee will work together to integrate the app to manage hydroxyurea treatments, which is a medication to reduce pain and the need for blood transfusions.
The focus will be on patients 15 years old and older, and the project will be rolled out in phases beginning with identifying barriers to care of sickle cell and running focus groups to establish just what they want out of an app. They plan to get about 100 beta testers in the Memphis area before looking for opportunities to scale it up nationwide in a larger study of several hundred patients.
Dr. Jane Hankins, associate member of St. Jude’s hematology department and principle investigator of the project, said the team is looking for ways to slow the progress of sickle cell as older teenagers transition to adult life. While healthcare professionals have made good progress using hydroxyurea to help children and adults take care of their disease, that transitional period in adolescence can present its own challenges.
“Medication adherence is hard for anybody, but it’s especially hard for someone who is becoming an adult and establishing their identity,” Hankins told MobiHealthNews. “I’ve had patients who were previously 100 percent compliant and then they hit adolescence and they change. Some just abandon their treatment altogether, they stop coming to clinic or the hospital, they stop taking their medication, they don’t want to accept their disease any more.”
Sickle cell is a lifelong condition, diagnosed shortly after birth, that requires a carefully-followed treatment plan to reduce the need for blood transfusions and pain. Unless someone gets a bone marrow transplant, they must adhere to the medication or transfusions to reduce symptoms and prevent organ failure.
“The hallmark of sickle cell is pain,” said Hankins. “And treatment reduces that, but if you aren’t compliant with your medication, it’s a problem.”
So, using an app could provide an approachable, non-demanding way for adolescents to stay on top of their medication without a family member or caregiver nagging them, and they could also access information and social support through the app.
Pfizer is proud to announce the Advancing Science through Pfizer – Investigator Research Exchange (ASPIRE) 2016 Investigator Awards in Sickle Cell Disease Research, a competitive, peer-reviewed grants program sponsored by Pfizer for investigators in the United States. Deadline for this grant is Monday October 17th
MISSION • To support basic science, translational and clinical research through a competitive grants program that advances medical knowledge in the pathogenesis and treatment of Sickle Cell Disease • To support innovative pilot studies focused on improving patient outcomes in Sickle Cell Disease • To support academic research as well as the career development of promising young and established scientists
AREAS OF RESEARCH FOCUS Pfizer will consider applications for research projects which address laboratory investigation or clinical research in Sickle Cell Disease. Examples of research topics are listed for guidance; however, other applications will be considered.
- Biomarkers of Sickle Cell Disease • Phenotypic differences in clinical course and/or response to therapy • Clinical trial endpoint validation • Patient Reported Outcomes (PRO), Health Related Quality of Life (HRQOL) • Improving care of specific complications of Sickle Cell Disease • Improving clinical care delivery models • Improving acute pain management
AVAILABLE AWARDS The 2016 US Sickle Cell Disease ASPIRE Program is open to US investigators. Review of applications will be performed by an independent, external panel of experts. Project duration should be 1 or 2 years, and the approximate total award will be up to $55,000 maximum, inclusive of overhead costs (capped at 28%).
For more information http://www.aspireresearch.org/ASPIRE-Sicklecell/index.html
New Sickle Cell Infographic From ASH
This “infographic” for sickle cell awareness was produced by the new Sickle Cell Disease Coalition, formed by American Society of Hematology a few weeks ago to align professional societies, Federal, and pharmaceutical stakeholders http://www.scdcoalition.org/
It appears to be formatted for viewing on a mobile phone. Please help distribute it.
Articles in the medical literature
1. Pediatr Res. 2016 Oct 5. doi: 10.1038/pr.2016.204. [Epub ahead of print]
Pediatric Sickle Cell Disease – Past Successes and Future Challenges.
Meier ER1, Rampersad A1.
Once a fatal disease of childhood, more than 95% of patients born today with sickle cell disease (SCD) in developed countries are expected to survive into adulthood, largely because of improvements in supportive and preventive care (newborn screening, penicillin prophylaxis, transcranial Doppler (TCD) screening). Hydroxyurea (HU) therapy, the only oral medication currently available to prevent SCD complications, has become more widespread over the past 20 years. The NHLBI recommends that HU be offered to all patients with HbSS beginning at nine months of age, and the recently published Abnormal TCD with Transfusions Changing to HU (TWiTCH) trial has shown HU as an acceptable alternative to transfusion therapy for patients at high risk of stroke. While hematopoietic stem cell transplant (HSCT) is a curative option for SCD, less than 25% of patients have a suitable donor. Alternative stem cell sources from unrelated donors and haplo-identical donors are currently under investigation as are gene therapy trials. This review will focus on early efforts to elucidate SCD pathophysiology as well as supportive and preventive care improvements. Findings from recent multi-center studies [Silent Infarct Transfusion (SIT) Trial and TWiTCH] will be summarized. Finally, HSCT trials and gene therapy will be reviewed.
PMID: 27706129 [PubMed – as supplied by publisher]
2. JMIR Res Protoc. 2016 Oct 3;5(4):e193.
ENHANCE-(Electronic Hydroxyurea Adherence): A Protocol to Increase Hydroxyurea Adherence in Patients with Sickle Cell Disease.
Creary S1, Chisolm DJ, O’Brien SH.
Hydroxyurea (HU) is the only disease-modifying medication for patients with sickle cell disease (SCD). HU can reduce SCD-related complications but only 35% to 50% of pediatric patients adhere to HU at the rates achieved in clinical trials and this limits its clinical effectiveness. Mobile Directly Observed Therapy (Mobile DOT) is a pilot-tested, electronic, multidimensional, HU adherence intervention that targets many components of the Health Behavior Model.
The aim of this study is to evaluate the impact of Mobile DOT on HU adherence in children with SCD. The objective of our study is to inform the development of future adherence interventions and pediatric SCD protocols.
This is a single-arm crossover study of pediatric patients with SCD. Participants self-record videos of their daily HU administrations and receive text message alerts to take HU, feedback on their HU adherence, and incentives when they achieve adherence goals during the 6-month Mobile DOT phase. Participants’ HU adherence during the Mobile DOT phase is compared with their baseline HU adherence (6 months prior to study entry) and to their HU adherence 6 months after completing the Mobile DOT phase. The primary outcome of this study is HU adherence measured by medication possession ratio.
The trial is ongoing. Preliminary review of participant satisfaction results suggest that most participants can complete Mobile DOT in less than 5 minutes per day and are satisfied with the intervention.
If effective, the Mobile DOT strategy will increase HU adherence and this could improve patients’ clinical outcomes and reduce costs of care.
PMID: 27697749 [PubMed – in process]
3. Ther Adv Hematol. 2016 Oct;7(5):302-315. Epub 2016 Jun 25.
The potential of gene therapy approaches for the treatment of hemoglobinopathies: achievements and challenges.
Goodman MA1, Malik P2.
Hemoglobinopathies, including β-thalassemia and sickle cell disease (SCD), are a heterogeneous group of commonly inherited disorders affecting the function or levels of hemoglobin. Disease phenotype can be severe with substantial morbidity and mortality. Bone marrow transplantation is curative, but limited to those patients with an appropriately matched donor. Genetic therapy, which utilizes a patient’s own cells, is thus an attractive therapeutic option. Numerous therapies are currently in clinical trials or in development, including therapies utilizing gene replacement therapy using lentiviruses and the latest gene editing techniques. In addition, methods are being developed that may be able to expand gene therapies to those with poor access to medical care, potentially significantly decreasing the global burden of disease.
PMID: 27695619 [PubMed – in process]
4. Expert Rev Hematol. 2016 Sep 28. [Epub ahead of print]
Epidemiology and treatment of relative anemia in children with sickle cell disease in sub-Saharan Africa.
Bello-Manga H1, DeBaun MR2, Kassim AA3.
Sickle cell disease (SCD) is the most common inherited hemoglobinopathy in sub-Saharan Africa with about 300,000 births annually. Children with SCD have pre-existing anemia that can be exacerbated when they have concomitant nutritional deficiencies, infections or exposure to environmental toxins. The resulting relative anemia in children with SCD is associated with increased risk of strokes; poor cognitive function, poor growth, and may also attenuate optimal response to hydroxyurea therapy, the only effective and practical treatment option for SCD in sub-Saharan Africa. This review will focus on the epidemiology, sequelae, and treatment of relative anemia in children with SCD living in low and middle-income countries.
The causes and treatment of relative anemia in children with SCD in sub-Saharan Africa. MEDLINE database was searched using medical subject headings (MeSH) and keywords for articles relative anemia in children with SCD in sub-Saharan Africa. Expert commentary: Anemia due to nutritional deficiencies, helminthiasis and malaria are prevalent in sub-Sharan Africa. There co-existence in children with SCD increases morbidity and mortality, thus diagnosing and managing the cause of this relative anemia will go a long way in improving SCD related outcomes in children in sub-Saharan Africa.
PMID: 27677923 [PubMed – as supplied by publisher]
5. Hemoglobin. 2016 Sep 28:1-5. [Epub ahead of print]
Comparison of Emergency Department Wait Times in Adults with Sickle Cell Disease Versus Other Painful Etiologies.
Pulte D1,2, Lovett PB2,3, Axelrod D2, Crawford A4, McAna J4, Powell R2.
Sickle cell disease is characterized by intermittent painful crises often requiring treatment in the emergency department (ED). Past examinations of time-to-provider (TTP) in the ED for patients with sickle cell disease demonstrated that these patients may have longer TTP than other patients. Here, we examine TTP for patients presenting for emergency care at a single institution, comparing patients with sickle cell disease to both the general population and to those with other painful conditions, with examination of both institutional and patient factors that might affect wait times. Our data demonstrated that at our institution patients with sickle cell disease have a slightly longer average TTP compared to the general ED population (+16 min.) and to patients with other painful conditions (+4 min.) However, when confounding factors were considered, there was no longer a significant difference between TTP of patients with sickle cell disease and the general population nor between patients with sickle cell disease and those with other painful conditions. Multivariate analyses demonstrated that gender, race, age, high utilizer status, fast track use, time of presentation, acuity and insurance type, were all independently associated with TTP, with acuity, time of presentation and use of fast track having the greatest influence. We concluded that the longer TTP observed in patients with sickle cell disease can at least partially be explained by institutional factors such as the use of fast track protocols. Further work to reduce TTP for sickle cell disease and other patients is needed to optimize care.
PMID: 27677560 [PubMed – as supplied by publisher]
6. Cochrane Database Syst Rev. 2016 Sep 27;9:CD003733. [Epub ahead of print]
Inhaled bronchodilators for acute chest syndrome in people with sickle cell disease.
Knight-Madden JM1, Hambleton IR.
Bronchodilators are used to treat bronchial hyper-responsiveness in asthma. Bronchial hyper-responsiveness may be a component of acute chest syndrome in people with sickle cell disease. Therefore, bronchodilators may be useful in the treatment of acute chest syndrome. This is an update of a previously published Cochrane Review.
To assess the benefits and risks associated with the use of bronchodilators in people with acute chest syndrome.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional searches were carried out on MEDLINE (1966 to 2002) and Embase (1981 to 2002).Date of the most recent search of the Group’s Haemoglobinopathies Trials Register: 11 July 2016.
Randomised or quasi-randomised controlled trials. Trials using quasi-randomisation methods will be included in future updates of this review if there is sufficient evidence that the treatment and control groups are similar at baseline.
DATA COLLECTION AND ANALYSIS:
We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease.
We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease.
If bronchial hyper-responsiveness is an important component of some episodes of acute chest syndrome in people with sickle cell disease, the use of inhaled bronchodilators may be indicated. There is need for a well-designed, adequately-powered randomised controlled trial to assess the benefits and risks of the addition of inhaled bronchodilators to established therapies for acute chest syndrome in people with sickle cell disease.
PMID: 27673392 [PubMed – as supplied by publisher]
7. PLoS One. 2016 Sep 26;11(9):e0162652. doi: 10.1371/journal.pone.0162652.
Albuminuria Is Associated with Endothelial Dysfunction and Elevated Plasma Endothelin-1 in Sickle Cell Anemia.
Ataga KI1, Derebail VK2, Caughey M3, Elsherif L4, Shen JH1, Jones SK1, Maitra P5, Pollock DM6, Cai J5, Archer DR7, Hinderliter AL3.
The pathogenesis of albuminuria in SCD remains incompletely understood. We evaluated the association of albuminuria with measures of endothelial function, and explored associations of both albuminuria and measures of endothelial function with selected biological variables (vascular endothelial growth factor [VEGF], endothelin-1 [ET-1], soluble fms-like tyrosine kinase-1 [sFLT-1], soluble vascular cell adhesion molecule-1 [soluble VCAM-1] and plasma hemoglobin).
Spot urine measurements for albumin-creatinine ratio (UACR) and 24-hour urine protein were obtained. Endothelial function was assessed using brachial artery ultrasound with measurements of flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NTMD) and hyperemic velocity.
Twenty three subjects with varying degrees of albuminuria were evaluated. UACR was significantly correlated with FMD (ρ = -0.45, p = 0.031). In univariate analysis, UACR was correlated with VEGF (ρ = -0.49; 95% CI: -0.75 –0.1, p = 0.015), plasma hemoglobin (ρ = 0.50; 95% CI: 0.11-0.75, p = 0.013) and ET-1 (ρ = 0.40; 95% CI: -0.03-0.69, p = 0.06). Multivariable analysis showed significant associations of ET-1 (estimate: 455.1 [SE: 198.3], p = 0.02), VEGF (estimate: -1.1 [SE: 0.53], p = 0.04) and sFLT-1 (estimate: -1.14 [SE: 0.49], p = 0.02) with UACR. Only ET-1 (estimate: -8.03 [SE: 3.87], p = 0.04) was significantly associated with FMD in multivariable analyses. Finally, UACR was correlated with both 24-hour urine protein (ρ = 0.90, p < 0.0001) and urine aliquots for albumin-creatinine ratio obtained from the 24-hour urine collection (ρ = 0.97, p < 0.0001).
This study provides more definitive evidence for the association of albuminuria with endothelial dysfunction in SCD. Elevated circulating levels of ET-1 may contribute to SCD-related glomerulopathy by mediating endothelial dysfunction.
PMID: 27669006 [PubMed – as supplied by publisher]
8. Hemoglobin. 2016 Sep 18:1-5. [Epub ahead of print]
Renal Failure in Sickle Cell Disease: Prevalence, Predictors of Disease, Mortality and Effect on Length of Hospital Stay.
Yeruva SL1, Paul Y1, Oneal P1, Nouraie M2.
Renal dysfunction in sickle cell disease is not only a chronic comorbidity but also a mortality risk factor. Though renal dysfunction starts early in life in sickle cell patients, the predictors that can identify sickle cell disease patients at risk of developing renal dysfunction is not known. We used the Truven Health MarketScan® Medicaid Databases from 2007 to 2012. Incidence of new acute renal failure (ARF) and chronic kidney disease (CKD) was calculated in this cohort. There were 9481 patients with a diagnosis of sickle cell disease accounting for 64,201 hospital admissions, during the study period. Both ARF and CKD were associated with higher risk of inpatient mortality, longer duration of the hospital stay and expensive hospitalizations. The yearly incidence of new ARF in sickle cell disease patients was 1.4% and annual CKD incidence was 1.3%. The annual rate of new ARF and CKD in the control group was 0.4 and 0.6%, respectively. The most important predictors of new CKD were proteinuria, ARF and hypertension. Chronic kidney disease, hypertension and sickle cell crisis were the most important predictors of new ARF. The annual rate of incidences of ARF and CKD were 2- to 3-fold higher in sickle cell disease compared to the non sickle cell disease group. Besides the common risk factors for renal disease in the general population, it is imperative to monitor the sickle cell disease patients with more severe disease to prevent them from developing renal dysfunction.
PMID: 27643740 [PubMed – as supplied by publisher]
9. Pediatr Blood Cancer. 2016 Sep 19. doi: 10.1002/pbc.26179. [Epub ahead of print]
Elective cholecystectomy reduces morbidity of cholelithiasis in pediatric sickle cell disease.
Goodwin EF1, Partain PI2, Lebensburger JD3, Fineberg NS1, Howard TH1.
Cholelithiasis is a frequent complication in pediatric sickle cell disease (SCD). Though it is standard practice to perform a cholecystectomy in pediatric SCD patients with symptoms of cholelithiasis, the use of elective cholecystectomy for asymptomatic patients remains controversial.
Records of 191 pediatric sickle cell patients with cholelithiasis who underwent cholecystectomy were retrospectively reviewed. Patients classified as follows: (i) elective-no preoperative symptoms, cholelithiasis on screening ultrasound, comprehensive preoperative plan; (ii) symptomatic-preoperative symptoms of cholelithiasis on diagnostic ultrasound, comprehensive preoperative plan; or (iii) emergent-hospitalization for acute cholecystitis symptoms, cholelithiasis on diagnostic ultrasound, limited preoperative preparation. We compared the morbidity of cholecystectomy by examining pre- and post-cholecystectomy hospital admission days, length of stay for cholecystectomy, and surgical complications.
Patients with SCD underwent a total of 191 cholecystectomies over a 10-year period: 51 elective, 110 symptomatic, and 30 emergent. Patients who required emergent cholecystectomy had a longer postoperative hospitalization time than elective or symptomatic cholecystectomy (7.3 vs 4.3, P < 0.001). Baseline values for total bilirubin and aspartate aminotransferase (AST) were significantly elevated (P < 0.02 and P < 0.07, respectively) in patients requiring emergent cholecystectomy.
This represents the largest reported retrospective review of pediatric cholelithiasis and cholecystectomy in SCD to date. These data strongly suggest that elective cholecystectomy decreases morbidity associated with emergent cholecystectomy. The overall outcomes for symptomatic and elective patients are favorable. However, our study indicates the need for prospective studies to identify clinical indicators for those emergent patients.
© 2016 Wiley Periodicals, Inc.
PMID: 27643455 [PubMed – as supplied by publisher]
10. Biol Blood Marrow Transplant. 2016 Sep 13. pii: S1083-8791(16)30318-4. doi: 10.1016/j.bbmt.2016.08.022. [Epub ahead of print]
Using Appropriate Methods in Cost-Effectiveness Analyses: The Case of Allogeneic Hematopoietic Cell Transplantation in Sickle Cell Disease.
Thielen FW1, Blommestein HM2, Uyl-de Groot CA3.
11. Blood. 2016 Sep 13. pii: blood-2016-05-715870. [Epub ahead of print]
A BMT CTN phase II trial of unrelated donor marrow transplantation for children with severe sickle cell disease.
Shenoy S1, Eapen M2, Panepinto JA3, Logan BR2, Wu J4, Abraham A5, Brochstein J6, Chaudhury S7, Godder K8, Haight AE9, Kasow KA10, Leung K11, Andreansky M12, Bhatia M13, Dalal J14, Haines H15, Jaroscak J16, Lazarus HM17, Levine JE18, Krishnamurti L19, Margolis D3, Megason GC20, Yu LC21, Pulsipher MA22, Gersten I4, DiFronzo N23, Horowitz MM2, Walters MC24, Kamani N25.
Children with sickle cell disease (SCD) experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplantation from an HLA-matched sibling can halt disease progression but is limited by donor availability. A multicenter phase II trial conducted from 2008-2014 enrolled 30 children aged 4-19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C and -DRB1 loci) unrelated donor transplantation. Conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short course methotrexate and methylprednisolone. Transplant indications included stroke (N=12), trans-cranial Doppler velocity >200 cm/second (N=2), ≥3 vaso-occlusive pain crises/year (N=12) or ≥2 acute chest syndrome episodes (N=4) in the 2 years preceding enrollment. Median follow up was 26 months (range 12-62); graft rejection was 10%. One and 2-year EFS were 76% (95% CI 56-88) and 69% (95% CI, 48-82), respectively. The corresponding rates for overall survival (OS) were 86% (95% CI 67-95) and 79% (95% CI 59-90). The day-100 incidence of grade II-IV acute GVHD was 28% (95% CI 13-45); 1-year incidence of chronic GVHD was 62% (95% CI 41-77); 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the pre-specified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The trial is registered to https://clinicaltrials.gov as NCT00745420.
Copyright © 2016 American Society of Hematology.
PMID: 27625358 [PubMed – as supplied by publisher]
12. Am J Hematol. 2016 Sep 13. doi: 10.1002/ajh.24551. [Epub ahead of print]
Transcranial Doppler Re-screening of Subjects who Participated in STOP and STOP II.
Adams RJ1, Lackland DT2, Brown L3, Brown D4, Voeks J2, Fullerton HJ5, Kanter J6, Kwiatkowski JL7.
In children with Sickle Cell Disease, the combination of risk stratification with Transcranial Doppler Ultrasound (TCD) and selective chronic red cell transfusion (CRCT-the STOP Protocol) is one of the most effective stroke prevention strategies in medicine. How fully it is being implemented is unclear. Nineteen of 26 sites that conducted the two pivotal clinical trials (STOP and STOP II) participated in Post STOP, a comprehensive medical records review assessing protocol implementation in the 10-15 years since the trials ended. Professional abstractors identified medical records in the Post STOP era in 2851 74% of the 3840 children who took part in STOP and/or STOP II, and documented TCD rescreening, maintenance of CRCT in those at risk, and stroke. Among 1896 children eligible for TCD rescreening (target group), evidence of any rescreening was found in 1090 (57%). There was wide site variation in TCD rescreening ranging from 18% to 91% of eligible children. Both younger age and having a conditional TCD during STOP/II were associated with a higher likelihood of having a TCD in Post STOP. Sixty eight new abnormal, high risk cases were identified. Despite clear evidence of benefit the STOP protocol is not fully implemented even at experienced sites. Site variation suggests that system improvements might remove barriers to implementation and result in even greater reduction of ischemic stroke in children with SCD. This article is protected by copyright. All rights reserved.
© 2016 Wiley Periodicals, Inc.
PMID: 27623561 [PubMed – as supplied by publisher]
13. JMIR Res Protoc. 2016 Sep 12;5(3):e185. doi: 10.2196/resprot.5872.
EXpanding Treatment for Existing Neurological Disease (EXTEND): An Open-Label Phase II Clinical Trial of Hydroxyurea Treatment in Sickle Cell Anemia.
Rankine-Mullings AE1, Little CR, Reid ME, Soares DP, Taylor-Bryan C, Knight-Madden JM, Stuber SE, Badaloo AV, Aldred K, Wisdom-Phipps ME, Latham T, Ware RE.
Cerebral vasculopathy in sickle cell anemia (SCA) begins in childhood and features intracranial arterial stenosis with high risk of ischemic stroke. Stroke risk can be reduced by transcranial doppler (TCD) screening and chronic transfusion therapy; however, this approach is impractical in many developing countries. Accumulating evidence supports the use of hydroxyurea for the prevention and treatment of cerebrovascular disease in children with SCA. Recently we reported that hydroxyurea significantly reduced the conversion from conditional TCD velocities to abnormal velocities; whether hydroxyurea can be used for children with newly diagnosed severe cerebrovascular disease in place of starting transfusion therapy remains unknown.
The primary objective of the EXpanding Treatment for Existing Neurological Disease (EXTEND) trial is to investigate the effect of open label hydroxyurea on the maximum time-averaged mean velocity (TAMV) after 18 months of treatment compared to the pre-treatment value. Secondary objectives include the effects of hydroxyurea on serial TCD velocities, the incidence of neurological and non-neurological events, quality of life (QOL), body composition and metabolism, toxicity and treatment response, changes to brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), genetic and serologic markers of disease severity, and cognitive and pulmonary function.
This prospective Phase II trial will enroll children with SCA in Jamaica, between the ages of 2 and 17 years, with either conditional (170-199 cm/sec) or abnormal (≥ 200 cm/sec) TCD velocities. Oral hydroxyurea will be administered daily and escalated to the maximum tolerated dose (MTD). Participants will be seen in the Sickle Cell Unit (SCU) in Kingston, Jamaica monthly until achieving MTD, and then every 3 months. TCD will be performed every 6 months.
Currently, 43 participants have been enrolled out of a projected 50. There was one withdrawal due to immigration, with no permanent screen failures. Of the 43 enrolled, 37 participants have initiated study treatment.
This trial investigates the effects of hydroxyurea treatment at MTD in children with conditional or abnormal TCD velocities before transfusion therapy and may represent an important advance towards establishing a suitable non-transfusion protocol for stroke prevention in children with SCA. The trial outcomes will have profound significance in developing countries where the disease burden is highest.
ClinicalTrials.gov NCT02556099; https://clinicaltrials.gov/ct2/show/NCT02556099 (Archived by WebCite at http://www.webcitation.org/6k1yMAa9G).
PMID: 27619954 [PubMed]
14. Br J Haematol. 2016 Sep 8. doi: 10.1111/bjh.14298. [Epub ahead of print]
A rapid, inexpensive and disposable point-of-care blood test for sickle cell disease using novel, highly specific monoclonal antibodies.
Quinn CT1, Paniagua MC1, DiNello RK2, Panchal A2, Geisberg M3.
Sickle cell disease (SCD) is a significant healthcare burden worldwide, but most affected individuals reside in low-resource areas where access to diagnostic testing may be limited. We developed and validated a rapid, inexpensive, disposable diagnostic test, the HemoTypeSC™ , based on novel monoclonal antibodies (MAbs) that differentiate normal adult haemoglobin (Hb A), sickle haemoglobin (Hb S) and haemoglobin C (Hb C). In competitive enzyme-linked immunosorbent assays, each MAb bound only its target with <0·1% cross-reactivity. With the HemoTypeSC™ test procedure, the sensitivity for each variant was <5·0 g/l. The accuracy of HemoTypeSC™ was evaluated on 100 whole blood samples from individuals with common relevant haemoglobin phenotypes, including normal (Hb AA, N = 20), carrier or trait (Hb AS, N = 22; Hb AC, N = 20), SCD (Hb SS, N = 22; Hb SC, N = 13), and Hb C disease (Hb CC, N = 3). The correct haemoglobin phenotype was identified in 100% of these samples. The accuracy of the test was not affected by Hb F (0-94·8% of total Hb) or Hb A2 (0-5·6% of total Hb). HemoTypeSC™ requires <1 μl of whole blood and no instruments or power sources. The total time-to-result is <20 min. HemoTypeSC™ may be a practical solution for point-of-care testing for SCD and carrier status in low-resource settings.
© 2016 John Wiley & Sons Ltd.
PMID: 27605462 [PubMed – as supplied by publisher]
Sickle Cell Conferences and Events
The Sickle Cell Disease (SCD) Program at Children’s National invites you to the 7th Annual Family Education Symposium on “Living Well with Sickle Cell”.
Saturday, October 29, 2016 11:30 AM – 4:30 PM
Sheikh Zayed Campus for Advanced Children’s Medicine Children’s National Health System 111 Michigan Ave NW, 2nd Floor, Auditorium
Washington, , DC, 20010
This year’s symposium will focus on helping patients and their families manage sickle cell disease while living life to the fullest.
Listserv address to join or leave: http://listserv.cc.emory.edu/cgi-bin/wa?A0=sicklecell