Publications by authors named "Abdullah Kutlar"

95 Publications

A critical evaluation of crizanlizumab for the treatment of sickle cell disease.

Expert Rev Hematol 2021 Dec 30:1-9. Epub 2021 Dec 30.

Division of Hematology/Oncology, Augusta University, Augusta, GA, USA.

Introduction: P-selectin is a key adhesion molecule in the pathogenesis of sickle cell disease, including acute painful event(s). Many of the mediators activated in prototypical pain crisis are also involved in other complications seen in this population. Crizanlizumab is a monoclonal antibody approved in the US in 2019 for patients of all genotypes of sickle cell disease. By blocking P-selectin, it effectively prevents acute painful event(s) and has a manageable safety profile.

Areas Covered: In this review, we provide an overview of the (i) biology of P-selectin in sickle cell disease, (ii) various agents inhibiting P-selectin, (iii) pharmacology of crizanlizumab, (iv) preclinical and clinical data on crizanlizumab, and (v) its potential for other indications, ongoing studies, regulatory status, and cost issues. Further, we describe its position among other approved agents in sickle cell disease and project future directions as well.

Expert Opinion: Crizanlizumab holds great promise in modulating the natural history of sickle cell disease and may have pleotropic effects. Studies are ongoing to define its role in preventing other sickle cell-related complications, non-sickle cell inflammatory states, and thrombotic disorders.
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http://dx.doi.org/10.1080/17474086.2022.2023007DOI Listing
December 2021

Indolent T-Lymphoblastic Proliferation in Idiopathic Multicentric Castleman Disease.

Acta Haematol 2021 Nov 24:1-7. Epub 2021 Nov 24.

Division of Hematology/Oncology, Augusta University, Augusta, Georgia, USA.

Benign and polyclonal proliferation of immature T cells in a lymph node with preserved morphological architecture is called indolent T-lymphoblastic proliferation (iT-LBP). Although overall rare, they have been described in association with both benign and malignant disorders including Castleman disease. We report the first case of idiopathic multicentric Castleman disease associated with iT-LBP, all previous reports of iT-LBP in Castleman disease were unicentric. A 37-year-old-male presented with 3 months of fevers and B-symptoms and was found to have enlargement of multiple bilateral lymph node sites on both sides of diaphragm along with splenomegaly. Anemia, elevated C-reactive protein, hypoalbuminemia, and elevated interleukin-6 levels were present. Biopsy of a lymph node showed features suggestive of idiopathic multicentric Castleman disease and iT-LBP. Bone marrow biopsy was unremarkable. Siltuximab and steroids were used to treat the condition.
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http://dx.doi.org/10.1159/000520240DOI Listing
November 2021

Electronic Health Record-Embedded Individualized Pain Plans for Emergency Department Treatment of Vaso-occlusive Episodes in Adults With Sickle Cell Disease: Protocol for a Preimplementation and Postimplementation Study.

JMIR Res Protoc 2021 Apr 16;10(4):e24818. Epub 2021 Apr 16.

Duke University, Durham, NC, United States.

Background: Individuals living with sickle cell disease often require aggressive treatment of pain associated with vaso-occlusive episodes in the emergency department. Frequently, pain relief is poor. The 2014 National Heart, Lung, and Blood Institute evidence-based guidelines recommended an individualized treatment and monitoring protocol to improve pain management of vaso-occlusive episodes.

Objective: This study will implement an electronic health record-embedded individualized pain plan with provider and patient access in the emergency departments of 8 US academic centers to improve pain treatment for adult patients with sickle cell disease. This study will assess the overall effects of electronic health record-embedded individualized pain plans on improving patient and provider outcomes associated with pain treatment in the emergency department setting and explore barriers and facilitators to the implementation process.

Methods: A preimplementation and postimplementation study is being conducted by all 8 sites that are members of the National Heart, Lung, and Blood Institute-funded Sickle Cell Disease Implementation Consortium. Adults with sickle cell disease aged 18 to 45 years who had a visit to a participating emergency department for vaso-occlusive episodes within 90 days prior to enrollment will be eligible for inclusion. Patients will be enrolled in the clinic or remotely. The target analytical sample size of this study is 160 patient participants (20 per site) who have had an emergency department visit for vaso-occlusive episode treatment at participating emergency departments during the study period. Each site is expected to enroll approximately 40 participants to reach the analytical sample size. The electronic health record-embedded individualized pain plans will be written by the patient's sickle cell disease provider, and sites will work with the local informatics team to identify the best method to build the electronic health record-embedded individualized pain plan with patient and provider access. Each site will adopt required patient and provider implementation strategies and can choose to adopt optional strategies to improve the uptake and sustainability of the intervention. The study is informed by the Technology Acceptance Model 2 and the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. Provider and patient baseline survey, follow-up survey within 96 hours of an emergency department vaso-occlusive episode visit, and selected qualitative interviews within 2 weeks of an emergency department visit will be performed to assess the primary outcome, patient-perceived quality of emergency department pain treatment, and additional implementation and intervention outcomes. Electronic health record data will be used to analyze individualized pain plan adherence and additional secondary outcomes, such as hospital admission and readmission rates.

Results: The study is currently enrolling study participants. The active implementation period is 18 months.

Conclusions: This study proposes a structured, framework-informed approach to implement electronic health record-embedded individualized pain plans with both patient and provider access in routine emergency department practice. The results of the study will inform the implementation of electronic health record-embedded individualized pain plans at a larger scale outside of Sickle Cell Disease Implementation Consortium centers.

Trial Registration: ClinicalTrials.gov NCT04584528; https://clinicaltrials.gov/ct2/show/NCT04584528.

International Registered Report Identifier (irrid): DERR1-10.2196/24818.
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http://dx.doi.org/10.2196/24818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087964PMC
April 2021

P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab.

J Pain Res 2021 30;14:849-856. Epub 2021 Mar 30.

Division of Hematology/Oncology, Augusta University, Augusta, GA, USA.

Microvascular vaso-occlusion driven pain crisis is the hallmark of sickle cell disease with profound morbidity and increased mortality. Selectins, most notably P-selectins have an integral role in this phenomenon. P-selection was first identified in 1989. In 2019, after 3 decades of basic, translational, and clinical work with this pathway, the US Food and Drug Administration approved a P-selectin antibody, crizanlizumab to reduce frequency of pain crisis in patients more than 16 years with sickle cell disease. We review the fundamentals of P-selectin pathobiology, P-selectin blocking agents, clinical data with the use of crizanlizumab and prospects of this novel class of drugs in the context of other treatments for painful vaso-occlusive episodes.
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http://dx.doi.org/10.2147/JPR.S278285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019662PMC
March 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

and Its Virulence Factors HO and Pneumolysin Are Potent Mediators of the Acute Chest Syndrome in Sickle Cell Disease.

Toxins (Basel) 2021 02 17;13(2). Epub 2021 Feb 17.

Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.

Sickle cell disease (SCD) is one of the most common autosomal recessive disorders in the world. Due to functional asplenia, a dysfunctional antibody response, antibiotic drug resistance and poor response to immunization, SCD patients have impaired immunity. A leading cause of hospitalization and death in SCD patients is the acute chest syndrome (ACS). This complication is especially manifested upon infection of SCD patients with ()-a facultative anaerobic Gram-positive bacterium that causes lower respiratory tract infections. has developed increased rates of antibiotics resistance and is particularly virulent in SCD patients. The primary defense against is the generation of reactive oxygen species (ROS) during the oxidative burst of neutrophils and macrophages. Paradoxically, itself produces high levels of the ROS hydrogen peroxide (HO) as a virulence strategy. Apart from HO, also secretes another virulence factor, i.e., the pore-forming exotoxin pneumolysin (PLY), a potent mediator of lung injury in patients with pneumonia in general and particularly in those with SCD. PLY is released early on in infection either by autolysis or bacterial lysis following the treatment with antibiotics and has a broad range of biological activities. This review will discuss recent findings on the role of pneumococci in ACS pathogenesis and on strategies to counteract the devastating effects of its virulence factors on the lungs in SCD patients.
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http://dx.doi.org/10.3390/toxins13020157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922783PMC
February 2021

Characteristics of sickle cell patients with frequent emergency department visits and hospitalizations.

PLoS One 2021 22;16(2):e0247324. Epub 2021 Feb 22.

Sickle Cell Center, Augusta University, Augusta, Georgia, United States of America.

Vaso-occlusive episodes (VOEs) are a hallmark of sickle cell disease (SCD), and account for >90% of health care encounters for this patient population. The Cooperative Study of Sickle Cell Disease, a large study enrolling >3000 patients, showed that the majority of SCD patients (80%) experienced 0-3 major pain crises/year. Only a small minority (~5%) experienced ≥6 VOEs/year. Our study sought to further understand this difference in VOE frequency between SCD patients. We analyzed 25 patients (13M/12F, mean age of 28.8) with ≥6 ED visits or hospitalizations/year (high utilizers), and compared these with 9 patients (6M/3F, mean age of 37.6) who had ≤2 ED visits or hospitalizations/year (low utilizers). All subjects were given a demographic survey along with questionnaires for depression, anxiety, and Health Locus of Control. Each subject then underwent quantitative sensory testing (QST) with three different modalities: pressure pain sensitivity, heat and cold sensitivity, and Von Frey monofilament testing. Laboratory and clinical data were collected through subjects' medical records. CBC and chemistry analysis showed high utilizers had higher WBC (p<0.01), ANC (p<0.01), total bilirubin (p = 0.02), and lower MCV (p = 0.03). Opioid use (morphine equivalents) over the past 6 months was significantly higher in the high utilizer group (12125.7 mg vs 2423.1 mg, p = 0.005). QST results showed lower pressure pain threshold at the ulna (224.4 KPa vs 338.9 KPa, p = 0.04) in the high utilizer group. High utilizers also had higher anxiety (9.0 vs 4.6, p = 0.04) and depression scores (10.0 vs 6.0, p = 0.051). While the low utilizer group had higher education levels with more associate and bachelor degrees (p = 0.009), there was no difference in income or employment. These data show that many biological and psychosocial factors contribute to high health care utilization in SCD. A multi-disciplinary and multi-faceted approach will be required to address this complex problem.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247324PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899345PMC
August 2021

Novel mechanism of hereditary pyropoikilocytosis phenotype due to co-inheritance of β globin and α spectrin mutations.

Am J Hematol 2021 05 25;96(5):E150-E154. Epub 2021 Feb 25.

Hematology, University of Utah & Huntsman Cancer Center, Salt Lake City, Utah.

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http://dx.doi.org/10.1002/ajh.26121DOI Listing
May 2021

Sickle cell disease: progress towards combination drug therapy.

Br J Haematol 2021 07 20;194(2):240-251. Epub 2021 Jan 20.

Department of Medicine, Center for Blood Disorders, Augusta University, Augusta, GA, USA.

Dr. John Herrick described the first clinical case of sickle cell anaemia (SCA) in the United States in 1910. Subsequently, four decades later, Ingram and colleagues characterized the A to T substitution in DNA producing the GAG to GTG codon and replacement of glutamic acid with valine in the sixth position of the β -globin chain. The establishment of Comprehensive Sickle Cell Centers in the United States in the 1970s was an important milestone in the development of treatment strategies and describing the natural history of sickle cell disease (SCD) comprised of genotypes including homozygous haemoglobin SS (HbSS), HbSβ thalassaemia, HbSC and HbSβ thalassaemia, among others. Early drug studies demonstrating effective treatments of HbSS and HbSβ thalassaemia, stimulated clinical trials to develop disease-specific therapies to induce fetal haemoglobin due to its ability to block HbS polymerization. Subsequently, hydroxycarbamide proved efficacious in adults with SCA and was Food and Drug Administration (FDA)-approved in 1998. After two decades of hydroxycarbamide use for SCD, there continues to be limited clinical acceptance of this chemotherapy drug, providing the impetus for investigators and pharmaceutical companies to develop non-chemotherapy agents. Investigative efforts to determine the role of events downstream of deoxy-HbS polymerization, such as endothelial cell activation, cellular adhesion, chronic inflammation, intravascular haemolysis and nitric oxide scavenging, have expanded drug targets which reverse the pathophysiology of SCD. After two decades of slow progress in the field, since 2018 three new drugs were FDA-approved for SCA, but research efforts to develop treatments continue. Currently over 30 treatment intervention trials are in progress to investigate a wide range of agents acting by complementary mechanisms, providing the rationale for ushering in the age of effective and safe combination drug therapy for SCD. Parallel efforts to develop curative therapies using haematopoietic stem cell transplant and gene therapy provide individuals with SCD multiple treatment options. We will discuss progress made towards drug development and potential combination drug therapy for SCD with the standard of care hydroxycarbamide.
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http://dx.doi.org/10.1111/bjh.17312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282668PMC
July 2021

Outcomes of an Emergency Department Observation Unit-Based Pathway for the Treatment of Uncomplicated Vaso-occlusive Events in Sickle Cell Disease.

Ann Emerg Med 2020 09;76(3S):S12-S20

Department of Emergency Medicine, Medical College of Georgia, Augusta University, Augusta, GA. Electronic address:

Study Objective: This was a prospective, pre-post, 13-year observational study documenting the multiyear implementation of an observation unit sickle cell pathway for patients with uncomplicated vaso-occlusive events.

Methods: The sickle cell pathway begins with rapid triage to identify patients with uncomplicated vaso-occlusive events for immediate transfer to the observation unit and initiation of patient-controlled analgesia followed by repeated evaluations of pain and identification of other complications. Data were abstracted from the electronic medical record or observation unit database. The sickle cell pathway was initiated in April 2006. Major revisions of it were carried out in June 2009 (physician evaluation occurs in sickle cell pathway and only patient-controlled analgesia administration of medications) and October 2010 (multidisciplinary management and individual dosing).

Results: Annual ED visits ranged between 287 and 528. The preimplementation hospital admission rate was 33% (123/368), 3-day return rate 16% (60/368), and 30-day return rate 67% (248/368). Refinements to the sickle cell pathway have resulted in a decrease in admission rate to 20% (258/1276); 3-day return rate, to 3.6% (46/1,276); and 30-day return rate, to 41% (525/1,276) for the past 3 years.

Conclusion: The use of a sickle cell pathway for the treatment of uncomplicated vaso-occlusive events has been effective in providing rapid treatment and reducing hospital admissions. However, it was not only the intervention and its refinement that made the sickle cell pathway successful. With the Consolidated Framework for Implementation Research, it was discerned that outer setting factors of organizational commitment to the care of patients with SCD, inner setting factors of learning climate and leadership engagement, individuals, and process contributed to the success of the sickle cell pathway.
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http://dx.doi.org/10.1016/j.annemergmed.2020.08.007DOI Listing
September 2020

Association between Vaso-occlusive Crises and Opioid Prescriptions among Patients with Sickle Cell Disease: A Retrospective Claims-based Study.

J Health Econ Outcomes Res 2020 26;7(1):94-101. Epub 2020 Jun 26.

Augusta University, Center for Blood Disorders, Augusta, GA.

Background/objectives: Among sickle cell disease (SCD) patients, vaso-occlusive crises (VOCs) are recurrent and unpredictable attacks of acute pain. These pain crises are often treated with analgesics, including opioids, which have been associated with misuse and overdose. The aim of this study was to examine the association between VOC events and opioid use and assess the association between opioid prescriptions and health care resource utilization among SCD patients.

Methods: This was a retrospective cohort study using Texas Medicaid medical and prescription claims between September 2011 and August 2016. The index date was the first SCD diagnosis. Patients (2-63 years) with at least one inpatient or two outpatient SCD diagnoses, who were continuously enrolled during 12 months postindex, were included in the study. The primary outcome was number of opioid prescriptions, while the independent variable was number of VOC events. Covariates included age, gender, nonopioid medication use, nonstudy SCD-related medication (penicillin and folic acid) use, evidence of blood transfusions, number of SCD-related complications, number of SCD-related comorbid conditions, and Charlson Comorbidity Index score. Negative binomial regression analysis was used to address study objectives.

Results: Of 3368 included patients, 1978 (58.7%) had at least one opioid prescription with a mean of 4.2 (SD=7.2). Overall, 2071 (61.5%) had at least one VOC event with an average of 2.9 (SD=4.4). The results from the negative binomial regression showed that for every increase in VOC events, the number of opioid prescriptions increased by 9.5% (Incidence rate ratio=1.095, 95% CI: 1.078-1.111; ≤ 0.0001). Other significant covariates associated with higher opioid use included age (13 and older compared to 2-12) and increase in the number of nonopioid pain medications, nonstudy SCD-related medications, and SCD-related complications.

Conclusions: The majority of SCD patients had at least one VOC event and were prescribed opioids during the 12-month study period. We found that each VOC event was associated with a 9.5% increase in the use of opioids. SCD guidelines recommend opioids for the treatment of VOC-related pain. Payers and providers should be aware of opioid use in this population, consider appropriate VOC prevention measures, and provide SCD patients with access to appropriate pain management.
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http://dx.doi.org/10.36469/jheor.2020.13348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343345PMC
June 2020

DIAPH1 Mutation as a Novel Cause of Autosomal Dominant Macrothrombocytopenia and Hearing Loss.

Acta Haematol 2021 26;144(1):91-94. Epub 2020 Jun 26.

Division of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, Georgia, USA.

Macrothrombocytopenia (MTP) is a group of rare disorders characterized by giant platelets, thrombocytopenia, and variable association with abnormal bleeding. Inherited MTP are frequently misdiagnosed as immune thrombocytopenia. Associated second-organ manifestation can help narrow down syndromic MTPs. We describe a case of autosomal dominant sensorineural hearing loss and MTP caused by a gain of function mutation in DIAPH1. This mutation causes altered megarkaryopoiesis and platelet cytoskeletal deregulation. Although hearing loss and MTP were likely progressive, clinically significant bleeding was not observed. DIAPH1-related MTP can be distinguished clinically from MYH9 mutation by the absence of cataracts and glomerular disease.
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http://dx.doi.org/10.1159/000506727DOI Listing
March 2021

American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.

Blood Adv 2020 06;4(12):2656-2701

Department of Emergency Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Background: The management of acute and chronic pain for individuals living with sickle cell disease (SCD) is a clinical challenge. This reflects the paucity of clinical SCD pain research and limited understanding of the complex biological differences between acute and chronic pain. These issues collectively create barriers to effective, targeted interventions. Optimal pain management requires interdisciplinary care.

Objective: These evidence-based guidelines developed by the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in pain management decisions for children and adults with SCD.

Methods: ASH formed a multidisciplinary panel, including 2 patient representatives, that was thoroughly vetted to minimize bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic reviews. Clinical questions and outcomes were prioritized according to importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment.

Results: The panel reached consensus on 18 recommendations specific to acute and chronic pain. The recommendations reflect a broad pain management approach, encompassing pharmacological and nonpharmacological interventions and analgesic delivery.

Conclusions: Because of low-certainty evidence and closely balanced benefits and harms, most recommendations are conditional. Patient preferences should drive clinical decisions. Policymaking, including that by payers, will require substantial debate and input from stakeholders. Randomized controlled trials and comparative-effectiveness studies are needed for chronic opioid therapy, nonopioid therapies, and nonpharmacological interventions.
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http://dx.doi.org/10.1182/bloodadvances.2020001851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322963PMC
June 2020

Characteristics and potential biomarkers of adult sickle cell patients with chronic pain.

Eur J Haematol 2020 Oct 1;105(4):419-425. Epub 2020 Jul 1.

Center for Blood Disorders Medical College of Georgia at Augusta University, Augusta, GA, USA.

Objectives: In this study, we investigated the evolution of chronic pain in sickle cell patients (SCD) as an age-dependent phenomenon and studied the frequency of vaso-occlusive episode frequency, opioid use, quantitative sensory testing (QST), and biomarkers of chronic pain (CP).

Methods: We undertook a cross-sectional study of the evolution of CP in SCD. A total of 72 subjects (age 15-66) were enrolled. VOE frequency, presence of CP hydroxyurea (HU) therapy, opioid use, and laboratory parameters were collected. QST was performed, and plasma tryptase, substance P, and NGF (Nerve Growth Factor) levels were assayed.

Results: There was an age-dependent increase in frequency of CP, VOEs, opioid use, and Von Frey monofilament values. CP patients had significantly higher opioid use (daily morphine equivalents) (52.8 mg vs 6.94 mg, P = .009), suggesting a correlation between opioid use and hyperalgesia. NGF levels were also significantly higher (P = .051). Our results confirm previous observations of an age-dependent increase in the proportion of patients with CP and support the contributing role of mast cell activation and neurogenic inflammation.

Conclusions: This is the first study of NGF as a possible biomarker of CP in SCD. If confirmed, this could provide a diagnostic marker and therapeutic target for CP in SCD.
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http://dx.doi.org/10.1111/ejh.13461DOI Listing
October 2020

Integration of Mobile Health Into Sickle Cell Disease Care to Increase Hydroxyurea Utilization: Protocol for an Efficacy and Implementation Study.

JMIR Res Protoc 2020 Jul 14;9(7):e16319. Epub 2020 Jul 14.

Bethesda, MA, United States.

Background: Hydroxyurea prevents disease complications among patients with sickle cell disease (SCD). Although its efficacy has been endorsed by the National Health Lung and Blood Institute evidence-based guidelines, its adoption is low, both by patients with SCD and providers. Mobile health (mHealth) apps provide benefits in improving medication adherence and self-efficacy among patients with chronic diseases and have facilitated prescription among medical providers. However, mHealth has not been systematically tested as a tool to increase hydroxyurea adherence nor has the combination of mHealth been assessed at both patient and provider levels to increase hydroxyurea utilization.

Objective: This study aims to increase hydroxyurea utilization through a combined two-level mHealth intervention for both patients with SCD and their providers with the goals of increasing adherence to hydroxyurea among patients and improve hydroxyurea prescribing behavior among providers.

Methods: We will test the efficacy of 2 mHealth interventions to increase both patient and provider utilization and knowledge of hydroxyurea in 8 clinical sites of the NHLBI-funded Sickle Cell Disease Implementation Consortium (SCDIC). The patient mHealth intervention, InCharge Health, includes multiple components that address memory, motivation, and knowledge barriers to hydroxyurea use. The provider mHealth intervention, Hydroxyurea Toolbox (HU Toolbox), addresses the clinical knowledge barriers in prescribing and monitoring hydroxyurea. The primary hypothesis is that among adolescents and adults with SCD, adherence to hydroxyurea, as measured by the proportion of days covered (the ratio of the number of days the patient is covered by the medication to the number of days in the treatment period), will increase by at least 20% after 24 weeks of receiving the InCharge Health app, compared with their adherence at baseline. As secondary objectives, we will (1) examine the change in health-related quality of life, acute disease complications, perceived health literacy, and perceived self-efficacy in taking hydroxyurea among patients who use InCharge Health and (2) examine potential increases in the awareness of hydroxyurea benefits and risks, appropriate prescribing, and perceived self-efficacy to correctly administer hydroxyurea therapy among SCD providers between baseline and 9 months of using the HU Toolbox app. We will measure the reach, adoption, implementation, and maintenance of both the InCharge Health and the HU Toolbox apps using the reach, effectiveness, adoption, implementation, and maintenance framework and qualitatively evaluate the implementation of both mHealth interventions.

Results: The study is currently enrolling study participants. Recruitment is anticipated to be completed by mid-2021.

Conclusions: If this two-level intervention, that is, the combined use of InCharge Health and HU Toolbox apps, demonstrates efficacy in increasing adherence to hydroxyurea and prescribing behavior in patients with SCD and their providers, respectively, both apps will be offered to other institutions outside the SCDIC through a future large-scale implementation-effectiveness study.

Trial Registration: ClinicalTrials.gov NCT04080167; https://clinicaltrials.gov/ct2/show/NCT04080167.

International Registered Report Identifier (irrid): DERR1-10.2196/16319.
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http://dx.doi.org/10.2196/16319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388044PMC
July 2020

Regulation of iron homeostasis through the erythroferrone-hepcidin axis in sickle cell disease.

Br J Haematol 2020 06 6;189(6):1204-1209. Epub 2020 Feb 6.

Sickle Cell Center, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Sickle cell disease (SCD) has a distinct pattern of transfusional iron overload (IO) when compared to transfusion-dependent β-thalassaemia major (TDT). We conducted a single institution prospective study to evaluate plasma biomarkers of iron regulation and inflammation in patients with SCD with IO (SCD IO cases, n = 22) and without IO (SCD non-IO cases, n = 11), and non-SCD controls (n = 13). Hepcidin was found to be inappropriately low, as evidenced by a significantly higher median hepcidin/ferritin ratio in non-SCD controls compared to SCD IO cases (0·3 vs. 0·02, P < 0·0001) and SCD non-IO cases (0·3 vs. 0·02, P < 0·0001), suggesting that certain inhibitory mechanism (s) work to suppress hepcidin in SCD. As opposed to the SCD non-IO state, where hepcidin shows a strong significant positive correlation with ferritin (Spearman ρ = 0·7, P = 0·02), this correlation was lost when IO occurs (Spearman ρ = -0·2, P = 0·4). Although a direct non-linear correlation between erythroferrone (ERFE) and hepcidin did not reach statistical significance both in the IO (Spearman ρ = -0·4, P = 0·08) and non-IO state (Spearman ρ = -0·6, P = 0·07), patients with highest ERFE had low hepcidin levels, suggesting that ERFE contributes to hepcidin regulation in some patients. Our results suggest a multifactorial mechanism of hepcidin regulation in SCD.
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http://dx.doi.org/10.1111/bjh.16498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011855PMC
June 2020

MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease.

Exp Hematol 2019 02 6;70:85-96.e5. Epub 2018 Nov 6.

Department of Pediatrics, Augusta University, Augusta, GA, USA; Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA. Electronic address:

Inherited genetic modifiers and pharmacologic agents that enhance fetal hemoglobin (HbF) expression reverse the clinical severity of sickle cell disease (SCD). Recent efforts to develop novel strategies of HbF induction include discovery of molecular targets that regulate γ-globin gene transcription and translation. The purpose of this study was to perform genome-wide microRNA (miRNA) analysis to identify genes associated with HbF expression in patients with SCD. We isolated RNA from purified reticulocytes for microarray-based miRNA expression profiling. Using samples from patients with contrasting HbF levels, we observed an eightfold upregulation of miR-144-3p (miR-144) and miR-144-5p in the low-HbF group compared with those with high HbF. Additional analysis by reverse transcription quantitative polymerase chain reaction confirmed individual miR-144 expression levels of subjects in the two groups. Subsequent functional studies in normal and sickle erythroid progenitors showed NRF2 gene silencing by miR-144 and concomitant repression of γ-globin transcription; by contrast, treatment with miR-144 antagomir reversed its silencing effects in a dose-dependent manner. Because NRF2 regulates reactive oxygen species levels, additional studies investigated mechanisms of HbF regulation using a hemin-induced oxidative stress model. Treatment of KU812 cells with hemin produced an increase in NRF2 expression and HbF induction that reversed with miR-144 pretreatment. Chromatin immunoprecipitation assay confirmed NRF2 binding to the γ-globin antioxidant response element, which was inhibited by miR-144 mimic treatment. The genome-wide miRNA microarray and primary erythroid progenitor data support a miR-144/NRF2-mediated mechanism of γ-globin gene regulation in SCD.
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http://dx.doi.org/10.1016/j.exphem.2018.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748328PMC
February 2019

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis.

Am J Hematol 2019 01 25;94(1):55-61. Epub 2018 Nov 25.

The University of Tennessee Health Science Center, Memphis, Tennessee.

The cell adhesion molecule P-selectin plays a key role in the pathogenesis of a vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double-blind, placebo-controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti-P-selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2-4/5-10), SCD genotype (HbSS/non-HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event-free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5-10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time-to-first VOC vs placebo in these subgroups. The rates of treatment-emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event-free and delays time-to-first VOC.
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http://dx.doi.org/10.1002/ajh.25308DOI Listing
January 2019

The missing middle of sickle therapeutics: Multi-agent therapy, targeting risk, using biomarkers.

Am J Hematol 2018 12 23;93(12):1439-1443. Epub 2018 Oct 23.

Division of Hematology/Oncology, Department of Medicine, Augusta University, Augusta, Georgia.

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http://dx.doi.org/10.1002/ajh.25289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283073PMC
December 2018

CB1R-Mediated Activation of Caspase-3 Causes Epigenetic and Neurobehavioral Abnormalities in Postnatal Ethanol-Exposed Mice.

Front Mol Neurosci 2018 20;11:45. Epub 2018 Feb 20.

Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, New York, NY, United States.

Alcohol exposure can affect brain development, leading to long-lasting behavioral problems, including cognitive impairment, which together is defined as fetal alcohol spectrum disorder (FASD). However, the fundamental mechanisms through which this occurs are largely unknown. In this study, we report that the exposure of postnatal day 7 (P7) mice to ethanol activates caspase-3 via cannabinoid receptor type-1 (CB1R) in neonatal mice and causes a reduction in methylated DNA binding protein (MeCP2) levels. The developmental expression of MeCP2 in mice is closely correlated with synaptogenesis and neuronal maturation. It was shown that ethanol treatment of P7 mice enhanced mRNA levels but reduced protein levels. The genetic deletion of CB1R prevented, and administration of a CB1R antagonist before ethanol treatment of P7 mice inhibited caspase-3 activation. Additionally, it reversed the loss of MeCP2 protein, cAMP response element binding protein (CREB) activation, and activity-regulated cytoskeleton-associated protein (Arc) expression. The inhibition of caspase-3 activity prior to ethanol administration prevented ethanol-induced loss of MeCP2, CREB activation, epigenetic regulation of Arc expression, long-term potentiation (LTP), spatial memory deficits and activity-dependent impairment of several signaling molecules, including MeCP2, in adult mice. Collectively, these results reveal that the ethanol-induced CB1R-mediated activation of caspase-3 degrades the MeCP2 protein in the P7 mouse brain and causes long-lasting neurobehavioral deficits in adult mice. This CB1R-mediated instability of MeCP2 during active synaptic maturation may disrupt synaptic circuit maturation and lead to neurobehavioral abnormalities, as observed in this animal model of FASD.
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http://dx.doi.org/10.3389/fnmol.2018.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826222PMC
February 2018

A thalidomide-hydroxyurea hybrid increases HbF production in sickle cell mice and reduces the release of proinflammatory cytokines in cultured monocytes.

Exp Hematol 2018 02 3;58:35-38. Epub 2017 Nov 3.

Hematology and Hemotherapy Center, University of Campinas-UNICAMP, Campinas, Brazil. Electronic address:

Fetal hemoglobin (HbF) induction by hydroxyurea (HU) therapy is associated with decreased morbidity and mortality in sickle cell anemia (SCA) patients, but not all patients respond to or tolerate HU. This provides a rationale for developing novel HbF inducers to treat SCA. Thalidomide analogs have the ability to induce HbF production while inhibiting the release of tumor necrosis factor-alpha. Molecular hybridization of HU and thalidomide was used to synthesize 3- (1,3-dioxoisoindolin-2-yl) benzyl nitrate (compound 4C). In this study, we show that compound 4C increases HbF production in a transgenic SCA mouse model and reduces the production of pro-inflammatory cytokines by SCA mouse monocytes cultured ex vivo. Therefore, compound 4C is a novel drug designed to treat SCA with a unique combination of HbF-inducing and anti-inflammatory properties.
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http://dx.doi.org/10.1016/j.exphem.2017.10.003DOI Listing
February 2018

Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness.

Haematologica 2017 12 29;102(12):1995-2004. Epub 2017 Sep 29.

Department of Biochemistry and Molecular Biology, Augusta University, GA, USA

Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood. To address this question, we examined HU-induced changes in the RNA and protein levels of transcription factors NF-Y, GATA-1, -2, BCL11A, TR4, MYB and NF-E4 that assemble the γ-globin promoter complex and regulate transcription of γ-globin gene. In erythroblasts cultured from peripheral blood CD34 cells of patients with SCD, we found that HU-induced changes in the protein but not the RNA levels of activator GATA-2 and repressors GATA-1, BCL11A and TR4 correlated with HU-induced changes in fetal hemoglobin (HbF) levels in the peripheral blood of HU high and low responders. However, HU did not significantly induce changes in the protein or RNA levels of activators NF-Y and NF-E4. Based on HU-induced changes in the protein levels of GATA-2, -1 and BCL11A, we calculated an Index of Hydroxyurea Responsiveness (IndexHU-3). Compared to the HU-induced fold changes in the individual transcription factor protein levels, the numerical values of IndexHU-3 statistically correlated best with the HU-induced peripheral blood HbF levels of the patients. Thus, IndexHU-3 can serve as an appropriate indicator for inherent HU responsiveness of patients with SCD.
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http://dx.doi.org/10.3324/haematol.2017.175646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709098PMC
December 2017

Crizanlizumab in Sickle Cell Disease.

N Engl J Med 2017 05;376(18):1796

Medical University of South Carolina, Charleston, SC.

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http://dx.doi.org/10.1056/NEJMc1703162DOI Listing
May 2017

Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice.

J Am Soc Nephrol 2017 Aug 27;28(8):2443-2458. Epub 2017 Mar 27.

Cardio-Renal Physiology and Medicine, Department of Medicine, and

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ET) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ET and ET receptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ET receptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ET receptor antagonism may provide a strategy for the prevention of renal complications of SCD.
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http://dx.doi.org/10.1681/ASN.2016070711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533228PMC
August 2017

Variant-aware saturating mutagenesis using multiple Cas9 nucleases identifies regulatory elements at trait-associated loci.

Nat Genet 2017 Apr 20;49(4):625-634. Epub 2017 Feb 20.

Division of Hematology/Oncology, Boston Children's Hospital; Department of Pediatric Oncology, Dana-Farber Cancer Institute; Harvard Stem Cell Institute; and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

Cas9-mediated, high-throughput, saturating in situ mutagenesis permits fine-mapping of function across genomic segments. Disease- and trait-associated variants identified in genome-wide association studies largely cluster at regulatory loci. Here we demonstrate the use of multiple designer nucleases and variant-aware library design to interrogate trait-associated regulatory DNA at high resolution. We developed a computational tool for the creation of saturating-mutagenesis libraries with single or multiple nucleases with incorporation of variants. We applied this methodology to the HBS1L-MYB intergenic region, which is associated with red-blood-cell traits, including fetal hemoglobin levels. This approach identified putative regulatory elements that control MYB expression. Analysis of genomic copy number highlighted potential false-positive regions, thus emphasizing the importance of off-target analysis in the design of saturating-mutagenesis experiments. Together, these data establish a widely applicable high-throughput and high-resolution methodology to identify minimal functional sequences within large disease- and trait-associated regions.
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http://dx.doi.org/10.1038/ng.3793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374001PMC
April 2017

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease.

N Engl J Med 2017 02 3;376(5):429-439. Epub 2016 Dec 3.

From the Division of Hematology-Oncology, University of North Carolina, Chapel Hill (K.I.A.), and the Division of Hematology-Oncology, East Carolina University, Greenville (D.L.) - both in North Carolina; the Sickle Cell Center, Medical College of Georgia, Augusta University, Augusta (A.K.); the Division of Pediatrics, Medical University of South Carolina, Charleston (J.K.); the Department of Hematology-Oncology, Santa Casa Medical School of São Paulo (R.C.), and the Division of Hematology, University of São Paulo (S.G.), São Paulo, the Hematology and Bone Marrow Transplantation Service, Hospital de Clínicas de Porto Alegre, Porto Alegre (J.F.), and the Hematology and Hemotherapy Center, University of Campinas, Campinas (M.P.C.) - all in Brazil; the Baptist Cancer Institute, Baptist Medical Center, Jacksonville, FL (T.H.G.); the Sickle Cell Unit, University of the West Indies, Mona, Jamaica (J.K.-M.); the Division of Pediatric Hematology-Oncology, University of Miami, Miami (O.A.A.); the Department of Medicine, University of Illinois at Chicago, Chicago (V.R.G.); the Division of General Internal Medicine, Virginia Commonwealth University Medical Center, Richmond (W.R.S.); and Selexys Pharmaceuticals, Oklahoma City (S.A.R., J.W.S., R.P.R.).

Background: The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease.

Methods: In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed.

Results: A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

Conclusions: In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).
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http://dx.doi.org/10.1056/NEJMoa1611770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481200PMC
February 2017

Progressing Preemptive Genotyping of CYP2C19 Allelic Variants for Sickle Cell Disease Patients.

Genet Test Mol Biomarkers 2016 Oct 23;20(10):609-615. Epub 2016 Aug 23.

2 Department of Medicine, Georgia Regents University , Augusta, Georgia .

Aims: Interindividual variability in drug response and adverse effects have been described for proton pump inhibitors, anticonvulsants, selective serotonin reuptake inhibitors, tricyclic antidepressants, and anti-infectives, but little is known about the safety and efficacy of these medications in patients with sickle cell disease (SCD). We genotyped the CYP2C19 gene which has been implicated in the metabolism of these drugs in an SCD patient cohort to determine the frequencies of reduced function, increased function, or complete loss-of-function variants.

Materials And Methods: DNAs from 165 unrelated SCD patients were genotyped for nine CYP2C19 (*2, *3, *4, *5, *6, *7,*8, *12, and *17) alleles using the iPLEX ADME PGx multiplex panel.

Results: Three CYP2C19 alleles (*2, *12, and *17) were detected with the following frequencies: 0.209, 0.006, and 0.236, respectively. The predicted phenotype frequencies were distributed as extensive (31.5%), intermediate (24.8%), poor (5.5%), ultrarapid (30.3%), and unknown metabolizers (7.9%).

Discussion: Prognostic genotyping is potentially useful for identifying SCD patients with allelic variants linked to proven clinical pharmacokinetic consequences for several drugs metabolized by the CYP2C19 gene. However, the main challenge to implementing a genetics-guided prescribing practice is ensuring concordance between CYP2C19 genotypes and metabolic phenotypes in SCD patients.
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http://dx.doi.org/10.1089/gtmb.2016.0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069730PMC
October 2016

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

Lancet 2016 Feb 6;387(10019):661-670. Epub 2015 Dec 6.

St Jude Children's Research Hospital, Memphis, TN, USA.

Background: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions.

Methods: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307.

Findings: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions).

Interpretation: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke.

Funding: National Heart, Lung, and Blood Institute, National Institutes of Health.
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http://dx.doi.org/10.1016/S0140-6736(15)01041-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724392PMC
February 2016

Intrapatient variability in fetal hemoglobin measurements over time in sickle cell patients not on fetal hemoglobin inducing agents.

Am J Hematol 2016 Mar;91(3):E11-2

Division of Pediatric Hematology, Oncology, and Marrow and Blood Cell Transplantation, Albert Einstein College of Medicine, Bronx, New York.

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http://dx.doi.org/10.1002/ajh.24261DOI Listing
March 2016
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