Sickle cell disease is a multisystem disorder associated with severe complications and premature death. To address the morbidity, disability, and mortality of inherited disorders, the implementation ...of newborn screening programmes are considered pivotal public health service intervention. Due to ethical consideration there are no RCTs that prove the benefits of comprehensive newborn screening (Lees, Davies and Dezateux, 2000). However, many evidences suggested early diagnosis and treatment can improve outcomes and survival of patients (Gaston et al., 1986; King et al., 2007). As such, an economic analysis reviewed many studies, cited that the pre-clinical diagnosis of SCD had twofold cost-effectiveness compared to symptomatic diagnosis (Grosse, Olney and Baily, 2005). The aim of this study was to assess the impact of the newborn screening program on the morbidity and mortality of disease among the children by assembling results from cohort studies.
DESIGN AND METHODS
The systematic review was performed in accordance with the PRISMA guidelines. Medline, EMBASE, and Cochrane Library were searched for cohort studies that addressed the sickle cell disease morbidity and mortality of the disease among children will consider eligible. The phenomena of interest were mortality, infection, stroke PICO have been translated to keywords and MeSH terms with search limit under 18 years old and date set until July 2020. Two reviewers assessed the quality of included cohort studies individually using Newcastle-Ottawa scale (NOS). Subsequently, the data were extracted in Microsoft Word. In case of disagreement, were settled by discussion. The incidence rates per 100 patient year and 95% confidence intervals were pooled to random-effects meta-analysis using RevMan5.4. Studies' heterogeneity identified by chi-squared test and the I2 statistic.
RESULTS
Eight studies included that met inclusion criteria two studies were from USA (Quinn et al., 2008 and Gill et al., 1995) , 1 from UK (Telfer et al., 2007), 1 from Belgium(Lê et al., 2010), 1 from Jamaica (King et al 2007), 1 from Africa (Rahimy et al, 2003), 1 from India (Upadhye et al., 2016) and 1 from Brazil (Rezende et al., 2018). The total number of participants in the 8 cohort studies were 2377 SCD patients (mean 297.1 and SE 73.9), that includes patients with the four common SCD genotypes: HbSS, HbSC, Hb Sβ+ and HbSβ0. The median age was 6.5 year (IQR: 4.95), with 9623 total years of follow up. The pooled incidence rate of SCD associated mortality per 100 patient year was 0.65 (95%CI 0.35-0.94; I2= 89%; p < 0.00001). While the infection incidence rate 17.74 (95%CI; 11.57-23.91; I2= 100%; p< 0.00001), Stroke 1.04(95% CI 0.60-1.47; I2= 78%; p< 0.0001), Acute chest syndrome 12.55(95% CI; 7.70-17.41; I2 =97%; p< 0.00001), Acute splenic sequestration crisis 1.95 (95% CI 1.31-2.59; I2= 69%; p=0.003) and Vaso-occlusive crisis 52.45(95% CI 45.67-59.14; I2= 92%; p< 0.00001).
DISCUSSION
In this systematic review and meta-analysis combining 8 cohort studies, pooled mortality rate was 0.65 per 100 patient-year, similar to (0.64) meta-analysis of 15 studies reported previously (Wastnedge, 2018). Furthermore, our study reported that the total infection rate was 17.7 per 100 patient-year. However, this result of infection cannot be considered a true gold standard and due to the variation in definitions used and other methodological heterogeneity. For example, Africa-based cohort study reported 23.2 per 100 patient-year attacks of malaria and fatal pneumococcal meningitis despite the use of antimalarial prophylaxis and anti-pneumococcal vaccine (Rahimy et al., 2003). Another notable result, Hemoglobin SC cohort study stated that the incidence of infections was, 62.2 episodes (59.8-64.6) per 100 patient-years. They assumed that might be due to higher impaired splenic function in HbSC patients compared to HbSS (Rezende et al., 2018).
CONCLUSION
This first systematic review and meta-analysis of cohort studies provided evidence supporting the sickle cell newborn screening program. However, still infection and pain episodes are the highest incidence symptoms. Despite children survival increasingly improved, disease burden remains at a peak in developing countries. One limitation of this study is high heterogeneity and this mainly due to countries disparity of included studies and variance in definition of events, particularly infection.
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Inusa:Novartis: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau; Global Blood Therapeutics: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau; Bluebird bio: Research Funding; AstraZeneca: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau; Vertex: Research Funding.
Background:Renal abnormalities in sickle cell disease commence early in childhood. Glomerular hyperfiltration and albuminuria are the most prevalent renal abnormalities in sickle cell disease. ...However, these renal abnormalities of SCD have not been considered exclusively in the adolescent age group.
Objective:To determine the prevalence of glomerular hyperfiltration and albuminuria as well as identify the determinants for glomerular hyperfiltration in adolescents with SCD.
Patients and Methods:Ethical permission was through the Trust audit and service evaluation governance review board to implement quality assessment of clinical service. Electronic patient records (charts) of 153 adolescents with SCD aged 10->19 years, attending the Paediatrics Haematology Clinic at Evelina children Hospital, London, United Kingdom. Clinical information obtained included demographics age, gender sickle cell type, as well as history of acute event, treatment history, anthropometric indices and blood pressure. The laboratory parameters obtained were urine albumin-creatinine ratio or protein-creatinine ratio, haemoglobin level, white blood cell count, red blood cell count, platelet count, reticulocyte count, foetal haemoglobin level, lactate dehydrogenase level, serum creatinine and serum ferritin level. The glomerular filtration rate was derived using the Bedside Schwartz’s method. Grouping of the adolescents was based on present and absence of glomerular hyperfiltration, which was defined as glomerular filtration rate > 140ml/min/m2. The presence of albuminuria was defined as urine albumin-to-creatinine ratio >3mg/mmol or protein- to- creatinine ratio of > 15mg/mmol. Investigated were the clinical and laboratory determinants of glomerular hyperfiltration in the total study population.
Result:Prevalence of glomerular hyperfiltration was 33.3% in the adolescents studied (age bracket please) , and that of albuminuria was 15.7% amongst the adolescents with SCD studies (microalbuminuria 14.4%, and 1.3% overt proteinuria) of which 13.7% of those with glomerular hyperfiltration also had albuminuria. The mean eGFR of the adolescents with SCD who had glomerular hyperfiltration was 160.2 ± 20.0 ml/min/1.73m2, and that of those with no glomerular hyperfiltration was 109.9 ± 19.3ml/min/m2. A significantly higher proportion of the adolescents with SCD who had glomerular hyperfiltration had the haemoglobin SS disease (47 (92.2%) versus 68 (66.7%);P=0.007). On univariable analysis, the adolescent with glomerular hyperfiltration had significantly lower weight (48.0 ± 18.0 versus 54.8 ± 17.0 kg;p= 0.02), height (155.1 ± 13.1 versus 160.6 ± 13.1 cm;p= 0.01), body mass index (19.4 ± 5.0 versus 21.0 ± 4.3 ;p= 0.04), haemoglobin level (88.7 ± 13.3 versus 98.1 ± 21.7 g/L;p= 0.001), and serum creatinine level (0.4 ± 0.1 versus 0.6 ± 0.2mg/dl;p= 0.0001) as compared to those with no glomerular hyperfiltration. The adolescents with glomerular hyperfiltration also had significantly higher lactate dehydrogenase level (525.9 ± 180.3 versus 449.6 ± 170.3 IU/L;p= 0.01) as compared to those with no glomerular hyperfiltration. However, no association was found on multivariable analysis.
Conclusion:This study revealed that the prevalence of glomerular hyperfiltration in the adolescent age group was high, and the high glomerular filtration rates begin to decline toward normal values in middle adolescent age not before.
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Inusa:AstraZeneca:Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau;Vertex:Research Funding;Global Blood Therapeutics:Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau;Bluebird bio:Research Funding;Novartis:Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau.
Prior studies have described high venous signal qualitatively using arterial spin labelling (ASL) in patients with sickle cell anemia (SCA), consistent with arteriovenous shunting. We aimed to ...quantify the effect and explored cross-sectional associations with arterial oxygen content (CaO2), disease-modifying treatments, silent cerebral infarction (SCI), and cognitive performance. 94 patients with SCA and 42 controls underwent cognitive assessment and MRI with single- and multi- inflow time (TI) ASL sequences. Cerebral blood flow (CBF) and bolus arrival time (BAT) were examined across gray and white matter and high-signal regions of the sagittal sinus. Across gray and white matter, increases in CBF and reductions in BAT were observed in association with reduced CaO2 in patients, irrespective of sequence. Across high-signal sagittal sinus regions, CBF was also increased in association with reduced CaO2 using both sequences. However, BAT was increased rather than reduced in patients across these regions, with no association with CaO2. Using the multiTI sequence in patients, increases in CBF across white matter and high-signal sagittal sinus regions were associated with poorer cognitive performance. These novel findings highlight the utility of multiTI ASL in illuminating, and identifying objectively quantifiable and functionally significant markers of, regional hemodynamic stress in patients with SCA.
Sickle cell disease (SCD) is the most common hereditary hemoglobinopathy. The underlying pathophysiology of the red blood cell (RBC) leads to pan-systemic complications which manifest at an early ...age. While curative and disease-modifying treatments exist for SCD, a key intervention in the management and treatment of SCD is RBC transfusion, which can alleviate or prevent many complications. SCD patients often require chronic RBC transfusion therapy which can result in complications, such as iron overload, alloimmunization and infection. In low- and middle-income countries (LMICs), SCD patients lack appropriate access to healthcare such as newborn screening, health education, prophylaxis for infection, and treatments to reduce both mortality and SCD-related adverse effects. Poor access to RBCs for transfusion, coupled with donated blood not meeting safety standards set by the World Health Organization, presents a significant barrier for patients requiring chronic transfusions in LMICs. Unmet needs associated with blood collection, blood component processing and recipient matching all pose a serious problem in many LMICs, although this varies depending on geographic location, political organizations and economy. This review aims to provide an overview of the global burden of SCD, focusing on the availability of current treatments and the burden of chronic RBC transfusions in patients with SCD.
Introduction:
Paediatric Inflammatory Multisystem Syndrome - temporally associated with SARS-CoV2 (PIMS-TS) is a newly described syndrome during the COVID-19 pandemic. It is characterised by a state ...of persistent fever, inflammation and organ dysfunction following exposure to SARS-CoV-2 virus. It shares similar clinical features to Kawasaki disease, toxic shock syndrome and macrophage activation syndrome. Like adult COVID-19 infection, profound inflammatory response significantly increases the risk of thromboembolism, which is a major cause of morbidity and mortality. In this review we share our experience, observation and prevention strategy with regard to thromboembolism in PIMS-TS.
Method:
Between the period of 14th March 2020 to 31st May 2020, Evelina London Children's Hospital admitted 68 patients with PIMS-TS from the South Thames Network. Patients were broadly treated with a combination of high dose aspirin and immunomodulation in the initial period. Realising its pro-thrombotic potential, from 1st May 2020, treatment strategy was changed to incorporate prophylactic subcutaneous low molecular weight heparin (dalteparin 100units/kg once daily) in combination with low dose aspirin (5mg/kg once daily, maximum 75mg) when a working diagnosis of PIMS-TS was made. We retrospectively collected data to understand the prevalence and pattern of thromboembolism in this cohort of patients.
Results:
Five patients (7.4%) developed thromboembolic complications during their acute illness with 6 recorded events overall. (Table 1) Three events happened without prophylactic anticoagulation cover. Four (5.9%) were cardiovascular/arterial events and 2 (2.9%) were venous thromboembolism. Those who required ventilation support and extracorporeal membrane oxygenation (ECMO) were associated with higher thrombotic rate using 2-tailed Fisher's exact test (ventilation: p=0.02; ECMO: p=0.004). One ischaemic cerebrovascular event resulted in death. Two bleeding events were recorded whilst on anticoagulation. One was iatrogenic following arterial line insertion and another a haemorrhagic transformation from an ischaemic stroke.
Coagulation markers (fibrinogen and D-dimer) followed the overall pattern observed in inflammatory markers (ferritin and C-reactive protein) on admission, at peak values and at 2-week follow up, suggesting a connection between the degree of inflammation and hypercoagulability and inferring immunothrombosis. (Table 2) Peak ferritin and D-dimer levels were significantly higher in the group with thromboembolism using 2-tailed Mann-Whitney U test (ferritin: p=0.038; D-dimer: p=0.034).
Conclusion:
Thromboembolism needs to be considered as a significant complication in patients with a diagnosis of PIMS-TS. We observed more cardiovascular/arterial events than venous events, which coincided with the fact that PIMS-TS patients commonly develop cardiac involvement and coronary abnormalities. In addition to rapid correction of hyper-inflammatory state using immunomodulation, we suggest the consideration of low dose aspirin (5mg/kg once daily, maximum 75mg) and prophylactic dalteparin (100units/kg once daily) to prevent both arterial and venous thrombosis after careful individual assessment and exclusion of co-existing factors that can cause increased bleeding risk. This may be especially relevant in those with already raised ferritin and D-dimer levels on admission.
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Inusa:Vertex: Research Funding; AstraZeneca: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau; Bluebird bio: Research Funding; Novartis: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau; Global Blood Therapeutics: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau.
Background:
Children with sickle cell disease (SCD) are at increased risk of cerebrovascular events such as stroke, silent infarcts and neurocognitive impairment. The role of Transcranial Doppler ...ultrasound scanning (TCD) to identify sickle cell anemia (SCA) children at high risk of stroke is well established. Adam et al in 1998 recommended those with abnormal cerebrovascular flow velocities are offered prophylactic blood transfusion therapy to prevent stroke between ages 2 to 16 years. Therefore, TCD screening for stroke prevention in now is a mandatory in all guidelines for the management of children with SCA. However, there is still no uniform implementation of the program globally and in European countries (Rees 2016). Moreover, the information available on the quality of the TCD screening is limited to educational experiences in a few countries (Inusa 2019) but to evaluation of stroke prevention programs has been performed in Europe.
As more disease modifying therapies become available for children with SCD, it is mandatory to know TCD availability, screening practices, and real-world data on stroke prevention in Europe.
EuroBloodNet is the European Reference Network (ERN) on rare Hematological Disorders, one of the 24 ERN established by the European Union to improve care of patients with rare disorders in Europe. EuroBloodNet's main goal is to improve the healthcare and overall quality of life of patients with a Rare Hematological Disease by: 1) Improving equal access to highly specialized healthcare delivery through a multidisciplinary patient centered approach; 2) Enhancing the best practices in prevention, diagnosis and safe clinical care across Europe based on promotion of evidence based guidelines.
We wanted to assess the state of the art of TCD screening and stroke prevention programs in European Expert Centers.
Methods: An online survey was developed by SCD experts in 5 European countries and sent to all Representatives of the Health Care Providers (HCP) and the Red Cell Disorder representatives in each HCP within the EuroBloodNet network, as well as to National Representatives of Scientific Societies within European Countries. Items in the survey are listed in Table 1.
Results
81 hematologists or pediatricians from 77 centers in 16 European countries responded to the survey (14/16 in Western Europe); 39/77 (51%) were EuroBloodNet Expert centers, 14/77 (18%) were under evaluation as being recognized; 67/77 specified their expertise: 24% were pediatric, 3% adult, 58% both; 12 centers had >200 patients in the age range 1-16 years.
36% Physicians reported not having a dedicated TCD/TCDi service for children with SCD so exams had to be performed by cardiologists (10%), general radiologists (28%), TCD is not performed (31%), or patients have to be sent in another center (31%). 74% reported requesting annual TCD for their patients, but to the question “What percentage of your patients receives annual TCD” only 28% confirmed that all their patients managed to actually receive annual TCD, due to lack of trained staff (43%), lack of TCD instruments (11%), refusal of patients due to logistical difficulties (22%) (i.e TCD in another city), lack of funds for dedicated staff or equipment (11%), or other reasons.
Only 74% of hematologists were aware of the protocol in use at their center by the staff performing TCD; the STOP criteria were applied by 64% of the physicians, mainly due non evaluation of the Internal Carotid Artery. The extracranial part of the carotid artery was evaluated only in 30% of the respondents.
In case of abnormal/conditional TCD results, the approach varies and is not uniform across centers.
Conclusions
Our data show that less than 30% of children with SCD followed in European Centers receive annual TCD according to recognized guidelines. This first multinational European survey allowed the identification of issues related to the lack of access to TCD, lack of trained staff, lack of adequate protocols for implementation of TCD and treatment afterwards, which will need to be addressed through dedicated actions.
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Casale: Novartis Farma SpA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mañú Pereira: Novartis: Research Funding; Agios Pharmaceuticals: Research Funding. de Montalembert: Vertex: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Colombatti: Global Blood Therapeutics: Research Funding; Addmedica: Consultancy; Forma Therapeutics: Consultancy; Novartis: Consultancy; NovoNordisk: Consultancy; BlueBirdBio: Consultancy; Global Blood Therapeutics: Consultancy; BlueBirdBio: Research Funding.
Background: Recent studies on the impact of migration on the geographical distribution of the HbS allele have highlighted sickle cell disease (SCD) as a global public health issue. Although ...considered a “rare disease” due to its global frequency in the 28 countries of the European Union, SCD is the most common genetic disease in France and the United Kingdom and its frequency is steadily rising in many other countries of central and southern Europe. At present, less than 50% of children with SCD have access to TCD screening in the USA and Europe. Most centers use the non-imaging approach, as described in the STOP trials, which is a “blind technique” where there is no guiding anatomical information and thus relies heavily on operator experience. Some centers now use imaging TCD which provides anatomical information enabling the Circle of Willis to be visualized and so facilitates identification of the basal cerebral arteries and orientation of the Doppler beam when acquiring blood velocities. The primary study objective was to determine the effectiveness of the modular training program in achieving the high level of scanning competency described in the STOP trial, irrespective of practitioner background and when using either non-imaging or imaging TCD. Methodology. The modular TCD training program was developed at the training center in London and delivered to trainees at all three centers (London-UK, Padova-Italy and Dublin, Ireland). The program comprised of a 2-day instructional course covering theory and practical aspects of TCD and incorporated significant hands-on instruction. This was followed by trainees scanning at their own hospital until they had collected a log book of at least 40 scans (within a one year period), after which a scan review and competency evaluation was performed. Results.Modular training program. Nine training courses were held (six in England, one in Ireland and two in Italy); these were attended by a total of 51 trainees (Table 1). Approximately half the trainees (45%) successfully completed the competency evaluation, 20 were still in training, two of whom had failed the assessment and eight withdrew from the program due to problems with local funding for staff or equipment. The ten trainees with an ultrasound background (clinical scientists) were able to acquire TCD skills rapidly as demonstrated by the high pass rate. The findings were more variable in the clinician group (pediatricians and nurses) with five requiring refresher courses and twelve failing to complete the minimum annual scan number (forty) due to small local sickle populations. Comparative analysis of TCD data obtained before and after training. A total of 555 patients were included in this study; 181 patients at Center 1 (52 males, mean age 7.9±3.8 (range 2-15.4 years), genotypes: 134 HbSS, 39 HbSC, 8 HbSβ thalassemia), 194 patients. Center 2 (53 males, mean age 7.4±3·2 (range 2-15.1 years), genotypes: 158 HbSS, 32 HbSC, 4 HbSβ) and 154 patients at Center 3 (50 males, mean age 6.4±3.5 (range 2-15.1 years), genotypes: 154 HbSS, 10HbSC, 16 HbSβ thalassemia). There was no significant difference in gender distribution (Chi-Square=0.313, p=0.85), but more young patients were recruited in Center 3 (ANOVA, F=8.9, p<0.001), more HbSC patients in Centers 1 and 2 and more Sβ thalassemia patients in Center 3 (Chi-Square=21.0, p<0.001).Conclusion: Diagnostic vascular ultrasound is highly operator-dependent; hence training and competency validation are essential in producing skilled TCD operators. The modular training program described here was effective in ensuring standardized TCD technique, irrespective of professional background. In this multi-center study TCD velocity measurements and STOP classification were consistent, irrespective of TCD mode and European country. We believe that this is the first modular training program that has demonstrated efficacy when delivered in different European countries. Delivery of this program in areas where TCD is under-provided will augment the number of trained TCD operators, thus facilitating access to specialist diagnostic services. This will have a significant impact on public health across Europe where SCD patients are increasing due to migration. Competency and quality assurance (QA) are important components of such a screening program; further work is in progress to develop an achievable QA program for ongoing regulation of this screening program.
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Colombatti:AddMedica: Consultancy; Novartis: Consultancy; Global Blood Therapeutics: Consultancy.
Pain is a hallmark of Sickle Cell Disease (SCD) affecting patients throughout their life; the first pain crisis may occur at any age and is often the first presentation of the disease. Universal ...newborn screening identifies children with SCD at birth, significantly improving morbidity and mortality. Without early screening, diagnosis is generally made after disease manifestations appear. The Consortium for the Advancement of Sickle Cell Research (CASiRe) is an international collaborative group evaluating the clinical severity of subjects with SCD using a validated questionnaire and medical chart review, standardized across 4 countries (United States, United Kingdom, Italy and Ghana). We investigated the age of first pain crisis in 555 sickle cell subjects, 344 adults and 211 children. Median age of the first crisis in the whole group was 4 years old, 5 years old among adults and 2 years old among children. Patients from the United States generally reported the first crisis earlier than Ghanaians. Experiencing the first pain crisis early in life correlated with the genotype and disease severity. Early recognition of the first pain crisis could be useful to guide counseling and management of the disease.
Background: Sickle cell anemia (SCA) is associated with cognitive challenges that often worsen as children age. Previous work has established relationships between hematological markers of disease ...severity (i.e., hemoglobin concentration) and various neurological outcomes, including cognitive impairment. However, most studies have related static, often isolated hemoglobin concentration (Hb) values obtained from a single time-point closest to data collection. Studies of pediatric patients with phenylketonuria and Type I diabetes have demonstrated that longitudinal change and variability in phenylalanine and glucose, respectively, are better indicators of neurological and cognitive outcomes than a single value alone. Our study aimed to be the first study of pediatric patients with SCA to examine the extent to which indices of Hb control (e.g., lifetime average and variability), collected routinely in this patient group, may provide additional prognostic information.
Methods: Data were collected from pediatric patients (aged 4-18 years at enrolment) with and without SCA enrolled on the Sleep Asthma Cohort-III (SAC-III) follow-up study. SAC is a mixed retrospective-prospective study assessing the impact of nocturnal oxygen desaturation on SCA complications. The present investigation assessed participants (see Figure 1 for complete participant demographics) who underwent cognitive evaluation using Wechsler scales measuring domains of IQ, processing speed (i.e., processing speed index PSI and Cancellation subtest), and executive function (working memory index WMI). Participant demographics and appropriate medical data and history (i.e., hydroxyurea therapy, silent infarction) were obtained via questionnaires and analysis of medical records. Hb (d/L) measures assessed included average lifetime values (i.e., mean and median), variability over the lifetime (i.e., standard deviation), and the single value obtained closest to data collection.
Results: Correlation analyses indicated a strong positive relationship between the mean and median Hb values along with large positive associations between the average and contemporaneous values. Small non-significant correlations were demonstrated between variability and average Hb values (see Figure 1). Initial hierarchical linear regression analyses demonstrated that neither hydroxyurea use nor silent infarct (SCI) status were predictors of any cognitive outcomes or Hb values, so they were not included in any further analyses. Separate regression analyses for each cognitive outcome found that mean lifetime Hb values was the only significant predictor of IQ (p = .04, η 2 = .13) and the Cancellation subtest (p = .005, η 2 = .22). Mean lifetime Hb values approached significance for PSI (p = .09, η 2 = .08), but was not a predictor for WMI (p = .33, η 2 = .03).
Conclusion: Our study demonstrated that despite strong correlations between Hb obtained closest to testing and average lifetime values (i.e., rs = .64 and .69), only lifetime Hb predicted cognitive outcomes, particularly processing speed scores from the Cancellation subtest. Variability was not strongly related to other indices of Hb control and did not predict any cognitive outcomes. These results mirror those obtained from other pediatric populations indicating that static, one time values may not best represent clinical manifestations of chronic illness, and the choice of Hb value can differentially influence research study results and clinical prognosis. Future longitudinal work in larger samples is needed, but Hb obtained over the lifetime appears to provide a more precise picture of patients' cognitive developmental trajectory than a single contemporaneous Hb value alone.
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Kirkham: Bluebird Bio: Honoraria; Novartis: Honoraria; Global Blood Therapeutics: Consultancy. Howard: Imara: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy; Novartis: Consultancy, Honoraria; Resonance Health: Honoraria; Novo Nordisk: Consultancy; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Consultancy; Bluebird Bio: Research Funding.
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Children with sickle cell disease (SCD) who have their disease managed with frequent blood transfusions often require iron chelation therapy to prevent iron overload. Deferoxamine (DFO) is an iron ...chelator approved for pediatric use that is often administered via infusion; however, postmarketing research revealed that adherence to treatment in pediatric populations is a key challenge experienced by patients and caregivers due to the burdensome nature of the administration route. Deferiprone (DFP), an oral iron chelator, has recently been approved as a first-line treatment for transfusional iron overload in pediatric and adult patients with SCD and other anemias. We previously reported that DFP is noninferior to DFO in patients with SCD and iron overload (as assessed by liver iron concentration LIC) and has an acceptable safety profile. Here, we report a subgroup analysis of the FIRST (NCT02041299) study to assess whether the efficacy and safety of DFP are comparable to DFO in children with SCD.
In this phase 4, multicenter, 2-arm, randomized, open-label study, eligible patients were randomized in a 2:1 ratio to receive DFP or DFO for 12 months. The subgroup analysis included children (2-16 years of age) with SCD or another rare anemia who were treated for transfusional iron overload. Children received either DFP orally tid or DFO by subcutaneous infusion 5-7 days a week. Iron load was monitored during the trial and dosage adjustments were allowed when necessary. The primary efficacy endpoint was the change in LIC from baseline to month 12, and data were analyzed for all patients who had a baseline and a follow-up LIC assessment (efficacy population). Absolute neutrophil counts were assessed weekly for the first 6 months, and then every 2 weeks until the end of the study. Additional safety assessments were done monthly with analysis including all patients who received at least 1 dose of the study drug (safety population). Statistical significance between DFP- and DFO-treated groups was calculated via t-test for continuous variables and Fisher's exact test for discrete variables.
Of the 228 patients in the safety population, 128 (n=86 in DFP; n=42 in DFO) were children. Five children withdrew from the study due to adverse events (AEs) and 19 withdrew for other reasons. Most children in each treatment group (DFP, 75.6 %; DFO, 80.9%) had a primary diagnosis of SCD (HbS); the remainder had another form of anemia that required chronic transfusions. At the time of first exposure, mean ages (SD) in the DFP- and DFO-treated groups were 9.9 (3.7) years and 10.9 (3.0) (P=0.09), respectively. There were no significant differences between the DFP- and DFO-treatment groups in sex (males 59.3% vs 57.1%; P=0.85), ethnicity (P=0.68), or race (P=0.34). Children treated with DFP or DFO showed no significant differences in overall incidence of AEs (P=0.77) (including neutropenias (P=0.30)), severe AEs (P=0.10), serious AEs (P=0.16), or withdrawals due to an AE (P=0.17). However, a difference in the overall incidence of nonserious AEs considered at least possibly related to DFP treatment (59.3% vs 33.3%; P=0.01) was found. Table 1 shows the most common (≥5%) AEs in children by treatment group. The only individual AE for which the rate was significantly higher in the DFP group vs the DFO group was elevated liver enzymes (P=0.03), a known transient reaction to DFP that typically resolves with continued DFP therapy. In DFP-treated children, there were no AEs observed that had not been previously reported in other patient populations; 1 child developed agranulocytosis; and children <6 years of age treated with DFP demonstrated a comparable safety profile to that of older children (6-16 years of age) treated with DFP. In the efficacy population, after 12 months of treatment, there was no significant difference in the mean (SD) LIC change from baseline in children treated with DFP (n=78) compared to DFO (n=40) (-3.39 ± 4.24 mg/g vs -2.99 ± 3.16 mg/g, respectively; P=0.57).
This subgroup analysis of children receiving chronic transfusion therapy for SCD or other anemias corroborates previous findings that treatment with DFP is comparable to DFO in reducing LIC. No new safety concerns were observed in children that have not been previously noted in other populations. Thus, the present findings may benefit children and their healthcare providers when considering effective iron chelation therapy that may also address treatment-adherence concerns.
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Hamdy: Amgen: Honoraria; Bayer: Honoraria; Novartis: Honoraria; ApoPharma: Honoraria; NovoNordisk: Honoraria; Roche: Honoraria; Takeda: Honoraria. Kwiatkowski: Terumo BCT: Research Funding; Sangamo: Research Funding; Bluebird Bio: Research Funding; Novartis: Research Funding; ApoPharma: Research Funding; Agios: Honoraria; Silence Therapeutics: Honoraria; Celgene: Honoraria; Imara: Other: Consultancy Fees; Bluebird Bio: Other: Consultancy Fees. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Lee: Chiesi Canada Corp: Current Employment. Temin: Chiesi Canada Corp: Current Employment. Fradette: Chiesi Canada Corp: Current Employment. Tricta: Chiesi Canada Corp: Current Employment.
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