Egyptian Pediatric Guidelines for the Management of Children with Isolated Thrombocytopenia Using the Adapted ADAPTE Methodology-A Limited-Resource Country Perspective.

BACKGROUND: Thrombocytopenia is a prevalent presentation in childhood with a broad spectrum of etiologies, associated findings, and clinical outcomes. Establishing the cause of thrombocytopenia and its proper management have obvious clinical repercussions but may be challenging. This article provides an adaptation of the high-quality Clinical Practice Guidelines (CPGs) of pediatric thrombocytopenia management to suit Egypt's health care context. METHODS: The Adapted ADAPTE methodology was used to identify the high-quality CPGs published between 2010 and 2020. An expert panel screened, assessed and reviewed the CPGs and formulated the adapted consensus recommendations based on the best available evidence. DISCUSSION: The final CPG document provides consensus recommendations and implementation tools on the management of isolated thrombocytopenia in children and adolescents in Egypt. There is a scarcity of evidence to support recommendations for various management protocols. In general, complete clinical assessment, full blood count, and expert analysis of the peripheral blood smear are indicated at initial diagnosis to confirm a bleeding disorder, exclude secondary causes of thrombocytopenia and choose the type of work up required. The International Society of Hemostasis and thrombosis-Bleeding assessment tool (ISTH-SCC BAT) could be used for initial screening of bleeding manifestations. The diagnosis of immune thrombocytopenic purpura (ITP) is based principally on the exclusion of other causes of isolated thrombocytopenia. Future research should report the outcome of this adapted guideline and include cost-analysis evaluations.

Transfusion of blood components in pediatric age groups: an evidence-based clinical practice guideline adapted for the use in Egypt using 'Adapted ADAPTE'.

Pediatric transfusion is a complex area of medicine covering a wide age range, from neonates to young adults. Compared to adult practice, there is a relative lack of high-quality research to inform evidence-based guidelines. We aimed to adapt the pre-existing high-quality practice guidelines for the transfusion of blood components in different pediatric age groups to be available for national use by general practitioners, pediatricians, and other health care professionals. The guideline panel included 17 key leaders from different Egyptian institutions. The panel used the Adapted ADAPTE methodology. The panel prioritized the health questions and recommendations according to their importance for clinicians and patients. The procedure included searching for existing guidelines, quality appraisal, and adaptation of the recommendations to the target context of use. The guideline covered all important aspects of the indications, dosing, and administration of packed red cells, platelets, and fresh frozen plasma. It also included transfusion in special situations, e.g., chronic hemolytic anemia and aplastic anemia, management of massive blood loss, malignancies, surgery, recommendations for safe transfusion practices, and recommendations for modifications of cellular blood components. The final version of the adapted clinical practice guideline (CPG) has been made after a thorough review by an external review panel and was guided by their official recommendations and modifications. A set of implementation tools included algorithms, tables, and flow charts to aid decision-making in practice. This adapted guideline serves as a tool for safe transfusion practices in different pediatric age groups.

Patient preference for deferasirox film-coated versus dispersible tablet formulation: a sequential-design phase 2 study in patients with thalassemia.

Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient preference between film-coated tablet (FCT) and dispersible tablet (DT) in transfusion-dependent thalassemia (TDT) or non-TDT (NTDT) patients treated with both formulations in a sequential manner. The primary endpoint was patient-reported preference for FCT over DT, while secondary outcomes included patient reported outcomes (PROs) evaluated by overall preference, and by age, thalassemia transfusion status, and previous ICT status. Out of 183 patients screened, 140 and 136 patients completed the treatment periods 1 and 2 of the core study, respectively. At week 48, the majority of patients preferred FCT over DT (90.3 vs. 7.5%; difference of percentage: 0.83 [95% confidence interval (CI), 0.75-0.89; P < 0.0001]). FCT scored better on secondary PROs and showed less severe gastrointestinal symptoms than DT, except in the change of modified Satisfaction with Iron Chelation Therapy (mSICT) preference scores, which were similar for both the formulations. Patients with TDT had stable ferritin levels, while it showed a downward trend up to week 48 in patients with NTDT on deferasirox treatment. Overall, 89.9% of patients reported ≥ 1 adverse event (AE), of which 20.3% experienced ≥ 1 serious AE. The most common treatment-emergent AEs were proteinuria, pyrexia, urine protein/creatinine ratio increase, diarrhea, upper respiratory tract infections, transaminase increase, and pharyngitis. Overall, this study reinforced the observations from the previous study by showing a distinct patient preference for FCT over DT formulation and further supported the potential benefits of life-long compliance with ICT.

Does TGFBR3 Polymorphism Increase the Risk of Silent Cerebral Infarction in Egyptian Children with Sickle Cell Disease?

OBJECTIVES: To evaluate the relationship between TGFBR3 rs284875 single nucleotide polymorphism (SNP) state and silent cerebral infarction (SCI) in asymptomatic patients with sickle cell disease (SCD). METHODS: A cross-sectional study was conducted on 50 children with SCD above 2 y of age followed up at the hematology outpatient clinic of Alexandria University Children's Hospital in Egypt. Twenty-four healthy children were included as a control group. All patients included in the study were subjected to complete history and clinical examination. Real-time polymerase chain reaction was performed on patients and controls for identification of SNP rs284875 of the TGFBR3 gene. A magnetic resonance imaging (MRI) of the brain were performed only on patients for detection of SCI. RESULTS: Fifty SCD patients were enrolled (26 males and 24 females), with a median age of 10.9 y (2.3-17.8 y), and 24 children as healthy control for the studied SNP. Thirty-five (70%) patients had homozygous SCD, while 30% had sickle ß-thalassemia. The brain MRI was normal in all the patients except for 2 patients who had features of SCI. The TGFBR3 rs284875 SNP was detected in 15 (30%) patients in the homozygous state (GG) versus only 1 (4.2%) child from the control group (p = 0.003). The prevalence of SCI was low in the study population and there was no statistically significant relationship between the TGFBR3 rs284875 SNP status and the presence of SCI in the brain MRI (p = 0.621). CONCLUSIONS: This study confirmed a low prevalence of SCI in the SCD patient included in the study. The TGFBR3 rs284875 SNP did not significantly increase SCI among those patients.

Beta Thalassemia Carrier Rate: Problem Burden among High School Children.

Background & Aim of the Work: ß-Thalassemia (ßT) is highly prevalent in some countries like Egypt. Accurate data about actual disease prevalence and heavily prevalent geographic locations are essential to help in early detection and in setting up effective preventive programs. We aim for screening ßT carriers among Egyptian high school students in the Delta region. SUBJECTS AND METHODS: A cross-sectional multicenter study was carried out on 4320 randomly selected students from four governorates of the Nile Delta region, Egypt. All patients were to be tested for their complete blood count. Those with microcytic hypochromic anemia not caused by iron deficiency were tested for ßT carrier status using high-performance liquid chromatography. RESULTS: The total prevalence of ßT carrier rate was 6.13%. The highest prevalence was detected in Al-Sharkia Governorate, reaching 7.89%, followed by 6.90% in Al-Gharbia Governorate. Al- Dakahilia and Al-Menoufia showed lower rates of 4.86% and 3.73%, respectively. CONCLUSION: Despite the premarital national screening program for ßT in Egypt, the carrier rate is still high. More effort should be done into the proper implementation of national prevention programs.

Dual gradient echo in-phase and out of phase sequences in assessment of hepatic iron overload in patients with beta-thalassemia, would be better?

PURPOSE: To evaluate the diagnostic accuracy of the dual gradient-echo (GRE) in- and out-of-phase sequences as a quantitative tool for hepatic iron overload in comparison with MRI R2* relaxometry in paediatric patients with beta-thalassemia. METHOD: Sixty-three patients with beta-thalassemia major (transfusion-dependent) or beta-thalassemia intermedia (transfusion- and non-transfusion-dependent) were referred from the paediatric department (haematology unit) to the radiology department at a university hospital. The paediatrician conducted a clinical examination for the studied group, assessed their laboratory data, conducted R2* relaxometry and dual gradient echo sequences to calculate R2* and relative signal intensity index at the axial mid-section of the liver, and studied their correlation. A 1.5 Tesla MR scanner was used (Achieva; Philips Medical Systems, the Netherlands). Data were fed to the computer and analysed using the IBM SPSS software package version 20.0 (Armonk, NY: IBM Corp). The Kolmogorov-Smirnov test was used to verify the normality of distribution. The significance of the results was determined at the 5% level. The Chi-square, Fisher's exact correction, Pearson coefficient, and Bland-Altman tests were used. RESULTS: Dual gradient-echo in- and out-of-phase sequences using visual assessment accurately assessed 93.65% of our patient group with hepatic iron overload. A significant correlation was found between the relative signal intensity index and hepatic MRI R2* relaxometry (p < 0.001, r = 0.861). CONCLUSIONS: Dual gradient-echo in and out-of-phase sequences are good imaging tools for hepatic iron detection and quantification. These sequences showed good correlation with R2* relaxometry (r = 0.861, p < 0.001).

Screening of behavioral disorders in children with hemophilia.

AIM: To screen types of behavioral problems among children with hemophilia and their relation to the disease parameters. METHODS: Fifty boys, 6-18 years old, with moderate and sever hemophilia were subjected to: history taking, joint evaluation using the Hemophilia Joint Health Score, and behavioral assessment using the Child Behavioral Check List. RESULTS: Patients experienced different patterns of behavior disorder. Patients' age significantly correlated with anxious/depressed behavior, somatic complaints, social problems, aggressive behavior, internalizing behavior, and total behavior problems. Hemophilia severity significantly correlated with social problems, thought problems, aggressive behavior, internalizing behavior, externalizing behavior, and total behavior disorders. Affected joint number significantly correlated with withdrawn/depressed behavior, social problems, thought problems, aggressive behavior, internalizing behavior, and total behavior disorders. A high Hemophilia Joint Health Score of the target joints was significantly correlated with social problems, rule-breaking behavior, aggressive behavior, externalizing behavior, and total behavior disorders. Hemophilic arthropathy duration significantly correlated with somatic complaints, social problems, thought problems, attention problems, aggressive behavior, internalizing behavior, externalizing behavior, and total behavior problems. CONCLUSION: Children with hemophilia had behavioral disorders. The most affected scale was aggressive behavior. The least affected scale was attention problems. Behavioral disorders in children with hemophilia are influenced by the age of the patient, the severity of the disease, the number of joints affected, the duration of hemophilic arthropathy, and the score of joint affected by Hemophilia Joint Health Score.

Low-dose immune tolerance induction therapy in children of Arab descent with severe haemophilia A, high inhibitor titres and poor prognostic factors for immune tolerance induction treatment success.

INTRODUCTION: Immune Tolerance Induction (ITI) is the first-choice therapy to eradicate Factor VIII (FVIII) neutralizing antibodies in patients with haemophilia A (HA). There is limited published data on ITI from East Mediterranean countries. AIM: To assess the effectiveness of a low-dose ITI regimen to eradicate FVIII neutralizing antibodies in children with severe HA and high-titre inhibitors. METHODS: A prospective, single-arm study was conducted in children with HA (FVIII < 1 IU/dl), high-titre inhibitors and poor prognostic factors for successful ITI. Patients were treated with ∼50 IU/kg plasma-derived FVIII containing von Willebrand factor (pdFVIII/VWF) concentrate (Koate-DVI, Grifols) three times a week. Time to achieve tolerance, total and partial success were analysed after ITI. Annual bleeding rate (ABR), number of target joints, FVIII recovery and school absence were compared before and after ITI. RESULTS: Twenty patients with median (range) age of 6.2 (3-12) years and pre-ITI inhibitor titre of 36.5 (12-169) BU were enrolled. ITI lasted ≤12 months (early tolerization) in 45% of patients. Median follow-up was 12 months (3-22) and total response rate was 80% (60% total success; 20% partial success). Patients with two and three poor prognosis factors achieved overall success rate of 60% and 50%, respectively. ABR, target joints and school absence were reduced after ITI by 60%, 50% and 44.1%, respectively. In successful ITI tolerized patients, FVIII recovery was 90 (60-100)%. CONCLUSION: A low-dose ITI therapy using a pdFVIII/VWF concentrate achieved at least partial tolerance in 80% of patients, and reduced annual bleeds in children with high inhibitor titres and at least one poor prognosis factor for ITI treatment success.

Prevalence of iron deficiency anemia and beta thalassemia carriers among relatives of beta thalassemia patients in Nile Delta region, Egypt: a multicenter study.

BACKGROUND: Screening of ß thalassemia among close relatives is more feasible in highly prevalent countries with limited resources. The purpose of this study is to determine the prevalence of ß thalassemia carriers and iron deficiency anemia among relatives of ß thalassemia patients in Mid Delta, Egypt. METHODS: This is a cross-sectional multi-center study conducted on 2118 relatives of patients with ß thalassemia from different Egyptian governorates in the Mid Delta region. They were subjected to history taking with precise determination of geographic location, general examination, and the following investigations: complete blood counts, serum ferritin for those who showed microcytic hypochromic anemia, and high-performance liquid chromatography for those who were not diagnosed as iron deficiency anemia. RESULTS: The total prevalence of iron deficiency anemia among close relatives of confirmed ß thalassemia patients in the Nile Delta region was 17.19%. The highest prevalence of iron deficiency anemia (45.05%) was reported in Al-Gharbia Governorate, followed by Al-Menoufia Governorate (21.67%), and the lowest prevalence was that of Al-Sharkia Governorate (4.91%). The differences were highly statistically significant (p < 0.001). ß thalassemia carrier prevalence rate in the studied relatives was 35.84%, with the highest prevalence detected in Al-Sharkia Governorate (51.32%), followed by Kafr-Alsheikh and Al-Dakahilia Governorates (41.78%, 37.13%) respectively, while Al-Menoufia Governorate had the lowest prevalence rate (25.00%). These differences were also highly statistically significant (p < 0.001). CONCLUSION: More than one-third of relatives of patients with ß thalassemia are carriers of the disease, while 17.19% suffer from iron deficiency anemia. This study demonstrates the importance of tracing the high number of beta thalassemia carriers among relatives of patients with ß thalassemia in Egypt.

SLC25A38 congenital sideroblastic anemia: Phenotypes and genotypes of 31 individuals from 24 families, including 11 novel mutations, and a review of the literature.

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders of erythropoiesis characterized by pathologic deposits of iron in the mitochondria of developing erythroblasts. Mutations in the mitochondrial glycine carrier SLC25A38 cause the most common recessive form of CSA. Nonetheless, the disease is still rare, there being fewer than 70 reported families. Here we describe the clinical phenotype and genotypes of 31 individuals from 24 families, including 11 novel mutations. We also review the spectrum of reported mutations and genotypes associated with the disease, describe the unique localization of missense mutations in transmembrane domains and account for the presence of several alleles in different populations.

Comparing the effect of acupressure and ginger on chemotherapy gastrointestinal side-effects in children with leukemia.

The biosocial data of 90 children with acute lymphoblastic leukemia, were collected along with assessment of gastrointestinal side-effects of chemotherapy using visual analogue scale. Ginger lozenges has more effect than acupressure in alleviating nausea and vomiting. Acupressure alleviate the nausea best in the group aged 13-15 years. Ginger helped more the other two groups (7-12 years, 69 % of the group didn't suffer from nausea), versus 50 % aged 13-15). Both acupressure and ginger affected girls more than boys in alleviating nausea. The acupressure effect on vomiting incidence didn't differ in both males and males, whilst ginger helped the males more.

Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: For decades, patients with sickle cell disease have had only a limited number of therapies available. In 2019, voxelotor (1500 mg), an oral once-daily sickle haemoglobin polymerisation inhibitor, was approved in the USA for the treatment of sickle cell disease in patients aged 12 years and older on the basis of HOPE trial data. To further describe the applicability of voxelotor as a treatment for this chronic illness, we report the long-term efficacy and safety of this drug at 72 weeks of treatment; the conclusion of the placebo-controlled HOPE trial. METHODS: HOPE is an international, randomised, double-blind, placebo-controlled, phase 3 trial done at 60 clinical sites in Canada, Egypt, France, Italy, Jamaica, Kenya, Lebanon, Netherlands, Oman, Turkey, the USA, and the UK. Patients (aged 12-65 years) with confirmed sickle cell disease, a haemoglobin concentration of 5·5-10·5 g/dL at enrolment, and who had between one and ten vaso-occlusive crisis events in the previous 12 months were enrolled. Patients receiving regularly scheduled transfusion therapy, who had received a transfusion in the previous 60 days, or who had been admitted to hospital for a vaso-occlusive crisis in the previous 14 days were excluded. Patients were randomly assigned (1:1:1) to receive either once-daily oral voxelotor 1500 mg, voxelotor 900 mg, or placebo for 72 weeks. Randomisation was done centrally by use of an interactive web response system, stratified by baseline hydroxyurea use (yes vs no), age group (adolescents [12 to <18 years] vs adults [18 to 65 years]), and geographic region (North America vs Europe vs other). The primary endpoint (already reported) was the proportion of patients who achieved a haemoglobin response at week 24. In this final analysis, we report prespecified long-term efficacy assessments by intention to treat, including changes in haemoglobin concentrations from baseline to week 72, changes in the concentration of haemolysis markers (absolute and percentage reticulocytes, indirect bilirubin concentrations, and lactate dehydrogenase concentrations) from baseline to week 72, the annualised incidence of vaso-occlusive crises, and patient functioning, as assessed with the Clinical Global Impression of Change (CGI-C) scale. Safety was assessed in patients who received at least one dose of treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT03036813. FINDINGS: Between Dec 5, 2016, and May 3, 2018, 449 patients were screened, of whom 274 were randomly assigned to the voxelotor 1500 mg group (n=90), the voxelotor 900 mg group (n=92), or the placebo group (n=92). At week 72, the adjusted mean change in haemoglobin concentration from baseline was 1·0 g/dL (95% CI 0·7 to -1·3) in the voxelotor 1500 mg group, 0·5 g/dL (0·3 to -0·8) in the voxelotor 900 mg group, and 0·0 g/dL (-0·3 to 0·3) in the placebo group, with a significant difference observed between the voxelotor 1500 mg group and the placebo group (p<0·0001), and between the voxelotor 900 mg group and the placebo group (p=0·014). Significant improvements in markers of haemolysis, as assessed by the difference in adjusted mean percentage change from baseline at week 72 versus placebo, were observed in the voxelotor 1500 mg group in indirect bilirubin concentrations (-26·6% [95% CI -40·2 to -12·9]) and percentage of reticulocytes (-18·6% [-33·9 to -3·3]). The proportion of patients in the voxelotor 1500 mg group who were rated as "moderately improved" or "very much improved" at week 72 with the CGI-C was significantly greater than in the placebo group (39 [74%] of 53 vs 24 [47%] of 51; p=0·0057). Serious adverse events unrelated to sickle cell disease were reported in 25 (28%) of 88 patients in the voxelotor 1500 mg group, 20 (22%) of 92 patients in the voxelotor 900 mg group, and 23 (25%) of 91 patients in the placebo group. Grade 3 or 4 adverse events were infrequent (ie, occurred in <10% of patients); anaemia occurred in five or more patients (two [2%] patients in the voxelotor 1500 mg group, seven [8%] patients in the voxelotor 900 mg group, and three [3%] patients in the placebo group). Of all 274 patients, six (2%) deaths occurred during the study (two deaths in each treatment group), all of which were judged as unrelated to treatment. INTERPRETATION: Voxelotor 1500 mg resulted in rapid and durable improvements in haemoglobin concentrations maintained over 72 weeks and has potential to address the substantial morbidity associated with haemolytic anaemia in sickle cell disease. FUNDING: Global Blood Therapeutics.

Intracranial hemorrhage in primary immune thrombocytopenia (ITP): 20 years' experience in pediatrics.

Incidence of intracranial hemorrhage (ICH) among children with primary immune thrombocytopenia (ITP) varies among different studies. We published data during the period of 1997-2007 of ICH in children with primary ITP, addressing risk factors and outcome. The aim of this study is to assess changes in incidence, risk factors, and outcome of ICH in children with ITP from last decade and to report the overall 20 years' experience. We compared 2008-2018 with the decade before it. Data of children with ITP and ICH during study period and ITP control cases were analyzed. Neurosurgical intervention and outcome were also reported. A total of 4340 children with primary ITP were evaluated. Twenty-five (0.63%) ICH events were reported over 2 decades. Head trauma, hematuria, and platelet counts < 10 × 109/L were the risk factors mostly associated with ICH. Overall mortality was 24%, and a further 28% had neurologic sequelae. Neurosurgical intervention was done in 12% of cases with good outcome.Conclusion: Persistent platelet counts < 10 × 109/L were a significant risk factor for ICH in both time periods, while head trauma and hematuria were more reported in the period of 2008-2018 as significant risk factors for ICH. Outcome was comparable in both periods. What is Known: • ICH is a rare complication of ITP; however, early recognition of risk factors and aggressive treatment might lead to complete recovery without sequalae. Platelet counts less than < 10 × 109/L are the main risk factor for ICH. Few studies reported other significant risk factors. What is New: • Hematuria and head trauma are significant risk factors for ICH in ITP, in addition to having a persistently low platelet count < 10 × 109/L. (more than 90 days in chronic ITP, 45 days in persistent and 21 days in acute ITP) • Combined treatment with IVIG and HDMP followed by platelet transfusion was associated with complete recovery without sequelae in almost 50% of patients.

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

Evaluation of multiplexed biomarkers in assessment of CSF infiltration in pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a very common pediatric malignancy with high survival rates. The course of treatment is modified according to the occurrence of central nervous system (CNS) disease. Aim: To relate serum and cerebrospinal fluid levels of five biomarkers (matrix metalloprotienase 9, CCL-2, sVCAM-1, IFN-γ and inducible protein 10) at diagnosis to the development of CNS infiltration. Methods: The present study was carried on 64 children with ALL and 20 controls. Multiplexed cytokines were measured by Luminex technology (Matrix metalloprotienase 9, CCL-2, sVCAM-1, IFN-γ and inducible protein 10). Results: Significantly higher sMMP-9 and lower sCCL2 were found in patients who developed CNS leukemia. Conclusion: Serum multiplexed parameters at diagnosis of childhood ALL may predict of development of CNS leukemia.

Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study.

BACKGROUND: DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) was a Phase 3, randomized, double-blind, placebo-controlled study conducted in children with sickle cell anemia at 51 sites in 13 countries across four continents. PROCEDURE: Data from DOVE were assessed for regional differences in subject phenotype and treatment. Demographics, baseline clinical and laboratory data, hydroxyurea (HU) use, vaso-occlusive crisis (VOCs; composite endpoint of painful crisis or acute chest syndrome (ACS, Beijing, China)), serious adverse events (SAEs, Florence, Italy), hospitalization, and treatments were compared across the Americas, Europe, North Africa/Middle East, and Sub-Saharan Africa (SSA). RESULTS: Race, body mass index, and blood pressures differed by region. Pre-enrollment VOCs were highest in the Americas. For subjects not on HU, baseline hemoglobin was lowest in SSA; reticulocyte count was lowest in the Americas. Within SSA, Kenya subjects presented higher baseline hemolysis. Painful crisis was the most common SAE, followed by ACS in the Americas and infections in other regions. VOC rate and percentage of VOC hospitalizations were highest in Europe. Regardless of region, most VOCs were treated with analgesics; approximately half were treated with intravenous fluids. The proportion of VOC-related transfusions was greatest in Europe. Lengths of hospital stay were similar across regions. CONCLUSIONS: Overall differences in SAEs and hospitalization for VOCs may be due to cultural diversities, resource utilization, disease severity, or a combination of factors. These data are of importance for the planning of future trials in SCA in a multinational setting.

A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease.

BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sß0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).

A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events.

BACKGROUND: Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. METHODS: Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. RESULTS: A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. CONCLUSIONS: Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).

Lymphadenopathy in a series of Egyptian pediatric patients and the role of pathology in the diagnostic workup.

Assessment of lymphadenopathy in children represents a diagnostic challenge because of the extensive differential diagnoses, including reactive and malignant conditions. Knowledge of the etiologic pattern of lymphadenopathy in a given geographical region is essential for making a confident diagnosis or for suspecting a disease. Hence, the present study was carried out to identify different etiologies of lymphadenopathy in children in our region and to assess parameters commonly associated with malignancy, with an emphasis on the role of pathology. One hundred and twenty patients aged 1 month to 18 years were included in the study. They were sorted into neoplastic and nonneoplastic (infectious and noninfectious) groups. In 56 patients, biopsy (fine needle aspiration cytology [FNAC], core needle, or excision biopsy) was essential to reach the final diagnosis. Sensitivity of FNAC in the differentiation between neoplastic and nonneoplastic lymphadenopathy was 92.3%, and specificity was 90.0%, with a diagnostic accuracy of 91.3%. We concluded that malignancy should be suspected in the following conditions: presence of abdominal or multiple symptoms; symptom duration of 1-6 months; generalized lymphadenopathy; multiple groups of lymph node (LN) involved; LN size > 2 cm; amalgamated, hard, fixed, and nontender LNs; certain abnormal complete blood count findings; blast cells in blood film; and elevated lactate dehydrogenase level. In such cases, LN biopsy is highly recommended. A final diagnosis was achieved after integrating information from history and clinical findings with the laboratory, radiological, pathological, and microbiological findings. Accordingly, an algorithm for primary diagnostic evaluation of children with lymphadenopathy is suggested.