@article {244649, title = {Deferiprone versus deferoxamine for transfusional iron overload in sickle cell disease and other anemias: Pediatric subgroup analysis of the randomized, open-label FIRST study.}, journal = {Pediatric blood \& cancer}, volume = {71}, year = {2024}, pages = {e30711}, abstract = {

BACKGROUND: Children with sickle cell disease (SCD) who are chronically transfused often, require iron chelation therapy. There are limited data that allow for comparison of the efficacy and safety of the iron chelator deferiprone versus deferoxamine in children with SCD.

METHODS: This post hoc analysis of the phase 3b/4, randomized, open-label FIRST (Ferriprox in Patients with IRon Overload in Sickle Cell Disease Trial) study (NCT02041299) included patients 17~years and younger with SCD or other anemias receiving deferiprone or deferoxamine.

RESULTS: Overall, 142 patients were evaluated; mean ages were 10.5 and 11.7~years in the deferiprone and deferoxamine groups, respectively. At 12~months: mean change from baseline in liver iron concentration was -3.3~mg/g dry weight (dw) with deferiprone and -3.4~mg/g dw with deferoxamine (p~=~.8216); relative mean change (coefficient of variation \%) in log cardiac T2* magnetic resonance imaging was 1.02 (21.8\%) with deferiprone and 0.95 (19.5\%) with deferoxamine (p~=~.0717); and the mean (standard error) change in serum ferritin levels was -133.0 (200.3) μg/L with deferiprone and -467.1 (244.1) μg/L with deferoxamine (p~=~.2924). The most common deferiprone-related adverse events (AEs) were upper abdominal pain (20.2\%), vomiting (13.8\%), pyrexia (9.6\%), decreased neutrophil count (9.6\%), increased alanine aminotransferase (ALT; 9.6\%), and increased aspartate aminotransferase (AST; 9.6\%). All cases of increased ALT, increased AST, and neutropenia resolved, most without intervention.

CONCLUSIONS: This post hoc analysis of pediatric patients from FIRST corroborated previous findings in adults that deferiprone is comparable to deferoxamine in reducing iron overload. No new safety concerns were observed. Deferiprone is an oral chelation option that could improve adherence and outcomes in children.

}, author = {HAMDY, MONA and Amal El-Beshlawy and Ver{\'\i}ssimo, M{\^o}nica P A and Kanter, Julie and Inusa, Baba and Williams, Suzan and Lee, David and Temin, Noemi Toiber and Fradette, Caroline and Tricta, Fernando and Ebeid, Fatma Se and Kwiatkowski, Janet L and Mohsen S. Elalfy} } @article {244648, title = {Management of transfusion-dependent β-thalassemia (TDT): Expert insights and practical overview from the Middle East.}, journal = {Blood reviews}, volume = {63}, year = {2024}, pages = {101138}, abstract = {

β-Thalassemia is one of the most common monogenetic diseases worldwide, with a particularly high prevalence in the Middle East region. As such, we have developed long-standing experience with disease management and devising solutions to address challenges attributed to resource limitations. The region has also participated in the majority of clinical trials and development programs of iron chelators and more novel ineffective erythropoiesis-targeted therapy. In this review, we provide a practical overview of management for patients with transfusion-dependent β-thalassemia, primarily driven by such experiences, with the aim of transferring knowledge to colleagues in other regions facing similar challenges.

}, author = {Amal El-Beshlawy and Dewedar, Hany and Hindawi, Salwa and Alkindi, Salam and Azza A. Tantawy and Yassin, Mohamed A and Taher, Ali T} } @article {244645, title = {Deferiprone for transfusional iron overload in sickle cell disease and other anemias: open-label study of up to 3 years.}, journal = {Blood advances}, volume = {7}, year = {2023}, pages = {611-619}, abstract = {

Long-term safety and efficacy data on the iron chelator deferiprone in sickle cell disease (SCD) and other anemias are limited. FIRST-EXT was a 2-year extension study of FIRST (Ferriprox in Patients With Iron Overload in Sickle Cell Disease Trial), a 1-year, randomized noninferiority study of deferiprone vs deferoxamine in these populations. Patients who entered FIRST-EXT continued to receive, or were switched to, deferiprone. Altogether, 134 patients were enrolled in FIRST-EXT (mean age: 16.2 years), with mean (SD) exposure to deferiprone of 2.1 (0.8) years over the 2 studies. The primary end point was safety. Secondary end points were change in liver iron concentration (LIC), cardiac T2*, serum ferritin (SF), and the proportion of responders (>=20\% improvement in efficacy measure). The most common adverse events considered at least possibly related to deferiprone were neutropenia (9.0\%) and abdominal pain (7.5\%). LIC (mg/g dry weight) decreased over time, with mean (SD) changes from baseline at each time point (year 1,~-2.64 [4.64]; year 2,~-3.91 [6.38]; year 3,~-6.64 [7.72], all P~\< .0001). Mean SF levels (μg/L) decreased significantly after year 2 (-771, P~= .0008) and year 3 (-1016, P~= .0420). Responder rates for LIC and SF increased each year (LIC: year 1, 46.5\%; year 2, 57.1\%; year 3, 66.1\%; SF: year 1, 35.2\%; year 2, 55.2\%; year 3, 70.9\%). Cardiac T2* remained normal in all patients. In conclusion, long-term therapy with deferiprone was not associated with new safety concerns and led to continued and progressive reduction in iron load in individuals with SCD or other anemias. The trial was registered at www.clinicaltrials.gov as $\#$NCT02443545.

}, attachments = {https://scholar.cu.edu.eg/sites/default/files/aieb/files/04-deferiprone_for_transfusional_iron_overload_in_sickle_cell_disease_and_other_anemias_open-label_study_of_up_to_3_year.pdf}, author = {Mohsen S. Elalfy and HAMDY, MONA and Amal El-Beshlawy and Ebeid, Fatma Se and Mohamed Badr and Kanter, Julie and Inusa, Baba and Adly, Amira A M and Williams, Suzan and Kilinc, Yurdanur and Lee, David and Fradette, Caroline and Rozova, Anna and Temin, Noemi Toiber and Tricta, Fernando and Kwiatkowski, Janet L} } @article {244644, title = {Egyptian Gaucher disease type 3 patients: a large cohort study spanning two decades (journal article)}, journal = {Journal of Rare Diseases}, volume = {2}, year = {2023}, pages = {1-6}, attachments = {https://scholar.cu.edu.eg/sites/default/files/aieb/files/s44162-023-00011-0-1.pdf}, author = {Amal El-Beshlawy and Khaled Abdel-Azim and Amina Abdel-Salam and Selim, Yasmeen M M and Said, Fadwa and Gebril, Nadine A and Fateen, Ekram and Pramod Mistry} } @article {244646, title = {Magnitude of cumulative iron overload correlates with the severity of anemia in untreated non-transfusion-dependent β-thalassemia.}, journal = {Annals of hematology}, volume = {102}, year = {2023}, pages = {467-469}, author = {Musallam, Khaled M and Maria Domenica Cappellini and Shahina Daar and Amal El-Beshlawy and Taher, Ali T} } @article {244643, title = {Clinical Characteristics, Molecular Background, and Survival of Egyptian Patients With Gaucher Disease Over a 20-Year Follow-up.}, journal = {Journal of pediatric hematology/oncology}, volume = {44}, year = {2022}, pages = {243-248}, abstract = {

This study analyzes the general disease characteristics, impact of enzyme replacement therapy (ERT), and overall survival (OS) of 156 Egyptian patients with Gaucher disease (GD) enrolled on hormone replacement from 1998 to 2017. The mean age at diagnosis was 32.46{\textpm}12.68 months. Anemia was noted at diagnosis in 50\%, thrombocytopenia in 30.7\%, severe splenomegaly in 58.7\%, severe hepatomegaly in 11.9\%, and skeletal findings were detected in 24.3\% of the patients. The most prevalent GD type was type 3 (54.5\%). Twenty-two of type 3 patients had no neurological manifestations at diagnosis, and 12 developed variable central nervous system manifestations during follow-up. The most common neurological features were limited eye movements, oculomotor apraxia, and squint. Of the 60 patients for whom genotypes were obtained, homozygous L444P was the most common (n=35/60, 58.3\%). Treatment with ERT (imiglucerase) revealed significant improvements in blood indices, organ volumes, and growth parameters (P\<0.05). Ten (11.7\%) type 3 patients did not develop any neurological manifestations under ERT over 20 years. Mortality was 16\%, and the 20-year OS was 73.3\%. We conclude that in Egypt, type 3 is the most prevalent phenotype of GD, and homozygous L444P is the predominant GBA genotype of GD. Early age at diagnosis and treatment with ERT over 20 years revealed significant improvements in disease manifestations, with an OS of 73.3\%.

}, author = {Amal El-Beshlawy and Abdel-Azim, Khaled and Amina Abdel-Salam and Gebril, Nadine A and Selim, Yasmeen M M and Said, Fadwa} } @article {211306, title = {Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study.}, journal = {Blood advances}, volume = {6}, year = {2022}, pages = {1243-1254}, abstract = {

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9\% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was -4.04 (0.48) mg/g dry weight for deferiprone vs -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01\% confidence interval, -0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1\% of patients), vomiting (14.5\%), pyrexia (9.2\%), increased alanine transferase (9.2\%) and aspartate transferase levels (9.2\%), neutropenia (2.6\%), and agranulocytosis (0.7\%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as $\#$NCT02041299.

}, author = {Kwiatkowski, Janet L and HAMDY, MONA and Amal El-Beshlawy and Ebeid, Fatma Se and Badr, Mohammed and Alshehri, Abdulrahman and Kanter, Julie and Inusa, Baba and Adly, Amira A M and Williams, Suzan and Kilinc, Yurdanur and Lee, David and Tricta, Fernando and Mohsen S. Elalfy} } @article {211304, title = {Genotype-phenotype associations in familial Mediterranean fever: a study of 500 Egyptian pediatric patients.}, journal = {Clinical rheumatology}, year = {2022}, abstract = {

INTRODUCTION: Familial Mediterranean fever (FMF) is the most prevalent monogenic autoinflammatory disease, caused by recessively inherited MEFV gene mutations. The most frequent MEFV mutations differ in penetrance and disease severity. We investigated the genotype-phenotype associations of the three most frequent MEFV gene mutations (M680I, M694V, and V726A) in Egyptian FMF children, regarding clinical features, severity, and colchicine response.

METHODS: We conducted a retrospective analysis of the medical registries of 500 FMF pediatric patients from Metropolitan Cairo between 2010 and 2015. The diagnosis was based on the Tel-Hashomer clinical diagnostic criteria. Clinical data and baseline investigations were collected. Mutation analysis was performed by the amplification-refractory mutation system (ARMS)-PCR method.

RESULTS: Males represented 54\% and ages ranged from 2 to 18~years. The most frequent symptoms were abdominal pain, fever, and arthralgia. Clinical features mostly associated with M694V mutation either homozygous or heterozygous whether simple, double, or triple. Of the patients, 94.6\% completely responded to colchicine. Among patients benefiting from colchicine, 42.5\% had M694V/V726A, 21.6\% had M694V/V726A/M680I, and 21.1\% had M694V genotype. Simple heterozygous M694V or V726A mutations conveyed a moderate phenotype in 57.1\% and 50\% of cases, respectively. Homozygous M694V mutation showed moderate and severe phenotypes in 21.7\% and 65.2\% of cases, respectively. Compound M694V/V726A mutation associated with moderate or severe disease in 48.3\% and 33.8\% of cases, respectively.

CONCLUSION: This study encompasses the largest group of Egyptian pediatric FMF up to date to explore their genotype-phenotype associations. Our results support the notion that the genotype influences the phenotype as regards clinical manifestations, disease severity, and colchicine response.

KEY POINTS: {\textbullet} This study encompasses the largest group of Egyptian pediatric patients affected by FMF up to date to explore their genotype-phenotype associations. {\textbullet} Our results support the notion that the genotype influences the phenotype as regards the clinical manifestations, the disease severity, and the response to colchicine treatment.

}, author = {Amal ElBeshlawy and Abdel Rahman Zekri and Ramadan, Manal S. and Selim, Yasmeen M M and Amina Abdel-Salam and Mohamed Tharwat Hegazy and Ragab, Lamis and Gaggiano, Carla and Cantarini, Luca and Ragab, Gaafar} } @article {244641, title = {Management of haemophilia A with inhibitors: A regional cross-talk.}, journal = {Haemophilia : the official journal of the World Federation of Hemophilia}, volume = {28}, year = {2022}, pages = {950-961}, abstract = {

INTRODUCTION: The development of inhibitors with factor VIII (FVIII) replacement therapy is one of the most common and challenging complications of haemophilia A (HA) treatment, jeopardising treatment efficacy and predisposing patients to high risks of morbidity and mortality. The management of patients with inhibitors is particularly challenging in countries where resources are limited.

AIM: To provide a comprehensive summary of the management of HA with inhibitors while focusing on differences in practice between Western and non-Western countries and how resource scarcity can impact HA management, leading to suboptimal outcomes in patients with inhibitors.

METHODS: Summary of key evidence and regional expert opinion.

RESULTS: We address, particularly, the diagnosis of and testing for inhibitors, as well as the epidemiology of inhibitors, including incidence, prevalence and disease burden. Secondly, we provide an overview of the current treatment landscape in HA with inhibitors regarding the eradication of inhibitors with immune tolerance induction and the treatment and prevention of bleeding with bypassing agents, non-factor replacement agents and other experimental therapies. This is complemented with insights from the authors around the applicability of, and challenges associated with, such therapies in their settings of practice.

CONCLUSIONS: We conclude by proposing some key steps towards bridging the gaps in the management of HA with inhibitors in resource-limited countries, including: (1) the collection of quality data that can inform healthcare reforms and policies; (2) improving disease knowledge among healthcare practitioners and patients with the aim of standardising disease management across centres and (3) working towards promoting equal access to HA care and therapies for everyone.

}, attachments = {https://scholar.cu.edu.eg/sites/default/files/aieb/files/haemophilia_-_2022_-_peyvandi_-_management_of_haemophilia_a_with_inhibitors_a_regional_cross-talk.pdf}, author = {Peyvandi, Flora and Kavakli, Kaan and Amal El-Beshlawy and Rangarajan, Savita} } @article {211302, title = {Navigating Hemostasis of Bleeding Among Children With β-Thalassemia.}, journal = {Journal of pediatric hematology/oncology}, year = {2022}, abstract = {

Bleeding phenotype is reported in β-thalassemia patients. However, the underlying etiology remains elusive. We aimed to assess coagulation profile and the platelet aggregation in β-thalassemia children with bleeding diathesis. Fifty β-thalassemia children with a positive bleeding history were recruited. Bleeding phenotype was explored through full history taking and thorough clinical examination. Complete blood count, prothrombin time, international normalized ratio, and platelets aggregometry were performed for children with negative workup. Mucosal bleeding was manifest among most of our patients (96\%). Two-third of patients had decreased aggregation with ristocetin (68\%), adenine di-phosphate (64\%), and arachidonic acid (64\%). While half of the patients (48\%) had deficient response to epinephrine. Collagen, ristocetin, and arachidonic acid induced aggregation were negatively correlated to frequency of blood transfusion (P=0.021, r=-0.325; P\<0.001, r=-0.465; P=0.018, r=-0.333, respectively). Aggregation to collagen and epinephrine demonstrated a negative correlation with age (P=0.04, r=-0.287; P=0.03, r=-0.315). Deferiprone was associated with a deficient response to ristocetin and collagen when compared with deferasirox or no chelation (P=0.021 and 0.006, respectively). Impaired ristocetin response was linked to hydroxyurea (P=0.035). Platelets function defect should be considered in β-thalassemia patients with bleeding symptoms.

}, author = {Amal El-Beshlawy and Rabah, Fatma and Hanan M. Hamed and Mahmoud, Amina Abdel-Salam and Al-Wakeel, Hanan A-H and Abdelhamid, Enas M and Marwa M. El-Sonbaty and El Sissy, Maha} } @article {211305, title = {Primary HBB gene mutation severity and long-term outcomes in a global cohort of β-thalassaemia.}, journal = {British journal of haematology}, volume = {196}, year = {2022}, pages = {414-423}, abstract = {

In β-thalassaemia, the severity of inherited β-globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long-term outcomes remain limited. We analysed data from 2109 β-thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as β /β , β /β , β /β , β /β , β /β , and β /β . Patients were followed from birth until death or loss to follow-up. The median follow-up time was 34{\textperiodcentered}1~years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, β and β mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with β /β , β /β , or β /β had a 2{\textperiodcentered}104-increased risk of death [95\% confidence interval (CI): 1{\textperiodcentered}176-3{\textperiodcentered}763, P~=~0{\textperiodcentered}011] and 2{\textperiodcentered}956-increased odds of multiple morbidity (95\% CI: 2{\textperiodcentered}310-3{\textperiodcentered}784, P~\<~0{\textperiodcentered}001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65~years were 36{\textperiodcentered}8\% for this subgroup compared with 90{\textperiodcentered}2\% for patients in lower genotype severity groups (P~\<~0{\textperiodcentered}001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with β-thalassaemia and suggests inclusion of both β and β mutations in strata of greatest severity.

}, author = {Musallam, Khaled M and Vitrano, Angela and Meloni, Antonella and Pollina, Sebastiano Addario and Di Marco, Vito and Ansari, Saqib Hussain and Filosa, Aldo and Ricchi, Paolo and Ceci, Adriana and Shahina Daar and Vlachaki, Efthymia and Singer, Sylvia T and Naserullah, Zaki A and Pepe, Alessia and Scondotto, Salvatore and Dardanoni, Gabriella and Karimi, Mehran and Amal El-Beshlawy and Hajipour, Mahmoud and Bonifazi, Fedele and Vichinsky, Elliott and Taher, Ali T and Sankaran, Vijay G and Maggio, Aurelio} } @article {244642, title = {Random Forest Clustering Identifies Three Subgroups of β-Thalassemia with Distinct Clinical Severity }, journal = {thalssemia reports}, volume = {12}, year = {2022}, pages = {14-23}, author = {Vitrano, Angela and Meloni, Antonella and Musallam, Khaled M and Pollina, Sebastiano Addario and Karimi, Mehran and Amal El-Beshlawy and Hajipour, Mahmoud and Di Marco, Vito and Ansari, Saqib Hussain and Filosa, Aldo and Ricchi, Paolo and Ceci, Adriana and Shahina Daar and Vlachaki, Efthymia and Singer, Sylvia Titi and Naserullah, Zaki A and Pepe, Alessia and Scondotto, Salvatore and Dardanoni, Gabriella and Bonifazi, Fedele and Sankaran, Vijay G and Vichinsky, Elliott and Taher, Ali T and Maggio, Aurelio and International Working Group on Thalassemia} } @article {211303, title = {Risk of mortality from anemia and iron overload in nontransfusion-dependent β-thalassemia.}, journal = {American journal of hematology}, volume = {97}, year = {2022}, pages = {E78-E80}, author = {Musallam, Khaled M and Vitrano, Angela and Meloni, Antonella and Pollina, Sebastiano Addario and Karimi, Mehran and Amal El-Beshlawy and Hajipour, Mahmoud and Di Marco, Vito and Ansari, Saqib Hussain and Filosa, Aldo and Ricchi, Paolo and Ceci, Adriana and Shahina Daar and Vlachaki, Efthymia and Singer, Sylvia Titi and Naserullah, Zaki A and Pepe, Alessia and Scondotto, Salvatore and Dardanoni, Gabriella and Bonifazi, Fedele and Sankaran, Vijay G and Vichinsky, Elliott and Taher, Ali T and Maggio, Aurelio} } @article {244639, title = {Transformative effect of a Humanitarian Program for individuals affected by rare diseases: building support systems and creating local expertise.}, journal = {Orphanet journal of rare diseases}, volume = {17}, year = {2022}, pages = {87}, abstract = {

Rare diseases affect \> 400 million people globally with a disproportionate burden falling on children, resulting in high morbidity and mortality rates. Affected individuals in some under-resourced countries have limited access to expert care or treatments; moreover, they suffer long diagnostic journeys during which debilitating and life-threatening complications occur. Lysosomal storage disorders (LSD) are prototype rare diseases due, in the main, to inherited deficiencies of lysosomal enzymes/transporters that affect up to 1 in 5000 newborns. Recognizing the need to provide treatment access to people with LSDs everywhere, a collaborative partnership was pioneered and set up 30~years ago. Partnering with local authorities, non-government organizations across six continents, local as well as international experts, a robust, sustainable Humanitarian Program emerged that now represents the most enduring charitable access program for LSD treatment. Here we present the history, process, lasting beneficial effect of the program to develop healthcare systems and infrastructures, and the lessons learned from addressing major unmet needs for LSDs.

}, attachments = {https://scholar.cu.edu.eg/sites/default/files/aieb/files/s13023-022-02192-1.pdf}, author = {Verma, I C and A. El-Beshlawy and Tylki-Szyma{\'n}ska, A and Martins, A and Duan, Y-L and Collin-Histed, T and van der Linde, M Schoneveld and Mansour, R and Dung, V C and Mistry, Pramod K} } @article {211307, title = {Clinical Characteristics, Molecular Background, and Survival of Egyptian Patients With Gaucher Disease Over a 20-Year Follow-up.}, journal = {Journal of pediatric hematology/oncology}, year = {2021}, abstract = {

This study analyzes the general disease characteristics, impact of enzyme replacement therapy (ERT), and overall survival (OS) of 156 Egyptian patients with Gaucher disease (GD) enrolled on hormone replacement from 1998 to 2017. The mean age at diagnosis was 32.46{\textpm}12.68 months. Anemia was noted at diagnosis in 50\%, thrombocytopenia in 30.7\%, severe splenomegaly in 58.7\%, severe hepatomegaly in 11.9\%, and skeletal findings were detected in 24.3\% of the patients. The most prevalent GD type was type 3 (54.5\%). Twenty-two of type 3 patients had no neurological manifestations at diagnosis, and 12 developed variable central nervous system manifestations during follow-up. The most common neurological features were limited eye movements, oculomotor apraxia, and squint. Of the 60 patients for whom genotypes were obtained, homozygous L444P was the most common (n=35/60, 58.3\%). Treatment with ERT (imiglucerase) revealed significant improvements in blood indices, organ volumes, and growth parameters (P\<0.05). Ten (11.7\%) type 3 patients did not develop any neurological manifestations under ERT over 20 years. Mortality was 16\%, and the 20-year OS was 73.3\%. We conclude that in Egypt, type 3 is the most prevalent phenotype of GD, and homozygous L444P is the predominant GBA genotype of GD. Early age at diagnosis and treatment with ERT over 20 years revealed significant improvements in disease manifestations, with an OS of 73.3\%.

}, author = {Amal El-Beshlawy and Abdel-Azim, Khaled and Amina Abdel-Salam and Gebril, Nadine A and Selim, Yasmeen M M and Said, Fadwa} } @article {205702, title = {A complication risk score to evaluate clinical severity of thalassaemia syndromes.}, journal = {British journal of haematology}, volume = {192}, year = {2021}, pages = {626-633}, abstract = {

The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion-dependent thalassaemia (TDT)], Group B [transfused non-TDT (NTDT)] and Group C (non-transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left-ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84{\textperiodcentered}5\%, 82{\textperiodcentered}1\% and 80{\textperiodcentered}0\% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients{\textquoteright} treatment.

}, author = {Vitrano, Angela and Meloni, Antonella and Pollina, Walter Addario and Karimi, Mehran and Amal El-Beshlawy and Hajipour, Mahmoud and Di Marco, Vito and Ansari, Saqib Hussain and Filosa, Aldo and Ricchi, Paolo and Ceci, Adriana and Shahina Daar and Singer, Sylvia Titi and Naserullah, Zaki A and Pepe, Alessia and Scondotto, Salvatore and Dardanoni, Gabriella and Bonifazi, Fedele and Vichinsky, Elliott and Maggio, Aurelio} } @article {223807, title = {Performance of a clinical risk prediction model for inhibitor formation in severe haemophilia A}, journal = {haemophilia}, volume = {27}, year = {2021}, pages = {e441-e449}, attachments = {https://scholar.cu.edu.eg/sites/default/files/aieb/files/haemophilia_-_2021_-_hassan_-_performance_of_a_clinical_risk_prediction_model_for_inhibitor_formation_in_severe_haemophilia_1.pdf}, author = {Amal El-Beshlawy} } @article {205704, title = {Performance of a clinical risk prediction model for inhibitor formation in severe haemophilia A.}, journal = {Haemophilia : the official journal of the World Federation of Hemophilia}, year = {2021}, abstract = {

BACKGROUND: There is a need to identify patients with haemophilia who have a very low or high risk of developing inhibitors. These patients could be candidates for personalized treatment strategies.

AIMS: The aim of this study was to externally validate a previously published prediction model for inhibitor development and to develop a new prediction model that incorporates novel predictors.

METHODS: The population consisted of 251 previously untreated or minimally treated patients with severe haemophilia A enrolled in the SIPPET study. The outcome was inhibitor formation. Model discrimination was measured using the C-statistic, and model calibration was assessed with a calibration plot. The new model was internally validated using bootstrap resampling.

RESULTS: Firstly, the previously published prediction model was validated. It consisted of three variables: family history of inhibitor development, F8 gene mutation and intensity of first treatment with factor VIII (FVIII). The C-statistic was 0.53 (95\% CI: 0.46-0.60), and calibration was limited. Furthermore, a new prediction model was developed that consisted of four predictors: F8 gene mutation, intensity of first treatment with FVIII, the presence of factor VIII non-neutralizing antibodies before treatment initiation and lastly FVIII product type (recombinant vs. plasma-derived). The C-statistic was 0.66 (95 CI: 0.57-0.75), and calibration was moderate. Using a model cut-off point of 10\%, positive- and negative predictive values were 0.22 and 0.95, respectively.

CONCLUSION: Performance of all prediction models was limited. However, the new model with all predictors may be useful for identifying a small number of patients with a low risk of inhibitor formation.

}, author = {Hassan, Shermarke and Palla, Roberta and Valsecchi, Carla and Garagiola, Isabella and Amal El-Beshlawy and Mohsen Elalfy and Ramanan, Vijay and Eshghi, Peyman and Karimi, Mehran and Gouw, Samantha Claudia and Mannucci, Pier Mannuccio and Rosendaal, Frits Richard and Peyvandi, Flora} } @article {223809, title = {Survival and causes of death in 2,033 patients with non-transfusion-dependent β-thalassemia}, journal = {Haematologica}, volume = {106}, year = {2021}, pages = {2489-2492}, attachments = {https://scholar.cu.edu.eg/sites/default/files/aieb/files/10251-article_text-75083-2-10-20210830_2.pdf}, author = {Amal El-Beshlawy} } @article {205701, title = {Survival and causes of death in 2033 patients with non-transfusion-dependent β-thalassemia.}, journal = {Haematologica}, year = {2021}, author = {Musallam, Khaled M and Vitrano, Angela and Meloni, Antonella and Pollina, Walter Addario and Karimi, Mehran and Amal El-Beshlawy and Hajipour, Mahmoud and Di Marco, Vito and Ansari, Saqib Hussain and Filosa, Aldo and Ricchi, Paolo and Ceci, Adriana and Shahina Daar and Vlachaki, Efthymia and Singer, Sylvia Titi and Naserullah, Zaki A and Pepe, Alessia and Scondotto, Salvatore and Dardanoni, Gabriella and Bonifazi, Fedele and Sankaran, Vijay G and Vichinsky, Elliott and Taher, Ali T and Maggio, Aurelio} } @article {223808, title = {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}, journal = {Lancet Haematol}, volume = {8}, year = {2021}, pages = {e323-e333}, attachments = {https://scholar.cu.edu.eg/sites/default/files/aieb/files/1-s20-s2352302621000594-main.pdf}, author = {Amal El-Beshlawy} } @article {205705, title = {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.}, journal = {The Lancet. Haematology}, volume = {8}, year = {2021}, pages = {e323-e333}, abstract = {

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{\textperiodcentered}5-10{\textperiodcentered}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{\textperiodcentered}0 g/dL (95\% CI 0{\textperiodcentered}7 to -1{\textperiodcentered}3) in the voxelotor 1500 mg group, 0{\textperiodcentered}5 g/dL (0{\textperiodcentered}3 to -0{\textperiodcentered}8) in the voxelotor 900 mg group, and 0{\textperiodcentered}0 g/dL (-0{\textperiodcentered}3 to 0{\textperiodcentered}3) in the placebo group, with a significant difference observed between the voxelotor 1500 mg group and the placebo group (p\<0{\textperiodcentered}0001), and between the voxelotor 900 mg group and the placebo group (p=0{\textperiodcentered}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{\textperiodcentered}6\% [95\% CI -40{\textperiodcentered}2 to -12{\textperiodcentered}9]) and percentage of reticulocytes (-18{\textperiodcentered}6\% [-33{\textperiodcentered}9 to -3{\textperiodcentered}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{\textperiodcentered}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.

}, author = {Howard, Jo and Ataga, Kenneth I and Brown, Robert C and Achebe, Maureen and Nduba, Videlis and Amal El-Beshlawy and Hoda Hassab and Agodoa, Irene and Tonda, Margaret and Gray, Sarah and Lehrer-Graiwer, Joshua and Vichinsky, Elliott} } @article {205700, title = {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.}, journal = {The Lancet. Haematology}, volume = {7}, year = {2020}, pages = {e469-e478}, abstract = {

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{\textperiodcentered}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 β-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{\textperiodcentered}2\%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54{\textperiodcentered}8\%] of 146 assigned deferasirox, difference 0{\textperiodcentered}4\%; 95\% CI -11{\textperiodcentered}9 to 12{\textperiodcentered}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.

}, author = {Maggio, Aurelio and Antonis Kattamis and Felisi, Mariagrazia and Reggiardo, Giorgio and Amal El-Beshlawy and Bejaoui, Mohamed and Sherief, Laila and Christou, Soteroula and Cosmi, Carlo and Della Pasqua, Oscar and Del Vecchio, Giovanni Carlo and Filosa, Aldo and Cuccia, Liana and Hoda Hassab and Kreka, Manika and Origa, Raffaella and Putti, Maria Caterina and Spino, Michael and Telfer, Paul and Tempesta, Bianca and Vitrano, Angela and Tsang, Yu Chung and Zaka, Ariana and Tricta, Fernando and Bonifazi, Donato and Ceci, Adriana} } @article {205710, title = {Jaw bones{\textquoteright} involvement and dental features of type I and type III Gaucher disease: a radiographic study of 42 paediatric patients.}, journal = {European archives of paediatric dentistry : official journal of the European Academy of Paediatric Dentistry}, volume = {21}, year = {2020}, pages = {241-247}, abstract = {

PURPOSE: Gaucher disease (GD) is a lysosomal storage disease caused by an autosomal recessive inherited deficiency of the lysosomal enzyme glucocerebrosidase. The aim of this study is to describe jaw bones{\textquoteright} involvement and dental radiographic features in paediatric Gaucher disease patients (type I and type III).

METHODS: The study population of this case-control study included: 42 Gaucher patients (study group) and 84 medically free children (control group). The radiographic images of both groups were analysed for the following findings: generalised bone rarefaction, localised rarefaction and enlarged bone marrow spaces, thinning of cortex, pseudocystic radiolucent lesions, anodontia and dental anomalies. Dental age assessment of Gaucher patients using the Demirjian{\textquoteright}s method was also performed.

RESULTS: Generalised rarefaction showed almost similar percentages in both types of Gaucher disease cases. Localised rarefaction was noted in 30.77\% and 18.75\% of Gaucher disease type III and type I, respectively. Pseudocystic radiolucent lesions, thinning of cortex, anodontia and dental anomalies were more prevalent in type III Gaucher patients. The mean chronological and mean dental ages in both sexes of Gaucher patients were not statistically significant.

CONCLUSION: Thinning of cortex, localised rarefaction and generalised rarefaction are the most common jaw bone findings in Gaucher patients.

}, author = {Y S A Mohamed and MK Zayet and O M Omar and A M El-Beshlawy} } @article {205699, title = {A study of red blood cell alloimmunization and autoimmunization among 200 multitransfused Egyptian β thalassemia patients.}, journal = {Scientific reports}, volume = {10}, year = {2020}, pages = {21079}, abstract = {

The development of hemolytic erythrocyte alloantibodies and autoantibodies complicates transfusion therapy in thalassemia patients.~These antibodies ultimately increase the need for blood and intensify transfusion complications. There is a scanty data on the frequency of RBC alloimmunization and autoimmunization in Egyptian β thalassemia patients as pretransfusion antibody screening is not routinely performed. We studied the frequency of alloimmunization and autoimmunization among 200 multiply transfused β thalassemia patients and investigated the factors that possibly affect antibody formation. Of the 200 patients in our study, 94 were males and 106 females, with the age range of 2-37~years. Alloantibodies were detected in 36 (18\%) of the patients, while autoantibodies were detected in 33 (16.5\%). The dominant alloantibodies were directed against Kell (33\%) and Rh (24.4\%) groups. Alloimmunization had a significant relationship with treatment duration and the frequency of transfusion (P = 0.007, 0.001, respectively). The presence of autoantibodies was significantly related to age (P = 0.001), total number of transfused units (P = 0.000) and splenectomy (P = 0.000). The high prevalence of alloimmunization in the study population disclosed the need for providing phenotypically matched cells for selective antigens especially for Kell and Rh subgroups to reduce risk of alloimmunization and increase the efficiency of blood transfusion.

}, author = {Amal El-Beshlawy and Salama, Alshymaa Ahmed and El-Masry, Mohamed Roshdy and Noha M ElHusseiny and Asmaa M Abdelhameed} } @article {205708, title = {Addendum to Letter to the Editor: Safety, efficacy, and authorization of eliglustat as a first-line therapy in Gaucher disease type 1.}, journal = {Blood cells, molecules \& diseases}, volume = {77}, year = {2019}, pages = {101-102}, author = {Mistry, Pramod K and Balwani, Manisha and Baris, Hagit N and Turkia, Hadhami Ben and Burrow, T Andrew and Charrow, Joel and Cox, Gerald F and Danda, Sumita and Dragosky, Marta and Drelichman, Guillermo and Amal El-Beshlawy and Fraga, Cristina and Freisens, Selena and Gaemers, Sebastiaan and Hadjiev, Evgueniy and Kishnani, Priya S and Lukina, Elena and Maison-Blanche, Pierre and Martins, Ana Maria and Pastores, Gregory and Petakov, Milan and Peterschmitt, M Judith and Rosenbaum, Hanna and Rosenbloom, Barry and Underhill, Lisa H and Cox, Timothy M} } @article {205707, title = {International sentinel site surveillance of patients with transfusional hemosiderosis treated with deferasirox in actual practice setting.}, journal = {Hematology (Amsterdam, Netherlands)}, volume = {24}, year = {2019}, pages = {238-246}, abstract = {

OBJECTIVE: The study evaluates the long-term deferasirox treatment of adult and pediatric patients with chronic transfusional iron overload in clinical practice.

METHODS: In this non-interventional study, patients were observed for up to 3 years from initiation of deferasirox treatment both prospectively and retrospectively for up to 1 year prior to enrollment. The primary end points were the proportion of patients with >=1 notable increase in serum creatinine (SCr), and >=1 notable increase in alanine aminotransferase (ALT).

RESULTS: Overall, 120 patients were enrolled and 51 completed the study, with a limited 3-year dropout rate of 12.5\% due to adverse events (AEs). Increase in SCr \> 33\% above baseline and the age-adjusted ULN (upper limit of normal) was observed in 14 patients (95\%CI, 7.1-19.2). The ALT levels \>5 {\texttimes} ULN was observed in 1 patient. Most frequent AEs reported during treatment with deferasirox include gastrointestinal disturbances.

CONCLUSIONS: The long-term treatment with deferasirox was manageable in most transfusion-dependent patients with no unexpected safety findings. Regular monitoring and an adjusted deferasirox dosing strategy per local labels allowed continued iron chelation treatment and control of transfusional iron in the majority of patients on study.

}, author = {Amal El-Beshlawy and Inusa, Baba and Beneitez Pastor, David and Xicoy, Blanca and Soledada Duran Nieto, Maria and Bruederle, Andreas and Azmon, Amin and Gilotti, Geralyn and Mohsen Elalfy} } @article {211300, title = {A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease.}, journal = {The New England journal of medicine}, volume = {381}, year = {2019}, pages = {509-519}, abstract = {

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 Sβ-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.).

}, author = {Vichinsky, Elliott and Hoppe, Carolyn C and Ataga, Kenneth I and Ware, Russell E and Nduba, Videlis and Amal El-Beshlawy and Hoda Hassab and Achebe, Maureen M and Alkindi, Salam and Brown, R Clark and Diuguid, David L and Telfer, Paul and Tsitsikas, Dimitris A and Elghandour, Ashraf and Gordeuk, Victor R and Kanter, Julie and Abboud, Miguel R and Lehrer-Graiwer, Joshua and Tonda, Margaret and Intondi, Allison and Tong, Barbara and Howard, Jo} } @article {205706, title = {Recent trends in treatment of thalassemia.}, journal = {Blood cells, molecules \& diseases}, volume = {76}, year = {2019}, pages = {53-58}, abstract = {

Thalassemia is a common inherited monogenic disease. It is characterized by chronic hemolysis, ineffective erythropoiesis (IE) and iron overload. Despite advances in transfusion practices and chelation therapy, still many limitations in delivering these standard therapies exist. Challenges of currently available standard care and advances in understanding the underlying pathophysiological mechanisms in thalassemia stimulated research towards development of novel therapeutic targets. Agents reducing IE as Jak 2 inhibitors and Activin II receptor traps are promising and are currently in clinical trials. Other approaches targeting iron dysregulation as mini-hepcidins, exogenous transferrin and erythroferrone inhibitors are in preclinical studies. Gene therapy, a rapidly evolving field, has exhibited remarkable progress in recent years. Studies have focused on β or γ-globin addition, over expression of endogenous γ-globin-activating transcription factors, silencing of γ-globin repressors and genome editing of β-globin mutations or γ-globin repressors. In this article we provide an overview of emerging recent trends in treatment of thalassemia targeting IE, iron dysregulation and novel curative treatments as gene therapy and gene editing.

}, author = {Amal El-Beshlawy and Mona El-Ghamrawy} } @article {211309, title = {Reversal of life-threatening hepatopulmonary syndrome in Gaucher disease by imiglucerase enzyme replacement therapy.}, journal = {Molecular genetics and metabolism reports}, volume = {20}, year = {2019}, pages = {100490}, abstract = {

Advanced liver disease complicated by hepatopulmonary syndrome is a recognized complication of Gaucher disease. Macrophage-targeted, recombinant enzyme replacement therapy is effective in reversing clinical manifestations attributed to the accumulation of glycolipid-laden macrophages but it is not known whether advanced fibrotic features of the disease can be ameliorated. We describe a splenectomized patient with Gaucher disease who developed massive hepatomegaly, cirrhosis of the liver and life-threatening hepatopulmonary syndrome. Treatment with Imiglucerase enzyme replacement therapy resulted in dramatic reversal of hepatopulmonary syndrome and liver disease. Our report suggests that Gaucher disease pathology involving advanced fibrosis and life-threatening complications can be reversed by imiglucerase enzyme therapy.

Synopsis: Effect of imiglucerase enzyme replacement therapy on Hepatopulmonary Syndrome in Gaucher Disease.

}, author = {Amal ElBeshlawy and Murugesan, Vagishwari and Mistry, Pramod Kumar and Khaled Eid} } @article {211308, title = {Role of factor VIII-binding capacity of endogenous von Willebrand factor in the development of factor VIII inhibitors in patients with severe hemophilia A.}, journal = {Haematologica}, volume = {104}, year = {2019}, pages = {e369-e372}, author = {Repess{\'e}, Yohann and Costa, Catherine and Palla, Roberta and Moshai, Elika Farrokhi and Borel-Derlon, Annie and D{\textquoteright}Oiron, Roseline and Rothschild, Chantal and Amal El-Beshlawy and Mohsen Elalfy and Ramanan, Vijay and Eshghi, Peyman and Oldenburg, Johannes and Pavlova, Anna and Rosendaal, Frits R and Peyvandi, Flora and Kaveri, Srinivas V and Lacroix-Desmazes, S{\'e}bastien} } @article {205712, title = {Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {16}, year = {2018}, pages = {778-790}, abstract = {

Essentials A residual factor VIII synthesis is likely to be protective towards inhibitor (INH) development. Mutation type-inhibitor risk association was explored in 231 patients with severe hemophilia A. A 2-fold increase in INH development for in silico null vs. non-null mutations was found. A 3.5-fold increase in INH risk for antigen negative vs. antigen positive mutations was found.

SUMMARY: Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type-inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95\% confidence interval [CI] 0.84-5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95\% CI 0.89-14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance.

}, author = {Spena, S and Garagiola, I and Cannav{\`o}, A and Mortarino, M and Mannucci, P M and Rosendaal, F R and Peyvandi, F} } @article {211299, title = {Safety, efficacy, and authorization of eliglustat as a first-line therapy in Gaucher disease type 1.}, journal = {Blood cells, molecules \& diseases}, volume = {71}, year = {2018}, pages = {71-74}, author = {Mistry, Pramod K and Balwani, Manisha and Baris, Hagit N and Turkia, Hadhami Ben and Burrow, T Andrew and Charrow, Joel and Cox, Gerald F and Danda, Sumita and Dragosky, Marta and Drelichman, Guillermo and Amal El-Beshlawy and Fraga, Cristina and Freisens, Selena and Gaemers, Sebastiaan and Hadjiev, Evgueniy and Kishnani, Priya S and Lukina, Elena and Maison-Blanche, Pierre and Martins, Ana Maria and Pastores, Gregory and Petakov, Milan and Peterschmitt, M Judith and Rosenbaum, Hanna and Rosenbloom, Barry and Underhill, Lisa H and Cox, Timothy M} } @article {150453, title = {Long-term safety and efficacy of deferasirox in young pediatric patients with transfusional hemosiderosis: Results from a 5-year observational study (ENTRUST).}, journal = {Pediatric blood \& cancer}, volume = {64}, year = {2017}, month = {2017 Sep}, abstract = {

BACKGROUND: Children with red blood cell disorders may receive regular transfusions from an early age and consequently accumulate iron. Adequate iron chelation therapy can prevent organ damage and delayed growth/development. Deferasirox is indicated for treatment of pediatric patients with chronic iron overload due to transfusional hemosiderosis; however, fewer than 10\% of patients in the registration studies were aged 2 to less than 6 years.

PROCEDURE: Deferasirox, a once-daily oral iron chelator, was evaluated in young pediatric patients with transfusional hemosiderosis during the observational 5-year ENTRUST study. Patients aged 2 to less than 6 years at enrollment received deferasirox according to local prescribing information, with the primary objective of evaluating safety, specifically renal and hepatic function. Serum ferritin was observed as a surrogate efficacy parameter.

RESULTS: In total, 267 patients (mean age 3.2 years) predominantly with β-thalassemia (n = 176, 65.9\%) were enrolled. Mean {\textpm} standard deviation deferasirox dose was 25.8 {\textpm} 6.5 mg/kg per day over a median of 59.9 months. A total of 145 patients (54.3\%) completed 5 years{\textquoteright} treatment. The proportion of patients with two or more consecutive postbaseline measurements (>=7 days apart) of serum creatinine higher than age-adjusted upper limit of normal (ULN) and alanine aminotransferase more than five times the ULN was 4.4\% (95\% confidence interval [CI]: 2.1-7.9) and 4.0\% (95\% CI: 1.8-7.4), respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5~years. There were no new safety signals.

CONCLUSIONS: Safety and efficacy of deferasirox in young pediatric patients in this long-term, observational study in everyday clinical practice were consistent with the known deferasirox profile.

}, keywords = {Benzoates, Chelation Therapy, Child, Preschool, Female, Hematologic Diseases, Hemosiderosis, Humans, Iron Chelating Agents, Male, Transfusion Reaction, Triazoles}, issn = {1545-5017}, doi = {10.1002/pbc.26507}, author = {Vichinsky, Elliott and Amal El-Beshlawy and Al Zoebie, Azzam and Kamdem, Annie and Koussa, Suzanne and Chotsampancharoen, Thirachit and Bruederle, Andreas and Gilotti, Geralyn and Han, Jackie and Mohsen Elalfy} } @article {150454, title = {A multicenter, open-label, phase III study of Abcertin in Gaucher disease.}, journal = {Medicine}, volume = {96}, year = {2017}, month = {2017 Nov}, pages = {e8492}, abstract = {

BACKGROUND: Gaucher disease (GD) is caused by a deficiency in the lysosomal enzyme glucocerebrosidase. Enzyme replacement therapy (ERT) is recommended for clinical improvement.

METHODS: The efficacy and safety of a new imiglucerase, Abcertin, were assessed in 7 Egyptian patients with treatment-na{\"\i}ve type 1 GD. Each patient was administered a biweekly 60 U/kg dose of Abcertin for 6 months. The primary endpoint was the change in hemoglobin concentration. The secondary endpoints were changes from baseline in platelet counts, spleen and liver volumes, biomarker levels, skeletal parameters, and bone mineral density.

RESULTS: The hemoglobin concentration increased by a mean of 1.96 {\textpm} 0.91 g/dL (range 1.11-2.80 g/dL) or 20.6\% (P = .001). Statistically significant increases in the platelet count and decreases in the spleen volume and biomarker levels were also observed. There were no severe drug-related adverse events. One patient developed anti-imiglucerase antibodies without neutralizing activity.

CONCLUSION: Our study results demonstrate the efficacy and safety of Abcertin in patients with type 1 GD. This suggests that Abcertin can be an alternative ERT option for type 1 GD.

}, keywords = {Adolescent, Area Under Curve, Biomarkers, Bone Density, Child, Child, Preschool, Egypt, Enzyme Replacement Therapy, Gaucher Disease, Glucosylceramidase, Half-Life, Hemoglobins, Humans, Liver, Male, Metabolic Clearance Rate, Organ Size, Recombinant Proteins, Spleen}, issn = {1536-5964}, doi = {10.1097/MD.0000000000008492}, author = {Lee, Beom Hee and Abdalla, Ahmed Fathy and Choi, Jin-Ho and Amal ElBeshlawy and Kim, Gu-Hwan and Heo, Sun Hee and Megahed, Ahmed Megahed Hassan and Elsayed, Mona Abdel Latif and Barakat, Tarik El-Sayed Mohammad and Eid, Khaled Mohamed Abd El-Azim and El-Tagui, Mona Hassan and Mahmoud, Mona Mohamed Hamdy and Fateen, Ekram and Park, June-Young and Yoo, Han-Wook} } @article {128861, title = {Limitations of serum ferritin to predict liver iron concentration responses to deferasirox therapy in patients with transfusion-dependent thalassaemia.}, journal = {European journal of haematology}, volume = {98}, year = {2017}, month = {2017 Mar}, pages = {280-288}, abstract = {

BACKGROUND: In transfusion-dependent anaemias, while absolute serum ferritin levels broadly correlate with liver iron concentration (LIC), relationships between trends in these variables are unclear. These relationships are important because serum ferritin changes are often used to adjust or switch chelation regimens when liver magnetic resonance imaging (MRI) is unavailable.

OBJECTIVES AND METHODS: This post hoc analysis of the EPIC study compared serum ferritin and LIC in 317 patients with transfusion-dependent thalassaemia before and after 1 yr of deferasirox.

RESULTS: Serum ferritin responses (decreases) occurred in 73\% of patients, 80\% of whom also have decreased LIC. However, 52\% of patients without a serum ferritin response did decrease LIC and by \>1 mg Fe/g dw (median 3.9) in 77\% of cases. Absolute serum ferritin and LIC values correlated significantly only when serum ferritin was \<4000 ng/mL (r = 0.59; P \< 0.0001) and not at higher levels (>=4000 ng/mL; r = 0.19). Serum ferritin response was accompanied by decreased LIC in 89\% and 70\% of cases when serum ferritin was \<4000 or >=4000 ng/mL, respectively.

CONCLUSIONS: As serum ferritin non-response was associated with LIC decrease in over half of patients, use of liver MRI may be particularly useful for differentiating true from apparent non-responders to deferasirox based on serum ferritin trends alone.

}, keywords = {Adolescent, Adult, Benzoates, Biomarkers, Blood Transfusion, Chelation Therapy, Child, Child, Preschool, Female, Ferritins, Humans, Iron, Iron Chelating Agents, Iron Overload, Liver, Male, Middle Aged, Prognosis, ROC Curve, Thalassemia, Treatment Outcome, Triazoles, Young Adult}, issn = {1600-0609}, doi = {10.1111/ejh.12830}, author = {John B. Porter and Mohsen Elalfy and Ali Taher and Yesim Aydinok and Lee, Szu-Hee and Sutcharitchan, Pranee and Ali El-Ali and Han, Jackie and Amal El-Beshlawy} } @article {150451, title = {Long-term hematological, visceral, and growth outcomes in children with Gaucher disease type 3 treated with imiglucerase in the International Collaborative Gaucher Group Gaucher Registry.}, journal = {Molecular genetics and metabolism}, volume = {120}, year = {2017}, month = {2017 Jan - Feb}, pages = {47-56}, abstract = {

In Gaucher disease (GD), deficiency of lysosomal acid β-glucosidase results in a broad phenotypic spectrum that is classified into three types based on the absence (type 1 [GD1]) or presence and severity of primary central nervous system involvement (type 2 [GD2], the fulminant neuronopathic form, and type 3 [GD3], the milder chronic neuronopathic form). Enzyme replacement therapy (ERT) with imiglucerase ameliorates and prevents hematological and visceral manifestations in GD1, but data in GD3 are limited to small, single-center series. The effects of imiglucerase ERT on hematological, visceral and growth outcomes (note: ERT is not expected to directly impact neurologic outcomes) were evaluated during the first 5years of treatment in 253 children and adolescents (\<18years of age) with GD3 enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. The vast majority of GBA mutations in this diverse global population consisted of only 2 mutations: L444P (77\%) and D409H (7\%). At baseline, GD3 patients exhibited early onset of severe hematological and visceral disease and growth failure. During the first year of imiglucerase treatment, hemoglobin levels and platelet counts increased and liver and spleen volumes decreased, leading to marked decreases in the number of patients with moderate or severe anemia, thrombocytopenia, and hepatosplenomegaly. These improvements were maintained through Year 5. There was also acceleration in linear growth as evidenced by increasing height Z-scores. Despite devastating disease at baseline, the probability of surviving for at least 5years after starting imiglucerase was 92\%. In this large, multinational cohort of pediatric GD3 patients, imiglucerase ERT provided a life-saving and life-prolonging benefit for patients with GD3, suggesting that, with proper treatment, many such severely affected patients can lead productive lives and contribute to society.

}, keywords = {Adolescent, Child, Child, Preschool, Enzyme Replacement Therapy, Female, Gaucher Disease, Glucosylceramidase, Humans, Male, Mutation, Registries, Survival Analysis, Treatment Outcome}, issn = {1096-7206}, doi = {10.1016/j.ymgme.2016.12.001}, author = {Amal El-Beshlawy and Tylki-Szymanska, Anna and Vellodi, Ashok and Belmatoug, Nadia and Grabowski, Gregory A and Kolodny, Edwin H and Batista, Julie L and Cox, Gerald F and Mistry, Pramod K} } @article {150455, title = {Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy.}, journal = {Blood}, volume = {129}, year = {2017}, month = {2017 04 27}, pages = {2375-2383}, abstract = {

In the phase 3 Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE), at 1 year, eliglustat was noninferior to imiglucerase enzyme therapy in maintaining stable platelet counts, hemoglobin concentrations, and spleen and liver volumes. After this primary analysis period, patients entered a long-term extension phase in which all received eliglustat. Duration on eliglustat ranged from 2 to 5 years, depending on timing of enrollment (which spanned 2 years), treatment group to which patients were randomized, and whether they lived in the United States when commercial eliglustat became available. Here we report long-term safety and efficacy of eliglustat for 157 patients who received eliglustat in the ENCORE trial; data are available for 46 patients who received eliglustat for 4 years. Mean hemoglobin concentration, platelet count, and spleen and liver volumes remained stable for up to 4 years. Year to year, all 4 measures remained collectively stable (composite end point relative to baseline values) in >=85\% of patients as well as individually in >=92\%. Mean bone mineral density z scores (lumbar spine and femur) remained stable and were maintained in the healthy reference range throughout. Eliglustat was well tolerated over 4 years; 4 (2.5\%) patients withdrew because of adverse events that were considered related to the study drug. No new or long-term safety concerns were identified. Clinical stability assessed by composite and individual measures was maintained in adults with Gaucher disease type 1 treated with eliglustat who remained in the ENCORE trial for up to 4 years. This trial was registered at www.clinicaltrials.gov as $\#$NCT00943111.

}, keywords = {Administration, Oral, Adult, Bone Density, Enzyme Inhibitors, Enzyme Replacement Therapy, Female, Femur, Gaucher Disease, Glucosylceramidase, Humans, Liver, Lumbar Vertebrae, Male, Middle Aged, Platelet Count, Pyrrolidines, Recombinant Proteins, Spleen}, issn = {1528-0020}, doi = {10.1182/blood-2016-12-758409}, author = {Cox, Timothy M and Drelichman, Guillermo and Cravo, Renata and Balwani, Manisha and Burrow, Thomas Andrew and Martins, Ana Maria and Lukina, Elena and Rosenbloom, Barry and Goker-Alpan, Ozlem and Watman, Nora and Amal El-Beshlawy and Kishnani, Priya S and Pedroso, Maria Lucia and Gaemers, Sebastiaan J M and Tayag, Regina and Peterschmitt, M Judith} } @article {150452, title = {Telomerase enzyme activity in Egyptian children with bone marrow failure and response to immunosuppressive therapy.}, journal = {Blood cells, molecules \& diseases}, volume = {63}, year = {2017}, month = {2017 03}, pages = {58-61}, issn = {1096-0961}, doi = {10.1016/j.bcmd.2017.01.012}, author = {Amal ElBeshlawy and Said, Fadwa and Mervat El Ansary and HAMDY, MONA and Abdel-Azim, Khalid and Abdel-Razek, Abdel-Rahman A and Abulata, Nelly and Amina Abdel-Salam} } @article {117501, title = {A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.}, journal = {The New England journal of medicine}, volume = {374}, year = {2016}, month = {2016 May 26}, pages = {2054-64}, abstract = {

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy.

METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age \<6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites.

RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (>=5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8\% (95\% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5\% (95\% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6\% (95\% CI, 11.2 to 26.0) and 28.4\% (95\% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87\% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95\% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95\% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95\% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95\% CI, 1.11 to 6.00).

CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

}, keywords = {Adolescent, Adult, Aged, Antibodies, Neutralizing, Child, Child, Preschool, Dose-Response Relationship, Drug, Drug Therapy, Combination, Factor VIII, Hemophilia A, Hemorrhage, Humans, Incidence, Infant, Injections, Subcutaneous, Isoantibodies, Male, Middle Aged, Proportional Hazards Models, von Willebrand factor, Young Adult}, issn = {1533-4406}, doi = {10.1056/NEJMoa1516437}, author = {Peyvandi, Flora and Mannucci, Pier M and Garagiola, Isabella and Amal El-Beshlawy and Mohsen Elalfy and Ramanan, Vijay and Eshghi, Peyman and Hanagavadi, Suresh and Varadarajan, Ramabadran and Karimi, Mehran and Manglani, Mamta V and Ross, Cecil and Young, Guy and Seth, Tulika and Apte, Shashikant and Nayak, Dinesh M and Santagostino, Elena and Mancuso, Maria Elisa and Sandoval Gonzalez, Adriana C and Mahlangu, Johnny N and Bonanad Boix, Santiago and Cerqueira, Monica and Ewing, Nadia P and Male, Christoph and Owaidah, Tarek and Soto Arellano, Veronica and Kobrinsky, Nathan L and Majumdar, Suvankar and Perez Garrido, Rosario and Sachdeva, Anupam and Simpson, Mindy and Thomas, Mathew and Zanon, Ezio and Antmen, Bulent and Kavakli, Kaan and Manco-Johnson, Marilyn J and Martinez, Monica and Marzouka, Esperanza and Mazzucconi, Maria G and Neme, Daniela and Palomo Bravo, Angeles and Paredes Aguilera, Rogelio and Prezotti, Alessandra and Schmitt, Klaus and Wicklund, Brian M and Zulfikar, Bulent and Rosendaal, Frits R} } @article {117503, title = {Erratum to: Response to hydroxycarbamide in pediatric β-thalassemia intermedia: 8 years{\textquoteright} follow-up in Egypt.}, journal = {Annals of hematology}, volume = {95}, year = {2016}, month = {2016 Apr}, pages = {851}, issn = {1432-0584}, doi = {10.1007/s00277-016-2635-9}, author = {Amal El-Beshlawy and Mona El-Ghamrawy and Mona Abou El-Ela and Said, Fadwa and Sonia Adolf and Abdel-Rahman Ahmed Abdel-Razek and Rania Ismail Magdy and Amina Abdel-Salam} } @article {107856, title = {Prevalence and distribution of iron overload in patients with transfusion-dependent anemias differs across geographic regions: results from the CORDELIA study.}, journal = {European journal of haematology}, volume = {95}, year = {2015}, month = {2015 Sep}, pages = {244-53}, abstract = {

OBJECTIVES: The randomized comparison of deferasirox to deferoxamine for myocardial iron removal in patients with transfusion-dependent anemias (CORDELIA) gave the opportunity to assess relative prevalence and body distribution of iron overload in screened patients.

METHODS: Patients aged >= 10 yr with transfusion-dependent anemias from 11 countries were screened. Data were summarized descriptively, overall and across regions.

RESULTS: Among 925 patients (99.1\% with β-thalassemia major; 98.5\% receiving prior chelation; mean age 19.2 yr), 36.7\% had myocardial iron overload (myocardial T2* <= 20 ms), 12.1\% had low left ventricular ejection fraction. Liver iron concentration (LIC) (mean 25.8 mg Fe/g dw) and serum ferritin (median 3702 ng/mL) were high. Fewer patients in the Middle East (ME; 28.5\%) had myocardial T2* <= 20 ms vs. patients in the West (45.9\%) and Far East (FE, 40.9\%). Patients in the West had highest myocardial iron burden, but lowest LIC (26.9\% with LIC \< 7 mg Fe/g dw) and serum ferritin. Among patients with normal myocardial iron, a higher proportion of patients from the ME and FE had LIC >= 15 than \< 7 mg Fe/g dw (ME, 56.7\% vs. 17.2\%; FE, 78.6\% vs. 7.8\%, respectively), a trend which was less evident in the West (44.6\% vs. 33.9\%, respectively). Transfusion and chelation practices differed between regions.

CONCLUSIONS: Evidence of substantial myocardial and liver iron burden across regions revealed a need for optimization of effective, convenient iron chelation regimens. Significant regional variation exists in myocardial and liver iron loading that are not well explained; improved understanding of factors contributing to differences in body iron distribution may be of clinical benefit.

}, issn = {1600-0609}, doi = {10.1111/ejh.12487}, author = {Yesim Aydinok and John B. Porter and Piga, Antonio and Mohsen Elalfy and Amal El-Beshlawy and Kilin{\c c}, Yurdanur and Vip Viprakasit and Yesilipek, Akif and Dany Habr and Quebe-Fehling, Erhard and Dudley J. Pennell} } @article {107866, title = {Early detection of right ventricular diastolic dysfunction by pulsed tissue Doppler echocardiography in iron loaded beta thalassemia patients.}, journal = {Pediatric cardiology}, volume = {36}, year = {2015}, month = {2015 Mar}, pages = {468-74}, abstract = {

Early heart iron overload in beta thalassemia major patients can be quantified through T2* cardiovascular magnetic resonance (CMR). To clarify the value of tissue Doppler imaging (TDI) in early detection of myocardial dysfunction in iron loaded thalassemia patients diagnosed by CMR. Two groups were included in the study; Group I: 69 asymptomatic thalassemia patients (28 females, 41 males), mean age 18.1~{\textpm}~7.03 years (range 6-39~years); Group II (n~=~41) healthy normal controls matched for age and sex. Serum ferritin and CMR were performed to assess the cardiac siderosis (T2*~\<~20~ms). Group I was subdivided into two subgroups; Group Ia (n~=~26) T2*~\<~20~ms and Group Ib (n~=~43) T2*~\>~20~ms. Conventional and Doppler echocardiography of LV, RV dimensions and functions and pulmonary artery pressure were evaluated. Right ventricular diastolic function assessed by tricuspid annular E{\textquoteright}/A{\textquoteright} was positively correlated with T2* value; lower tricuspid E{\textquoteright}/A{\textquoteright} ratios were correlated with lower T2* values (r~=~0.366, P~=~0.002). Tricuspid annular A{\textquoteright} was significantly higher in group Ia compared to group Ib (16.7~{\textpm}~5.2 vs 12.1~{\textpm}~4.0~cm/s, P~\<~0.001). Tricuspid E{\textquoteright}/A{\textquoteright}~\<~1 was common in group Ia compared to group Ib (19/26 (73.0) vs 3/43 (6.97\%), P~\<~0.001). By multivariate analysis, right ventricular diastolic dysfunction (tricuspid E{\textquoteright}/A{\textquoteright}~\<~1) was associated with serum ferritin and T2* level of the thalassemia patients. TDI is a promising tool for quantitative assessment of myocardial function and early detection of right ventricular diastolic dysfunction in iron loaded beta thalassemia major patients.

}, keywords = {Adolescent, Adult, beta-Thalassemia, Cardiomyopathies, Case-Control Studies, Child, Diastole, Echocardiography, Doppler, Pulsed, Female, Ferritins, Hemosiderosis, Humans, Magnetic Resonance Imaging, Male, Ventricular Function, Right, Young Adult}, issn = {1432-1971}, doi = {10.1007/s00246-014-1035-y}, author = {Agha, Hala Mounir and Amal Beshlawy and HAMDY, MONA and Sobeih, Alae and Zahrae, Fatma El and Abd El Satar, Inas Abd and AbdelMassih, Antoine and Said, Fadwa and Aziz, Ossama Abd El and Mona El Tagui and Dudley J. Pennell} } @article {107855, title = {Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload.}, journal = {Blood}, volume = {125}, year = {2015}, month = {2015 Jun 18}, pages = {3868-77}, abstract = {

Deferasirox (DFX) monotherapy is effective for reducing myocardial and liver iron concentrations (LIC), although some patients may require intensive chelation for a limited duration. HYPERION, an open-label single-arm prospective phase 2 study, evaluated combination DFX-deferoxamine (DFO) in patients with severe transfusional myocardial siderosis (myocardial [m] T2* 5-\<10 ms; left ventricular ejection fraction [LVEF] >=56\%) followed by optional switch to DFX monotherapy when achieving mT2* \>10 ms. Mean dose was 30.5 mg/kg per day DFX and 36.3 mg/kg per day DFO on a 5-day regimen. Geometric mean mT2* ratios (Gmeanmonth12/24/Gmeanbaseline) were 1.09 and 1.30, respectively, increasing from 7.2 ms at baseline (n = 60) to 7.7 ms at 12 (n = 52) and 9.5 ms at 24 months (n = 36). Patients (17 of 60; 28.3\%) achieved mT2* >=10 ms and >=10\% increase from baseline at month 24; 15 switched to monotherapy during the study based on favorable mT2*. LIC decreased substantially from a baseline of 33.4 to 12.8 mg Fe/g dry weight at month 24 (-52\%). LVEF remained stable with no new arrhythmias/cardiac failure. Five patients discontinued with mT2* \<5 ms and 1 died (suspected central nervous system infection). Safety was consistent with established monotherapies. Results show clinically meaningful improvements in mT2* in about one-third of patients remaining on treatment at month 24, alongside rapid decreases in LIC in this heavily iron-overloaded, difficult-to-treat population. Combination therapy may be useful when rapid LIC reduction is required, regardless of myocardial iron overload. This trial was registered at www.clinicaltrials.gov as $\#$NCT01254227.

}, keywords = {Adolescent, Adult, Benzoates, Blood Transfusion, Child, Deferoxamine, Female, Heart, Humans, Iron Chelating Agents, Iron Overload, Liver, Male, Myocardium, Siderophores, Triazoles, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2014-07-586677}, author = {Yesim Aydinok and Antonis Kattamis and Cappellini, M Domenica and Amal El-Beshlawy and Origa, Raffaella and Mohsen Elalfy and Kilin{\c c}, Yurdanur and Perrotta, Silverio and Karakas, Zeynep and Vip Viprakasit and Dany Habr and Constantinovici, Niculae and Shen, Junwu and John B. Porter} } @article {107859, title = {Peripheral expression of hepcidin gene in Egyptian β-thalassemia major.}, journal = {Gene}, volume = {564}, year = {2015}, month = {2015 Jun 15}, pages = {206-9}, abstract = {

Iron overload is the major cause of morbidity and mortality in transfusion dependent β-thalassemia major patients. There is a sophisticated balance of body iron metabolism of storage and transport which is regulated by several factors including the peptide hepcidin. Hepcidin is the main iron regulatory molecule; it is secreted mainly by the liver and other tissues including monocytes and lymphocytes. Expression of hepcidin in such cells is unclear and has been studied in few reports with controverted result. Peripheral expression of hepcidin was measured using quantitative real time PCR (qRT-PCR) in 50 β-thalassemia major patients, in addition to 20 healthy volunteers as a control group. Hepcidin levels in β-thalassemia major patients showed statistically significant decrease in comparison to the control group, and was correlated to cardiac iron stores (T2*). However, hepcidin level was not different among the patients according to the HCV status or whether splenectomized or not. In conclusion; peripheral expression of hepcidin, in iron overloaded β-thalassemia major patients, is a reflection of hepatic expression. It can be used as a molecular predictor for the severity of cardiac iron overload and can be used as a future target for therapy in β-thalassemia major patients.

}, keywords = {Adolescent, Adult, beta-Thalassemia, Child, Egypt, Female, Hepcidins, Humans, Iron Overload, Liver, Lymphocytes, Male, Monocytes, Real-Time Polymerase Chain Reaction, Young Adult}, issn = {1879-0038}, doi = {10.1016/j.gene.2015.03.048}, author = {Azza Aboul-Enein and Amal El-Beshlawy and HAMDY, MONA and Iman Shaheen and Zainab El-Saadany and Ahmed Samir and Hala Abd El-Samie} } @article {107853, title = {Sustained improvements in myocardial T2* over 2 years in severely iron-overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine.}, journal = {American journal of hematology}, volume = {90}, year = {2015}, month = {2015 Feb}, pages = {91-6}, abstract = {

Long-term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion-dependent beta thalassemia patients. In a 1-year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving deferasirox for 24 months (n = 74; geometric mean [Gmean ] ratio of month 24/baseline 1.38 [95\% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; Gmean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* \< 10 vs. >= 10 ms) or liver (LIC \<15 vs. >=15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 {\textpm} 18.0 to 14.4 {\textpm} 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 {\textpm} 15.6 to 11.0 {\textpm} 12.1 mg Fe/g dw in DFO patients. The long-term safety profile of deferasirox or DFO was consistent with previous reports; serious drug-related AEs were reported in 6.8\% of deferasirox and 6.9\% of DFO patients. Continued treatment of severely iron-overloaded beta thalassemia patients with deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron (Clinicaltrials.gov identifier: NCT00600938).

}, keywords = {Adolescent, Adult, Benzoates, beta-Thalassemia, Blood Transfusion, Chelation Therapy, Child, Deferoxamine, Female, Humans, Iron, Iron Chelating Agents, Iron Overload, Liver, Male, Myocardium, Prospective Studies, Treatment Outcome, Triazoles}, issn = {1096-8652}, doi = {10.1002/ajh.23876}, author = {Dudley J. Pennell and John B. Porter and Piga, Antonio and Lai, Yong-Rong and Amal El-Beshlawy and Mohsen Elalfy and Yesilipek, Akif and Kilin{\c c}, Yurdanur and Dany Habr and Musallam, Khaled M and Shen, Junwu and Yesim Aydinok} } @article {107860, title = {Serum ferritin level and morbidity risk in transfusion-independent patients with β-thalassemia intermedia: the ORIENT study.}, journal = {Haematologica}, volume = {99}, year = {2014}, month = {2014 Nov}, pages = {e218-21}, keywords = {beta-Thalassemia, Ferritins, Humans, Iron Overload, morbidity, risk}, issn = {1592-8721}, doi = {10.3324/haematol.2013.097220}, author = {Musallam, Khaled M and Maria Domenica Cappellini and Shahina Daar and Karimi, Mehran and Amal El-Beshlawy and Graziadei, Giovanna and Magestro, Matthew and Wulff, Jerome and Pietri, Guilhem and Taher, Ali T} } @article {107857, title = {A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA).}, journal = {Blood}, volume = {123}, year = {2014}, month = {2014 Mar 6}, pages = {1447-54}, abstract = {

Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 β-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95\% confidence interval [CI], 0.998, 1.133). The lower 95\% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4\%) and deferoxamine (30.8\%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as $\#$NCT00600938.

}, keywords = {Adolescent, Adult, Benzoates, beta-Thalassemia, Child, Deferoxamine, Female, Ferritins, Heart, Humans, Iron, Iron Chelating Agents, Iron Overload, Male, Medication Adherence, Myocardium, Treatment Outcome, Triazoles, Troponin T, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2013-04-497842}, author = {Dudley J. Pennell and John B. Porter and Piga, Antonio and Lai, Yongrong and Amal El-Beshlawy and Belhoul, Khawla M and Mohsen Elalfy and Yesilipek, Akif and Kilin{\c c}, Yurdanur and Lawniczek, Tomasz and Dany Habr and Weisskopf, Marianne and Zhang, Yiyun and Yesim Aydinok} } @article {117513, title = {Low prevalence of cardiac siderosis in heavily iron loaded Egyptian thalassemia major patients.}, journal = {Annals of hematology}, volume = {93}, year = {2014}, month = {2014 Mar}, pages = {375-9}, abstract = {

Myocardial siderosis in thalassemia major remains the leading cause of death in developing countries. Once heart failure develops, the outlook is usually poor with precipitous deterioration and death. Cardiovascular magnetic resonance (CMR) can measure cardiac iron deposition directly using the magnetic relaxation time T2*. This allows earlier diagnosis and treatment and helps to reduce mortality from this cardiac affection. This study aims to determine the prevalence of cardiac siderosis in Egyptian patients who are heavily iron loaded and its relation to liver iron concentration, serum ferritin, and left ventricular ejection fraction. Eighty-nine β-thalassemia patients receiving chelation therapy (mean age of 20.8 {\textpm} 6.4 years) were recruited in this study. Tissue iron levels were determined by CMR with cardiac T2* and liver R2*. The mean {\textpm} standard deviation (range) of cardiac T2* was 28.5 {\textpm} 11.7 ms (4.3 to 53.8 ms), the left ventricular ejection fraction (LVEF) was 67.7 {\textpm} 4.7 \% (55 to 78 \%), and the liver iron concentration (LIC) was 26.1 {\textpm} 13.4 mg Fe/g dry weight (dw) (1.5 to 56 mg Fe/g dw). The mean serum ferritin was 4,510 {\textpm} 2,847 ng/ml (533 to 22,360 ng/ml), and in 83.2 \%, the serum ferritin was \>2,500 ng/ml. The prevalence of myocardial siderosis (T2* of \<20 ms) was 24.7 \% (mean age 20.9 {\textpm} 7.5 years), with mean T2* of 12.7 {\textpm} 4.4 ms, mean LVEF of 68.6 {\textpm}5.8 \%, mean LIC of 30.9 {\textpm} 13 mg Fe/g dw, and median serum ferritin of 4,996 ng/ml. There was no correlation between T2* and age, LVEF, LIC, and serum ferritin (P = 0.65, P = 0.085, P = 0.99, and P = 0.63, respectively). Severe cardiac siderosis (T2* of \<10 ms) was present in 7.9 \%, with a mean age of 18.4 {\textpm} 4.4 years. Although these patients had a mean T2* of 7.8 {\textpm} 1.7 ms, the LVEF was 65.1 {\textpm} 6.2 \%, and only one patient had heart failure (T2* of 4.3 ms and LVEF of 55 \%). LIC and serum ferritin results were 29.8 {\textpm} 17.0 mg/g and 7,200 {\textpm} 6,950 ng/ml, respectively. In this group of severe cardiac siderosis, T2* was also not correlated to age (P = 0.5), LVEF (P = 0.14), LIC (P = 0.97), or serum ferritin (P = 0.82). There was a low prevalence of myocardial siderosis in the Egyptian thalassemia patients in spite of very high serum ferritin and high LIC. T2* is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy. The possibility of a genetic component for the resistance to cardiac iron loading in our population should be considered.

}, keywords = {Adolescent, Adult, beta-Thalassemia, Blood Transfusion, Cardiomyopathies, Chelation Therapy, Child, Cohort Studies, Egypt, Ferritins, Heart Failure, Heart Ventricles, Hemosiderosis, Hospitals, Pediatric, Humans, Iron, Liver, Magnetic Resonance Imaging, Prevalence, Stroke Volume, Young Adult}, issn = {1432-0584}, doi = {10.1007/s00277-013-1876-0}, author = {Amal ElBeshlawy and Mona El Tagui and HAMDY, MONA and Mona El Ghamrawy and Azim, Khaled Abdel and Salem, Doria and Said, Fadwa and Ahmed Samir and St Pierre, Timothy and Dudley J. Pennell} } @article {107858, title = {Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration.}, journal = {Magnetic resonance in medicine}, volume = {71}, year = {2014}, month = {2014 Jun}, pages = {2215-23}, abstract = {

PURPOSE: Magnetic resonance imaging (MRI)-based techniques for assessing liver iron concentration (LIC) have been limited by single scanner calibration against biopsy. Here, the calibration of spin-density projection-assisted (SDPA) R2-MRI (FerriScan{\textregistered}) in iron-overloaded β-thalassemia patients treated with the iron chelator, deferasirox, for 12 months is validated.

METHODS: SDPA R2-MRI measurements and percutaneous needle liver biopsy samples were obtained from a subgroup of patients (n = 233) from the ESCALATOR trial. Five different makes and models of scanner were used in the study.

RESULTS: LIC, derived from mean of MRI- and biopsy-derived values, ranged from 0.7 to 50.1 mg Fe/g dry weight. Mean fractional differences between SDPA R2-MRI- and biopsy-measured LIC were not significantly different from zero. They were also not significantly different from zero when categorized for each of the Ishak stages of fibrosis and grades of necroinflammation, for subjects aged 3 to \<8 versus >=8 years, or for each scanner model. Upper and lower 95\% limits of agreement between SDPA R2-MRI and biopsy LIC measurements were 74 and -71\%.

CONCLUSION: The calibration curve appears independent of scanner type, patient age, stage of liver fibrosis, grade of necroinflammation, and use of deferasirox chelation therapy, confirming the clinical usefulness of SDPA R2-MRI for monitoring iron overload.

}, keywords = {Adolescent, Adult, Benzoates, Biopsy, Needle, Calibration, Chelation Therapy, Child, Child, Preschool, Female, Humans, Iron, Iron Chelating Agents, Iron Overload, Liver, Magnetic Resonance Imaging, Male, Prospective Studies, Treatment Outcome, Triazoles}, issn = {1522-2594}, doi = {10.1002/mrm.24854}, author = {St Pierre, Tim G and Amal El-Beshlawy and Mohsen Elalfy and Abdullah Al Jefri and Kusai Al Zir and Shahina Daar and Dany Habr and Ulrike Kriemler-Krahn and Ali Taher} } @article {117515, title = {Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration.}, journal = {Magnetic resonance in medicine}, volume = {71}, year = {2014}, month = {2014 Jun}, pages = {2215-23}, abstract = {

PURPOSE: Magnetic resonance imaging (MRI)-based techniques for assessing liver iron concentration (LIC) have been limited by single scanner calibration against biopsy. Here, the calibration of spin-density projection-assisted (SDPA) R2-MRI (FerriScan{\textregistered}) in iron-overloaded β-thalassemia patients treated with the iron chelator, deferasirox, for 12 months is validated.

METHODS: SDPA R2-MRI measurements and percutaneous needle liver biopsy samples were obtained from a subgroup of patients (n = 233) from the ESCALATOR trial. Five different makes and models of scanner were used in the study.

RESULTS: LIC, derived from mean of MRI- and biopsy-derived values, ranged from 0.7 to 50.1 mg Fe/g dry weight. Mean fractional differences between SDPA R2-MRI- and biopsy-measured LIC were not significantly different from zero. They were also not significantly different from zero when categorized for each of the Ishak stages of fibrosis and grades of necroinflammation, for subjects aged 3 to \<8 versus >=8 years, or for each scanner model. Upper and lower 95\% limits of agreement between SDPA R2-MRI and biopsy LIC measurements were 74 and -71\%.

CONCLUSION: The calibration curve appears independent of scanner type, patient age, stage of liver fibrosis, grade of necroinflammation, and use of deferasirox chelation therapy, confirming the clinical usefulness of SDPA R2-MRI for monitoring iron overload.

}, keywords = {Adolescent, Adult, Benzoates, Biopsy, Needle, Calibration, Chelation Therapy, Child, Child, Preschool, Female, Humans, Iron, Iron Chelating Agents, Iron Overload, Liver, Magnetic Resonance Imaging, Male, Prospective Studies, Treatment Outcome, Triazoles}, issn = {1522-2594}, doi = {10.1002/mrm.24854}, author = {St Pierre, Tim G and Amal El-Beshlawy and Mohsen Elalfy and Abdullah Al Jefri and Kusai Al Zir and Shahina Daar and Dany Habr and Ulrike Kriemler-Krahn and Ali Taher} } @article {117510, title = {A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.}, journal = {American journal of hematology}, volume = {89}, year = {2014}, month = {2014 Jul}, pages = {709-13}, abstract = {

This placebo-controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), a fetal globin gene-inducing short-chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12-55 years) and 37 subjects (49\%) were treated previously with hydroxycarbamide. Sixty subjects (79\%) had Hb SS and 16 (21\%) had S/β(0) thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK-1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9\% (95\% confidence interval (CI): 0.1-1.6\%) with HQK-1001 and 0.2\% (95\% CI: -0.7-1.1\%) with placebo. Absolute increases in Hb F greater than 3\% were noted in 9 of 38 subjects (24\%) administered HQK-1001 and 1 of 38 subjects (3\%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK-1001 and 1.7 with placebo. The most common adverse events in the HQK-1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK-1001 at this dose and schedule are not recommended in SCD. Intermittent HQK-1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation.

}, keywords = {Administration, Oral, Adolescent, Adult, Anemia, Sickle Cell, Antisickling Agents, Butyrates, Child, Dose-Response Relationship, Drug, Double-Blind Method, Female, Fetal Hemoglobin, Humans, Male, Middle Aged, Placebos, Young Adult}, issn = {1096-8652}, doi = {10.1002/ajh.23725}, author = {Reid, Marvin E and Amal ElBeshlawy and Inati, Adlette and Kutlar, Abdullah and Abboud, Miguel R and Haynes, Johnson and Ward, Richard and Sharon, Bruce and Taher, Ali T and Smith, Wally and Manwani, Deepa and Ghalie, Richard G} } @article {117508, title = {Response to hydroxycarbamide in pediatric β-thalassemia intermedia: 8 years{\textquoteright} follow-up in Egypt.}, journal = {Annals of hematology}, volume = {93}, year = {2014}, month = {2014 Dec}, pages = {2045-50}, abstract = {

Hydroxycarbamide (hydroxyurea or HU) has been shown to increase fetal hemoglobin (HbF) in patients with β-thalassemia intermedia (TI). The reported effects of HU in increasing the total hemoglobin (Hb) have been inconsistent. Studies of long-term therapy with HU in pediatric TI are rather uncommon. A retrospective observational study was carried out to evaluate the clinical responses to HU in Egyptian patients with β-TI. One hundred patients; children (n = 82, mean age 9.9 {\textpm} 4.1 years) and adults (n = 18) were studied for the mean Hb, HbF\%, median serum ferritin, transfusion history, and splenic size before and after HU therapy (mean dose 20.0 {\textpm} 4.2 mg/kg/day, range 10-29 mg/kg/day) over a follow-up period 4 to 96 months (mean 35.4 {\textpm} 19.2 months). Molecular studies were also done for group of patients (n = 42). The overall response rate to HU was 79 \%; 46 \% were minor responders (with a reduction in transfusion rate by 50 \% or more and/or an increase in their total hemoglobin level by 1-2 g/dl) and 33 \% major responders (becoming transfusion-free and/or having an increase in total hemoglobin level by \>2 g/dl). Mean hemoglobin increased among responders from 6.9 {\textpm} 0.9 g/dl to 8.3 {\textpm} 1.4 g/dl (p \< 0.001). A significant rise in mean HbF (27.0 vs. 42.5 \%; p \< 0.011) and a decrease in median serum ferritin (800 vs. 644 ng/ml; p \< 0.001) were also observed among responders (n = 45). Transfusions stopped in 44 \% of pretreatment frequently transfused responders (n = 11/25). Splenic size decreased in 37 \% of patients (n = 30/81). The predominant β-thalassemia mutation was 1-6 (T \> C) in 32/42 (76 \%) of studied patients; 28/32 were responders. Bivariate analysis showed no predictors of response as regards sex, pediatric and adult age, splenic status, or genotype. Hydroxycarbamide is a good therapeutic modality in the management of pediatric as in adult TI patients. It can minimize the need for blood transfusion, concomitant iron overload, and blood-born viral transmission especially in developing countries like Egypt.

}, keywords = {Adolescent, Adult, Age Factors, beta-Thalassemia, Blood Transfusion, Child, Child, Preschool, Combined Modality Therapy, Drug Evaluation, Egypt, Ferritins, Fetal Hemoglobin, Humans, Hydroxyurea, Iron Overload, neutropenia, Retrospective Studies, Splenectomy, Splenomegaly, Treatment Outcome, Young Adult}, issn = {1432-0584}, doi = {10.1007/s00277-014-2154-5}, author = {Amal El-Beshlawy and Mona El-Ghamrawy and Mona Abou El-Ela and Said, Fadwa and Sonia Adolf and Abdel-Rahman Ahmed Abdel-Razek and Rania Ismail Magdy and Amina Abdel-Salam} } @article {107865, title = {Continuation of deferiprone therapy in patients with mild neutropenia may not lead to a more severe drop in neutrophil count.}, journal = {European journal of haematology}, volume = {92}, year = {2014}, month = {2014 Apr}, pages = {337-40}, abstract = {

Approximately 6\% of patients with thalassemia receiving deferiprone develop neutropenia. Present practice is to monitor absolute neutrophil count (ANC) weekly and to interrupt treatment at the first sign of neutropenia, lest continuation lead to progressive neutrophil reduction. In a 6-month study evaluating the safety and efficacy of a liquid form of deferiprone in 100 children, ANC was initially checked weekly for all patients. For individuals experiencing mild neutropenia, deferiprone was continued but monitoring was increased to daily until resolution. Therapy was to be suspended only if the episode was prolonged or if it worsened. Four patients experienced single episodes of mild neutropenia, and two others each experienced two episodes. All eight episodes resolved within 4-7~d despite continued therapy. (One patient later developed agranulocytosis and had treatment terminated.) This study showed that not all cases of mild neutropenia during deferiprone therapy develop into agranulocytosis, and suggests that many may not be caused by deferiprone. Transient declines in ANC to levels defined as neutropenic are common even in healthy individuals, particularly children; and it could be that the frequent monitoring of ANC mandated during deferiprone therapy may reveal cases of transient neutropenia that would otherwise have gone undetected and resolved on their own without clinical consequences. In patients with thalassemia, several factors increase the probability of a transient fall in ANC. These findings raise the question of whether deferiprone should be routinely stopped in cases of mild neutropenia, provided that such patients have their ANC monitored more frequently during the neutropenic episode.

}, keywords = {beta-Thalassemia, Child, Child, Preschool, Female, Humans, Iron Chelating Agents, leukocyte count, Male, neutropenia, Neutrophils, Pyridones}, issn = {1600-0609}, doi = {10.1111/ejh.12241}, author = {El-Beshlawy, Amal M and El-Alfy, Mohsen S and Sari, Teny T and Chan, Lee L and Tricta, Fernando} } @article {117516, title = {International survey of T2* cardiovascular magnetic resonance in β-thalassemia major.}, journal = {Haematologica}, volume = {98}, year = {2013}, month = {2013 Sep}, pages = {1368-74}, abstract = {

Accumulation of myocardial iron is the cause of heart failure and early death in most transfused thalassemia major patients. T2* cardiovascular magnetic resonance provides calibrated, reproducible measurements of myocardial iron. However, there are few data regarding myocardial iron loading and its relation to outcome across the world. A survey is reported of 3,095 patients in 27 worldwide centers using T2* cardiovascular magnetic resonance. Data on baseline T2* and numbers of patients with symptoms of heart failure at first scan (defined as symptoms and signs of heart failure with objective evidence of left ventricular dysfunction) were requested together with more detailed information about patients who subsequently developed heart failure or died. At first scan, 20.6\% had severe myocardial iron (T2*<= 10 ms), 22.8\% had moderate myocardial iron (T2* 10-20 ms) and 56.6\% of patients had no iron loading (T2*\>20 ms). There was significant geographical variation in myocardial iron loading (24.8-52.6\%; P\<0.001). At first scan, 85 (2.9\%) of 2,915 patients were reported to have heart failure (81.2\% had T2* \<10 ms; 98.8\% had T2* \<20 ms). During follow up, 108 (3.8\%) of 2,830 patients developed new heart failure. Of these, T2* at first scan had been less than 10 ms in 96.3\% and less than 20 ms in 100\%. There were 35 (1.1\%) cardiac deaths. Of these patients, myocardial T2* at first scan had been less than 10 ms in 85.7\% and less than 20 ms in 97.1\%. Therefore, in this worldwide cohort of thalassemia major patients, over 43\% had moderate/severe myocardial iron loading with significant geographical differences, and myocardial T2* values less than 10 ms were strongly associated with heart failure and death.

}, keywords = {beta-Thalassemia, Cohort Studies, Data Collection, Heart Failure, Humans, Internationality, Iron Overload, Magnetic Resonance Imaging, Cine}, issn = {1592-8721}, doi = {10.3324/haematol.2013.083634}, author = {Carpenter, John-Paul and Roughton, Michael and Dudley J. Pennell} } @article {117514, title = {A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.}, journal = {American journal of hematology}, volume = {88}, year = {2013}, month = {2013 Nov}, pages = {E255-60}, abstract = {

2,2-Dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S/β(0) thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg/kg (n = 15), 40 mg/kg (n = 18) and 50 mg/kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48\%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80\%), and 12 (23\%) had increases >=4\%. The mean increase in Hb F was 2\% [95\% confidence interval (CI), 0.8-3.2\%] in 21 subjects receiving HQK-1001 alone and 2.7\% (95\% CI, 1.7-3.8\%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95\% CI, 0.5-1.0 g/dL), and 13 subjects (25\%) had increases >=1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. .

}, keywords = {Administration, Oral, Adolescent, Adult, Anemia, Sickle Cell, Antisickling Agents, beta-Thalassemia, Butyrates, Child, Cohort Studies, Dose-Response Relationship, Drug, Female, Fetal Hemoglobin, Gastritis, Hematinics, Heterozygote, Humans, Hydroxyurea, Incidence, Male, Middle Aged, Patient Dropouts, Promoter Regions, Genetic, Sickle Cell Trait, Up-Regulation, Young Adult}, issn = {1096-8652}, doi = {10.1002/ajh.23533}, author = {Kutlar, Abdullah and Reid, Marvin E and Inati, Adlette and Taher, Ali T and Abboud, Miguel R and Amal El-Beshlawy and Buchanan, George R and Smith, Hedy and Ataga, Kenneth I and Perrine, Susan P and Ghalie, Richard G} } @article {117517, title = {Intrafamilial transmission of hepatitis C infection in Egyptian multitransfused thalassemia patients.}, journal = {Journal of tropical pediatrics}, volume = {59}, year = {2013}, month = {2013 Aug}, pages = {309-13}, abstract = {

OBJECTIVE: Detecting the current prevalence of hepatitis C virus (HCV) among Egyptian multitransfused thalassemic patients and evaluating the risk of its transmission within their family members.

METHODS: Multitransfused Egyptian thalassemia patients (n = 137) were tested for HCV infection. Household contacts of positive members were compared with household contacts of HCV-negative patients. Antibodies to HCV were detected by enzyme immunoassay. Antibody-positive cases were retested for viral load using reverse transcriptase polymerase chain reaction. HCV genotyping was performed on positive samples of the patients and the positive household contacts.

RESULTS: In all, 34.4\% of patients (n = 47) were positive for HCV antibodies and RNA. The study of 24 families of HCV-positive patients showed 14 affected family members (19.2\%). In 27 families of HCV-negative patients, four family members were affected (4.9\%). HCV genotyping of seven families was similar in both patients and their family members.

CONCLUSION: Our results support the role of intrafamilial transmission in the spread of HCV.

}, keywords = {Adolescent, Adult, Blood Transfusion, Child, Contact Tracing, Egypt, Enzyme-Linked Immunosorbent Assay, Family, Family Health, Female, Genotype, Hepacivirus, Hepatitis C, Hepatitis C Antibodies, Humans, Middle Aged, Prevalence, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, RNA, Viral, Thalassemia, Viral Load, Young Adult}, issn = {1465-3664}, doi = {10.1093/tropej/fmt017}, author = {Said, Fadwa and Amal ElBeshlawy and HAMDY, MONA and El Raziky, Mona and Sherif, Mai and Abdel kader, Ahmed and Ragab, Lamis} } @article {117518, title = {Intrafamilial transmission of hepatitis C infection in Egyptian multitransfused thalassemia patients.}, journal = {Journal of tropical pediatrics}, volume = {59}, year = {2013}, month = {2013 Aug}, pages = {309-13}, abstract = {

OBJECTIVE: Detecting the current prevalence of hepatitis C virus (HCV) among Egyptian multitransfused thalassemic patients and evaluating the risk of its transmission within their family members.

METHODS: Multitransfused Egyptian thalassemia patients (n = 137) were tested for HCV infection. Household contacts of positive members were compared with household contacts of HCV-negative patients. Antibodies to HCV were detected by enzyme immunoassay. Antibody-positive cases were retested for viral load using reverse transcriptase polymerase chain reaction. HCV genotyping was performed on positive samples of the patients and the positive household contacts.

RESULTS: In all, 34.4\% of patients (n = 47) were positive for HCV antibodies and RNA. The study of 24 families of HCV-positive patients showed 14 affected family members (19.2\%). In 27 families of HCV-negative patients, four family members were affected (4.9\%). HCV genotyping of seven families was similar in both patients and their family members.

CONCLUSION: Our results support the role of intrafamilial transmission in the spread of HCV.

}, keywords = {Adolescent, Adult, Blood Transfusion, Child, Contact Tracing, Egypt, Enzyme-Linked Immunosorbent Assay, Family, Family Health, Female, Genotype, Hepacivirus, Hepatitis C, Hepatitis C Antibodies, Humans, Middle Aged, Prevalence, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, RNA, Viral, Thalassemia, Viral Load, Young Adult}, issn = {1465-3664}, doi = {10.1093/tropej/fmt017}, author = {Said, Fadwa and Amal ElBeshlawy and HAMDY, MONA and El Raziky, Mona and Sherif, Mai and Abdel kader, Ahmed and Ragab, Lamis} } @article {117520, title = {Revised recommendations for the management of Gaucher disease in children.}, journal = {European journal of pediatrics}, volume = {172}, year = {2013}, month = {2013 Apr}, pages = {447-58}, abstract = {

UNLABELLED: Gaucher disease is an inherited pan-ethnic disorder that commonly begins in childhood and is caused by deficient activity of the lysosomal enzyme glucocerebrosidase. Two major phenotypes are recognized: non-neuropathic (type 1) and neuropathic (types 2 and 3). Symptomatic children are severely affected and manifest growth retardation, delayed puberty, early-onset osteopenia, significant splenomegaly, hepatomegaly, thrombocytopenia, anemia, severe bone pain, acute bone crises, and fractures. Symptomatic children with types 1 or 3 should receive enzyme replacement therapy, which will prevent debilitating and often irreversible disease progression and allow those with non-neuropathic disease to lead normal healthy lives. Children should be monitored every 6 months (physical exam including growth, spleen and liver volume, neurologic exam, hematologic indices) and have one to two yearly skeletal assessments (bone density and imaging, preferably with magnetic resonance, of lumbar vertebrae and lower limbs), with specialized cardiovascular monitoring for some type 3 patients. Response to treatment will determine the frequency of monitoring and optimal dose of enzyme replacement. Treatment of children with type 2 (most severe) neuropathic Gaucher disease is supportive. Pre-symptomatic children, usually with type 1 Gaucher, increasingly are being detected because of affected siblings and screening in high-prevalence communities. In this group, annual examinations (including bone density) are recommended. However, monitoring of asymptomatic children with affected siblings should be guided by the age and severity of manifestations in the first affected sibling. Treatment is necessary only if signs and symptoms develop.

CONCLUSION: Early detection and treatment of symptomatic types 1 and 3 Gaucher disease with regular monitoring will optimize outcome. Pre-symptomatic children require regular monitoring. Genetic counseling is important.

}, keywords = {Absorptiometry, Photon, beta-Glucosidase, Child, Child, Preschool, Clinical Protocols, Disease Progression, Enzyme Replacement Therapy, Gaucher Disease, Genetic Counseling, Glucosylceramidase, Humans}, issn = {1432-1076}, doi = {10.1007/s00431-012-1771-z}, author = {Kaplan, Paige and Baris, Hagit and De Meirleir, Linda and Di Rocco, Maja and Amal El-Beshlawy and Huemer, Martina and Martins, Ana Maria and Nascu, Ioana and Rohrbach, Marianne and Steinbach, Lynne and Cohen, Ian J} } @article {117521, title = {Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with β-thalassemia major.}, journal = {Haematologica}, volume = {97}, year = {2012}, month = {2012 Jun}, pages = {842-8}, abstract = {

BACKGROUND: Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important.

DESIGN AND METHODS: Seventy-one patients in the EPIC cardiac substudy elected to continue into the 3(rd) year, allowing cardiac iron removal to be analyzed over three years.

RESULTS: Mean deferasirox dose during year 3 was 33.6 {\textpm} 9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms {\textpm} 39.1\% at baseline to 17.1 ms {\textpm} 62.0\% at end of study (P\<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43 {\textpm} 1.2 mg Fe/g dry weight (dw) at baseline to 1.80 {\textpm} 1.4 mg Fe/g dw at end of study (P\<0.001). After three years, 68.1\% of patients with baseline T2* 10 to \<20 ms normalized (>= 20 ms) and 50.0\% of patients with baseline T2* \>5 to \<10 ms improved to 10 to \<20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drug-related adverse event in year 3 was increased serum creatinine (n = 9, 12.7\%).

CONCLUSIONS: Three years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1\% (32 of 47) of patients with T2* 10 to \<20 ms.

}, keywords = {Adolescent, Adult, Benzoates, beta-Thalassemia, Blood Transfusion, Cardiomyopathies, Chelation Therapy, Child, Drug Administration Schedule, Heart, Humans, Iron, Iron Chelating Agents, Iron Overload, Longitudinal Studies, Magnetic Resonance Angiography, Triazoles}, issn = {1592-8721}, doi = {10.3324/haematol.2011.049957}, author = {Dudley J. Pennell and John B. Porter and Maria Domenica Cappellini and Lee Lee Chan and Amal El-Beshlawy and Yesim Aydinok and Hishamshah Ibrahim and Chi-Kong Li and Vip Viprakasit and Mohsen S. Elalfy and Antonis Kattamis and Gillian Smith and Dany Habr and Gabor Domokos and Bernard Roubert and Ali Taher} } @article {117519, title = {Study of serum hepcidin in hereditary hemolytic anemias.}, journal = {Hemoglobin}, volume = {36}, year = {2012}, month = {2012}, pages = {555-70}, abstract = {

The aim of this study was to assess the level of hepcidin in hereditary chronic hemolytic anemias and to correlate the serum hepcidin levels to the need for blood transfusions (frequency of blood transfusions and the serum ferritin level). Seventy pediatric patients with hereditary chronic hemolytic anemias, attending to hematology clinics of Cairo University and Misr University for Science and Technology (MUST) hospitals were the subjects of this study [53 patients with β-thalassemia major (β-TM), 10 patients with β-thalassemia intermedia (β-TI), four patients with congenital spherocytosis and three patients with sickle cell disease) (38 males and 32 females)]; their ages ranged from 1-14 years. Seventy normal children, age- and sex-matched, served as the control group. The results of this study revealed decreased hepcidin levels in patients (all types of congenital chronic hemolytic anemias) [mean {\textpm} SD (standard deviation) = 22.9 {\textpm} 6.0] compared to controls (mean {\textpm} SD = 132.4 {\textpm} 16.7) with highly significant statistical difference in between. Hepcidin levels were higher in β-TM patients (mean {\textpm} SD = 23.7 {\textpm} 6.2) than in β-TI patients (mean {\textpm} SD = 21.8 {\textpm} 4.0), the hepcidin to ferritin ratio was significantly less than one. In β-TM patients, the mean {\textpm} SD was 0.03 {\textpm} 0.004, and in β-TI patients the mean {\textpm} SD = 0.025 {\textpm} 0.002, with highly significant statistical difference with hepcidin-to-ferritin ratios in controls being mean {\textpm} SD = 2.3 {\textpm} 0.7. Hepcidin and hepcidin/ferritin ratios can be used as good markers of hemolytic anemia and iron overload as they have very high sensitivity (99.0 and 99.0\%, respectively) and very high specificity (98.0 and 97.0\%, respectively). Our findings highlight the potential usefulness of hepcidin measurement as a diagnostic tool. The use of hepcidin as an adjuvant therapy with iron chelators is important as it has a vital role in combating hemosidrosis.

}, keywords = {Adolescent, Anemia, Sickle Cell, Antimicrobial Cationic Peptides, beta-Thalassemia, Blood Transfusion, C-Reactive Protein, Child, Child, Preschool, Female, Ferritins, Hepcidins, Humans, Infant, Iron, Iron Overload, Male, Spherocytosis, Hereditary}, issn = {1532-432X}, doi = {10.3109/03630269.2012.721151}, author = {Amal ElBeshlawy and Ibrahim Alaraby and Abdel Kader, Mohamed S E M and Dina H Ahmed and Hossam E M Abdelrahman} } @article {117525, title = {Achieving treatment goals of reducing or maintaining body iron burden with deferasirox in patients with β-thalassaemia: results from the ESCALATOR study.}, journal = {European journal of haematology}, volume = {87}, year = {2011}, month = {2011 Oct}, pages = {349-54}, abstract = {

This analysis evaluated the effects of deferasirox on liver iron concentration in moderate and heavily iron-overloaded patients with β-thalassaemia from the ESCALATOR trial (n = 231). Mean liver iron concentrations (LIC) decreased significantly from 21.1 {\textpm} 8.2 to 14.2 {\textpm} 12.1 mg Fe/g dry weight (dw) at 2 yr (P \< 0.001) in patients with LIC >= 7 mg Fe/g dw at baseline; patients with LIC \< 7 mg Fe/g dw maintained these levels over the treatment period. The proportion of patients with LIC \< 7 mg Fe/g dw increased from 9.4\% at core baseline to 39.3\% by the end of year 2. The results showed that deferasirox enabled therapeutic goals to be achieved, by maintaining LIC in patients with LIC \< 7 mg Fe/g dw at a mean dose of 22.4 {\textpm} 5.2 mg/kg/d and significantly reducing LIC in patients with LIC >= 7 mg Fe/g dw at a mean dose of 25.7 {\textpm} 4.2 mg/kg/d, along with a manageable safety profile.

}, keywords = {Adolescent, Benzoates, beta-Thalassemia, Body Burden, Child, Child, Preschool, Female, Humans, Iron, Iron Chelating Agents, Male, Prospective Studies, Triazoles}, issn = {1600-0609}, doi = {10.1111/j.1600-0609.2011.01661.x}, author = {Ali Taher and Mohsen S. Elalfy and Kusai Al Zir and Shahina Daar and Abdullah Al Jefri and Dany Habr and Ulrike Kriemler-Krahn and Bernard Roubert and Amal El-Beshlawy} } @article {117524, title = {Importance of optimal dosing >= 30 mg/kg/d during deferasirox treatment: 2.7-yr follow-up from the ESCALATOR study in patients with β-thalassaemia.}, journal = {European journal of haematology}, volume = {87}, year = {2011}, month = {2011 Oct}, pages = {355-65}, abstract = {

Following 1-yr deferasirox therapy in the ESCALATOR study, 57\% of previously chelated patients with β-thalassaemia achieved treatment success (maintenance of or reduction in liver iron concentration (LIC) vs. baseline LIC). Seventy-eight per cent had dose increases at median of 26 wk, suggesting that 1-yr results may not have reflected full deferasirox efficacy. Extension data are presented here. Deferasirox starting dose was 20 mg/kg/d (increases to 30/40 mg/kg/d permitted in the core/extension, respectively). Efficacy was primarily assessed by absolute change in LIC and serum ferritin. Overall, 231 patients received deferasirox in the extension; 67.4\% (P \< 0.0001) achieved treatment success. By the end of the extension, 66.2\% of patients were receiving doses >= 30 mg/kg/d. By the end of the 1-yr extension, mean LIC had decreased by 6.6 {\textpm} 9.4 mg Fe/g dw (baseline 19.6 {\textpm} 9.2; P \< 0.001) and median serum ferritin by 929 ng/mL (baseline 3356; P \< 0.0001). There was a concomitant improvement in liver function markers (P \< 0.0001). Fewer drug-related adverse events were reported in extension than core study (23.8\% vs. 44.3\%). Doses >= 30 mg/kg/d were generally required because of high transfusional iron intake and high baseline serum ferritin levels, highlighting the importance of administering an adequate dose to achieve net negative iron balance.

}, keywords = {Benzoates, beta-Thalassemia, Female, Humans, Iron Chelating Agents, Male, Triazoles}, issn = {1600-0609}, doi = {10.1111/j.1600-0609.2011.01662.x}, author = {Ali Taher and Mohsen S. Elalfy and Kusai Al Zir and Shahina Daar and Abdullah Al Jefri and Dany Habr and Ulrike Kriemler-Krahn and Ali El-Ali and Bernard Roubert and Amal El-Beshlawy} } @article {117523, title = {Challenges of adherence and persistence with iron chelation therapy.}, journal = {International journal of hematology}, volume = {94}, year = {2011}, month = {2011 Nov}, pages = {453-60}, abstract = {

Due to advances in medical sciences, many chronic diseases that formerly resulted in early death can now be effectively managed with long-term treatment regimens. Patients with potentially fatal anemias, for example, can be treated with ongoing blood transfusions and iron chelation therapy. Ensuring adherence and persistence is challenging, as the benefits of therapy are not perceived immediately. Poor adherence severely compromises the effectiveness of treatment and, therefore, improving compliance in terms of quality of life and health economics is critical. Although adherence to chelation therapy is generally poor, the availability of oral iron chelators may help to improve patient compliance. For chronic conditions such as thalassemia major, even when oral chelation therapy is available, support by an integrated team including a clinical psychologist and nurse specialist working with the treatment center is recommended to achieve optimal results.

}, keywords = {Administration, Oral, Adolescent, Anemia, Sickle Cell, Benzoates, beta-Thalassemia, Child, Deferoxamine, Dosage Forms, Humans, Infusions, Intravenous, Iron Chelating Agents, Iron Overload, Patient Care Team, patient compliance, Pyridones, Time Factors, Triazoles}, issn = {1865-3774}, doi = {10.1007/s12185-011-0927-3}, author = {John B. Porter and Michael Evangeli and Amal El-Beshlawy} } @article {117526, title = {The effect of reducing repetition time TR on the measurement of liver R2 for the purpose of measuring liver iron concentration.}, journal = {Magnetic resonance in medicine}, volume = {65}, year = {2011}, month = {2011 May}, pages = {1346-51}, abstract = {

The effects of reducing the pulse repetition time from 2500 ms to 1000 ms when using spin-density-projection-assisted R2-magnetic resonance imaging for the purpose of measuring liver iron concentration were evaluated. Repeated liver R2 measurements were made using both protocols on 60 subjects with liver iron concentrations ranging from 0.5 to 48.6 mg Fe (g dry tissue)(-1). The mean total scan time at repetition time 1000 ms was 42\% of that at repetition time 2500 ms. The repeatability coefficients for the two protocols were not significantly different from each other. A systematic difference in the measured R2 using each protocol was found indicating that an adjustment factor is required when one protocol is used to replace the other. The 95\% limits of agreement between the two protocols were not significantly different from their repeatability coefficients indicating that the protocols can be interchanged without any significant change in accuracy or precision of liver iron concentration measurement.

}, keywords = {Adolescent, Adult, Aged, beta-Thalassemia, Child, Egypt, Female, Humans, Iron Overload, Liver, Magnetic Resonance Imaging, Male, Middle Aged, Myelodysplastic Syndromes, Reproducibility of Results, Statistics, Nonparametric, Time Factors, Turkey}, issn = {1522-2594}, doi = {10.1002/mrm.22712}, author = {Pavitt, Helen L and Yesim Aydinok and Amal El-Beshlawy and Bayraktaroglu, Selen and Ahmed S. Ibrahim and Mona M. Hamdy and Pang, Wenjie and Sharples, Christopher and St Pierre, Timothy G} } @article {117527, title = {Continued improvement in myocardial T2* over two years of deferasirox therapy in β-thalassemia major patients with cardiac iron overload.}, journal = {Haematologica}, volume = {96}, year = {2011}, month = {2011 Jan}, pages = {48-54}, abstract = {

BACKGROUND: The efficacy of cardiac iron chelation in transfusion-dependent patients has been demonstrated in one-year prospective trials. Since normalization of cardiac T2* takes several years, the efficacy and safety of deferasirox was assessed for two years in patients with β-thalassemia major in the cardiac sub-study of the EPIC trial.

DESIGN AND METHODS: Eligible patients with myocardial T2* greater than 5 to less than 20 ms received deferasirox, with the primary endpoint being the change in T2* from baseline to two years.

RESULTS: Baseline myocardial T2* was severe (\> 5 to \< 10 ms) in 39 patients, and moderate-to-mild (10 to \< 20 ms) in 62 patients. Mean deferasirox dose was 33.1 {\textpm} 3.7 mg/kg/d in the one-year core study increasing to 36.1 {\textpm} 7.7 mg/kg/d during the second year of treatment. Geometric mean myocardial T2* increased from a baseline of 11.2 to 14.8 ms at two years (P \< 0.001). In patients with moderate-to-mild baseline T2*, an increase was seen from 14.7 to 20.1 ms, with normalization (>= 20 ms) in 56.7\% of patients. In those with severe cardiac iron overload at baseline, 42.9\% improved to the moderate-to-mild group. The incidence of drug-related adverse events did not increase during the extension relative to the core study and included (>= 5\%) increased serum creatinine, rash and increased alanine aminotransferase.

CONCLUSIONS: Continuous treatment with deferasirox for two years with a target dose of 40 mg/kg/d continued to remove iron from the heart in patients with β-thalassemia major and mild, moderate and severe cardiac siderosis. (Clinicaltrials.gov identifier: NCT 00171821).

}, keywords = {Adolescent, Adult, Benzoates, beta-Thalassemia, Child, Female, Ferritins, Humans, Iron, Iron Chelating Agents, Iron Overload, Magnetic Resonance Imaging, Male, Middle Aged, Myocardium, Prognosis, Prospective Studies, Triazoles, Ventricular Function, Left, Young Adult}, issn = {1592-8721}, doi = {10.3324/haematol.2010.031468}, author = {Dudley J. Pennell and John B. Porter and Maria Domenica Cappellini and Lee Lee Chan and Amal El-Beshlawy and Yesim Aydinok and Hishamshah Ibrahim and Chi-Kong Li and Vip Viprakasit and Mohsen Saleh Elalfy and Antonis Kattamis and Gillian Smith and Dany Habr and Gabor Domokos and Bernard Roubert and Ali Taher} } @article {117522, title = {Risk factors for pulmonary hypertension in patients with β thalassemia intermedia.}, journal = {European journal of internal medicine}, volume = {22}, year = {2011}, month = {2011 Dec}, pages = {607-10}, abstract = {

BACKGROUND: Pulmonary hypertension (PHT) is a common yet poorly understood complication of β thalassemia intermedia (TI).

METHODS: We herein evaluated risk factors for PHT in TI, through comparing 64 TI patients with evidence of PHT by symptomatology and echocardiography (Group I) to age- and sex-matched TI patients without PHT (Group II). Retrieved data included demographics, laboratory parameters, clinical characteristics, and received treatments that may influence PHT development; and reflected the period prior to PHT occurrence in Group I.

RESULTS: The mean age of Group I patients at development of PHT was 37.3{\textpm}10.6years; with 44\% being males. Among studied parameters, Group I patients were more likely to be splenectomized (4.9-times), transfusion-naive (3.5-times); hydroxyurea-naive (2.6-times), or iron chelation-naive (2.3-times); and have nucleated red blood cell count >=300{\texttimes}10(6)/l (2.59-times) or a previous history of thromboembolic events (3.69-times).

CONCLUSION: TI patients who eventually develop PHT may be identified early on by being splenectomized, having high nucleated red blood cell counts and a previous history of thromboembolism. Prospective clinical trials that evaluate the efficacy, safety, and cost effectiveness of transfusion, iron chelation, and hydroxyurea therapy in preventing PHT in TI are invited.

}, keywords = {Adult, beta-Thalassemia, Blood Coagulation, Erythrocyte Count, Female, Ferritins, Genotype, Humans, Hypertension, Pulmonary, Logistic Models, Male, Middle Aged, Multivariate Analysis, Retrospective Studies, Risk Factors, Splenectomy, Thromboembolism}, issn = {1879-0828}, doi = {10.1016/j.ejim.2011.05.013}, author = {Karimi, Mehran and Musallam, Khaled M and Maria Domenica Cappellini and Shahina Daar and Amal El-Beshlawy and Belhoul, Khawla and Saned, Mohamed-Salaheldin and Temraz, Sally and Koussa, Suzanne and Taher, Ali T} } @article {117528, title = {The safety, tolerability, and efficacy of a liquid formulation of deferiprone in young children with transfusional iron overload.}, journal = {Journal of pediatric hematology/oncology}, volume = {32}, year = {2010}, month = {2010 Nov}, pages = {601-5}, abstract = {

Limited data are available on the use of deferiprone in children younger than 10 years of age. This study evaluated the safety and efficacy of a new liquid formulation of deferiprone for the treatment of transfusional iron overload in children 1-10 years old. One hundred children (91 thalassemia major, 8 Hb E-β thalassemia, and 1 sickle cell disease) were enrolled for a 6-month treatment with deferiprone (50 to 100 mg/kg/d). The safety profile was similar to or better than that reported in earlier studies with deferiprone tablets in older children and adults. No unexpected adverse reactions were observed. Gastrointestinal intolerance (GI) was observed in 11\% and an increased serum ALT in 12\% of the children. Both events were transient. Mild neutropenia, observed in 6\% of patients, did not progress to agranulocytosis and resolved despite continuous deferiprone treatment. Two patients experienced agranulocytosis that resolved without complications upon discontinuation of therapy. Deferiprone use was associated with a significant decline in mean serum ferritin level from 2532{\textpm}1463 μg/L at baseline to 2176{\textpm}1144 μg/L (P\<0.0005). The results of this study show a favorable benefit/risk ratio of deferiprone oral solution for the treatment of young children with transfusional iron overload.

}, keywords = {Administration, Oral, Agranulocytosis, Anemia, Sickle Cell, beta-Thalassemia, Blood Transfusion, Chemistry, Pharmaceutical, Child, Child, Preschool, Female, Humans, Infant, Iron Chelating Agents, Iron Overload, Male, Pyridones}, issn = {1536-3678}, doi = {10.1097/MPH.0b013e3181ec0f13}, author = {ElAlfy, Moshen S and El Alfy, Moshen and Sari, Teny Tjitra and Lee, Chan Lee and Tricta, Fernando and Amal El-Beshlawy} } @article {117537, title = {Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia.}, journal = {Blood}, volume = {115}, year = {2010}, month = {2010 Mar 25}, pages = {2364-71}, abstract = {

Cardiac iron overload causes most deaths in beta-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with beta-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n = 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56\% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n = 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean +/- coefficient of variation) improved from a baseline of 11.2 ms (+/- 40.5\%) to 12.9 ms (+/- 49.5\%) (+16\%; P \< .001). LVEF (mean +/- SD) was unchanged: 67.4 (+/- 5.7\%) to 67.0 (+/- 6.0\%) (-0.3\%; P = .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (+/- 25.6\%) to 32.5 ms (+/- 25.1\%) (+2\%; P = .57) and LVEF increased from baseline 67.7 (+/- 4.7\%) to 69.6 (+/- 4.5\%) (+1.8\%; P \< .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials.gov as NCT00171821.

}, keywords = {Adolescent, Adult, Benzoates, beta-Thalassemia, Child, Dose-Response Relationship, Drug, Female, Ferritins, Heart Failure, Humans, Iron, Iron Chelating Agents, Iron Overload, Male, Myocardium, Prospective Studies, Triazoles, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2009-04-217455}, author = {Dudley J. Pennell and John B. Porter and Maria Domenica Cappellini and Amal El-Beshlawy and Lee Lee Chan and Yesim Aydinok and Mohsen Saleh Elalfy and Sutcharitchan, Pranee and Chi-Kong Li and Hishamshah Ibrahim and Vip Viprakasit and Antonis Kattamis and Gillian Smith and Dany Habr and Gabor Domokos and Bernard Roubert and Ali Taher} } @article {117534, title = {Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study.}, journal = {Blood}, volume = {115}, year = {2010}, month = {2010 Mar 11}, pages = {1886-92}, abstract = {

Despite recent advances in understanding the pathophysiologic mechanisms behind the thalassemia intermedia (TI) phenotype, data on the effects of treatment are deficient. To provide such data, we evaluated 584 TI patients for the associations between patient and disease characteristics, treatment received, and the rate of complications. The most common disease-related complications were osteoporosis, extramedullary hematopoeisis (EMH), hypogonadism, and cholelithiasis, followed by thrombosis, pulmonary hypertension (PHT), abnormal liver function, and leg ulcers. Hypothyroidism, heart failure, and diabetes mellitus were less frequently observed. On multivariate analysis, older age and splenectomy were independently associated with an increased risk of most disease-related complications. Transfusion therapy was protective for thrombosis, EMH, PHT, heart failure, cholelithiasis, and leg ulcers. However, transfusion therapy was associated with an increased risk of endocrinopathy. Iron chelation therapy was in turn protective for endocrinopathy and PHT. Hydroxyurea treatment was associated with an increased risk of hypogonadism yet was protective for EMH, PHT, leg ulcers, hypothyroidism, and osteoporosis. Attention should be paid to the impact of age on complications in TI, and the beneficial role of splenectomy deserves revisiting. This study provides evidence that calls for prospective evaluation of the roles of transfusion, iron chelation, and hydroxyurea therapy in TI patients.

}, keywords = {Adolescent, Adult, Aged, Child, Child, Preschool, Endemic Diseases, Endocrine System Diseases, Female, Hematopoiesis, Extramedullary, Humans, Hypertension, Pulmonary, Liver Diseases, Male, Middle Aged, Professional Practice, Retrospective Studies, Thalassemia, Thrombosis, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2009-09-243154}, author = {Taher, Ali T and Musallam, Khaled M and Karimi, Mehran and Amal El-Beshlawy and Belhoul, Khawla and Shahina Daar and Saned, Mohamed-Salaheldin and El-Chafic, Abdul-Hamid and Fasulo, Maria R and Cappellini, Maria D} } @article {117532, title = {Screening of growth hormone deficiency in short thalassaemic patients and effect of L-carnitine treatment.}, journal = {Archives of medical science : AMS}, volume = {6}, year = {2010}, month = {2010 Mar 1}, pages = {90-5}, abstract = {

INTRODUCTION: Evaluation of growth hormone (GH) in short thalassaemic patients and effect of L-carnitine therapy in those with hormone deficiency.

MATERIAL AND METHODS: The study included 30 β-thalassaemic patients aged 13.8 {\textpm}1.7 years and 30 children with constitutional short stature as controls. Anthropometric measurements (basal and after 6 months), thyroid profile, insulin-like growth factor-1 (IGF-1) and GH provocation by 2 tests were carried out. Eight patients with inadequate GH response to both clonidine and ITT were given L-carnitine treatment for 6 months. They were re-evaluated (clinically, anthropometrically and in the laboratory by doing GH stimulation test) after 6 months of therapy.

RESULTS: Twelve (40\%) patients had sub-clinical hypothyroidism and 10 (33.3\%) had growth hormone deficiency (GHD). Peak GH and growth velocity (cm and standard deviation score [SDS]) were significantly lower while weight (SDS) and weight/height SDS were significantly higher than in patients with constitutional short stature (p \< 0.05). A significant positive correlation was found between height and target height (cm). Haemoglobin levels, peak GH, IGF-1 and growth velocity (cm \& SDS) were significantly higher and the number of blood transfusions was significantly lower in GH deficiency patients after L-carnitine treatment (p \< 0.05). Delta changes were higher in height (cm \& SDS), estimated mature height and sitting height and lower in target height - height (SDS and cm) six months after L-carnitine treatment in β-thalassaemic patients with GHD (p \< 0.05).

CONCLUSIONS: Growth hormone deficiency is an aetiological factor in thalassaemic patients with short stature. L-carnitine can promote GH secretion and growth.

}, issn = {1896-9151}, doi = {10.5114/aoms.2010.13513}, author = {Amal ElBeshlawy and Abd El Dayem, Soha M and Fatma El Mougy and Gafar, Esmat Abd El and Samir, Hend} } @article {117539, title = {Study of protein C, protein S, and antithrombin III in newborns with sepsis.}, journal = {Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies}, volume = {11}, year = {2010}, month = {2010 Jan}, pages = {52-9}, abstract = {

OBJECTIVE: The aim of this study is to clarify the effect of sepsis on the physiologic inhibition system of coagulation including protein S, protein C, and antithrombin III, and to study their further effect on thromboembolic accidents of septic newborns.

DESIGN: Clinical study including 30 septic neonates and 30 normal neonates served as control group.

DATA SOURCES: MEDLINE, pediatric textbooks, Neonatal Intensive Care Unit, Department of Pediatrics, Faculty of Medicine, Cairo University.

RESULTS: The results of this study showed marked decrease in the level of the physiologic inhibition system of coagulation including antithrombin III, protein C, and protein S in 100\% of cases, compared to the control group (p \< .001). Disseminated intravascular coagulation developed and death occurred in 33.3\% of cases, necrotizing enterocolitis developed in 40\% of cases, rectal bleeding developed in 33.3\%, hematuria developed in 20\% of cases, hematemesis developed in 26.7\% of cases, intracranial hemorrhage developed in 23.3\% of cases, and convulsions developed in 23.3\% of cases.

CONCLUSIONS: In this study we have tried to evaluate the effect of sepsis on the physiologic inhibition system of coagulation in neonates. We should expect the effect of sepsis and its severity and perform the necessary laboratory investigations for coagulation including antithrombin III, protein C and protein S levels to help prevent thromboembolic accidents in neonates with sepsis, including disseminated intravascular coagulation, necrotizing enterocolitis and intracranial hemorrhage. Based on the findings of our study and the results of the other studies, we are in agreement that protein C is a very useful biomarker in severe sepsis, and it is a possible tool for monitoring treatment with activated protein C. We also encourage further placebo-controlled clinical trials to investigate the role of activated protein C and antithrombin III in severe neonatal sepsis and especially in the states before disseminated intravascular coagulation and the disseminated intravascular coagulation states, on the condition that they are guided by the experience and recommendations gained from the PROWESS, ENHANCE, and RESOLVE clinical trials. Protein C might be more effective if dosed according to protein C levels rather according to weight. Furthermore, we encourage future research on activated protein C mutants, which are anticipated to appear very soon because they can reduce some side effects associated with the use of recombinant human activated protein C, such as intracranial hemorrhage and bleeding tendencies, because they have reduced anticoagulant activity while retaining the cytoprotective effects.

}, keywords = {Antithrombin III, Blood Coagulation, Enterocolitis, Necrotizing, Humans, Infant, Newborn, Intracranial Hemorrhages, Protein C, Protein S, Sepsis, Severity of Illness Index, Thromboembolism}, issn = {1529-7535}, doi = {10.1097/PCC.0b013e3181c59032}, author = {Amal ElBeshlawy and Ibrahim Alaraby and Abou Hussein, Heba and Heba Hassan Abou-Elew and Mohamed Salah Eldin Mohamed Abdel Kader} } @article {117529, title = {ThalassoChip, an array mutation and single nucleotide polymorphism detection tool for the diagnosis of β-thalassaemia.}, journal = {Clinical chemistry and laboratory medicine}, volume = {48}, year = {2010}, month = {2010 Dec}, pages = {1713-8}, abstract = {

BACKGROUND: The detection and diagnosis of β-thalassaemia for populations with molecular heterogeneity, or diverse ethnic groups, has increased the need for the development of an array high-throughput diagnostic tool that can deliver large scale genetic detection. We report on the update and validation of the ThalassoChip, a β-thalassaemia genetic diagnostic tool which is based on arrayed primer extension (APEX) technology.

METHODS: ThalassoChip slides with new and redesigned probes were prepared for testing the microarray. Six hundred and sixty DNA samples collected from eight Mediterranean countries were used for standardisation, optimisation and validation of the ThalassoChip. The β-globin gene region was amplified by PCR, the products were hybridised to the probes after fragmentation and the APEX reaction followed.

RESULTS: The ThalassoChip was updated with new probes and now has the ability to detect 57 β-globin gene mutations and three single nucleotide polymorphisms (SNPs) in a single test. The ThalassoChip as well as the PCR and APEX reactions were standardised and optimised using 500 DNA samples that were previously genotyped using conventional diagnostic techniques. Some probes were redesigned in order to improve the specificity and sensitivity of the test. Validation of the ThalassoChip performed using 160 samples analysed in blinded fashion showed no error.

CONCLUSIONS: The updated version of the ThalassoChip is versatile, robust, cost-effective and easily adaptable, but most notably can provide comprehensive genetic diagnosis for β-thalassaemia and other haemoglobinopathies.

}, keywords = {beta-Globins, beta-Thalassemia, DNA Probes, Hemoglobinopathies, High-Throughput Screening Assays, Humans, Mutation, Polymorphism, Single Nucleotide, Sensitivity and Specificity}, issn = {1437-4331}, doi = {10.1515/CCLM.2010.331}, author = {Shammas, Christos and Papasavva, Thessalia and Felekis, Xenia and Christophorou, Christos and Roomere, Hanno and Synodinos, Jan Traeger and Kanavakis, Emmanuel and El-Khateeb, Mohammed and Hamamy, Hanan and Mahmoud, Tamara and Shboul, Mohammad and Amal ElBeshlawy and Filon, Dvora and Ibtessam R. Hussein and Galanello, Renzo and Romeo, Giovanni and Kleanthous, Marina} } @article {117530, title = {Age-related complications in treatment-na{\"\i}ve patients with thalassaemia intermedia.}, journal = {British journal of haematology}, volume = {150}, year = {2010}, month = {2010 Aug}, pages = {486-9}, keywords = {Adolescent, Adult, Age Factors, Anemia, Hemolytic, beta-Thalassemia, Child, Child, Preschool, Female, Hematopoiesis, Extramedullary, Humans, Male, Middle Aged, Registries}, issn = {1365-2141}, doi = {10.1111/j.1365-2141.2010.08220.x}, author = {Taher, Ali T and Musallam, Khaled M and Amal El-Beshlawy and Karimi, Mehran and Shahina Daar and Belhoul, Khawla and Saned, Mohamed-Salaheldin and Graziadei, Giovanna and Cappellini, Maria D} } @article {117533, title = {Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry.}, journal = {Journal of inherited metabolic disease}, volume = {33}, year = {2010}, month = {2010 Aug}, pages = {339-46}, abstract = {

OBJECTIVE: To describe demographic, genetic, and clinical characteristics of patients with neuronopathic Gaucher disease (NGD).

METHODS: All patients enrolled in the Neurological Outcomes Subregistry of the International Collaborative Gaucher Group (ICGG) Gaucher Registry as of June 2007 were identified.

RESULTS: The study cohort comprised 131 patients from 17 countries who were enrolled in the Neurological Outcomes Subregistry. The onset of neurological manifestations had occurred before 2 years of age in 47\% (61 out of 131 patients), 2 years of age or older in 41\% (54 out of 131), and could not be ascertained in the remaining 12\% (16 out of 131). The most common manifestations were inability to look to the extreme up or down (45\%, 55 out of 123), abnormally slow object tracking (43\%, 53 out of 123), convergent squint (36\%, 44 out of 121), and ataxia (15 to 20\%, 18-27 out of 117). Seizures were reported in 19 out of 122 patients (16\%), and myoclonic seizures were reported in 3 out of 121 patients (2\%). The most common genotypes were L444P/L444P (76 out of 108, 70\%), L444P/D409H (9 out of 108, 8\%), D409H/D409H (8 out of 108, 7\%), and L444P/rare allele (6 out of 108, 6\%); full sequencing was not performed in all patients.

CONCLUSIONS: Neurological manifestations of GD often begin to appear before the age of 2 years. The most common neurological signs and manifestations are brainstem abnormalities and fine motor dysfunction. The most common genotype is L444P/L444P.

}, keywords = {Brain Stem, Child, Preschool, Cooperative Behavior, Cross-Sectional Studies, Epilepsy, Female, Gaucher Disease, Genotype, Humans, Infant, International Cooperation, Male, Movement Disorders, Ocular Motility Disorders, Registries}, issn = {1573-2665}, doi = {10.1007/s10545-009-9009-6}, author = {Tylki-Szyma{\'n}ska, Anna and Vellodi, Ashok and Amal El-Beshlawy and Cole, J Alexander and Kolodny, Edwin} } @article {117538, title = {Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias.}, journal = {Haematologica}, volume = {95}, year = {2010}, month = {2010 Apr}, pages = {557-66}, abstract = {

UNLABELLED: Background Following a clinical evaluation of deferasirox (Exjade) it was concluded that, in addition to baseline body iron burden, ongoing transfusional iron intake should be considered when selecting doses. The 1-year EPIC study, the largest ever investigation conducted for an iron chelator, is the first to evaluate whether fixed starting doses of deferasirox, based on transfusional iron intake, with dose titration guided by serum ferritin trends and safety markers, provides clinically acceptable chelation in patients (aged \>or=2 years) with transfusional hemosiderosis from various types of anemia.

DESIGN AND METHODS: The recommended initial dose was 20 mg/kg/day for patients receiving 2-4 packed red blood cell units/month and 10 or 30 mg/kg/day was recommended for patients receiving less or more frequent transfusions, respectively. Dose adjustments were based on 3-month serum ferritin trends and continuous assessment of safety markers. The primary efficacy end-point was change in serum ferritin after 52 weeks compared with baseline.

RESULTS: The 1744 patients enrolled had the following conditions; thalassemia (n=1115), myelodysplastic syndromes (n=341), aplastic anemia (n=116), sickle cell disease (n=80), rare anemias (n=43) and other transfused anemias (n=49). Overall, there was a significant reduction in serum ferritin from baseline (-264 ng/mL; P\<0.0001), reflecting dosage adjustments and ongoing iron intake. The most common (\>5\%) adverse events were gastrointestinal disturbances (28\%) and skin rash (10\%). Conclusions Analysis of this large, prospectively collected data set confirms the response to chelation therapy across various anemias, supporting initial deferasirox doses based on transfusional iron intake, with subsequent dose titration guided by trends in serum ferritin and safety markers (clinicaltrials.gov identifier: NCT00171821).

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, anemia, Benzoates, Blood Transfusion, Child, Child, Preschool, Female, Ferritins, Humans, Iron Chelating Agents, Iron Overload, Iron, Dietary, Male, Middle Aged, Prospective Studies, Thalassemia, Tissue Distribution, Triazoles, Young Adult}, issn = {1592-8721}, doi = {10.3324/haematol.2009.014696}, author = {Maria Domenica Cappellini and Porter, John and Amal El-Beshlawy and Chi-Kong Li and Seymour, John F and Mohsen Elalfy and Gattermann, Norbert and Giraudier, St{\'e}phane and Lee, Jong-Wook and Lee Lee Chan and Lin, Kai-Hsin and Rose, Christian and Ali Taher and Thein, Swee Lay and Vip Viprakasit and Dany Habr and Gabor Domokos and Bernard Roubert and Antonis Kattamis} } @article {117531, title = {Improved treatment satisfaction and convenience with deferasirox in iron-overloaded patients with beta-Thalassemia: Results from the ESCALATOR Trial.}, journal = {Acta haematologica}, volume = {123}, year = {2010}, month = {2010}, pages = {220-5}, abstract = {

Patient-reported outcomes of once-daily oral deferasirox (Exjade) in iron-overloaded patients with beta-thalassemia not achieving successful chelation with prior deferoxamine and/or deferiprone were investigated in a prospective, open-label, 1-year, multicenter study in the Middle East (ESCALATOR). The initial dose of deferasirox was 20 mg/kg/day, with subsequent dose adjustments. At baseline and the end of study (EOS), patients (n = 237) completed a 5-point rating scale for treatment satisfaction and convenience, and recorded time lost to treatment. At EOS, 90.7\% of patients were {\textquoteright}satisfied{\textquoteright}/{\textquoteright}very satisfied{\textquoteright} with their iron chelation therapy (ICT) versus 23.2\% at baseline. 92.8\% (EOS) versus 21.5\% (baseline) of patients considered their therapy to be {\textquoteright}convenient{\textquoteright}/{\textquoteright}very convenient{\textquoteright}. Time lost to therapy for daily activities was substantially reduced (3.2 +/- 8.6 [mean +/- SD; EOS] vs. 30.1 +/- 44.2 [baseline] h/month). Patients reported greater satisfaction and convenience, and lower impact on daily activities, with deferasirox than with previous ICT. This may help improve adherence to lifelong ICT in iron-overloaded beta-thalassemia patients.

}, keywords = {Adolescent, Adult, Benzoates, beta-Thalassemia, Child, Child, Preschool, Female, Humans, Iron Chelating Agents, Iron Overload, Male, Middle East, Patient Satisfaction, Prospective Studies, Triazoles}, issn = {1421-9662}, doi = {10.1159/000313447}, author = {Ali Taher and Abdullah Al Jefri and Mohsen Saleh Elalfy and Kusai Al Zir and Shahina Daar and Rofail, Diana and Baladi, Jean Fran{\c c}ois and Dany Habr and Ulrike Kriemler-Krahn and Amal El-Beshlawy} } @article {117541, title = {The effect of freezing on the recovery and expansion of umbilical cord blood hematopoietic stem cells.}, journal = {Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation}, volume = {7}, year = {2009}, month = {2009 Mar}, pages = {50-5}, abstract = {

OBJECTIVES: Cell populations residing in waste tissues (cord blood, umbilical cord, and placenta) may be collected without any medical or ethical contraindications concerning the mother or newborn baby. Cord blood hematopoietic stem cells are routinely used for clinical transplants; however, the low cell dose of the graft limits their therapeutic efficacy as it is associated with increased delayed or failed engraftment. The cell dose can be increased, and the efficacy of cord blood transplant potentially improved, by ex vivo expansion before transplant.

MATERIALS AND METHODS: Twelve umbilical cord blood samples were included. The effect of cord blood storage at -80 degrees C on CD34+ cell count (mean -/+ standard deviation [SD]), cell viability (mean -/+ SD percent), and cell cycle status (percent quiescent versus dividing) was estimated. Ex vivo culture of cord blood mononuclear cells was done before storage, and after 1 week of freezing, and after 2 weeks of freezing. Ex vivo liquid culture was performed with media supplemented with stem cell factor, interleukin-3 (IL-3), and both.

RESULTS: The count of CD34+ cells in pre-expansion aliquots decreased from 15.00 +/- 9.96 x 106 cells before freezing to 7.70 -/+ 3.20 x 106 cells after 2 weeks of freezing (P = .024). Cell viability in pre-expansion aliquots decreased from 99.5\% -/+ 1.0\% before freezing, to 52.5\% -/+ 27.5\% after 1 week of freezing (P = .013) and to 32.5\% -/+ 9.5\% after 2 weeks of freezing (P = .001). Mean fold of cell expansion and proportion of quiescent versus dividing cells did not change significantly from before to after freezing, and was not significantly different for culture with stem cell factor, IL-3, or both.

CONCLUSION: Although freezing decreased cell count and viability, it did not impair the expansion potential of cord blood hematopoietic cells. Whether IL-3 or stem cell factor should be considered as essential components of expansion media is uncertain.

}, keywords = {Antigens, CD34, Cell Count, Cell Cycle, Cell Proliferation, Cell Separation, cell survival, Cells, Cultured, Cryopreservation, Culture Media, Female, Fetal Blood, Fetal Stem Cells, Hematopoietic Stem Cells, Humans, Interleukin-3, Pregnancy, Stem Cell Factor, Time Factors}, issn = {1304-0855}, author = {Amal ElBeshlawy and Metwally, Hala G and Khalil Abdelkhalek and Hammoud, Rania F and Mousa, Somaia M.} } @article {117542, title = {Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with beta-thalassaemia: the ESCALATOR study.}, journal = {European journal of haematology}, volume = {82}, year = {2009}, month = {2009 Jun}, pages = {458-65}, abstract = {

OBJECTIVE: Many patients with transfusional iron overload are at risk for progressive organ dysfunction and early death and poor compliance with older chelation therapies is believed to be a major contributing factor. Phase II/III studies have shown that oral deferasirox 20-30 mg/kg/d reduces iron burden, depending on transfusional iron intake.

METHODS: The prospective, open-label, 1-yr ESCALATOR study in the Middle East was designed to evaluate once-daily deferasirox in patients \> or =2 yr with beta-thalassaemia major and iron overload who were previously chelated with deferoxamine and/or deferiprone. Most patients began treatment with deferasirox 20 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as a reduction in liver iron concentration (LIC) of \> or =3 mg Fe/g dry weight (dw) if baseline LIC was \> or =10 mg Fe/g dw, or final LIC of 1-7 mg Fe/g dw for patients with baseline LIC of 2 to \<10 mg Fe/g dw.

RESULTS: Overall, 233/237 enrolled patients completed 1 yr{\textquoteright}s treatment. Mean baseline LIC was 18.0 +/- 9.1 mg Fe/g dw, while median serum ferritin was 3356 ng/mL. After 1 yr{\textquoteright}s deferasirox treatment, the intent-to-treat population experienced a significant treatment success rate of 57.0\% (P = 0.016) and a mean reduction in LIC of 3.4 mg Fe/g dw. Changes in serum ferritin appeared to parallel dose increases at around 24 wk. Most patients (78.1\%) underwent dose increases above 20 mg/kg/d, primarily to 30 mg/kg/d. Drug-related adverse events were mostly mild to moderate and resolved without discontinuing treatment.

CONCLUSIONS: The results of the ESCALATOR study in primarily heavily iron-overloaded patients confirm previous observations in patients with beta-thalassaemia, highlighting the importance of timely deferasirox dose adjustments based on serum ferritin levels and transfusional iron intake to ensure patients achieve their therapeutic goal of maintenance or reduction in iron burden.

}, keywords = {Adolescent, Adult, Benzoates, beta-Thalassemia, Child, Preschool, Deferoxamine, Drug-Related Side Effects and Adverse Reactions, Female, Ferritins, Humans, Iron, Iron Chelating Agents, Iron Overload, Liver, Male, Pyridones, Treatment Outcome, Triazoles, Young Adult}, issn = {1600-0609}, doi = {10.1111/j.1600-0609.2009.01228.x}, author = {Ali Taher and Amal El-Beshlawy and Mohsen S. Elalfy and Kusai Al Zir and Shahina Daar and Dany Habr and Ulrike Kriemler-Krahn and Hmissi, Abdel and Abdullah Al Jefri} } @article {117540, title = {An electronic infrastructure for research and treatment of the thalassemias and other hemoglobinopathies: the Euro-mediterranean ITHANET project.}, journal = {Hemoglobin}, volume = {33}, year = {2009}, month = {2009}, pages = {163-76}, abstract = {

Hemoglobin (Hb) disorders are common, potentially lethal monogenic diseases, posing a global health challenge. With worldwide migration and intermixing of carriers, demanding flexible health planning and patient care, hemoglobinopathies may serve as a paradigm for the use of electronic infrastructure tools in the collection of data, the dissemination of knowledge, the harmonization of treatment, and the coordination of research and preventive programs. ITHANET, a network covering thalassemias and other hemoglobinopathies, comprises 26 organizations from 16 countries, including non-European countries of origin for these diseases (Egypt, Israel, Lebanon, Tunisia and Turkey). Using electronic infrastructure tools, ITHANET aims to strengthen cross-border communication and data transfer, cooperative research and treatment of thalassemia, and to improve support and information of those affected by hemoglobinopathies. Moreover, the consortium has established the ITHANET Portal, a novel web-based instrument for the dissemination of information on hemoglobinopathies to researchers, clinicians and patients. The ITHANET Portal is a growing public resource, providing forums for discussion and research coordination, and giving access to courses and databases organized by ITHANET partners. Already a popular repository for diagnostic protocols and news related to hemoglobinopathies, the ITHANET Portal also provides a searchable, extendable database of thalassemia mutations and associated background information. The experience of ITHANET is exemplary for a consortium bringing together disparate organizations from heterogeneous partner countries to face a common health challenge. The ITHANET Portal as a web-based tool born out of this experience amends some of the problems encountered and facilitates education and international exchange of data and expertise for hemoglobinopathies.

}, keywords = {Europe, Geography, Hemoglobinopathies, Humans, Information Systems, International Cooperation, Internet, Mediterranean Region, Research Design, Thalassemia}, issn = {1532-432X}, doi = {10.1080/03630260903089177}, author = {Lederer, Carsten W and Basak, A Nazli and Yesim Aydinok and Christou, Soteroula and Amal El-Beshlawy and Eleftheriou, Androulla and Fattoum, Slaheddine and Felice, Alex E and Fibach, Eitan and Galanello, Renzo and Gambari, Roberto and Gavrila, Lucian and Giordano, Piero C and Grosveld, Frank and Hassapopoulou, Helen and Hladka, Eva and Kanavakis, Emmanuel and Locatelli, Franco and Old, John and Patrinos, George P and Romeo, Giovanni and Ali Taher and Traeger-Synodinos, Joanne and Vassiliou, Panayiotis and Villegas, Ana and Voskaridou, Ersi and Wajcman, Henri and Zafeiropoulos, Anastasios and Kleanthous, Marina} } @article {117535, title = {Fetal globin induction in beta-thalassemia.}, journal = {Hemoglobin}, volume = {33 Suppl 1}, year = {2009}, month = {2009}, pages = {S197-203}, abstract = {

Thalassemia patients with persistently high levels of fetal globin typically have less severe anemia, have milder clinical syndromes, and are often transfusion independent. Therefore, the search for molecules exhibiting the property of inducing gamma-globin gene expression and fetal hemoglobin (HbF) production is of great interest. Different pharmacological agents have been studied, namely erythropoietin, short chain fatty acids and cytotoxic agents, azacytidine, and hydroxycarbamide. Hemoglobin F inducers from natural plants, such as angelicin and resveratrol, are powerful inducers of erythroid differentiation and increase HbF in erythroid progenitors of thalassemia patients. Induction of HbF in beta-thalassemia patients is expected to be crucial for developing countries unable to sustain the high cost of clinical management of beta-thalassemia patients.

}, keywords = {beta-Thalassemia, Fetal Hemoglobin, gamma-Globins, Gene Expression Regulation, Humans}, issn = {1532-432X}, doi = {10.3109/03630260903351882}, author = {Amal El-Beshlawy and HAMDY, MONA and Mona El Ghamrawy} } @article {117536, title = {Prevention of hemoglobinopathies in Egypt.}, journal = {Hemoglobin}, volume = {33 Suppl 1}, year = {2009}, month = {2009}, pages = {S14-20}, abstract = {

The hemoglobin disorders are the most common clinically serious single gene disorders in the world. In Egypt, beta-thalassemia is the most common type with a carrier rate varying from 5.3 to \> or =9\% and a gene frequency of 0.03. So, it was estimated that 1,000/1.5 million per year live births will suffer from thalassemia disease in Egypt (total live births 1,936,205 in 2006). beta-Thalassemia creates a social and financial burden for the patients{\textquoteright} family and the Egyptian government. The high frequency of beta-thalassemia carriers with increasing rate of newly born cases is a pressing reason for the importance to develop prevention program for beta-thalassemia in Egypt. Sickle-cell disease (SCD) is not frequent in Egypt except in the Oases where the carrier rate varies from 9 to 22\%. Our objectives were to provide an in-depth analysis of the current status of hemoglobinopathies in Egypt and what we need for prevention of these diseases.

}, keywords = {Anemia, Sickle Cell, Egypt, Genetic Counseling, Genetic Testing, Hemoglobinopathies, Heterozygote Detection, Humans, Premarital Examinations, Prenatal Diagnosis, Thalassemia}, issn = {1532-432X}, doi = {10.3109/03630260903346395}, author = {Amal El-Beshlawy and Ilham Youssry} } @article {117546, title = {Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience.}, journal = {Annals of hematology}, volume = {87}, year = {2008}, month = {2008 Jul}, pages = {545-50}, abstract = {

Patients with thalassemia major requiring regular blood transfusions accumulate iron that is toxic to the heart, liver, and endocrine systems. The following prospective, randomized trial was carried out to determine the effectiveness, in children and young adults, of combined deferiprone (DFP) and deferoxamine (DFO) in reducing transfusional iron overload compared to either drug alone and to assess the safety and tolerability of DFP. Sixty-six patients were randomized into three treatment arms: daily DFP combined with DFO twice weekly; daily DFP only; and DFO only 5 days/week. Fifty-six patients completed the 54 weeks and were assessed by different indices. A significant reduction of liver iron concentration and serum ferritin was observed in all three arms while significant reduction of liver iron score was observed in patients on combination therapy only. Cardiac function did not significantly change in any arm. Compliance improved in patients who received combined therapy. Toxicity of DFP was mild to moderate and acceptable; most commonly, transient arthropathy and nausea/vomiting were observed. Thus, combination therapy has shown to be effective in reducing iron overload in thalassemia patients.

}, keywords = {Adolescent, Adult, Blood Transfusion, Chelation Therapy, Child, Child, Preschool, Deferoxamine, Drug Administration Schedule, Drug Therapy, Combination, Egypt, Female, Ferritins, Humans, Iron Chelating Agents, Iron Overload, Liver, Male, patient compliance, Prospective Studies, Pyridones, Thalassemia}, issn = {1432-0584}, doi = {10.1007/s00277-008-0471-2}, author = {Amal El-Beshlawy and Manz, Chantal and Naja, Mohammed and Mona El Tagui and Tarabishi, Claudia and Ilham Youssry and Sobh, Hewida and HAMDY, MONA and Sharaf, Iman and Mostafa, Azza and Olfat Shaker and Hoffbrand, A V and Ali Taher} } @article {117544, title = {Assessment of puberty in relation to L-carnitine and hormonal replacement therapy in beta-thalassemic patients.}, journal = {Journal of tropical pediatrics}, volume = {54}, year = {2008}, month = {2008 Dec}, pages = {375-81}, abstract = {

OBJECTIVE: To investigate puberty in a group of thalassemic patients with delayed or arrested pubertal development and to compare the effects of hormonal and L-carnitine therapy on puberty in those patients.

PATIENTS: Thirty-two -thalassemic patients with arrested or failure of puberty were enrolled for 1 year in this study.

METHOD: Clinical pubertal assessment and laboratory investigations were done for all patients at the beginning, 6 months later clinical pubertal assessment was done. Patients were divided into two groups (16 each): first group received L-carnitine therapy, while the second group received hormonal therapy. Pubertal and laboratory assessment were done 6 months after hormonal and L-carnitine therapy.

RESULTS: Failure of puberty was confirmed in 71.4\% of boys and 33.3\% of girls, while arrested puberty was observed in 28.6\% of boys and 66.7\% of girls. All girls had amenorrhea, primary amenorrhea in 88.9\% and secondary amenorrhea in 11.1\%. Menses occurred in 20\% of female patients after L-carnitine therapy and in 37.5\% of them after hormonal therapy. Improvement of pubertal staging was observed in 50\% of males after L-carnitine therapy compared to 75\% of them after hormonal therapy. While improvement of pubertal staging was seen in 90\% of females after L-carnitine therapy compared to 100\% of females after hormonal treatment. However, these results showed no significant difference between both groups.

CONCLUSION: Delayed puberty in beta-thalassemia major is either due to failure of gonads or failure of the whole hypothalamic pituitary gonadal axis. L-carnitine as well as hormonal replacement therapy had a positive effect on puberty in the thalassemic patients. Further studies are needed to clarify the role of L-carnitine on puberty in these patients.

}, keywords = {Adolescent, Adult, beta-Thalassemia, Carnitine, Estrogens, Female, Follow-Up Studies, Hormone Replacement Therapy, Humans, Male, Prevalence, Progesterone, Puberty, Delayed, Testosterone}, issn = {1465-3664}, doi = {10.1093/tropej/fmn043}, author = {Amal ElBeshlawy and Mohtar, Galila and Abd El Ghafar, Esmat and Abd El Dayem, Soha M and El Sayed, Manal Hamdy and Azza Ahmed Aly and Farok, Manal} } @article {117543, title = {Pulmonary hypertension in beta-thalassemia major and the role of L-carnitine therapy.}, journal = {Pediatric hematology and oncology}, volume = {25}, year = {2008}, month = {2008 Dec}, pages = {734-43}, abstract = {

Cardiac complications, such as pulmonary hypertension (PHT), are the leading cause of death in beta-thalassemia patients. L-Carnitine, due to its role in fatty acid oxidation, might help control the elevation in pulmonary artery systolic pressure (PASP). The objectives of this study were to assess the prevalence of PHT in beta-thalassemia major patients, identify clinical predictors for its development, and determine the potential effects of L-carnitine. In total, 32 patients with beta-thalassemia major were recruited; 16 age- and sex-matched children constituted the control group. Cardiac evaluation was performed by using echocardiography. The patients with PHT received 50 mg/kg/day L-carnitine orally for 3 months and were then reevaluated. Based on PASP, the patients were divided into group A without PHT and group B with PHT. The prevalence of PHT was 37.5\%. The other echocardiographic measurements were not significantly different between groups A and B. PASP did not have any significant correlation with the following variables: age, total number of blood units received, splenic status, serum ferritin level, and ejection fraction. Following the administration of L-carnitine, there was a significant decrease in the mean PASP from 33.96 +/- 7.85 to 24.11 +/- 7.61. All cardiac dimensions decreased following L-carnitine, but the changes were not statistically significant. Even though beta-thalassemia major resulted in an elevation in the PASP in only a fraction of the patients, it seems to have an impact on the heart dimensions and function of all patients. No clinical predictors were identified. Oral administration of L-carnitine appears to significantly improve PASP.

}, keywords = {Administration, Oral, Adolescent, beta-Thalassemia, Carnitine, Case-Control Studies, Child, Child, Preschool, Echocardiography, Female, Heart Diseases, Humans, Hypertension, Pulmonary, Male, Prevalence, Regression Analysis}, issn = {1521-0669}, doi = {10.1080/08880010802244035}, author = {Amal El-Beshlawy and Ilham Youssry and El-Saidi, Sonia and El Accaoui, Ramzi and Mansi, Yassmin and Makhlouf, Ali and Ali Taher} } @article {117545, title = {Correction of aberrant pre-mRNA splicing by antisense oligonucleotides in beta-thalassemia Egyptian patients with IVSI-110 mutation.}, journal = {Journal of pediatric hematology/oncology}, volume = {30}, year = {2008}, month = {2008 Apr}, pages = {281-4}, abstract = {

The splicing mutation in intron 1 of beta-globin gene (IVS1-110) is the most common mutation in Egyptian thalassemics that causes aberrant splicing of pre-mRNA and deficient beta-globin chain synthesis. Antisense oligonucleotides (ASONs) are compounds that redirect pre-mRNA splicing and modify gene expression. Our aim was ex vivo correction of the aberrant splicing of beta-globin110 pre-mRNA by ASON against the 3{\textquoteright} aberrant splice site. Peripheral blood mononuclear cells of 10 thalassemic patients with IVS1-110 mutation were duplicated and 1 was treated with 20 micromoL/mL morpholino ASON targeted against the 3{\textquoteright} aberrant splice site. The level of total hemoglobin (Hb), fetal Hb, and mRNA were estimated in the duplicate samples. Five cases (50\%) showed correction with ASON treatment, of which 2 cases showed the appearance of corrected mRNA band with absence of the aberrant band and 3 cases showed an increased ratio of the corrected to the aberrant mRNA band from 2:1 to 3:1, and 4:1. The total Hb showed significant increase in the 5 corrected cases. In conclusion, ASON can restore correct splicing of beta-globin pre-mRNA leading to correct gene product in cultured erythropoietic cells. These results suggest the applicability of ASON for the treatment of thalassemia.

}, keywords = {Adolescent, Adult, Alternative Splicing, beta-Thalassemia, Child, Child, Preschool, Egypt, Female, Globins, Homozygote, Humans, Introns, Male, Mutation, Oligonucleotides, Antisense, Reverse Transcriptase Polymerase Chain Reaction, RNA Precursors, RNA Splicing}, issn = {1077-4114}, doi = {10.1097/MPH.0b013e3181639afe}, author = {Amal El-Beshlawy and Mostafa, Azza and Ilham Youssry and Hala Gabr and Mansour, Iman M and El-Tablawy, Manar and Mona Aziz and Hussein, Ibtissam R} } @article {117549, title = {Effect of L-carnitine on the physical fitness of thalassemic patients.}, journal = {Annals of hematology}, volume = {86}, year = {2007}, month = {2007 Jan}, pages = {31-4}, abstract = {

Poor physical fitness is a common problem among thalassemic patients. L-Carnitine plays an essential role in fatty acid beta-oxidation, a process especially important in the organs that preferentially use fatty acid as a source of energy such as the myocardium and the skeletal muscles. The main objective of this study is to assess the effect of the administration of oral L-carnitine on exercise tolerance and physical fitness in patients with thalassemia major. Thirty patients followed up at the New Cairo University Children Hospital were included in this study. Clinical, laboratory, and cardiopulmonary exercise testing were performed before and after 6 months of oral L-carnitine therapy (50 mg/kg/day). The oxygen consumption, cardiac output, and oxygen pulse at maximal exercise significantly increased after L-carnitine therapy (p\<0.001, p=0.002 and p\<0.001, respectively). However, there was no significant change in minute ventilation and ventilatory equivalent of carbon dioxide (p=0.07 and p=0.06, respectively). A weak but positive correlation between the age of the patients and the degree of improvement in exercise parameters was noted. There was also significant increase in the blood transfusion intervals after L-carnitine administration (p=0.008). However, there was no significant change in hemoglobin concentration (p=0.4). L-Carnitine seems to be a safe and effective adjunctive therapeutic approach in thalassemic patients. It improves their cardiac performance and physical fitness. The younger the patients are, the higher is the degree of improvement in their exercise parameters.

}, keywords = {Administration, Oral, Adolescent, Adult, beta-Thalassemia, Blood Transfusion, Carnitine, Child, Combined Modality Therapy, Exercise Tolerance, Female, Humans, Male, Oxygen Consumption, Physical Fitness}, issn = {1432-0584}, doi = {10.1007/s00277-006-0181-6}, author = {Amal El-Beshlawy and El Accaoui, Ramzi and Abd El-Sattar, Mansour and Gamal El-Deen, Mohamed Hany and Ilham Youssry and Shaheen, Naglaa and HAMDY, MONA and Mona El-Ghamrawy and Ali Taher} } @article {117547, title = {Skin iron concentration: a simple, highly sensitive method for iron stores evaluation in thalassemia patients.}, journal = {Hemoglobin}, volume = {31}, year = {2007}, month = {2007}, pages = {357-65}, abstract = {

Iron overload is a potentially fatal complication in thalassemia patients. Accurate assessment of body iron is of utmost importance for these patients. The available methods for iron stores evaluation have limitations. We assessed biochemically the skin iron concentration (SIC) and determined the relation between the hepatic and skin iron level in thalassemia major patients to develop a simple, sensitive, quantitative measure of the body iron stores. Thirty-one cases with thalassemia major were assessed for iron overload. Liver and skin biopsies were performed for the patients and skin biopsies were taken from the 31 controls. The biopsies were subjected to biochemical assay of iron and histologic sections were examined. The SIC of the studied cases was significantly higher than that of the control group with a mean of 2.705 +/- 1.14 and 0.275 +/- 0.13 mg/g dry skin weight, respectively, p \< 0.001. There was significant correlation between the SIC and the liver iron concentration (LIC) (r = 0.43, p = 0.01). The amount of liver iron is equivalent to [(3.5 x SIC) + 12.9]. With the use of this equation, we could reliably estimate an LIC value as high as 21.2 mg/g dry liver weight with a standard error of 4.07. Biochemical assay of the skin iron concentration is a reliable quantitative indicator of the body iron stores in patients with thalassemia major.

}, keywords = {Case-Control Studies, Humans, Iron, Iron Overload, Liver, Sensitivity and Specificity, Skin, Thalassemia, Tissue Distribution}, issn = {0363-0269}, doi = {10.1080/03630260701503833}, author = {Ilham Youssry and Nabil A. Mohsen and Olfat G Shaker and Ahmed El-Hennawy and Fawzy, Rania and Abu-Zeid, Nagwa M and Amal El-Beshlawy} } @article {117548, title = {Study of beta-Thalassemia mutations using the polymerase chain reaction-amplification refractory mutation system and direct DNA sequencing techniques in a group of Egyptian Thalassemia patients.}, journal = {Hemoglobin}, volume = {31}, year = {2007}, month = {2007}, pages = {63-9}, abstract = {

The aim of this study was the molecular characterization of beta-thalassemia (thal) mutations in a group of 95 Egyptian thalassemic patients from Fayoum in Upper Egypt, Cairo, Alexandria and Tanta in Lower Egypt and the Nile Delta. To identify these anomalies, the polymerase chain reaction-amplification refractory mutation system (PCR-ARMS) technique was used, complemented by direct DNA sequencing for uncharacterized cases. In 80 of the 95 patients, the beta-thal mutation was detected by PCR-ARMS. The most common allele encountered in our study was IVS-I-6 (T--\>C) (36.3\%); the second most common mutation was IVS-I-110 (G--\>A) (25.8\%). In addition, we report three homozygous cases for the promoter region -87 (C--\>G) allele with a frequency of 3.2\%. DNA sequencing of uncharacterized cases (14 cases, 15 alleles) revealed six cases (six alleles) of codon 27 (G--\>T), and three cases (three alleles) of the IVS-II-848 (C--\>A) mutation. Codon 37 (G--\>A) in the homozygous state was found in one patient with positive consanguinity. The frameshift codon 5 (-CT) mutation was detected in two of our uncharacterized cases. The codon 15 (TGG--\>TGA) mutations was detected in one patient (one allele, 0.5\%). All studied cases were fully characterized by this strategy. Screening for beta-thalassemic mutations using ARMS-PCR for the seven most frequent alleles in Egypt succeeded in determining the beta-globin genotype in 84.2\% of our patients (91.6\% of the expected alleles). To improve the efficiency of routine screening, the PCR-ARMS mutation panel should be updated to include the reported rare alleles. Direct DNA sequencing is an additional way to allow a full characterization of beta-thal patients in the Egyptian population.

}, keywords = {Amino Acid Sequence, Base Sequence, beta-Thalassemia, Child, Child, Preschool, consanguinity, DNA Mutational Analysis, Egypt, Female, Genetic Testing, Genetics, Population, Globins, Humans, Male, Mutation, Nucleic Acid Amplification Techniques, Point Mutation, Polymerase Chain Reaction}, issn = {0363-0269}, doi = {10.1080/03630260601057104}, author = {El-Gawhary, Somaia and El-Shafie, Shahira and Manal Niazi and Mona Aziz and Amal El-Beshlawy} } @article {117551, title = {Thrombopoietin level is increased in the serum of asphyxiated neonates: a prospective controlled study.}, journal = {Journal of perinatology : official journal of the California Perinatal Association}, volume = {25}, year = {2005}, month = {2005 May}, pages = {320-4}, abstract = {

BACKGROUND: Thrombopoietin (TPO) is a growth factor that controls platelet production. Despite the known association of chronic hypoxia and acute asphyxia with hematologic changes, TPO had not been studied in neonatal asphyxia.

OBJECTIVE: To assess TPO concentrations in the serum of asphyxiated and nonasphyxiated neonates, and examine any correlation with the severity of asphyxia.

DESIGN/METHODS: This prospective study was carried out on 32 asphyxiated neonates and 30 control subjects admitted at Cairo University Medical Center. Asphyxia was defined if two of the following were found: (1) Apgar score /=-10 and (3) clinical evidence of perinatal asphyxia. Encephalopathy was classified clinically according to Sarnat{\textquoteright}s stages during the first day of life. Platelet count and TPO level (pg/ml) were measured at 1st, 3rd and 7th day of life.

RESULTS: : TPO measured on the first day of life did not differ between cases and controls (900.2+/-526.4 vs 726.6+/-441.9 pg/ml, p=0.2). It increased on the 3rd day of life and was significantly higher in asphyxiated infants compared to controls (1291.4+/-627.9 vs 885.5+/-400.3 pg/ml, respectively; p=0.004). This difference remained significant in a logistic regression model controlling for birth weight, sex and mode of delivery (regression coefficient=476.9+/-146.8; p=0.002). In asphyxiated infants (n=32), encephalopathy was classified as mild (n=17), moderate (n=10) and severe (n=5). TPO correlated with the degree of clinical severity on the 7th day of life (r=0.59, p=0.003). TPO did not differ between survivors (n=24) and nonsurvivors (n=8) within the asphyxia group (1197.1+/-596.8 vs 1613.1+/-605.9 pg/ml; p=0.09). Platelet counts correlated negatively with TPO measured on day 1 (r=-0.415; p=0.02), day 3 (r=-0.64; p=0.001) and day 7 (r=-0.562; p=0.007).

CONCLUSIONS: TPO increased and correlated with severity of asphyxia at 3 and 7 days of life. It correlated negatively with the platelet count at all times.

}, keywords = {Apgar Score, Asphyxia Neonatorum, Biomarkers, Case-Control Studies, Critical Care, Enzyme-Linked Immunosorbent Assay, Female, Humans, Infant, Newborn, Intensive Care Units, Neonatal, Logistic Models, Male, Probability, Prognosis, Prospective Studies, Reference Values, risk assessment, Sensitivity and Specificity, Severity of Illness Index, Survival Analysis, Thrombopoietin}, issn = {0743-8346}, doi = {10.1038/sj.jp.7211287}, author = {Hany Aly and Amal ElBeshlawy and Badrawi, Nadia and Mohsen, Lamiaa and Mansour, Eman and Nermin Ramy and Patel, Kantilal} } @article {117550, title = {The Egyptian experience with oral iron chelators.}, journal = {Hematology (Amsterdam, Netherlands)}, volume = {10 Suppl 1}, year = {2005}, month = {2005}, pages = {174-5}, abstract = {

As no physiological mechanism exist for excreting transfusional iron overload in thalassemia, chelation therapy is the mandatory way to remove iron to prevent end organ damage and prolong survival. Desferoxamine (DFO) has been the major iron chelating agent used extensively worldwide for more than three decades for treatment of transfusional iron overload. However compliance has been a major obstacle in achieving an optimal therapeutic results. During the last 20 years the search for an affective oral iron chelators alternatives to Sc. DFO has been intensive. Different compounds have been studied, most of them although effective in animals have shown unacceptable toxicity with the exception of Deferiprone (L1) and ICL670.

}, keywords = {Benzoates, Egypt, Humans, Iron Chelating Agents, Iron Overload, Pyridones, Treatment Outcome, Triazoles}, issn = {1024-5332}, doi = {10.1080/10245330512331390302}, author = {Amal ElBeshlawy} } @article {117553, title = {Study of protein C, protein S, and antithrombin III in hypoxic newborns.}, journal = {Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies}, volume = {5}, year = {2004}, month = {2004 Mar}, pages = {163-6}, abstract = {

OBJECTIVE: The aim of this study was to clarify the effect of hypoxia on the physiologic inhibition system of coagulation including protein S, protein C, and antithrombin III and to study their effect on thromboembolic accidents of hypoxic newborns.

DESIGN: Clinical study including ten hypoxic-ischemic neonates and ten normal neonates as a control group.

DATA SOURCES: MEDLINE, pediatric textbooks, neonatal intensive care unit, Department of Paediatrics, Faculty of Medicine, Cairo University.

RESULTS: The results of this study revealed a marked decrease in the level of the physiologic inhibition system of coagulation including antithrombin III, protein C, and protein S in 100\% of the hypoxic-ischemic neonates compared with the control group (p \<.001) before the occurrence of thromboembolic complications. Fifty percent of the hypoxic-ischemic neonates developed disseminated intravascular coagulation and died, 40\% developed necrotizing enterocolitis and rectal bleeding, 20\% developed hematuria, 30\% developed hematemesis, 20\% developed intracranial hemorrhage, and 100\% had convulsions.

CONCLUSIONS: In this study, we evaluated the effect of asphyxia on the physiologic inhibition system of coagulation in neonates. Care providers should suspect hypoxia resulting from any obstructed labor and perform the necessary laboratory investigations for coagulation, including antithrombin III, protein C, and protein S levels, to help prevent thromboembolic accidents in asphyxiated neonates, including disseminated intravascular coagulation, necrotizing enterocolitis, and intracranial hemorrhage. Based on the development of antithrombin III and protein C concentrates, which are commercially available, require minimal monitoring, and have very few side effects, the time is ripe for evaluation of optimal treatment for thromboembolic accidents after neonatal asphyxia. This could be even more important if successful neuroprotectant strategies are also developed.

}, keywords = {Antithrombin III, Asphyxia, Disseminated Intravascular Coagulation, Enterocolitis, Necrotizing, Female, Hematemesis, hematuria, Humans, Hypoxia-Ischemia, Brain, Infant, Newborn, Intracranial Hemorrhages, Male, Protein C, Protein S, Seizures}, issn = {1529-7535}, doi = {10.1097/01.PCC.0000113261.13338.C3}, author = {Amal ElBeshlawy and Abou Hussein, Heba and Heba Hassan Abou-Elew and Mohamed Salah Eldin Mohamed Abdel Kader} } @article {117552, title = {Improvement of cardiac function in thalassemia major treated with L-carnitine.}, journal = {Acta haematologica}, volume = {111}, year = {2004}, month = {2004}, pages = {143-8}, abstract = {

INTRODUCTION: Heart disease secondary to chronic anemia and hemosiderosis remains the major cause of morbidity and mortality in thalassemic patients. Chronic anemia and the tissue hypoxia it induces impair free fatty acid oxidation and ATP production in myocardial cells. The use of L-carnitine, a butyric acid derivative, may help overcome some of these defects.

OBJECTIVE: To investigate the effect of L-carnitine therapy on cardiac function in thalassemia major patients.

MATERIALS AND METHODS: Cardiac function was evaluated in 30 patients attending our clinic. The mean (+/-SD) age was 15.87 +/- 3.19 years. The studies we performed included echocardiography, Doppler and multigated equilibrium radionuclide angiography (MUGA). Systolic and diastolic function was evaluated before starting L-carnitine treatment and after 6 months of oral L-carnitine (50 mg/kg/day).

RESULTS: Echocardiography studies revealed no significant changes in systolic and diastolic function after L-carnitine therapy (p \> 0.05). Analysis of the data taken by MUGA performed in 20 of the patients, however, showed a significant improvement of diastolic function after 6 months of L-carnitine therapy. The mean peak filling rate (end-diastolic volume/s) increased from 3.15 +/- 1.06 to 3.61 +/- 1.68 (p \< 0.03). The time to peak (during filling) decreased significantly from 143.45 +/- 42.04 to 117.70 +/- 24.40 s (p \< 0.02). Systolic function showed a significant increase in the left ventricular ejection fraction from 58.25 +/- 9.92 to 63.95 +/- 10.11\% (p = 0.0001).

CONCLUSION: L-carnitine may be an effective drug for improving the cardiac status of thalassemic patients. MUGA is the most accurate technique of those used here for assessing left ventricular function in these patients.

}, keywords = {Adolescent, Adult, Angiography, beta-Thalassemia, Carnitine, Child, Electrocardiography, Female, Heart Diseases, Heart Function Tests, Humans, Male, Stroke Volume, Ventricular Function, Left}, issn = {0001-5792}, doi = {10.1159/000076522}, author = {Amal El-Beshlawy and Ragab, Lamis and Alia Abdelfattah and Ibrahim, Ilham Youssry and HAMDY, MONA and Makhlouf, Ali and Aoun, Elie and Hoffbrand, Victor and Ali Taher} } @article {117554, title = {Study of 22 Egyptian patients with Diamond-Blackfan anemia, corticosteroids, and cyclosporin therapy results.}, journal = {Pediatrics}, volume = {110}, year = {2002}, month = {2002 Oct}, pages = {e44}, abstract = {

OBJECTIVE: Diamond-Blackfan anemia is a rare congenital hypoproliferative anemia of infancy and early childhood. Treatment with corticosteroids is commonly used, but with limited success. Trials with cyclosporin-A (CSA) are not frequently reported. Therefore, in this study we analyzed our results in the management of this rare disease by different medical treatments.

DESIGN: The results of 22 patients diagnosed at our Hematology Center in the New Cairo University Children{\textquoteright}s Hospital during the period 1991-2001 were retrospectively analyzed. Our patients first received prednisolone (2 mg/kg/d) for different courses according to their response. Since the year 2000, the steroid nonresponders received CSA (3-12 mg/kg/d) for 6 months unless treatment complications developed.

RESULTS: The age at the onset of the disease ranged from 1 to 24 months (median: 2.5 months). The mean values of the hemoglobin, the reticulocyte count, and the myeloid/erythroid ratio at the onset of the disease were 4.75 +/- 1.79 g/dL, 0.14 +/- 0.16, and 39.4 +/- 27.08, respectively. Patients received prednisolone from 0.25 to 10 years (median: 2 years). Ten patients were nonresponders (45.5\%), and 5 patients (22.7\%) responded to corticosteroid therapy. Two of 5 responders are off treatment with a hemoglobin level of \>9 g/dL, and 3 of 5 are currently corticosteroid-dependent. Of 10 patients not responding to steroids, 8 received CSA for 6 months. Four patients (50\%) responded to CSA therapy. A significant positive association was found between CSA dose and response.

CONCLUSION: CSA therapy should be tried in steroid-resistant Diamond-Blackfan anemia patients before blood transfusion or corticosteroid therapy complications are instituted.

}, keywords = {Age of Onset, Anemia, Diamond-Blackfan, Child, Child, Preschool, Cyclosporine, Drug Therapy, Combination, Egypt, Female, Glucocorticoids, Hemoglobins, Humans, Immunosuppressive Agents, Infant, Lectins, Male, Methylprednisolone, Prednisolone, Prednisone, Pregnancy, Pregnancy Complications, Hematologic, Reticulocyte Count, Retrospective Studies, Treatment Outcome}, issn = {1098-4275}, author = {Amal El-Beshlawy and Ibrahim, Ilham Youssry and samia rizk and Eid, Khalid} }