Efficacy and safety of deferasirox at low and high iron burdens: results from the EPIC magnetic resonance imaging substudy

The effect of deferasirox dosing tailored for iron burden and iron loading based on liver iron concentration (LIC) was assessed over 1 year in less versus more heavily iron-overloaded patients in a substudy of the Evaluation of Patients' Iron Chelation with ExjadeA (R). Deferasirox starting dose was 10-30 mg/kg/day, depending on blood transfusion frequency, with recommended dose adjustments every 3 months. Therapeutic goals were LIC maintenance or reduction in patients with baseline LIC < 7 or a parts per thousand yen7 mg Fe/g dry weight (dw), respectively. Changes in LIC (R2-magnetic resonance imaging) and serum ferritin after 1 year were assessed. Adverse events (AEs) and laboratory parameters were monitored throughout. Of 374 patients, 71 and 303 had baseline LIC < 7 and a parts per thousand yen7 mg Fe/g dw, respectively; mean deferasirox doses were 20.7 and 27.1 mg/kg/day (overall average time to dose increase, 24 weeks). At 1 year, mean LIC and median serum ferritin levels were maintained in the low-iron cohort (-0.02 A +/- 2.4 mg Fe/g dw, -57 ng/mL; P = not significant) and significantly decreased in the high-iron cohort (-6.1 A +/- 9.1 mg Fe/g dw, -830 ng/mL; P < 0.0001). Drug-related gastrointestinal AEs, mostly mild to moderate, were more frequently reported in the < 7 versus a parts per thousand yen7 mg Fe/g dw cohort (39.4 versus 20.8 %; P = 0.001) and were not confounded by diagnosis, dosing, ethnicity, or hepatitis B and/or C history. Reported serum creatinine increases did not increase in low- versus high-iron cohort patients. Deferasirox doses of 20 mg/kg/day maintained LIC < 7 mg Fe/g dw and doses of 30 mg/kg/day were required for net iron reduction in the high-iron cohort, with clinically manageable safety profiles. The higher incidence of gastrointestinal AEs at lower iron burdens requires further investigation

PENGARUH PEMBELAJARAN KEWIRAUSAHAAN DAN EKSTRAKURIKULER WAJIB KEPRAMUKAAN TERHADAP KARAKTER KEWIRAUSAHAAN (Studi Kasus Peserta Didik Kelas XI SMA YPI Bandung)

Penelitian ini bertujuan untuk memperoleh data mengenai 1. Pembinaan karakter kewirausahaan pada pembelajaran kewirausahaan pokok pembahasan produksi ikan konsumsi peserta didik kelas XI SMA YPI Bandung, 2. Pembinaan karakter kewirausahaan di Gugus depan 03021-03022 pangkalan SMA YPI Bandung, 3. Karakter kewirausahaan peserta didik kelas XI SMA YPI Bandung, 4. Pengaruh pembinaan karakter kewirausahaan melalui pembelajaran kewirausahaan pokok bahasan produksi ikan konsumsi peserta didik kelas XI SMA YPI Bandung, 5. Pengaruh pembinaan karakter kewirausahaan dalam ekstrakurikuler wajib kepramukaan di Gugus depan 03021-03022 pangkalan SMA YPI Bandung. Metode penelitian yang dipergunakan metode survei tingkat eksplanasi asosiatif kausal. Teknik pengumpulan data dengan cara studi pustaka, kuesioner, dan observasi. Populasi pada penelitian ini, yaitu peserta didik kelas XI SMA YPI Bandung semester I yang berjumlah 22 orang. Hipotesis pada penelitian ini, yaitu 1. Terdapat pengaruh pembelajaran kewirausahaan terhadap karakter kewirausahaan peserta didik kelas XI SMA YPI Bandung, 2 Terdapat pengaruh ekstrakurikuler kepramukaan terhadap karakter kewirausahaan peserta didik kelas XI SMA YPI Bandung. Teknik pengolahan data menggunakan uji validitas, uji reliabilitas, uji normalitas data, analisis regresi linier sederhana, dan koefisien determinasi dengan menggunakan program SPSS 20.0 for windows. Hasil pengolahan data menunjukkan bahwa, 1. Pembinaan karakter kewirausahaan pada pembelajaran kewirausahaan peserta didik kelas XI SMA YPI menunjukkan kategori Baik dengan rata-rata 3,85, 2. Pembinaan karakter kewirausahaan di Gugus depan 03021-03022 pangkalan SMA YPI Bandung menunjukkan kategori Baik dengan rata-rata 3,78, 3. Karakter kewirausahaan peserta didik kelas XI SMA YPI Bandung menujukkan kategori Sangat Baik dengan rata-rata 4,04, 4. T¬erdapat pengaruh pembelajaran kewirausahaan terhadap karakter kewirausahaan peserta didik senilai 4,7 % itu berarti Y sebagian kecil dipengaruhi oleh X1, arti Ha1 dapat diterima dan Ho1 ditolak, 5. Terdapat pengaruh ekstrakurikuler kepramukaan terhadap karakter kewirausahaan peserta didik senilai 27,6 % itu berarti Y hampir setengahnya dipengaruhi oleh X2, arti Ha2 dapat diterima dan Ho2 ditolak. Kesimpulan dari penelitian ini yaitu secara parsial terdapat pengaruh positif pembelajaran kewirausahaan dan ekstrakurikuler kepramukaan terhadap karakter kewirausahaan peserta didik kelas XI SMA YPI Bandung. Sebagai akhir penelitian penulis menyampaikan saran kepada sekolah, guru, dan pembina Pramuka agar pembelajaran dan pelatihan dioptimalkan sebagai salah satu strategi untuk meningkatkan karakter kewirausahaan peserta didik. Kata kunci: Pembelajaran Kewirausahaan, Ekstrakurikuler Kepramukaan, Karakter Kewirausahaan

Amustaline-glutathione pathogen-reduced red blood cell concentrates for transfusion-dependent thalassaemia

Transfusion-dependent thalassaemia (TDT) requires red blood cell concentrates (RBCC) to prevent complications of anaemia, but carries risk of infection. Pathogen reduction of RBCC offers potential to reduce infectious risk. We evaluated the efficacy and safety of pathogen-reduced (PR) Amustaline-Glutathione (A-GSH) RBCC for TDT. Patients were randomized to a blinded 2-period crossover treatment sequence for six transfusions over 8–10 months with Control and A-GSH-RBCC. The efficacy outcome utilized non-inferiority analysis with 90% power to detect a 15% difference in transfused haemoglobin (Hb), and the safety outcome was the incidence of antibodies to A-GSH-PR-RBCC. By intent to treat (80 patients), 12·5 ± 1·9 RBCC were transfused in each period. Storage durations of A-GSH and C-RBCC were similar (8·9 days). Mean A-GSH-RBCC transfused Hb (g/kg/day) was not inferior to Control (0·113 ± 0·04 vs. 0·111 ± 0·04, P = 0·373, paired t-test). The upper bound of the one-sided 95% confidence interval for the treatment difference from the mixed effects model was 0·005 g/kg/day, within a non-inferiority margin of 0·017 g/kg/day. A-GSH-RBCC mean pre-transfusion Hb levels declined by 6·0 g/l. No antibodies to A-GSH-RBCC were detected, and there were no differences in adverse events. A-GSH-RBCCs offer potential to reduce infectious risk in TDT with a tolerable safety profile

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

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 ± 9.4 mg Fe/g dw (baseline 19.6 ± 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

Worldwide survey of T2* cardiovascular magnetic resonance in Thalassaemia

Introduction Thalassaemia major (TM) affects hundreds of thousands of patients worldwide but only a minority have access to regular blood transfusion and chelation therapy. Cardiovascular magnetic resonance (CMR) T2* measurement provides an accurate, reproducible measurement of cardiac iron which is the cause of heart failure and early death in many transfused TM patients. This technique has been adopted as part of routine management in many countries where survival is now approaching normal but little is known about the severity and effects of myocardial iron loading in different geographical regions. Purpose The aim of this study was to describe the burden of disease of myocardial siderosis (measured by T2*) in different populations throughout the world and to assess the relationship between T2* and outcome such as heart failure and cardiac death. Methods 34 worldwide centres were involved in this survey of 3376 patients from Europe, the Middle East, North America, South America, North Africa, Australia and Asia. Anonymised data on myocardial T2* values were analysed in conjunction with clinical outcomes (heart failure and death). Results Overall, 57.5% of patients had no significant iron loading (T2* >20ms), 22.6% had moderate cardiac iron (10ms50%) in South-East Asia had cardiac iron (T2* >20ms) at baseline. At the time of the first scan, 100 patients (3.3%) had confirmed heart failure, the majority of whom (77.0%) had myocardial T2* <10ms with almost all (99%) having T2* <20ms. There were 113 patients who subsequently developed heart failure. 92.0% of these had T2* <10ms and 99.1% had a T2* <20ms. There were 39 deaths. Cardiac T2* values were <10ms in 79.5%, with 92.3% <20ms. Conclusions Even in this well-treated cohort with access to transfusion, chelation and CMR, there is a large proportion of TM patients with moderate to severe cardiac iron loading. Low T2* (<10ms) is associated with cardiac failure and death. There is a huge unmet worldwide need in terms of access to specialist medical care (including transfusion and chelation therapy) together with advanced monitoring techniques (such as CMR)

Recommendations for Pregnancy in Rare Inherited Anemias

Rare inherited anemias are a subset of anemias caused by a genetic defect along one of the several stages of erythropoiesis or in different cellular components that affect red blood cell integrity, and thus its lifespan. Due to their low prevalence, several complications on growth and development, and multi-organ system damage are not yet well defined. Moreover, during the last decade there has been a lack of proper understanding of the impact of rare anemias on maternal and fetal outcomes. In addition, there are no clear-cut guidelines outlining the pathophysiological trends and management options unique to this special population. Here, we present on behalf of the European Hematology Association, evidence- and consensus-based guidelines, established by an international group of experts in different fields, including hematologists, gynecologists, general practitioners, medical geneticists, and experts in rare inherited anemias from various European countries for standardized and appropriate choice of therapeutic interventions for the management of pregnancy in rare inherited anemias, including Diamond-Blackfan Anemia, Congenital Dyserythropoietic Anemias, Thalassemia, Sickle Cell Disease, Enzyme deficiency and Red cell membrane disorders

Health related quality of life in Malaysian children with thalassaemia

BACKGROUND: Health Related Quality of Life (HRQoL) studies on children with chronic illness such as thalassaemia are limited. We conducted the first study to investigate if children with thalassaemia have a lower quality of life in the four dimensions as measured using the PedsQL 4.0 generic Scale Score: physical, emotional, social and role (school) functioning compared to the healthy controls allowing for age, gender, ethnicity and household income. METHODS: The PedsQL 4.0 was administered to children receiving blood transfusions and treatments at Hospital Kuala Lumpur, Malaysia using PedsQL 4.0 generic Scale Score. Accordingly, the questionnaire was also administered to a control group of healthy school children. Socio-demographic data were also collected from patients and controls using an interview schedule designed for the study. RESULTS: Of the 96 thalassaemia patients approached, 78 gave consent to be interviewed giving a response rate of 81.3%. Out of 235 healthy controls approached, all agreed to participate giving a response rate of 100%. The mean age for the patients and schoolchildren is 11.9 and 13.2 years respectively. The age range for the patients and the schoolchildren is between 5 to 18 years and 7 to 18 years respectively. After controlling for age and demographic background, the thalassaemia patients reported having significantly lower quality of life than the healthy controls. CONCLUSION: Thalassaemia has a negative impact on perceived physical, emotional, social and school functioning in thalassaemia patients which was also found to be worse than the children's healthy counterparts. Continuing support of free desferal from the Ministry of Health should be given to these patients. More understanding and support especially from health authorities, school authorities and the society is essential to enhance their quality of life

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia

BACKGROUND: Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.)