Search

Luspatercept has been shown to act as a ligand trap, selectively suppressing the deleterious effects of GDF11 that blocks terminal erythroid maturation, restoring normal erythroid differentiation and improving anemia in animal models of β-thalassemia. Effective doses of luspatercept achieved hemoglobin increase within 7 days of the first dose, and plasma half-life supports subcutaneously administration every 21 days in adults with β-thalassemia. A Phase 3, placebo-controlled 1-year study with starting dose of 1.0 up to 1.25 mg/kg every 21 days achieved ≥33% reduction in red cell transfusion volume in 21.4% of adult transfusion-dependent β-, HbE/β-thalassemia patients on luspatercept vs. 4.5% on placebo over a fixed 12-week period, and 41.1% of patients in luspatercept vs. 2.7% placebo in any 24-week period. Luspatercept allowed ≥1.0 and ≥1.5 g/dL increase in hemoglobin from baseline in 77% and 52.1% of adult non-transfusion-dependent β-, HbE/β-thalassemia patients vs. 0% placebo over a 12-week interval. Although not significant, a greater improvement in patient-reported outcomes was observed with luspatercept. Luspatercept had a manageable safety profile with notable adverse effects of venous thromboembolism in 3.6% of transfusion-dependent β-thalassemia vs. 0.9% of placebo and extramedullary hematopoiesis in 6% of non-transfusion-dependent β-thalassemia vs. 2% of placebo. The pediatric study started patients’ enrollment.

β‐thalassemia major is an inherited hemoglobinopathy that requires lifelong red blood cell transfusions and iron chelation therapy to prevent complications due to iron overload. Traditionally, β‐thalassemia has been more common in certain regions of the world such as the Mediterranean, Middle East, and Southeast Asia. However, the prevalence of β‐thalassemia is increasing in other regions, including Northern Europe and North America, primarily due to migration. This review summarizes the available data on the changing incidence and prevalence of β‐thalassemia as well as factors influencing disease frequency. The data suggest that the epidemiology of β‐thalassemia is changing: Migration has increased the prevalence of the disease in regions traditionally believed to have a low prevalence, while, at the same time, prevention and screening programs in endemic regions have reduced the number of affected individuals. Various approaches to prevention and screening have been used. Region‐specific prevention and treatment programs, customized to align with local healthcare resources and cultural values, have been effective in identifying patients and carriers and providing information and care. Significant challenges remain in universally implementing these programs.

Background: Proper clinical use of blood and blood products requires competent theoretical and practical knowledge of transfusion medicine. The Curriculum Development and Standard Determination System Medical Specialization Board is prepared Hematology Specialist Education Core Curriculum in Turkey. In this study, we aimed to determine the access of hematologists to the learning objectives defined by curriculum for the transfusion medicine and the factors affecting it.Methods: Hematologists who have been members of Turkish Hematology Society since 2013 have been included in the study, The survey questions were prepared based on the curriculum for transfusion medicine. The study was applied to hematologists with "survey monkey" application. The questionnaire consisted of a competence self-assessment with Likert scale and theoretical multiple-choice knowledge questions. Results: Of the 213 hematologists, 54 (25%) were included in the study. Hematologists rated their competences in the clinical competence areas as 3,65 ± 0,73 (median 3,60) as "I know but not t a sufficient level". The participants 'perception of competence was "I know, but not at a sufficient level'" with an average of 3.31 ± 0.84 (median3.5) in the blood banking field, while the average in hemapheresis and transfusion medicine was 4.04 ± 0.63 (median 4) as "enough". In interventional procedures, hematologists stated that their vocational competences were 2,79± 0,92 (median 2,93) on average as "I have an idea- I know, but not enough". The correct answer to 13 theoretical questions was an average of 6,96 ± 1,89 (median 7). Hematologists performing blood rotation felt significantly more competent than the physicians who could not do the rotation in the blood bank, blood banking t(52) = -3.9, p < .001 , transfusion medicine and interventional competence t(52) = -2.2, p = .04 . Physicians who believed that they are sufficient in the blood banking area, were more confident in transfusion medicine r(54) = .67, p

Monitoring liver and cardiac iron stores by magnetic resonance imaging (MRI) enables identifying patients at risk of organ-specific morbidity and better tailoring of iron chelation therapy in thalassemia. Nevertheless, serum ferritin (SF) remains the only tool for monitoring iron status in most resource-poor regions. In this study, we assessed the impact of using MRI techniques to guide iron chelation therapy on iron overload outcomes in a cohort of 99 patients with thalassemia major (TM, mean age at baselines 20.7 +/- 6.9 years) followed from 2006 to 2019. We also assessed the ability of SF trends to predict changes in consecutive liver iron concentration (LIC) and cardiac T2* (cT2*) measurements. The most commonly used chelator was deferasirox at baseline (65%) and final (72%) assessments. Overall, patients with safe LIC values (< 7 mg/g dw) increased from 57 to 77%, and safe cT2* values (> 20 ms) increased from 72 to 86%. We obtained the most significant improvement in patients with severe and moderate liver (p = 0.006 and p < 0.001) and cardiac (p < 0.0013 and p < 0.0001) iron overload at baseline. SF trends were in the same direction in 64% of changes in LIC, but only 42% of changes were proportional. Most of the changes in SF (64%) and LIC (61%) could not predict changes in cT2*. Moreover, downward trends in SF and LIC were associated with worsening cardiac iron in 29% and 23.5% of consecutive cT2* measurements. Liver and cardiac MRI-driven oral iron chelation improved the iron status of subjects with TM and demonstrated the importance of using validated MRI techniques in critical clinical decisions.

Introduction: Cytomegalovirus (CMV) infections in developing countries are experienced at an early age. This study was performed to investigate the frequency of reactivation and risk factors of infection acquired at an early age of nontransplant acute lymphoblastic leukemia (ALL) patients receiving immunosuppressive therapy with weekly monitoring of CMV levels in Turkey. Materials and Methods: This was a retrospective, single-center study of 172 pediatric patients (102 boys and 70 girls) with ALL. All patients were monitored routinely for CMV-DNA at the initial presentation of leukemia and twice a week during chemotherapy. The CMV immunoglobulin (Ig)M/IgG titers were measured at admission. Results: CMV seropositivity at baseline was 90,11%. The overall prevalence of CMV infection (viremia) was 70.34%, 116 of whom were seropositive for CMV IgG and 5 of whom were negative for CMV at the time of ALL diagnosis. Reactivation was more common than de novo CMV infections (P=0.000). CMV seropositivity at the beginning of the leukemia diagnosis was found to be an independent predictor for developing CMV infection (P=0.001). A total of 60 CMV infection episodes were treated with antivirals. Four of these included organ involvement. The duration of CMV-DNA viremia episodes was longer in patients with CMV-DNA >= 1000 copies/mL (n=45) than in those with lower CMV-DNA levels (P=0.002). Infection was shown not to be associated with chemotherapy phase. Conclusion: This study suggests the importance of monitoring for CMV infections in developing countries because of frequent reactivations in seropositive ALL patients. It should be kept in mind that low CMV-DNA levels may also lead to organ involvement.

WOS: 000478608100031, PubMed ID: 31148155, 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 center dot 5 +/- 1 center dot 9 RBCC were transfused in each period. Storage durations of A-GSH and C-RBCC were similar (8 center dot 9 days). Mean A-GSH-RBCC transfused Hb (g/kg/day) was not inferior to Control (0 center dot 113 +/- 0 center dot 04 vs. 0 center dot 111 +/- 0 center dot 04, P = 0 center dot 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 center dot 005 g/kg/day, within a non-inferiority margin of 0 center dot 017 g/kg/day. A-GSH-RBCC mean pre-transfusion Hb levels declined by 6 center dot 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., Ege University Hospital Blood Centre, Izmir, Turkey

International audience; 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.

Background: Proper clinical use of blood products requires competent theoretical and practical knowledge of transfusion medicine. In this study, we aimed to evaluate levels of transfusion medicine knowledge and attainment of educational targets and identify factors affecting the education of transfusion medicine. Methods: A multicentric survey study was performed among final-year medical students. The questions were prepared based on learning objectives for transfusion medicine curriculum. The questionnaire focused on the safety of blood transfusion administration. Results: The survey included 727 (24%) of 3009 students enrolled in 13 medical schools. In the competence self-assessment, 65% of the students reported that transfusion medicine education was insufficient. Only 14% felt competent in recognizing transfusion complications and applying first-line treatment. For initiating and monitoring transfusions, 41% stated they could manage under supervision and 7% stated they had sufficient practice, while the remaining 52% considered themselves completely insufficient in this area. The 10 questions assessing basic knowledge and attainment of educational targets had 53 choices. This indicates that intern doctors were not able to recognize 50% of the correct and 30% of the incorrect information. Conclusion: A large proportion of medical students did not have adequate theoretical knowledge or self-assessed practical competency in transfusion medicine.

Effective iron chelation therapy is an important part of treatment in patients with transfusion-dependent thalassaemia and lower-risk myelodysplastic syndromes (MDS). Key strategies for optimising iron chelation therapy include ensuring good adherence and preventing and managing adverse events (AEs). Good adherence to iron chelation therapy with deferoxamine and deferasirox has been linked to improved survival and/or reductions in complications related to iron overload; however, maintaining good adherence to iron chelators can be challenging. Patients with transfusion-dependent thalassaemia or lower-risk MDS showed better adherence to the deferasirox film-coated tablet (FCT) formulation than to the deferasirox dispersible tablet formulation in the ECLIPSE trial, reflecting in part the improved palatability and convenience of deferasirox FCT. As well as affecting adherence, AEs may lead to dose reduction, interruption or discontinuation, resulting in suboptimal iron chelation therapy. Preventing and successfully managing AEs may help limit their impact on adherence, and following dosage and administration recommendations for iron chelators such as deferasirox may help minimise AEs and optimise treatment in patients with transfusion-dependent thalassaemia and lower-risk MDS.

Introduction of MRI techniques for identifying and monitoring tissue iron overload and the current understanding of iron homeostasis in transfusion-dependent (TDT) and non-transfusion-dependent thalassemia have allowed for a more robust administration of iron chelation therapies. The development of safe and efficient oral iron chelators and the insights gained from large-scale prospective studies using these agents have improved iron overload management. A significant reduction in iron toxicity-induced morbidity and mortality and improvements in quality of life were observed in TDT. The appropriate management of tissue-specific iron loading in TDT has been portrayed using evidence-based data obtained from investigational studies.

WOS: 000426572200002, PubMed ID: 28404539, Objective: The Turkish Society of Pediatric Hematology set up a National Hemoglobinopathy Registry to demonstrate the demographic and disease characteristics of patients and assess the efficacy of a hemoglobinopathy control program (HCP) over 10 years in Turkey. Materials and Methods: A total of 2046 patients from 27 thalassemia centers were registered, of which 1988 were eligible for analysis. This cohort mainly comprised patients with beta-thalassemia major (n = 1658, 83.4%) and intermedia (n = 215, 10.8%). Results: The majority of patients were from the coastal areas of Turkey. The high number of patients in Southeastern Anatolia was due to that area having the highest rates of consanguineous marriage and fertility. The most common 11 mutations represented 90% of all beta-thalassemia alleles and 47% of those were IVS1-110(G->A) mutations. The probability of undergoing splenectomy within the first 10 years of life was 20%, a rate unchanged since the 1980s. Iron chelators were administered as monotherapy regimens in 95% of patients and deferasirox was prescribed in 81.3% of those cases. Deferasirox administration was the highest (93.6%) in patients aged, Ege Children's Foundation; Novartis Pharmaceuticals CorporationNovartis, The authors thank Caglar Serdar, Aylin Gokduman, and Tolga Turgay of Plexus Information Technologies for their website support. The current study and the work presented here are from an Investigator Initiated Trial, which was sponsored by the Ege Children's Foundation and funded by Novartis Pharmaceuticals Corporation.

63rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) -- DEC 11-14, 2021 -- Atlanta, GA, [No Abstract Available], Amer Soc Hematol

Introduction: Growth retardation (GR) and pubertal disturbances are the earliest consequences of iron toxicity resulting from the pituitary iron deposition in children and adolescents with thalassemia major (TM). It is suggested that adequate transfusion regimens together with appropriate management of iron chelation with timely initiation and dose tailoring by close monitoring using surrogate markers of the iron load may achieve a normal pattern of complication-free survival in TM. Objectives: The purpose of this study was to evaluate the fact that the current approach to the management of the disease has provided a normal growth progression and sexual development in patients (pts) with TM. Methods: We recruited male (M) and female (F) TM pts born after 2000 and followed-up (FU) in Ege University Thalassemia Center. The pts. with an acute or chronic illness that may interfere with growth and development or stem cell transplantation recipients were excluded. The Committee of Clinical Investigation at Ege University Hospital (19.02.2020, 20-2.1T/2) approved this study. Height (H) and weight (W) assessments were performed by using the Harpenden stadiometer and puberty was evaluated by Tanner staging at 3 monthly intervals. H-standard deviation scores (h-SDS) were calculated. Target-H based on mid-parental-H for M & F pts was estimated. All pts. were evaluated annually for bone mineral density (BMD) using dual-energy X-ray absorptiometry (Hologic QDR-4500W, USA) after 8 years (y) of age. The mean SDS of the lumbar spine (L1-4) BMD between -1 and -2.5 was defined as osteopenia and Transfused pRBC units (U) and average pre-transfusion hemoglobin (Hb) per year were recorded. Serum ferritin (SF) was monitored at monthly intervals. Myocardial (T2*) and liver (R2) iron were assessed by a 1.5 Tesla magnetic resonance imaging (MRI) machine (Siemens, Symphony Vision 16034 scanner) after 8 y. Annual median SF, prescribed chelator(s), mean chelator doses were recorded by reviewing pts' records. Transfusional iron intake (TII) was estimated as the total amount of pure RBCs (each U, 250 ml with 57% Hct) transfused in a y (ml) x 1.08. Daily TII was expressed as annual TII (mg)/ mean kg b.w./days of the y. Results: We recruited 30 TM (28 β/β, 1 β/δβ, and 1 non-deletional HbH) pts (13 F and 17 M). Demographics for the population are summarized in Table1. All pts maintained annual mean pre-transfusion Hb> 9 g/dl. Twenty-two of 24 pts maintained Deferasirox (DFX) chelation during 9 ± 3.6 y (median 9, range 2-13 y) and achieved optimum SF levels at all times (Figure a). The dose tailoring of DFX found parallel to the changes in TII during FU (Figure b). Liver iron concentration (LIC) and myocardial T2* (mT2*) in 22 pts on DFX chelation were between 0.9-5.4 (2.1 ± 1.3 SD) mg Fe/g d.w. and 19.4-43.5 (28 ± 6.7 SD) ms, respectively, in all assessments. The only pt with mT2* of 19.4 ms revealed mT2* of >20 ms on FU scans. The puberty initiated at 12.8 ± 1.1 y in M (n=12) & 11.2 ± 1.3 y in F (n=12) and progressed without hormone replacement in all, regardless of the chelator. Overall, growth reduced compared to the non-thalassemic population after 8 y with clear evidence of growth catch-up by the introduction of puberty. h-SDS detected Conclusions: Puberty was the main determinant of growth and bone maturation in TM. Despite, puberty has achieved within physiological limits in M & F pts, a slight delay was observed compared to the non-thalassemic population. The relative delay in pubertal spurt may lead to overdiagnosis of growth and bone-maturation failure and unnecessary intervention in adolescent TM pts. This hypothesis as well as the appropriateness of current management guidelines remains to be elucidated. Disclosures No relevant conflicts of interest to declare.

Purpose To compare the effects of the care bundles including chlorhexidine dressing and advanced dressings on the catheter-related bloodstream infection (CRBSI) rates in pediatric hematology-oncology patients with central venous catheters (CVCs). Method Twenty-seven PHO patients were recruited to participate in a prospective, randomized study in Turkey. The researcher used care bundles with chlorhexidine dressing in the experimental group (n = 14), and care bundles with advanced dressings in the control group (n = 13). Results According to the study results, 28.6% of the patients in the experimental group had CRBSI, while this rate was 38.5% in the control group patients. The CRBSI rate in the experimental group was 3.9, and the control group had 4.4 per 1000 inpatient catheter days. There was no exit-site infection in the experimental group. However, the control group had 1.7 per 1000 inpatient catheter days. Conclusions Even though there was no difference between the two groups in which the researcher implemented care bundles with chlorhexidine dressing and advanced dressings in terms of CRBSI development, there was reduction in the CRBSI rates thanks to the care bundle approach. It is possible to control the CRBSI rates using care bundles in pediatric hematology-oncology patients.

In beta-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by beta-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle-promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-X(L). The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.

Objective: In recent years, the rates of marriage and pregnancy are increasing in patients with thalassemia major. The aim of the present study was to investigate the fertility rate of thalassemic patients and the course of pregnancies in terms of mother and infant health. Materials and Methods: In this observational study patients with major hemoglobinopathy were evaluated regarding marital status, the need for assisted reproductive techniques, fertility rate, iron status, and pregnancy complications. Results: Seventeen female patients gave birth to 21 healthy infants. About one-third of the patients needed assisted reproductive techniques. Thalassemia major patients showed increased serum ferritin levels from 1203±1206 µg/L at baseline to 1880±1174 µg/L at the end of pregnancy. All babies are still alive and healthy. Conclusion: Pregnancy in patients with thalassemia can be safe for the mother and newborn with close monitoring and a multidisciplinary approach., Amaç: Son yıllarda, talasemi majör olgularının evlilik ve gebelik oranları giderek artmaktadır. Bu çalışmanın amacı, talasemi hastalarının fertilite oranlarının araştırılması ve anne ve bebek sağlığı açısından gebelik sonuçlarının değerlendirilmesidir. Gereç ve Yöntemler: Bu gözlemsel çalışmada; majör hemoglobinopatili hastalar; evlenme ve çocuk sahibi olma oranları, yardımcı üreme tekniklerine gereksinimleri, demir statüleri ve gebelik komplikasyonları açısından değerlendirilmiştir. Bulgular: On yedi talasemik kadın hasta, toplam 21 sağlıklı bebek doğurmuştur. Hastaların üçte biri bebek sahibi olabilmek için yardımcı üreme tekniğine ihtiyaç duymuştur. Talasemi majör olgularının serum ferritin değerleri hamileliğin başında ortalama 1203±1206 ug/L saptanmış olup, hamileliğin sonunda 1880±1174 ug/L seviyesine yükselmiştir. Tüm bebekler halen hayatta ve sağlıklıdırlar. Sonuç: Talasemi olgularında hamilelik süreci yakın takip ve multidisipliner yaklaşım ile beraber güvenli olarak geçirilebilecektir.

EgeUn###, Central line–associated bloodstream infections (CLABSIs) are still a major cause of morbidity and mortality in pediatric hematology-oncology patients in many countries. This cross-sectional study was a retrospective review of CLABSI in inpatient pediatric hematology-oncology cases with long-term central venous catheter at the Pediatric Hematology Department from January 2013 to June 2014. Characteristics of CLABSI events in pediatric patients with hematologic malignancies and related nonmalignant hematologic conditions are documented. CLABSI developed in 61.8% (n = 21) of the 34 hospitalized patients included in the study. The CLABSI rate was 7.8 per 1,000 inpatient central venous catheter days. Coagulase-negative staphylococci was the predominant pathogen in 47.6% of the patients with CLABSI. The high rate of CLABSI requires prevention strategies to reduce CLABSI immediately. This study provides guidance in prioritizing strategies for reducing rates of infection. © 2019 by Association of Pediatric Hematology/Oncology Nurses.

Amac : Bu calismada akut lenfoblastik losemi (ALL) on tanili olgularda t(12;21) translokasyonu gercek zamanli kantitatif revers transkriptaz polimeraz zincir reaksiyonu (qRT-PZR) yontemi kullanilarak kantite edildi. Hastalar ve yontemler : Ocak 2009 - Aralik 2013 tarihleri arasinda Ege Universitesi Tip Fakultesi Tibbi Biyoloji Anabilim Dali’na basvuran 175 pediatrik ve 138 eriskin olmak uzere toplam 313 olguya ait kan ve kemik iligi orneklerinde t(12;22) (p13;q22) translokasyonu RNA sonuclari kantitatif olarak degerlendirildi. Olgulara ait 75 kan ve 484 kemik iligi orneklerinden total RNA veya haberci RNA izole edildi. RNA izolasyonlarinin ardindan tamamlayici DNA sentezi gerceklestirildi. t(12;21) (p13;q22) translokasyon calismasi LightCycler t(12;21) Kit’i ile fuzyon transkripte ozgul bicimde tasarlanmis primer ve problarla (Way2Gene) uygun olacak sekilde gerceklestirildi. Son adim olarak, t(12;21) translokasyon sonuclarinin kantitatif olarak degerlendirilmesi gercek zamanli qRT-PZR yontemi kullanilarak LightCycler2 ile gerceklestirildi. Bulgular : Otuz dort pediatrik olgu orneginde (%19) ve 17 eriskin olgunun orneginde (%12) TEL-AML-1 (ETV6-RUNX1) pozitif bulundu. TEL-AML1 (ETV6-RUNX1) kantitasyon degeri ortalamasi pediatrik olgularda 0.90±3.21, eriskin olgularda ise 0.34±1.20 olarak belirlendi. Sonuc : Elde ettigimiz veriler, gercek zamanli qRT-PZR yontemi ile ALL hastalarinda yeni tani doneminde ve tedavi surecinde t(12;21) translokasyonunun kantitatif tayininin hem taninin kesinlestirilmesinde hem de molekuler remisyon saglanmasina yonelik tedaviyi yonlendirmesinde degerli bir yontem oldugunu desteklemektedir.

WOS: 000370467700004, PubMed ID: 26852651, Efficacy and safety of iron chelation therapy with deferasirox in iron-overloaded non-transfusion-dependent thalassaemia (NTDT) patients were established in the THALASSA study. THETIS, an open-label, single-arm, multicentre, Phase IV study, added to this evidence by investigating earlier dose escalation by baseline liver iron concentration (LIC) (week 4: escalation according to baseline LIC; week 24: adjustment according to LIC response, maximum 30 mg/kg/day). The primary efficacy endpoint was absolute change in LIC from baseline to week 52. 134 iron-overloaded non-transfusion-dependent anaemia patients were enrolled and received deferasirox starting at 10 mg/kg/day. Mean actual dose +/- SD over 1 year was 14.70 +/- 5.48 mg/kg/day. At week 52, mean LIC SD decreased significantly from 15.13 +/- 10.72 mg Fe/g dw at baseline to 8.46 +/- 6.25 mg Fe/g dw (absolute change from baseline, -6.68 +/- 7.02 mg Fe/g dw [95% CI: -7.91, -5.45]; P, Novartis Pharma AG; Novartis Pharmaceuticals, This study was funded by Novartis Pharma AG. We thank Rebecca Helson, PhD, of Mudskipper Business Ltd. for medical editorial assistance. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals.

Introduction. LPS-responsive beige-like anchor (LRBA) protein deficiency is a disease of immune dysregulation with autoimmunity affecting various systems. Case Presentation. Two male siblings with a novel LRBA mutation had different primary findings at admission: the younger sibling had chronic early-onset diarrhoea and the elder one had autoimmune haemolytic anaemia. During long-term follow-up for IPEX phenotype, both developed hypogammaglobulinaemia, enteropathy and lung involvement. The patients partially responded to immunosuppressive therapies. A homozygous c.2496C>A, p.Cys832Ter (p.C832*) mutation in the LRBA gene causing a premature stop codon was detected. After molecular diagnosis, abatacept, as a target-specific molecule, was used with promising results. Conclusion. LRBA deficiency is a recently defined defect, with variable presentations in different patients; a single, definitive treatment option is thus not yet available.

WOS: 000434010200026, PubMed ID: 29756724, Toxic epidermal necrolysis and Stevens-Johnson syndrome are rare mucocutaneous diseases which are associated with a prolonged course and potentially lethal outcome. They are mostly drug induced and mortality rates are very high. Although mostly skin is involved, multiple organ systems such as cardiovascular, pulmonary, gastrointestinal, and urinary systems may be affected. Here, we report a case of Stevens-Johnson Syndrome associated with methotrexate treatment who developed acute cardiac failure and gastrointestinal hemorrhage beside skin findings. He had been treated with intravenous immunglobulin and methylprednisolone succesfully and continued chemotherapy with methotrexate treatment again.

Amaç: t(4;11), MLL-AF4 translokasyonu sonucu oluşan, 4q21 kromozomal bandına yerleşim gösteren AF4 geninin 11q23 kromozomal bandına yerleşim gösteren MLL genine füzyonu sonucu gelişen kromozomal bir anomalidir. Bu çalışmada, retrospektif olarak 2009-2013 yılları arasındaki akut lenfoblastik lösemi (ALL) hastalarındaki t(4;11) MLL- AF4 translokasyonunun analiz sonuçlarının incelenmesi amaçlandı. Gereç ve Yöntem: Ege Üniversitesi Tıp Fakültesi Tıbbi Biyoloji Anabilim Dalı’na 2009-2013 yılları arasında akut lösemi ön tanısıyla 176 çocuk (70 kız, 106 erkek) ve 144 yetişkin (60 kadın, 84 erkek) olgunun kan veya kemik iliği örnekleri incelendi. Bu olgulara ait 71 kan ve 473 kemik iliği örneğinin t(4;11) translokasyon RNA sonuçları, gerçek zamanlı RT-PCR yöntemi ile kantitatif olarak değerlendirildi. İlk aşamada, kan ve kemik iliği örneklerinden izole edilen total RNA veya mRNA’dan konvansiyonel bir PCR cihazı ile komplementer DNA sentezlendi. İkinci aşamada, gerçek zamanlı PCR cihazı ile t(4;11) kantitasyonu gerçekleştirildi. Olguların kantitatif olarak değerlendirilmesi, pozitif kontrol ve negatif kontrolün karşılaştırılması ile örneklerin negatif yada pozitif (pozitif olgu kopya sayısının referans kopya sayısına oranı) olması şeklinde yapıldı. Bulgular: Çalışmamızda 98’i takip hastası olmak üzere toplam 320 hasta t(4;11) MLL-AF4 translokasyonu için değerlendirildi. Çalışmaların sonucunda toplam 34 olgu (24 çocuk, 10 yetişkin) pozitif ve diğer örnekler negatif olarak bulundu. Sonuç: Bu değerlendirmenin sonuçları, RT-PCR yöntemi ile ALL hastalarında yeni tanı döneminde ve tedavi sürecinde t(4;11) MLL-AF4 translokasyonunun kantitatif tayini, hem tanının kesinleştirilmesinde hem de moleküler remisyon sağlanmasına yönelik tedaviyi yönlendirmesinde değerli bir yöntem olduğunu desteklemektedir., Aim: t(4,11) is a chromosomal abnormality formed by the translocation MLL-AF4, which is the result of the fusion of the AF4 gene, localized on 4q21 chromosomal band, to the MLL gene, localized on 11q23 chromosomal band. The aim of this study is to examine the results of the analysis of t (4;11) MLL-AF4 translocation in acute lymphoblastic leukemia (ALL) patients retrospectively. Materials and Methods: Peripheral blood or bone marrow samples of 176 children (70 girls, 106 boys) and 144 adults (60 women, 84 men) with a preliminary diagnosis of acute leukemia between 2009-2013 were analyzed in the Medical Biology Department of Ege University Faculty of Medicine. The translocation RNA results of 71 peripheral blood and 473 bone marrow samples of these patients were evaluated quantitatively for t(4;11) with real-time RT- PCR. t(4;11) quantitation was performed by real-time qRT-PCR instrument after the synthesis of complementary DNA with conventional PCR from total RNA or mRNA isolated from blood and bone marrow. Quantitative analysis of the patients was performed by comparing positive and negative controls and samples classified as positive or negative (the ratio of the number of positive copies to the number of reference copies). Results: A total of 320 patients, with 98 having also follow-ups, were evaluated for t(4;11) translocation. Totally 34 patients (24 children and 10 adults) were found positive and the other samples were negative. Conclusion: The assessment of these results supports that, quantitative determination of t(4;11) with RT-PCR method among newly diagnosed ALL patients and ALL patients undergoing treatment, is a valuable method for both confirming the diagnosis and guiding the treatment intended to achieve molecular remission.

Amac: Bu calismada, Ege Universitesi Tip Fakultesi Tibbi Biyoloji Anabilim Dali'na 2009-2013 yillari arasinda akut myeloid losemi (AML) on tanisi ile basvuran 402 olgunun (322 yetiskin, 80 cocuk) kan veya kemik iligi orneklerinin inv16 kantitasyon analizlerinin RT-PCR yontemi ile degerlendirilmesi amaclandi. Gerec ve Yontem: Hastalardan alinan kan ve kemik iligi orneklerinden total RNA/mRNA izolasyonunu takiben cDNA'lari elde edilerek revers-transkriptaz-polimeraz zincir reaksiyonu (RT-PCR) yontemiyle inv16 kantitasyonu LightCycler2 cihazinda gerceklestirildi. Bulgular: Dort yuz iki olgu, inv(16) CBFBETA-MYH11 inversiyonu acisindan degerlendirildi. Yapilan analiz sonucunda 12 (% 4) eriskin ve 7 (% 9) cocuk olmak uzere toplam 19 olguda inv16 pozitifligi saptandi. Sonuc: Inv16 kantitatif analizi, AML hastalarinin klinik degerlendirilmesinde, hastaligin seyri ve remisyon saglanmasina yonelik tedavi protokollerinin uygulanmasinda etkili bir yontem oldugunu desteklemektedir. AML hasta grubunu iceren daha genis kapsamli calismalar yapilarak elde edilen sonuclar desteklenmelidir.

Despite improvements in diagnosis and treatment, invasive fungal infections (IFIs) are still a major cause of morbidity and mortality in immunocompromised patients. The data on IFI among children with acute lymphoblastic leukaemia (ALL) are still scarce, and our aim was to estimate the risk, aetiology and outcome of proven and probable IFIs in children with ALL who did not receive primary prophylaxis over an 8-year period. Between January 2005 and February 2013, 125 children who were treated for ALL at the Pediatric Hematology Department of the Medical School of Ege University were retrospectively reviewed. Proven and probable IFIs were defined according to revised definitions of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group. The proven and probable IFI incidence was 30/125 (24%). Profound neutropenia was detected in 18 (60%) patients, and prolonged neutropenia was detected in 16 (53.3%) of the patients. The most isolated agents were non-albicans Candida spp. The crude and attributable mortality was 20% and 13.3% respectively. Profound neutropenia was associated with mortality (P < 0.05). The younger patients were especially at risk for proven IFI. Prolonged neutropenia, to be in the induction phase of chemotherapy, and profound neutropenia were found to be the most common predisposing factors for IFI episodes.

PubMedID: 25345697 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

PubMed ID: 28940308, Our phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent ß-thalassemia. SP-420 was administered as a single dose of 1.5 (n = 3), 3 (n = 3), 6 (n = 3), 12 (n = 3), and 24 (n = 6) mg/kg or as a twice-daily dose of 9 mg/kg (n = 6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for C max and AUC 0-? over the dose range evaluated. The median t max ranged from 0.5 to 2.25 h and was not dose dependent. The study was prematurely terminated by the sponsor due to renal adverse events (AE) including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal AE observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP-420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug. © 2017 Wiley Periodicals, Inc., This was a phase Ib, dose-escalation study assessing SP-420 in b-thalassemia patients with chronic transfusional iron overload requiring treatment with an iron chelator. Patients were enrolled from study centers in Canada, Lebanon, Thailand, and the United States from December 2014 through August 2015. This study was funded by Sideris Pharmaceuticals.

Introduction: β-thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect characterized by ineffective erythropoiesis and impaired RBC maturation. Luspatercept is a first-in-class erythroid maturation agent under development to treat patients with β-thalassemia. Luspatercept binds to select TGFβ superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis (Suragani RN, et al. Nat Med. 2014;20:408-14). We report the results of a phase 3, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of luspatercept in adult β-thalassemia patients requiring regular RBC transfusions. ClinicalTrials.gov identifier: NCT02604433. Methods: Eligible patients were aged ≥ 18 years; had β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed); and required regular transfusions of 6-20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥ 35 days during that time. Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg, or placebo, subcutaneously every 3 weeks for ≥ 48 weeks. Patients in both treatment arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level. The primary endpoint was a ≥ 33% reduction in transfusion burden (with a reduction of ≥ 2 RBC units) during weeks 13-24, when compared with a 12-week baseline period. Key secondary endpoints included: ≥ 33% reduction in RBC transfusion burden at weeks 37-48, ≥ 50% reduction in transfusion burden at weeks 13-24, ≥ 50% reduction in transfusion burden at weeks 37-48, and mean change in transfusion burden at weeks 13-24. Achievement of ≥ 33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated. Results: † A total of 336 patients were randomized, of whom 332 were treated. Median age was 30 years (range 18-66) and 58% of patients were female. Patients received a median of 6 RBC units in the 12 weeks prior to treatment. 58% of patients in each arm had undergone splenectomy. B0/B0 genotype (classification according to the HbVar database) was observed in 68 of 224 (30.4%) and 35 of 112 (31.3%) patients in the luspatercept and placebo arms, respectively. 48 of 224 (21.4%) patients in the luspatercept arm achieved the primary endpoint versus 5 of 112 (4.5%) patients receiving placebo (odds ratio 5.79, P < 0.0001). 44 of 224 (19.6%) patients receiving luspatercept achieved a ≥ 33% reduction in RBC transfusion burden at weeks 37-48 compared with 4 of 112 (3.6%) patients receiving placebo (P < 0.0001). Of 224 patients receiving luspatercept, 17 (7.6%) and 23 (10.3%) achieved a ≥ 50% reduction in RBC transfusion burden at weeks 13-24 and 37-48, respectively, compared with 2 (1.8%) and 1 of 112 (0.9%) patients receiving placebo (P = 0.0303 and P = 0.0017, respectively). The difference of mean change from baseline in transfusion burden from week 13 to week 24 was 1.35 units (P < 0.0001). 158 of 224 (70.5%) patients receiving luspatercept achieved a ≥ 33% RBC transfusion reduction over any consecutive 12 weeks compared with 33 of 112 (29.5%) patients receiving placebo (P < 0.0001); statistically significant differences were also noted for all other transfusion burden reduction endpoints. Adverse events (AEs) observed in the study were generally consistent with previously reported phase 2 data. Treatment-emergent AEs leading to dose delay or dose reduction were similar between treatment arms. No patient deaths were reported for those treated with luspatercept. Conclusions: Treatment with luspatercept resulted in significant reductions in RBC transfusion burden in adults with transfusion-dependent β-thalassemia. Luspatercept was generally well tolerated in this patient population. † As of May 11, 2018, cutoff date. Disclosures Cappellini: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Vifor: Membership on an entity's Board of Directors or advisory committees. Viprakasit:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Taher:Protagonist Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Ionis Pharmaceuticals: Consultancy; La Jolla Pharmaceutical: Research Funding; Celgene Corp.: Research Funding. Georgiev:Alnylam: Consultancy. Coates:Celgene Corp.: Consultancy; ApoPharma: Consultancy, Honoraria; Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria. Voskaridou:Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Forni:Novartis: Research Funding; Roche: Research Funding; Celgene: Research Funding. Perrotta:Acceleron Pharma: Research Funding; Novartis: Research Funding. Lal:Celgene Corporation: Research Funding; Bluebird Bio: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding; Insight Magnetics: Research Funding; Novartis: Research Funding; Terumo Corporation: Research Funding. Kattamis:ApoPharma: Honoraria; Vifor Pharma: Consultancy; CELGENE: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Vlachaki:Novartis: Honoraria. Origa:Cerus Corporation: Research Funding; Bluebird Bio: Consultancy; Novartis: Honoraria; Apopharma: Honoraria. Aydinok:TERUMO: Research Funding; Protagonist: Other: SSC; CRISPR Tech: Other: DMC; Cerus: Honoraria, Research Funding; La Jolla Pharmaceuticals: Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding. Ho:Takeda: Honoraria, Other: travel to meeting; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Other: Travel to meeting. Chew:Celgene: Research Funding. Tantiworawit:Celgene: Honoraria, Research Funding, Speakers Bureau. Shah:Novartis: Honoraria, Speakers Bureau; Sobi/Apotex: Honoraria; Celgene Corp: Other: Steering committee; Roche: Other: Advisory board meeting. Neufeld:Celgene Corp.: Consultancy, Other: Steering committee; Acceleron Pharma: Consultancy. Laadem:Celgene: Employment, Equity Ownership. Shetty:Celgene: Employment, Equity Ownership. Zou:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene Corporation: Employment, Other: grants. Zinger:Celgene Corporation: Employment. Linde:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership; Fibrogen: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene Corporation: Research Funding; Hybrigenics: Research Funding; Erythec: Research Funding; Novartis: Research Funding. Porter:Cerus: Honoraria; Agios: Honoraria; Novartis: Consultancy. Piga:La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Honoraria; Apopharma: Honoraria, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Acceleron: Research Funding.

Introduction: Transfusion dependent thalassemia (TDT) requires regular transfusion of red cell concentrates (RBCC) to prevent the complications of anemia and excessive erythroid expansion. Despite donor testing, long-term transfusion has a substantial cumulative risk of transfusion-transmitted infection (TTI) due to undetected viruses, bacteria, and protozoa. Splenectomized (-S) TDT patients may have greater TTI morbidity than patients with spleens (+S); but may benefit from reduced use of red blood cell concentrates (RBCC) and reduced transfusion iron (Fe) loading. Pathogen reduction (PR) of RBCC with amustaline-glutathione (A-GSH) offers potential to reduce the risk of TTI. Objectives: To determine, the impact of PR-RBCC on hemoglobin (Hb) use, transfused Fe burden, incidence of RBC antibodies, and safety in -S and +S TDT patients. Methods: TDT patients at 3 sites, not stratified by spleen status, were prospectively enrolled in a two- period cross-over study randomized by sequence for RBCC preparation. Leukocyte reduced PR-RBCC (Test) were treated with 0.2mM amustaline and 20 mM GSH, re-suspended in saline-adenine-glucose mannitol (SAGM), and stored up to 35 days at 4°C. Leukocyte reduced conventional RBCC (Control) were suspended in SAGM and stored for up to 35 days at 4°C. Patients received 6 transfusions in each treatment sequence of Test or Control RBCC over ~ 5 months. Clinicians, blinded to RBCC Hb content and treatment sequence, ordered RBCC to maintain targeted pre-transfusion Hb thresholds of ~ 9-10 g/dL. Transfusion intervals or number of RBCC transfused were adjusted for clinical management. The primary efficacy outcome was assessed by non-inferiority (NI) analysis for Hb use (expressed as g/kg body weight/ day) using a pre-specified NI margin (≤ 15% of the observed Control mean). Results : Overall, mean (SD) Hb content (g) of 1024 Test RBCC = 54.6±5.9 (range: 39-73) and of 1008 Control RBCC = 55.6 ± 5.9 (range: 35-74) and varied widely. By intent-to-treat (ITT), 80 patients (40 +S and 40 -S) were transfused. For ITT patients (Table), the baseline Hb level (BL-Hb, g/dL) at first transfusion of Control periods was significantly lower than at Test periods; but the mean number of RBCC transfused, RBCC storage days, total Hb dose (g), and transfusion intervals were not significantly different for Test and Control. ITT analysis for all transfusion episodes showed Hb use for Test RBCC (0.110 g/kg/d) was not different from Control RBCC (0.112 g/kg/day). Non-inferiority was demonstrated (T-C = - 0.002 g/kg/d: 95% CI: -0.005, 0.001). ITT Test patients received a slightly lower mean total Hb dose (- 14g), and mean pre-transfusion Hb levels declined after 6 transfusions (9.4 to 8.8 g/dL). -S patients had lower BL-Hb levels (g/dL) than S+ patients in Test (9.2 vs 9.7) and Control (8.8 vs 9.2) periods (Table). -S patients received a lower mean total Hb dose of Test than Control RBCC (p=0.019); and had a decline in mean pre-transfusion Hb levels during Test periods (from 9.2 to 8.7 g/dL). Transfusion intervals were significantly longer for -S patients than +S patients with both Test and Control RBCC (p< 0.001 by 2-sample t test, respectively); and -S patients had lower Hb use than +S patients. However, Hb use of Test and Control RBCC was comparable within -S and + S cohorts (Table). Transfused Fe was less for -S patients for Test and Control RBCC. During 6 Test and 3 Control treatment periods, 8 patients (6 -S, 2 +S) had worsening anemia with pre-transfusion Hb levels (6.0-7.8 g/dL) substantially below the targeted transfusion threshold, but without evidence of hemolysis. Each of these patients received one or more Hb doses below the average RBCC transfusion episode dose (Test: 114.5 g) or (Control: 116.7 g); and 3 patients had concurrent infections. None of 80 patients had evidence of increased RBC clearance, developed antibodies to PR-RBCC, or had treatment emergent RBC alloantibodies in either treatment period. There were no differences in the overall safety profiles for Test and Control RBCC. Conclusions: Amustaline-GSH PR treatment of RBCCs offers the potential to reduce TTI risk without impacting Hb use or Fe burden in TDT. However, Hb content of Test and Control RBCC varies widely and may contribute to unexpected changes in pre-transfusion Hb levels. Spleen status affected Hb use comparably for PR-RBCC and Control RBCC, and remains an important factor in assessing transfusion requirements and Fe loading. Table. Table. Disclosures Aydinok: TERUMO: Research Funding; Cerus: Honoraria, Research Funding; CRISPR Tech: Other: DMC; Protagonist: Other: SSC; La Jolla Pharmaceuticals: Research Funding; Celgene: Research Funding; Novartis: Research Funding, Speakers Bureau. Piga:Apopharma: Honoraria, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Honoraria; Acceleron: Research Funding; Novartis: Research Funding. Origa:Novartis: Honoraria; Bluebird Bio: Consultancy; Cerus Corporation: Research Funding; Apopharma: Honoraria. Mufti:Cerus Corporation: Employment, Equity Ownership. Erikson:Cerus Corporation: Employment, Equity Ownership. North:Cerus Corporation: Employment, Equity Ownership. Waldhaus:Cerus Corporation: Employment, Equity Ownership. Ernst:Cerus Corporation: Employment, Equity Ownership. Lin:Cerus Corporation: Employment, Equity Ownership. Huang:Cerus Corporation: Employment, Equity Ownership. Benjamin:Cerus Corporation: Employment, Equity Ownership. Corash:Cerus Corporation: Employment, Equity Ownership.

Hyperleukocytosis in patients with leukemia is associated with early mortality, especially due to the pulmonary and neurological complications of leukostasis. The prompt use of leukapheresis may improve patients' survival in the initial treatment period. The medical records of all previously untreated acute leukemia patients were reviewed to determine whether there was hyperleukocytosis at presentation. This study summarizes a single-center experience of leukapheresis that was applied to 12 children with acute leukemia and hyperleukocytosis. The median leukocyte count at diagnosis was 589,000/mm(3) (range: 389,000-942,000/mm(3)) for ALL patients and 232,000/mm(3) (range: 200,000-282,000/mm(3)) for AML patients. A central venous catheter (CVC) was inserted, and leukapheresis procedures were repeated at 12-hour intervals. A total of 29 leukapheresis cycles were performed on 12 children. The median number of cycles of leukapheresis required by each patient was two (range: 1-4). The median absolute and percentage reductions in white blood cell (WBC) count after the first cycle of leukapheresis were 113,000/mm(3) (range: 55,000-442,000/mm(3)) and 36% (range: 16-57.4%), respectively. As a laboratory finding, mild hypocalcemia was the most frequently observed complication. No patients developed any other problem related to the procedure. Our results showed that leukapheresis is a safe and effective procedure if performed by experienced staff.

PubMed ID: 23812939, 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*?10ms), 22.8% had moderate myocardial iron (T2* 10-20ms) and 56.6% of patients had no iron loading (T2*>20ms). There was significant geographical variation in myocardial iron loading (24.8-52.6%; P

Acquired severe aplastic anemia (SAA) is a life threatening bone marrow failure characterized by pancytopenia and hypocellular bone marrow. Matched sibling donor is not available for majority of the patients and many children receive immunosuppressive therapy (IST). Although horse antithymocyte globuline (ATG) is the preferred option, our patients received rabbit ATG; since horse ATG is not available in Turkey. We reviewed the medical records of children with SAA who were treated with rabbit ATG, cyclosporine, and granulocyte colony stimulating factor (GCSF) between 2006 and 2012. Fifteen children with SAA aged between 1.5 and 17 years received rabbit ATG as first line treatment. Only two of them showed partial response and the others did not give any response at 3rd, 6th, and 12th months after the first course of IST. The second course of ATG was given to 8 of the patients; Rabbit ATG at the same dosage was used for 3 of them, and others were given horse ATG. None of the patients responded to the second course of ATG. Invasive fungal infection (IFI) which was seen in 80% of the patients was the most significant problem. Overall survival rate was 60%. The median time between the diagnosis and initiation of IST was 57 (range; 29-144) days. This delay might be significantly contributed to unresponsiveness. In our series, the use of rabbit ATG was not effective for these patients as first line treatment modality. Response rate was very low and the incidence of fungal infections was very high in the SAA patients who received rabbit ATG.

WOS: 000401520200012, PubMed ID: 28169428, The genetic basis of haemophagocytic lymphohistiocytosis (HLH) has not been elucidated in 10% of affected patients. In this study, we report four HLH episodes in three patients with HAX1 gene mutations. We screened the mutations associated with congenital neutropenia (CN) because the neutropenia persisted following HLH treatment. There were homozygous HAX1 mutations detected in all patients. This is the first case series of patients with CN caused by HAX1 mutation who presented with HLH. We hypothesize that severe neutropenia persists after an HLH episode in children without HLH mutations (especially infants) because these patients have CN caused by HAX1 mutations.

Malaria was expected to be a major problem during blood donation in Turkey due to existence of malaria cases in southeastern region of Turkey. The present study aimed for the first time, to investigate malaria in "donors deferred for malaria risk" and to determine the regional rates of malaria deferral in Turkey. Blood samples were collected from several Blood Banks of southeastern provinces where local malaria cases still exist and from Blood Bank of Ege University Medical School (EUMS) located in western Turkey where malaria is eradicated decades ago. Plasmodium spp. and specific antibodies were investigated by stained smears, antigen detection, PCR and ELISA. Among the donors deferred for malaria risk, Plasmodium spp. were not detected by microscopy, PCR or antigen detection. Seroprevalances were 2% and 3.92% in western and southeastern regions, respectively. Rate of donor deferral for malaria risk was 0.9% in EUMS and deferrals were exclusively because of travel to southeastern Turkey. In southeastern provinces, deferrals were mainly due to malaria like fever history. The present study first time assessed regional rates of donor deferral due to malaria risk in Turkey. Previously, malaria was expected to be a major problem during blood donation in Turkey due to existence of malaria cases in southeastern region of Turkey. The results of the study showed that 97% of the deferrals were unnecessary. In conclusion, to reduce unnecessary donor deferrals in Turkey, in addition to comprehensive questioning for malaria history, the usage of a malaria antibody screening method should be initiated prior to deferral decision.

Thalassemia is the most common form of inherited anemia worldwide. The World Health Organization reports suggest that about 60,000 infants are born with a major thalassemia every year. Although individuals originating from the tropical belt are most at risk, it is a growing global health problem due to extensive population migrations. Despite important advances on curative approaches such as stem cell transplantation and promising results of gene therapy, blood transfusions and iron chelation still remain as cornerstones of disease management. The purpose of this article is to focus on mainly the clinical aspects and management of beta-thalassemia major.

Objectives: An observational study was conducted to explore postmarketing safety and efficacy of Deferasirox (DFX) in comparison with conventional Desferrioxamine (DFO) in chelation-naive children with transfusional iron overload. Methods: Transfusion-dependent children (aged ≤5 yr) who had serum ferritin above 1000 μg/L and had been prescribed either first-line DFX or DFO for at least 12 months to maintain serum ferritin between 500 and 1000 μg/L were included. Initial DFX dose was 20 mg/kg/d for 7 d a week, and DFO dose was 25–35 mg/kg/d subcutaneously, given for 5 d a week. Dose adjustments were based on serum ferritin changes and safety markers. The primary efficacy endpoint was change in serum ferritin from baseline. The effect of transfusional iron loading rate (ILR) and different doses of chelators on serum ferritin was also assessed. Results: A total of 111 patients were observed for a median of 2.29 yr on DFX (n = 71) and 2.75 yr on DFO (n = 40). Absolute change in serum ferritin from baseline to the last available observation was not significant with DFX (91 μg/L, P = 0.5) but significantly higher with DFO (385 μg/L, P

Iron-induced cardiac disease is the leading cause of death in thalassemia major (TM). Splenectomy is performed in TM to reduce transfusion requirements and iron intake. Prevalence of myocardial siderosis and its relationship with splenectomy in 146 patients with TM were investigated. The patients with myocardial siderosis (T2*

Aplastic anemia is a rare complication after liver transplantation. Its incidence has been estimated to be 0.007%. Aplastic anemia was observed in 23.2 33% of patients who underwent liver transplantation for fulminant non-A-E viral hepatitis. In this paper, we describe a child suffering from aplastic anemia who eventually died from sepsis after liver transplantation for non-A-E fulminant hepatic failure.

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. Magn Reson Med, 2011. © 2010 Wiley-Liss, Inc.

WOS: 000275981900009, PubMed ID: 19996412, 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. (Blood. 2010; 115: 2364-2371), Novartis Pharma AG; Novartis Pharmaceuticals; British Heart FoundationBritish Heart Foundation [PG/09/074/27961]; National Institute for Health ResearchNational Institute for Health Research (NIHR) [NF-SI-0508-10081], This study was sponsored by Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals.

Dorfman-Chanarin syndrome is a rare, autosomal recessive inherited lipid storage disease with congenital ichthyotic erythroderma due to an acylglycerol recycling defect. It is characterized by accumulation of neutral lipids in different tissues. Liver, muscle, ear, eye, and central nervous system are generally involved, so we presented a patient with severe ichthyosis, lipid vacuoles in neutrophils, and multiorgan involvement including a very rare complication, renal involvement. A 7-month-old girl was presented with frequent respiratory infection, congenital ichthyotic erithroderma and suspicion for immune deficiency. On her physical examination hepatomegaly, developmental delay, palmar and plantar hyperkeratosis and increased deep tendon reflexes with clonus and high tonus were found. Laboratory investigations revealed elevation at transaminases levels, hypoalbuminemia, hypergammaglobulinemia, presence of autoantibodies and eosinophilia. Vacuolization in leukocytes confirmed Dorfman-Chanarin syndrome, whereas no mutation at RAG1-2 and ARTEMIS genes ruled-out immune deficient status of the patient. At the age of eight months the patient died from severe renal failure. Her necropsies demonstrated microvesicular lipid accumulation not only at the liver but also at the renal species. The variability of involvement of different systems in Dorfman-Chanarin syndrome is well described, however the renal findings has not been reported previously at the literature.

A 9-year-old girl diagnosed with acute myeloblastic leukemia M4 developed isolated cutaneous relapse. She was given chemotherapy including idarubicin, fludarabine, and cytarabine. Although she developed very severe pancytopenia, increase in the number and size of the lesions was seen. Total skin electron beam therapy was applied to the skin lesions for a total of 18 Gy. All lesions responded to total skin electron beam therapy, some of them completely disappeared. After resolution of the skin findings, she underwent bone marrow transplantation from her matched brother. Twenty-six months after hematopoietic stem cell transplantation she is alive without any event.

Molecular test results of 231 individuals referred to our molecular genetics laboratory for analysis of α-globin gene mutations between the years 2007 and 2013 were evaluated. Analysis of α-thalassemia gene mutations was performed using reverse dot-blot hybridisation, which includes 21 common mutations. Twelve distinct α-thalassemia mutations and 23 different genotypes have been detected in the Aegean region of Turkey. The most frequent mutations were –α3.7 (52.28 %), –(α)20.5 (14.74 %), --MED (10.53 %), and αPA-1α (8.77 %). Three α-thalassemia mutations (αcd142α, --SEA, and αICα), which are more prevalent in Southeast Asia, are identified for the first time in Turkey in this study. We find that a broad spectrum of α-thalassemia mutations is present in the Aegean region of Turkey. The results obtained in this study may help inform decisions in the design and implementation of prevention strategies and diagnostic approaches.

Cardiac complications are considered to be the primary cause of death in patients with β thalassaemia major. QT dispersion is a marker variability of ventricular repolarization and is elevated in various high risk groups of patients. This study was carried out in patients with β thalassaemia major to evaluate QT dispersion and to investigate the relationship between QT dispersion and body iron load. Sixty-two β thalassaemia major patients were enrolled into the study. The average serum ferritin levels and liver iron concentration was assessed. For each patient, QT–QTc intervals and QT–QTc dispersions were calculated and V1S and V5R were measured. All the subjects underwent two-dimensional M mode echocardiogram and Doppler study. LVMI was found higher in thalassaemia major patients compared to control group. β thalassaemia major patients showed significantly higher mean QT, QTc, QTd, and QTcd values compared to the control group. The mean V5R and V1S amplitudes were also higher in β thalassaemia major patients. There was a positive correlation between LVMI and QTc, QTd and QTcd. However, there was no significant correlation between QT dispersion and serum ferritin and liver iron concentration. Prospective longitudinal studies are needed to assess the prognostic significance of these findings. Am. J. Hematol., 2006. © 2006 Wiley-Liss, Inc.

Cardiac complication is one of the major causes of death in patients with thalassaemia major. Heart rate variability is a non-invasive index of neuronal modulation of heart rate. In this study, autonomic functions of the heart in a preclinical stage of heart disease were evaluated in 48 thalassaemic patients with time domain heart rate variability analysis; the control group consisted of 45 healthy subjects.Mean RR time in the study and control group was 0.73 +/- 0.1, and 0.82 +/- 0.1 ms respectively (p0.001). In the study group; SDNN, SDNN-i, SDANN-i, RMSSD, and PNN50 were found to be 167.4 +/- 86.2 ms, 153.9 +/- 108.1 ms, 111.4 +/- 60.4 ms, 108.9 +/- 86.7 ms, and 14.5 +/- 13.4%, respectively. Time domain parameters were significantly lower in the study group than the control group (p0.00 1). There was a significant positive correlation between the mean RR time and SDNN, SDNN-i, SDANN-i, RMSSD, and PNN50 (for the RMSSD p0.05, r = 0.31; for the others p = 0.000, and r values were 0.65, 0.65, 0.38, 0.37 for the SDNN, SDNN-i, SDANN-i, and PNN50, respectively).The analysis of heart rate variability might be helpful to detect cardiac complications in the preclinical stage of the cardiac involvement.

Iron-deficiency anemia (IDA) is the most common nutritional deficiency in childhood throughout the world. Although it has been shown that IRA is associated with elevated plasma copper and depleted zinc levels in children, there are conflicting results on the effect of iron supplementation on the absorption of these elements. The aim of this study was to investigate the effects of ferrous and ferric iron supplementation on the trace element status in children (n=25, aged 8-168 mo) with IDA. Fourteen of them were treated with ferric hydroxide-polymaltose complex (Ferrum, Vifor, Switzerland) (6 mg/d in the first 3 mo for initial therapy and 3 mg/kg for 3 mo as maintenance); the others were treated with a ferrous sulfate complex (FerroSanol, Schwarz, Germany) (6 mg/d in the first 3 mo for initial therapy and 3 mg/kg for 3 mo as maintenance). Plasma copper, zinc, and ceruloplasmin levels as well as hematological parameters were determined at baseline and the first, third, and sixth month of the treatment period. The hemoglobin and iron levels of patients in both groups were higher in the first and sixth months compared to baseline. Although the ceruloplasmin levels were depleted (48.9 mg/dL vs 41.4 mg/dL, p=0.035) during ferrous iron treatment, the copper and zinc levels remained unchanged. On the other hand, ferric iron supplementation led to an increase in zinc levels in the sixth month of treatment (0.77 mg/L vs 1.0 mg/L, p=0.021). The plasma copper levels were lower in the ferrous iron-treated group at the end of the first month of treatment than in the ferric irontreated group (1.06 mg/L vs 1.29 mg/L, p=0.008). In conclusion, our data showed that copper and ceruloplasmin metabolisms were affected by ferrous iron supplementation, whereas ferric iron kept them to normal levels of zinc, possibly by affecting their absorption. We conclude that the copper and zinc status of patients with IDA should be taken into consideration before and after iron therapy.

Transfusion-dependent children, mostly with thalassaemia major, but also and occasionally to a more significant degree, with inherited bone marrow failures, can develop severe iron overload in early life. Moreover, chronic conditions associated with ineffective erythropoiesis, such as non-transfusion-dependent thalassaemia (NTDT), may lead to iron overload through increased gut absorption of iron starting in childhood. Currently, the goal of iron chelation has shifted from treating iron overload to preventing iron accumulation and iron-induced end-organ complications, in order to achieve a normal pattern of complication-free survival and of quality of life. New chelation options increase the likelihood of achieving these goals. Timely initiation, close monitoring and continuous adjustment are the cornerstones of optimal chelation therapy in children, who have a higher transfusional requirements compared to adults in order to reach haemoglobin levels adequate for normal growth and development. Despite increased knowledge, there are still uncertainties about the level of body iron at which iron chelation therapy should be started and about the appropriate degree of iron stores' depletion.