Akif Yesilipek

A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA).

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.

Hemopoietic stem cell transplantation in thalassemia: a report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry, 2000–2010

Allogeneic hemopoietic stem cell transplantation (HSCT) is the only method currently available to cure transfusion-dependent thalassemia major that has been widely used worldwide. To verify transplantation distribution, demography, activity, policies and outcomes inside the European Group for Blood and Marrow Transplantation (EBMT), we performed a retrospective non-interventional study, extracting data from the EBMT hemoglobinopathy prospective registry database. We included 1493 consecutive patients with thalassemia major transplanted between 1 January 2000 and 31 December 2010. In total, 1359 (91%) transplants were performed on patients <18 years old, 1061 were from a human leukocyte Ag-identical sibling donor. After a median observation time of 2 years, the 2-year overall survival (OS) and event-free survival (EFS; that is, thalassemia-free survival) were 88±1% and 81±1%, respectively. Transplantation from a human leukocyte Ag-identical sibling offered the best results, with OS and EFS of 91±1% and 83±1%, respectively. No significant differences in survival were reported between countries. The threshold age for optimal transplant outcomes was around 14 years, with an OS of 90–96% and an EFS of 83–93% when transplants were performed before this age. Allogeneic HSCT for thalassemia is a curative approach that is employed internationally and produces excellent results.

Renal function after hematopoietic stem cell transplantation in children

The aim of this study was to assess glomerular and tubular renal function after HSCT in children in a prospective trial.

Prognostic Factors in Pediatric Cancer Patients Admitted to the Pediatric Intensive Care Unit

Higher mortality and morbidity are well established in children with malignancies in whom intensive care admissions are required. A retrospective cohort study was conducted to assess the risk factors for children with cancer in the pediatric intensive care unit (PICU) for short-term outcome (survival vs. nonsurvival when leaving the PICU). The records of 36 children with a median age of 5 years (range: 0.5 to 21) between August 2004 and August 2007 were reviewed. Mortality rate was 55%, higher than the yearly overall PICU mortality rate of 12% (P<0.0001). The mean Pediatric Risk of Mortality Score (PRISM) III score among survivors was lower than that among nonsurvivors (9.4±5.7 vs. 16.4±5.3, P=0.001). Comparison of observed and predicted mortality derived from the PRISM III score showed that distribution of outcome was not different and the prediction model performed well (goodness of fit test: χ2=3.64, df=6, P=0.725). The mortality rates were 66.6% and 33.3% in patients with high (>10 points) and low (≤10 points) PRISM III score, respectively (P=0.05). Mortality rate was significantly related to presence and number of organ system dysfunction (P=0.031 and P=0.013, respectively), sepsis (P=0.05), mechanical ventilation (P=0.005), and positive inotropic support (P=0.003). By using multiple logistic regressions, the independent risk factor was PRISM III score at the time of admission to PICU (P=0.05). The PRISM III score performed well as a predictor of outcome. For decision to admit such patients to the PICU or to forgo life-sustaining therapies, other factors such as need for mechanical ventilation and positive inotropic support, presence and numbers of organ system dysfunction should be taken into consideration as well.

Piperacillin/tazobactam versus cefepime for the empirical treatment of pediatric cancer patients with neutropenia and fever: A randomized and open‐label study

This is a prospective, randomized, and open‐label clinical trial that examines the efficiency and safety of PIP/TAZO monotherapy in comparison to cefepime (CEF), for the empirical treatment of pediatric cancer patients with neutropenia and fever.

Molecular analysis of beta-thalassemia and sickle cell anemia in Antalya.

We have studied 918 chromosomes for mutations leading to β-thalassemia and sickle cell anemia, which are the two most frequently found monogenic disorders in Antalya, Turkey. Three hundred and seventy-seven postnatal and 82 prenatal cases were studied between 2000 and May 2003 in our center using reverse dot blot hybridization (RDBH) with 22 probes specific for Mediterranean populations. In this study, IVSI-110 (G→A) appeared to be the most common mutation with an occurrence rate of 44.4% among the 16 different mutations found to be associated with β-thalassemia. Heterozygosity for IVSI-110 was the most prevalent combination, whereas 34 of our 377 postnatal cases showed homozygosity for this mutation, a genotype leading to β-thalassemia major. The total percentage of postnatal patients clinically diagnosed as β-thalassemia major was 18.6%, whereas 5% of the cases were diagnosed clinically as β-thalassemia intermedia. One new Hb variant, Hb Antalya, and one new mutation, Cod 3 (+T) were found. HbS accounted for 10.3% of all mutations; homozygosity was found in 1.9% of all cases. Of the 82 cases analysed prenatally for β-globin gene mutations and by cytogenetic techniques for possible chromosomal abnormalities, 21 fetuses were found to be affected with β-globin gene mutations. One of these fetuses was also found to have a 45,X karyotype, and 1 had a 46,XY/47,XY,+22 karyotype. Quite a high rate of consanguineous marriages in Antalya (35.17%) renders mutation screening, genetic counseling, and educational programs held by our Thalassemia Unit essential. This study was the first to be performed specifically in our region where hemoglobinopathies are most frequent as a consequence of migrations of racially and culturally distinct groups to the area in the distant past.

Sustained improvements in myocardial T2*over 2 years in severely iron-overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine

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 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 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). Am. J. Hematol. 90:91–96, 2015.

Heart Rate Variability in Patients with Thalassemia Major

Cardiac dysfunction, including congestive heart failure and fatal arrhythmia, is a frequent cause of death among children with thalassemia major (TM). Autonomic nervous system activity typically is measured by a series of cardiovascular autonomic function tests, but these tests are unsuitable for young patients because they are invasive or complex. Heart rate variability assessment is a technique that measures the beat-to-beat variability in R-R intervals. This variability reflects changes in autonomic activity and their impact on cardiovascular function. This study examined 32 patients with TM to evaluate heart rate variability (HRV) in a preclinical phase of cardiac involvement. The study patients showed no evidence of heart failure or signs of peripheral or autonomic neuropathy. All HRV parameters were significantly reduced in the TM patient group compared with the control group. The results of this study can be interpreted as evidence of early cardiac autonomic neuropathy in young thalassemic patients. Therefore, all TM patients should be screened using HRV analysis for that complication.

Prevalence and distribution of iron overload in patients with transfusion-dependent anemias differs across geographic regions: results from the CORDELIA study

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.

Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment of severe congenital neutropenia (SCN), but data on outcome are scarce. We report on the outcome of 136 SCN patients who underwent HSCT between 1990 and 2012 in European and Middle East centers. The 3-year overall survival (OS) was 82%, and transplant-related mortality (TRM) was 17%. In multivariate analysis, transplants performed under the age of 10 years, in recent years, and from HLA-matched related or unrelated donors were associated with a significantly better OS. Frequency of graft failure was 10%. Cumulative incidence (day +90) of acute graft-versus-host disease (GVHD) grade 2-4 was 21%. In multivariate analysis, HLA-matched related donor and prophylaxis with cyclosporine A and methotrexate were associated with lower occurrence of acute GVHD. Cumulative incidence (1 year) of chronic GVHD was 20%. No secondary malignancies occurred after a median follow-up of 4.6 years. These data show that the outcome of HSCT for SCN from HLA-matched donors, performed in recent years, in patients younger than 10 years is acceptable. Nevertheless, given the TRM, a careful selection of HSCT candidates should be undertaken.