Klf10 Gene, a Secondary Modifier and a Pharmacogenomic Biomarker of Hydroxyurea Treatment Among Patients With Hemoglobinopathies.

BACKGROUND: The klf10 gene could indirectly modify γ-globin chain production and hence the level of fetal hemoglobin (HbF) ameliorating the phenotype of ß-hemoglobinopathies and the response to hydroxycarbamide (hydroxyurea [HU]) therapy. In this study, we aimed to evaluate the frequency of different genotypes for the klf10 gene in ß-thalassemia major (B-TM), ß-thalassemia intermedia (B-TI), and sickle cell disease (SCD) patients by polymerase chain reaction and to assess its relation to disease phenotypes and HU response. METHODS: This cross-sectional study included 75 patients: 50 B-TM, 12 SCD, and 13 B-TI patients (on stable HU dose). The relation of the klf10 gene polymorphism (TIEG, TIEG1, EGRα) (rs3191333: c*0.141C>T) to phenotype was studied through baseline mean corpuscular volume, HbF, and transfusion history, whereas evaluation of response to HU therapy was carried out clinically and laboratory. RESULTS: The frequency of the mutant klf10 genotype (TT) and that of the mutant allele (T) was significantly higher among B-TM patients compared with those with B-TI and SCD patients. Only homozygous SCD patients for the wild-type allele within the klf10 gene had a significantly lower transfusion frequency. The percentage of HU responders and nonresponders between different klf10 polymorphic genotypes among B-TI or SCD patients was comparable. CONCLUSIONS: Although the klf10 gene does not play a standalone role as an HbF modifier, our data support its importance in ameliorating phenotype among ß-hemoglobinopathies.

Von Willebrand Factor and Factor VIII levels in Egyptian children with newly diagnosed acute lymphoblastic leukemia in relation to peripheral blast cells and steroid therapy.

BACKGROUND: Endothelial dysfunction has been reported in children with acute lymphoblastic leukemia (ALL). The aim of this study is to assess Von Willebrand Factor antigen (VWF antigen) and Factor VIII (FVIII) in newly diagnosed ALL patients, in relation to peripheral blast (PB) cells, steroid therapy, and any prognostic potential. PROCEDURE: VWF antigen and FVIII were assessed initially (D0) and at day 8 (D8) steroid therapy for 32 newly diagnosed ALL patients with and without peripheral blood blast cells. RESULTS: At diagnosis, patients with PBs had a significantly higher levels of VWF antigen (102.7 ± 22.9% vs. 56.9 ± 8%, P<0.001) and FVIII (93.4 ± 15.9% vs. 6 62.6 ± 18.1%, P<0.001) than those without. Following steroid therapy, both factors decreased in those with PBs, whereas an increase above baseline was observed in those without PBs. Furthermore, there was a significant positive correlation between PBs and both VWF antigen (P<0.001) and FVIII levels (P=0.002). High-risk patients were comparable with standard-risk group in mean values of VWF antigen (P=0.234) and FVIII (P=0.891) at diagnosis. After 12 months from diagnosis, all patients without PB achieved and maintained complete remission. Those with initial PB reported relapse (12.5%) or death (4.2%) during follow-up. CONCLUSIONS: Markers of endothelial dysfunction namely VWF and FVIII were related to circulating blast cells and steroids therapy through lysis of lymphoblasts results in reduction of both factors, with risk of thrombosis during induction with marked disintegration of malignant cells.

Survival analysis after diagnosis with malignancy of Egyptian adolescent patients: a single-center experience.

BACKGROUND: Adolescents with malignancy represent a unique population in oncology, receiving care in pediatric or adult oncology institutions. Previously, adolescents and young adults (AYAs) had good survival rates; yet in the last few decades, AYAs have shown inferior survival rates compared with children due to the increasingly reported AYA-specific malignancies with poor survival rates. This study evaluates the clinicoepidemiological aspects of adolescent cancer diagnosed in a Pediatric Oncology Unit over a 10-year period, the associated risk factors, and the survival rate. METHODS: Retrospective data analysis of patients aged 10 to 19 years diagnosed in the Pediatric Oncology Unit, Children's Hospital Ain Shams University, Cairo, Egypt, during the period from January 1, 2000 to January 1, 2010. RESULTS: There were 158 patients (20% of total number of patients diagnosed during the same period), 84 male (53.2%) and 74 female (46.8%). Hematological malignancies were the most common (91.8%), with acute lymphoblastic leukemia being the most prevalent malignancy (61.5%), and solid tumors represented 8.2% of the total number of patients. The 5- and 10-year overall survival rates were 45.2% and 40.2%, respectively. The 5- and 10-year event-free survival rates for hematological malignancies were 39.9% and 37.3%, and for solid tumors it was 36.4%. Infection was the main cause of death (50%). CONCLUSIONS: Age-related survival gap exists for adolescent cancer patients compared with children. Further studies are needed to provide evidence about optimal treatment regimens in this age group.

Morbidities and mortality in transfusion-dependent Beta-thalassemia patients (single-center experience).

BACKGROUND: The improvement of quality and duration of life of transfusion-dependent B thalassemia patients over the last years discloses several complications due to the underling disorder, iron overload and the treatment with iron chelators. Our Aim was to assess the morbidity patterns and mortality rate of transfusion-dependent thalassemia patients, and compare the outcomes in relation to age of onset, type, duration, and compliance to iron chelation therapy and frequency of blood transfusion. PROCEDURE: This retrospective study included 447 transfusion-dependent ß-thalassemia patients who attended the Thalassemia Center, Ain Shams University Children's Hospital over the last 10 years in the period between January 2000 and January 2010. Data were collected from the patients or their caregivers, as well as by reviewing follow up sheets for examinations and investigations done to detect morbidities as well as iron chelation therapies given. Determination of mortality rate and the causes of death were also done. RESULTS: Results revealed that the most common morbidities were endocrinologic (44.7%) followed by cardiovascular (41.3%) and hepatic (40.5%), then renal (4%). The different iron chelation therapy groups showed a comparable prevalence of different morbidities. The mortality rate was 1.5% and infection was the most common cause of death. The 5, 10, 20 years' survival rate among the studied patients was 80%, 50%, 20%, respectively. CONCLUSION: In the past 10 years, the survival and morbidity rates in our center have markedly improved as a result of regular blood transfusion, new iron chelators, and better compliance of the patients.

Bone mass and biochemical markers of bone turnover in children and adolescents with chronic immune thrombocytopenia: relation to corticosteroid therapy and vitamin D receptor gene polymorphisms.

Optional drug therapy in refractory chronic immune thrombocytopenia (ITP) includes standard oral, pulsed high-dose steroid therapy, intravenous gamma globulin, anti-D, and immunosuppressive therapy or thrombopoietin receptor agonists. This work aimed to study the bone mass in children and adolescents with chronic ITP in relation to biochemical markers of bone turnover, cumulative steroid therapy, and the possible modulating effect of vitamin D receptor (VDR) gene polymorphisms. Thirty-six children and adolescents with chronic ITP were recruited from the Hematology Clinic, Children's Hospital, Ain Shams University and the Hematology Clinic of the National Research Centre in Egypt and compared with 43 healthy age- and sex-matched controls. The total cumulative dose of steroids was calculated. Bone markers (serum osteocalcin (OC) and propeptide I precollagen (PICP) and urinary deoxypyridinoline (DPD) excretion), analysis of VDR gene distribution, and dual energy X-ray absorptiometry at lumbar and hip regions were performed for patients and controls. Compared to controls, chronic ITP patients had higher body mass index (BMI) and lower height for age standard deviation score (SDS). Chronic ITP patients had lower levels of OC and C-terminal propeptide of type I procollagen (PICP) and higher urinary DPD excretion, and bone mineral density (BMD) was significantly lower for both spine and hip z-score (<0.001). BMD was inversely correlated with urinary DPD excretion, age, BMI, and cumulative steroid dose. There was significant negative correlation between cumulative oral steroid dose and BMD (r = -0.4, P = 0.01 and r = -0.45, p = 0.001 for spine and hip z-scores, respectively), but the correlation was non-significant in relation to cumulative pulsed steroid therapy. FokI polymorphism was significantly related to BMD for both spine and hip z-score (p = 0.015 and p = 0.008, respectively), but there was no relation between BMD and Bsm1 polymorphism. FokI gene polymorphism may be one of the contributing factors in bone loss in patients on chronic steroid therapy. High cumulative doses of corticosteroids increased bone resorption in young chronic ITP patients. Longitudinal studies are needed to confirm the effect of different steroid protocols on bone turnover. Protocols of therapy of chronic ITP should restrict corticosteroid use in growing children and favor alternative less harmful therapies.

Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia.

Romiplostim, a thrombopoiesis-stimulating peptibody, represents a new therapeutic option in adult refractory chronic immune thrombocytopenia (ITP). This study aimed to assess the short-term efficacy and safety of romiplostim in children with chronic ITP. Eight non-splenectomized patients with chronic ITP refractory to standard lines of medical therapy were recruited from the Pediatric Hematology Unit, Children's Hospital, Ain Shams University, Cairo, Egypt. One patient was initially excluded because of increased bone marrow reticulin (grade 3). Therapy was initiated in seven patients, aged 3.4-15.2 years (median 5.5 years), and the disease duration ranged from 13 months to 7.3 years (median 2.4 years); none were splenectomized. Romiplostim dose was started as 1 µgm/kg/week and the dose escalated by 1 µgm/kg/week according to platelet count. The duration of therapy varied between 1 and 22 weeks (median 12 weeks). Results revealed that four out of the seven patients achieved variable response. Four patients demonstrated rapid increase in platelet count when pulse steroid therapy was added. Most reported adverse events were mild and transient. This case series study reveals variable response rate in children with chronic ITP to romiplostim therapy; addition of steroids especially in emergency bleeding situations could potentiate romiplostim thrombopoietic effect even in patients initially refractory to steroids. Romiplostim safety and efficacy in pediatric ITP needs further long-term studies.