Gail Megason

Hepatic iron overload in children with sickle cell anemia on chronic transfusion therapy.

Hepatic iron overload is a serious complication of chronic transfusion therapy in patients with sickle cell disease (SCD). No firm consensus has been reached with regard to correlation between hepatic iron content (HIC) and variables including age, number of transfusions, and serum iron makers. Also, the role of HIC in determining hepatic injury is not well established. There is scarcity of data on chronically transfused children with SCD and no other confounding liver pathology. We aimed to further explore relationships between these variables in a cohort of children with SCD on chronic transfusion therapy naive to chelation. Liver biopsies obtained before starting chelation therapy from 27 children with sickle cell anemia receiving chronic transfusion therapy were evaluated for histologic scoring and determination of HIC. Average serum ferritin and iron saturation values were determined for 6 months before biopsy. Duration and total volume of transfusion were obtained from the medical records. All children were negative for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus infections. Mean age at biopsy was 10.95±3.34 years. Mean duration and total volume of transfusions were 50.0±26.6 months and 17.4±9.6 L, respectively. Pearson product-moment bivariate correlation coefficients indicated significant correlations between HIC and histologic iron score, serum ferritin, iron saturation, age, and transfusion volume. After adjusting for transfusion volume, a significant correlation was only seen between HIC and transfusion volume. Mean HIC was 21.8±10.4 mg/g dry weight, with fibrosis observed in 10 patients and lobular inflammation in 9. HIC was higher in biopsies with fibrosis (28.2±3.8 mg/g) than biopsies without fibrosis (17.6±18.3 mg/g; P=0.012). HIC did not differ between biopsies with lobular inflammation (25.5±4.0 mg/g) and biopsies without inflammation (19.9±2.5 mg/g; P=0.22). These findings show that transfusion volume provides more insight on hepatic iron overload than serum iron markers.

Specificity of hematopoietic stem cell homing

Homing of hematopoietic stem cells (HSC) may be defined as the cells’ ability to seek marrow stroma selectively, to interact with it and subsequently to lodge within it to initiate hematopoiesis. This complex process is no doubt mediated through multiple recognition/adhesion events. Homing may proceed through one of several alternative mechanisms, however, such as through physical trapping of stem cells by marrow ultrastructural elements or through the providing of a selective survival and/or proliferative advantage by marrow. A third alternative that provides for the central element of stem cell homing—its high degree of specificity—is through the action of a specific homing protein in HSC. There are data to support this latter mechanism of stem cell homing as the correct one, and the nature of this protein may be similar to that of the lymphocyte homing receptors that are lectin‐like molecules. Lectin–carbohydrate interactions are known to provide enormous specificity to cell recognition processes and to participate in cellular targeting. Leukemic cells have recently been demonstrated to home to marrow stroma and proliferate in the same way as normal stem cells. Thus, identification of proteins or other adhesion molecules that participate in normal and malignant cell homing could lead to more specific recruitment regimens for tumour‐free collections.

Outcome of hematopoietic cell transplantation in children with sickle cell disease, a single center's experience.

Multicenter trials have shown that hematopoietic cell transplantation (HCT) has an excellent outcome in children with sickle cell disease (SCD). As a single center, we performed a total of 11 transplants in 10 patients (6 males, 4 females) with SCD between 1997 and 2005. Eight patients had hemoglobin SS disease and two patients had HbSβ0 thalassemia. The median age of HCT was 10.1 (range 2.8–16.3) years. All donors were HLA-identical siblings; six patients received bone marrow (BM), two patients received mobilized peripheral blood, one patient received umbilical cord blood (UCB) and one patient received both UCB and BM from the same donor. Myeloablative conditioning regimen consisted of busulfan, horse antithymocyte globulin and cyclophosphamide. One patient had a gradual decrease in donor chimerism to 15% and subsequently received a second bone marrow transplant using a reduced intensity conditioning regimen consisting of alemtuzumab, fludarabine and melphalan leading to stable full engraftment. Currently, 9 out of 10 patients are alive with a median follow-up of 5.5 (range 2.9–11) years. As a single institutions experience with HCT in children with SCD, we report an excellent outcome, and a second HCT may be considered for patients with impending engraftment failure as a cure for SCD.

Alarmingly high prevalence of obesity in haemophilia in the state of Mississippi.

Summary.  The state of Mississippi has consistently been ranked as the state with most number of obese people in the United States with prevalence rates of >30%. Our aims in this study were to estimate the prevalence of overweight and obesity in children and adults diagnosed with haemophilia in Mississippi, and to assess whether race/ethnicity and the severity of haemophilia are important risk factors. A retrospective chart review was performed for all haemophilic patients seen at the Mississippi Hemophilia Treatment Center. Patients were classified into two major age groups: age 2–19.9 years and ≥20 years. Body mass index (BMI) was calculated from the height and weight in kg m−2 from the last clinic visit. Out of a total of 132 haemophilic patients, 61% were white and 37% were African American. Overall, 51% of the haemophilic patients were either obese or overweight. The prevalence of obesity in the  adult (≥20 years old) haemophilic patients was 36% and an additional 32% were overweight. A significantly greater proportion of patients >20 years old were overweight or obese as compared with the patients in the 2–19.9 year age range (P < 0.002). However, race/ethnicity and severity of haemophilia were not significant risk factors for overweight and obesity. There is a very high prevalence of obesity in the Mississippi haemophilic population, especially in adults. Particular attention at clinic visits should be paid to the BMI in order to identify patients that are overweight or obese to allow for early and appropriate intervention.

Compound heterozygous mutation with a novel splice donor region DNA sequence variant in the succinate dehydrogenase subunit B gene in malignant paraganglioma

Pheochromocytoma and paraganglioma (PGL) are rare neuroendocrine tumors in children. Apparently sporadic cases of PGL may harbor germline mutations in the succinate dehydrogenase (SDHx) gene. SDHB mutations are associated with malignant disease. We report a 13‐year‐old African American boy with diffusely metastatic PGL and compound heterozygous mutation leading to a novel splice donor region DNA sequence variant in the SDHB gene. Family history was positive for non‐classical congenital adrenal hyperplasia and pituitary adenoma. After surgical resection of the primary PGL and chemotherapy, he was treated with metaiodobenzy lguanidine (MIBG) combined with arsenic trioxide. At 3‐year follow‐up, he had stable disease. Pediatr Blood Cancer 2010;54:473–475.

Open-label bendamustine monotherapy for pediatric patients with relapsed or refractory acute leukemia: Efficacy and tolerability

This open-label, single-arm, phase I/II, dose-escalation study was designed to determine the recommended phase II dose (RP2D), pharmacokinetics, tolerability, and efficacy of bendamustine in pediatric patients (age ranging from 1 to 20 y) with histologically proven relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Patients (27 with ALL, 16 with AML) received intravenous bendamustine on days 1 and 2 of each treatment cycle. Phase I involved planned dose escalation of bendamustine to establish the RP2D for phase II. Objectives included overall response rate, duration of response, and tolerability. Eleven patients were treated in phase I, and the RP2D was 120 mg/m2. In phase II, 32 patients received bendamustine 120 mg/m2. Two patients with ALL (bendamustine 90 mg/m2) experienced complete response (CR). Among patients who received bendamustine 120 mg/m2, 2 experienced partial response (PR); 7 had stable disease. The overall response rate (CR+CR without platelet recovery [CRp]) was 4.7% and biological activity rate (CR+CRp+PR) was 9.3%. No AML patients responded. The most common adverse events were anemia, neutropenia, thrombocytopenia, pyrexia, nausea, vomiting, and diarrhea. Bendamustine monotherapy has acceptable tolerability in heavily pretreated children with relapsed/refractory ALL or AML and appears to have some activity in ALL, warranting further studies in combination trials.

Population pharmacokinetics and pharmacokinetics/pharmacodynamics of bendamustine in pediatric patients with relapsed/refractory acute leukemia

Abstract Objective: The pharmacokinetic (PK) profile of bendamustine has been characterized in adults with indolent non-Hodgkin lymphoma (NHL), but remains to be elucidated in pediatric patients with hematologic malignancies. This analysis used data from a nonrandomized pediatric study in patients with relapsed/refractory acute lymphocytic leukemia or acute myeloid leukemia. Methods: Bendamustine 90 or 120 mg/m2 (60-minute infusion) was administered on days 1 and 2 of 21 day cycles. The population PK base model was adjusted for body surface area (BSA), and the appropriateness of the final model was evaluated by visual predictive check. A covariate analysis explored PK variability. Bayesian PK parameter estimates and concentration–time profiles for each patient were generated. Bendamustine PK in pediatric patients was compared with that of adults with indolent NHL. PK/pharmacodynamic analyses were conducted for fatigue, nausea, vomiting, and infection. Results: Thirty-eight patients (median age: 7 years; range: 1–19 years) receiving bendamustine 120 mg/m2 and an additional five patients receiving bendamustine 90 mg/m2 (median age: 12 years; range: 8–14 years) were included in the population PK analysis. Peak plasma concentrations of bendamustine (Cmax) occurred at the end of infusion (about 1 h). Decline from peak showed a rapid distribution phase (t½α = 0.308 h) and a slower elimination phase (t½β = 1.47 h). Model-predicted mean Cmax and area under the curve values from time 0–24 h were 6806 ng/mL and 8240 ng*h/mL, respectively. When dosed based upon BSA, it appeared that age, body weight, race, mild renal (n = 3) or hepatic (n = 2) dysfunction, cancer type, and cytochrome P450 1A2 inhibitors (n = 17) or inducers (n = 3) did not affect systemic exposure, which was comparable between pediatric and adult patients. Infection was the only adverse event associated with bendamustine Cmax. However, due to the small sample size for some subgroups, the observed trends should be interpreted with caution. Conclusions: At the recommended dose (120 mg/m2), bendamustine systemic exposure was similar across the pediatric population and comparable to adults. The similarity in exposure despite the large range of BSA across pediatric and adult populations confirms the appropriateness of BSA-based dosing, which was utilized to attain systemic exposures in pediatric patients reflective of the therapeutic range in adults. Probability of occurrence of infection increased with higher bendamustine Cmax.

Outcome of overt stroke in sickle cell anaemia, a single institution's experience

Stroke is a traumatic complication in sickle cell anaemia (SCA) that is associated with significant morbidity and a risk of recurrent overt stroke of 2·2–6·4 events per 100 patient‐years. A retrospective study was performed on all paediatric SCA patients diagnosed with a history of overt stroke between 1997 and 2010. A total of 31 children with SCA had new onset overt stroke. The mean age of the active patients (n = 27) was 17·9 years (range 6·8–27·6 years) with a total period of observation of 305 patient‐years. Twenty‐two of 27 (81%) were receiving long term red blood cell transfusions and 16 (59%) were taking the anti‐platelet agent, aspirin, since diagnosis of the stroke. Two of 27 (7%) patients had a second overt stroke with an overall risk of recurrent stroke of 0·66/100 patient‐years (one stroke was ischaemic and the other haemorrhagic). In patients taking aspirin with 180 patient‐years of follow up, the recurrence rate of haemorrhagic stroke was 0·58/100 patient‐years. We have an excellent outcome for overt stroke in paediatric SCA patients with a low rate of recurrent stroke. Further studies are needed to determine the risk‐benefit ratio of aspirin therapy in the prevention of recurrent stroke in paediatric SCA.

Risk for Psychosocial Problems in Pediatric Cancer: Impact of Socioeconomics

The aim of this study was to investigate demographic and socioeconomic variables associated with risk for patient and family problems over the course of 1 year in a largely low-income and rural pediatric oncology population. Caregivers (n = 163) completed the Psychosocial Assessment Tool 2.0 up to 4 times during regular clinic visits. Multilevel modeling examined change over time, as well as demographic and socioeconomic variables associated with psychosocial risk. Results suggest that pediatric oncology patients with caregivers of lower educational attainment and financial difficulties are at significantly greater risk for psychosocial problems, and should be offered early psychological intervention.

Gender Differences in Incidence Rates of Childhood B-Precursor Acute Lymphocytic Leukemia in Mississippi

The authors studied pediatric patients with B-precursor acute lymphocytic leukemia (ALL) to determine whether Mississippi’s gender incidences correlate with national statistics. Furthermore, data on gender incidences in each of the risk categories of low, standard, and high were collected. A retrospective chart review was performed of pediatric B-precursor ALL patients diagnosed at the Children’s Cancer Clinic at the University of Mississippi Medical Center from 1995 to 2005. The gender incidences in Mississippi were found to be comparable with the national average for ALL (1.34:1 vs 1.3:1) overall. However, the national average includes T-cell ALL, which is known to be significantly more prevalent in boys. Of greater significance, boys were noted to present with high-risk B-precursor ALL 4 times more than girls, suggesting the need for further investigation into possible causes of this phenomenon.