Suvankar Majumdar

Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia

BACKGROUND Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. METHODS In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). CONCLUSIONS Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant

Background The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. Methods We infused a single‐stranded adeno‐associated viral (AAV) vector consisting of a bioengineered capsid, liver‐specific promoter and factor IX Padua (factor IX–R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values. Results No serious adverse events occurred during or after vector infusion. Vector‐derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady‐state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow‐up of 492 weeks among all the participants (range of follow‐up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver‐enzyme levels developed in 2 participants and resolved with short‐term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion. Conclusions We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene‐derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092.)

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.

Overweight and obesity in hemophilia: a systematic review of the literature.

CONTEXT As life expectancy in individuals with congenital hemophilia approaches that of the general population, we hypothesize that public health risks, including overweight and obesity, also follow a similar trend. EVIDENCE ACQUISITION A search of the literature included terms relating to overweight, sequelae of being overweight, and hemophilia. Studies were included if they reported the frequency or clinical significance of known complications of overweight and obesity, including musculoskeletal disease, aerobic capacity, cardiovascular disease, diabetes, hyperlipidemia, decreased quality of life, and change in pharmacokinetics of infused clotting factor in hemophilia. Recommendations from medical organizations were searched for preventive and management strategies applicable to this population. EVIDENCE SYNTHESIS Overweight and obesity are now more prevalent in the hemophilia population than previous generations, with rates similar to and, in certain subsets even higher, than that of the general population. Increased BMI leads to limitations in joint range of motion in the general population and even more so in persons with hemophilia. CONCLUSIONS Overweight and obesity in hemophilia are an increasing problem. Simple steps can be taken to encourage patients to decrease caloric intake and increase physical activity. Prevention and management of overweight, obesity, and their sequelae must be addressed in clinical practice in order to maximize the overall health of the hemophilia population.

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.

Successful prophylactic treatment for bleeding in a girl with severe hereditary prothrombin deficiency using a prothrombin complex concentrate (Bebulin VH).

The authors describe the evaluation and course of severe hereditary prothrombin deficiency in a 14-year-old girl first diagnosed at age 4 years. Detailed is the evolution of her treatment from episodic fresh-frozen plasma after bleeding events to prophylactic home infusions with the prothrombin complex concentrate Bebulin® VH. Pharmacokinetic data on factor II recovery and half-life are presented. The patient has been essentially free of abnormal bleeding while on this prophylactic regimen for 17 months, with no toxicities and with a much improved quality of life.

The use and effectiveness of complementary and alternative medicine for pain in sickle cell anemia

Pain is the clinical hallmark for sickle cell disease (SCD). The objective of this study was to survey the extent and effectiveness of complementary and alternative medicine (CAM) use for pain control among adults with SCD. Of a total of 227 African-American adults with SCD, 208 (92%) admitted to using at least one type of CAM. The three most common types of CAM were prayer (61%), relaxation technique (44%), and massage (35%). Multiple logistic regression showed that marital status was associated with use of relaxation techniques (p = 0.044), and age between 18 and 24 years and at least a high school level of education were associated with use of prayer (p = 0.008 and p = 0.004 respectively). Our study showed that CAM use is common among adult patients with SCD. Further well designed prospective studies are needed to help develop best practices that emphasize an optimized balance of conventional and evidence based CAM therapies.

Quality of life among pediatric patients with cancer: Contributions of time since diagnosis and parental chronic stress

Pediatric cancer is associated with a host of negative psychosocial consequences; however, outcomes vary extensively suggesting a need to better understand this variation. Empirical research suggests a positive association between time since diagnosis (TSD) and Quality of Life (QoL). In addition to TSD, family stressors have been found to be particularly important in predicting QoL among children. The current study examined parental chronic stress beyond TSD in explanation of QoL functioning among a sample of pediatric patients with cancer.

Pharmacoeconomic impact of obesity in severe haemophilia children on clotting factor prophylaxis in a single institution.

Haemophilia is an extremely costly condition and the most expensive component of haemophilia care is the cost of clotting factor itself accounting for over 90% of the total cost [1]. Due to the extremely high cost of clotting factor, the Veteran Health Care Act of 1992 allowed comprehensive haemophilia treatment centres across the United States to purchase clotting factor at a discounted rate, the so called Federal 340B drug programme , in order to support the cost of dispensing drugs to indigent patients in outpatient facilities [2]. While many studies have evaluated the economic impact of haemophilia, taking into account the regimen of clotting factor administered to patients (on-demand versus prophylaxis), the cost of physician visits, the cost of hospitalizations for treating bleeding complications etc., no studies or analyses have been reported to date on the possible effect of weight reduction on the cost of treatment in haemophilia [1,3]. We have recently shown in an earlier study that there is an alarmingly high prevalence of overweight and obesity in the haemophilia population in the state of Mississippi [4]. As the dosage recommendation for replacement with factor VIII or IX concentrate is based on the weight in kilogramme of the individual patient we hypothesized that this high prevalence of overweight/obesity has an enormous impact on the cost of treatment in haemophilia. The primary aim of the current study was to perform a hypothetical cost assessment of weight reduction for treatment with prophylactic clotting factor in a selected group of haemophilia patients that were above their ideal body weight (IBW). Participant information was collected through a chart review and from a previously compiled database that contains the heights, weights and BMI for the entire Mississippi haemophilia population [4]. Patients aged 2–18 years old on clotting factor prophylaxis for severe haemophilia were identified from the database as this would allow us to perform a cost analysis on a patient population that was taking clotting factor regularly. The ideal body weight of each patient was calculated from the participant s height using the following Traub–Johnson equation [5]: