Lakshmanan Krishnamurti

Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study

BACKGROUNDnThe oral thrombopoietin receptor agonist eltrombopag is approved for treatment of adults with chronic immune thrombocytopenia. In the PETIT trial, we aimed to investigate the efficacy and safety of eltrombopag in children with persistent or chronic immune thrombocytopenia.nnnMETHODSnPETIT was a three-part, randomised, multicentre, placebo-controlled study done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. Patients aged 1-17 years with immune thrombocytopenia lasting for 6 months or longer and platelets less than 30 × 10(9) per L who had received at least one previous treatment were enrolled. We enrolled patients into three cohorts consisting of patients aged 12-17, 6-11, and 1-5 years. We established patients starting doses with an open-label, dose-finding phase with five patients in each cohort. During the dose-finding phase, patients aged 6-17 years started eltrombopag at 25 mg once per day (12·5 mg for those weighing <27 kg) and patients aged 1-5 years received 0·7 mg/kg per day to a maximum of 2 mg/kg unless otherwise approved. We permitted dose adjustments on the basis of platelet response up to a maximum dosage of 75 mg per day. Additional patients were then recruited and randomly assigned (2:1) to receive either eltrombopag or placebo tablets (or oral suspension formulation if aged 1-5 years) once per day for 7 weeks at the previously established doses. Starting doses for the double-blind phase were 37·5 mg/day for patients aged 12-17 years; 50 mg/day for patients weighing 27 kg or more (25 mg for east Asian patients) and 25 mg/day for patients weighing less than 27 kg (12·5 mg once per day for east Asian patients) for patients aged 6-11 years; and 1·5 mg/kg once per day (0·8 mg/kg once per day for east Asian patients) for patients aged 1-5 years. Randomisation was done by the GlaxoSmithKline Registration/Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who completed treatment were then enrolled into an open-label phase and all patients could receive up to 24 weeks of eltrombopag. The primary outcome was the proportion of patients achieving a platelet count of 50 × 10(9) per L or more at least once from weeks 1-6 (days 8 to 43) of the randomised phase of the study in the absence of rescue therapy. We assessed efficacy in the intent-to-treat population, which consisted of all patients assigned to treatment, and we assessed safety in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT00908037.nnnFINDINGSnBetween Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort, into the open-label dose-finding phase who did not progress into the double-blind phase. From March 17, 2010, to Jan 15, 2013, we randomly assigned 67 patients to treatment, with 45 patients assigned to receive eltrombopag (16 children aged 12-17 years, 19 aged 6-11 years, and ten aged 1-5 years) and 22 to receive placebo (eight children aged 12-17 years, nine aged 6-11 years, and five aged 1-5 years). However, two patients assigned to receive eltrombopag did not receive the study drug and one was lost to follow-up, and one patient assigned to receive placebo was given eltrombopag. From weeks 1 to 6, 28 (62%) patients who received eltrombopag, compared with seven (32%) who received placebo, achieved the primary endpoint of platelet count 50 × 10(9) per L or more at least once without rescue (odds ratio 4·31, 95% CI 1·39-13·34, p=0·011). The most common adverse events with eltrombopag were headache (13 [30%] patients receiving eltrombopag vs nine [43%] patients receiving placebo), upper respiratory tract infection (11 [25%] patients vs two [10%] patients), and diarrhoea (seven [16%] patients vs one [5%] patient). Grade 3 or 4 adverse events occurred in five (11%) patients receiving eltrombopag and four (19%) patients receiving placebo, and serious adverse events (four [9%] patients receiving eltrombopag and two (10%) patients receiving placebo) were similarly infrequent in both groups. No thrombotic events or malignancies occurred. Increased alanine aminotransferase concentrations caused two (3%) of 65 patients to discontinue eltrombopag in the open-label phase.nnnINTERPRETATIONnOur results showed that eltrombopag could be used to increase platelet counts and reduce clinically significant bleeding in children with persistent or chronic immune thrombocytopenia. Prevalence of increased liver laboratory values was similar to that seen in adults.nnnFUNDINGnGlaxoSmithKline.

Clinical trial implementation and recruitment: Lessons learned from the early closure of a randomized clinical trial

BACKGROUNDnThe NHLBI-sponsored Sickle Cell Disease Clinical Research Network (SCDCRN) conducted a multi-center, acute intervention randomized clinical trial of two methods of Patient Controlled Analgesia for acute pain. This trial was terminated early due to low enrollment. We analyzed the perceived barriers and recruitment difficulties as reported by the coordinators and principal investigators.nnnMETHODSnParticipating sites completed a missed eligibility log of subjects admitted in pain crisis throughout the study and a survey at the end of the trial. The survey covered site-specific factors, policies, and procedures in study implementation, recruitment strategies, and eligibility factors. The New England Research Institutes (NERI) collected de-identified surveys from 31 respondents at 29 of 31 participating sites.nnnRESULTSnFrom December 2009 to June 2010, 1116 patient encounters for SCD and pain occurred at participating institutions: 38 subjects were enrolled (14 pediatric and 24 adults) and 34 completed the trial, below the projected 278 subjects. Fourteen sites enrolled subjects and seventeen did not. Recruitment barriers included insufficient staff, subject ineligibility or in too much pain to consent, competing protocols, and concerns regarding pain control. Recruitment methods were referrals from urgent care, SCD clinics and in house databases. No use of media or outside physicians was reported.nnnCONCLUSIONnWe identified multiple barriers to patient accrual including short duration of enrollment period, protocol design, complex dosing schedule, requirement for staff availability during week-end and after hours, multiple departments involvement, protocol acceptance, eligibility criteria, competing protocols, and limited staff. Each of these areas should be targeted for intervention in order to plan and conduct successful future clinical trials.

Attitudes and Beliefs of African-Americans Toward Genetics, Genetic Testing, and Sickle Cell Disease Education and Awareness

Research among African-Americans indicates this population perceives sickle cell (SCD) to be a serious disease and sickle cell trait (SCT) screening an important intervention. However, studies have consistently demonstrated a lower than desired uptake of SCD education, inadequate knowledge regarding personal and family trait status, and a low perceived susceptibility of giving birth to a child with the disease. We examined general attitudes and beliefs regarding genetics and genetic testing including prenatal testing and newborn screening; we used this information as the foundation to more specifically assess attitudes and beliefs regarding SCD and perceived barriers to SCD education and awareness. Thirty-five African-American adult men and women participated in one of four focus groups. Thematic analysis identified that both prenatal testing and newborn screening are acceptable forms of genetic testing. Based largely on their personal experiences, participants possessed an understanding of the natural progression of SCD but had a limited understanding of the inheritance and probable risk of giving birth to a child with the disease. Barriers to education and greater awareness of SCD were classified as personal, familial, and societal. Community based interventions focused on sharing the stories of individuals with first-hand experiences with SCD should be considered.

Systematic follow-up and case management of the abnormal newborn screen can improve acceptance of genetic counseling for sickle cell or other hemoglobinopathy trait

Purpose: Sickle cell or other hemoglobinopathy trait detected on the newborn screen provides an opportunity for genetic counseling of families at risk of having a child with a major hemoglobinopathy. However, follow-up of hemoglobinopathy trait is often fragmented and acceptance of counseling is low. We describe the results of systematic follow-up and case management of abnormal newborn screen and the effect on acceptance of counseling.Methods: From July 1997 to June 2002, families of a newborn with hemoglobinopathy trait were notified by mail. In April 2003, an intensive trait follow-up protocol including letters, telephone calls, educational videos, and genetic counseling was implemented. Demographic information and follow-up activity were documented and tracked using an electronic database.Results: From July 1997 to June 2002, 3095 families were notified by letter of a newborn with hemoglobinopathy trait and were offered genetic counseling. Of these, 165 (5.3%) received counseling by telephone and 60 (2%) underwent extended family testing. From April to December 2003, 694 families with a newborn with hemoglobinopathy trait were notified by mail. Of these, 362 (52%) families were reached by telephone. Of those contacted by telephone, 92% received genetic counseling via telephone, 57% were interested in family testing, and 12% scheduled an appointment. Additionally, 27% of families were mailed an educational video. Among those declining extended family testing, 26% preferred to consult their pediatrician.Conclusions: Systematic follow-up and case management of abnormal newborn screen can improve the acceptance of genetic counseling.

A pilot study of electronic directly observed therapy to improve hydroxyurea adherence in pediatric patients with sickle‐cell disease

Poor hydroxyurea (HU) adherence limits effective HU use in patients with sickle cell disease (SCD). Electronic directly observed therapy (DOT) may limit costs and achieve high HU adherence in children with SCD. This study aimed to determine if electronic DOT was feasible, acceptable, and could achieve ≥90% HU adherence.

Analysis of national and single-center incidence and survival after liver transplantation for hepatoblastoma: New trends and future opportunities

BACKGROUNDnLiver transplantation (LTx) for hepatoblastoma appears to be increasing. Favorable tumor histology is increasingly linked to survival after surgical resection and could also determine posttransplantation outcomes.nnnMETHODSnTo evaluate national trends in tumor and LTx incidence as the basis for observations at some LTx centers, and determinants of survival after LTx for hepatoblastoma, we queried the National Cancer Institutes Surveillance, Epidemiology and End Results (SEER) registry representing 9.451% of the U.S. population (1975-2007), the United Network for Organ Sharing (UNOS, 1988-2010, n = 332), and Childrens Hospital of Pittsburgh database (CHP, 1987-2011, n = 35).nnnRESULTSnIn the United States, hepatoblastoma cases increased 4-fold, LTx for hepatoblastoma increased 20-fold, and hepatoblastoma surpassed other unresectable liver malignancies requiring LTx by nearly 3-fold. Actuarial 5-year patient survival exceeded 75%. Recurrences in 16% were greater after segmental LTx in the total U.S. experience (P = .049). At CHP, 5 children died from recurrences (n = 4) and sepsis (n = 1). Tumors were epithelial (57%) or mixed epithelial-stromal (42%), Childrens Oncology Group stage III (77%) or IV (23%). Recurrences were related to previous pulmonary metastases (P = .016), and tumor necrosis <50% (P = .013), but not to small cell undifferentiated tumor histology (P = NS). Hepatic artery thrombosis was more common after LTx for hepatoblastoma compared with nonmalignant indications (P = .0089). Thirty-three children received pre-LTx chemotherapy, 88.6% with cisplatin, and 85.7% received post-LTx chemotherapy.nnnCONCLUSIONnOutcomes after LTx for hepatoblastoma may benefit from improved detection and treatment of pretransplantation metastases, adequate tumor lysis after chemotherapy, and perioperative antithrombotic agents but are unaffected by undifferentiated tumor histology.

Health beliefs among African American women regarding genetic testing and counseling for sickle cell disease.

Purpose: The Health Belief Model can help in understanding low acceptance of disease prevention and screening. We studied health beliefs of African American women to determine causes of low acceptance of genetic testing and counseling despite high prevalence of sickle cell disease and heterozygotes in this population.Methods: An anonymous questionnaire using a 12-question measure with a 5-point Likert scale response was administered to 101 African American women attending an obstetrics and gynecology clinic to determine knowledge of sickle cell disease, perception of risk, severity, likelihood of benefit and barriers to counseling.Results: The cumulative mean perceived scores on the 5-point Likert scale were 4.22 ± 0.88 for severity of sickle cell disease, 4.10 ± 1.03 for benefit of genetic testing, 2.28 ± 1.00 for barriers to testing, and 2.62 ± 1.06 for risk of having a child with sickle cell disease. High average level knowledge was associated with high perception of severity and benefit to screening (P < 0.05).Conclusion: African American women have a relatively high belief of the severity of sickle cell disease and benefits of genetic counseling but frequently do not appear to believe that they are at risk of having a child with the disease. This should be taken into account in the design of educational and counseling strategies.

Hematopoietic Stem Cell Transplantation for Hemoglobinopathies: Current Practice and Emerging Trends

Despite improvements in the management of thalassemia major and sickle cell disease, treatment complications are frequent and life expectancy remains diminished for these patients. Hematopoietic stem cell transplantation (HSCT) is the only curative option currently available. Existing results for HSCT in patients with hemoglobinopathy are excellent and still improving. New conditioning regimens are being used to reduce treatment-related toxicity and new donor pools accessed to increase the number of patients who can undergo HSCT.

Management of Sickle Cell Disease in Primary Care

S ickle cell disease (SCD) is a hereditary hemoglobinopathy that is manifested by chronic hemolytic anemia and intermittent occlusion of small blood vessels leading to chronic tissue ischemia, chronic organ damage, and dysfunction. In the United States, approximately 2000 infants affected by this disorder are born each year. Over the past few decades, there has been a significant decrease in the morbidity and improvement in the life expectancy of patients with SCD due to early detection as well

Impact of individualized pain plan on the emergency management of children with sickle cell disease

Vaso‐occlusive crisis (VOC) the hallmark of sickle cell disease (SCD) is often treated inadequately in the emergency department (ED). We hypothesized that pain management plans individualized for each patient can improve pain management and lead to high levels of patient satisfaction.