Isaac Odame

Sickle Cell Disease in Africa: A Neglected Cause of Early Childhood Mortality

Sickle cell disease (SCD) is common throughout much of sub-Saharan Africa, affecting up to 3% of births in some parts of the continent. Nevertheless, it remains a low priority for many health ministries. The most common form of SCD is caused by homozygosity for the β-globin S gene mutation (SS disease). It is widely believed that this condition is associated with very high child mortality, but reliable contemporary data are lacking. We have reviewed available African data on mortality associated with SS disease from published and unpublished sources, with an emphasis on two types of studies: cross-sectional population surveys and cohort studies. We have concluded that, although current data are inadequate to support definitive statements, they are consistent with an early-life mortality of 50%–90% among children born in Africa with SS disease. Inclusion of SCD interventions in child survival policies and programs in Africa could benefit from more precise estimates of numbers of deaths among children with SCD. A simple, representative, and affordable approach to estimate SCD child mortality is to test blood specimens already collected through large population surveys targeting conditions such as HIV, malaria, and malnutrition, and covering children of varying ages. Thus, although there is enough evidence to justify investments in screening, prophylaxis, and treatment for African children with SCD, better data are needed to estimate the numbers of child deaths preventable by such interventions and their cost effectiveness.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia - TCD with Transfusions Changing to Hydroxyurea (TWiTCH): A multicentre, open-label, phase 3, non-inferiority trial

Background For children with sickle cell anaemia and elevated transcranial Doppler (TCD) flow velocities, regular blood transfusions effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxyurea in this setting is unknown. Methods TWiTCH was a multicentre Phase III randomised open label, non-inferiority trial comparing standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with abnormal TCD velocities but no severe vasculopathy. Iron overload was managed with chelation (Standard Arm) and serial phlebotomy (Alternative Arm). The primary study endpoint was the 24-month TCD velocity calculated from a general linear mixed model, with non-inferiority margin = 15 cm/sec. Findings Among 121 randomised participants (61 transfusions, 60 hydroxyurea), children on transfusions maintained <30% sickle haemoglobin, while those taking hydroxyurea (mean 27 mg/kg/day) averaged 25% fetal haemoglobin. The first scheduled interim analysis demonstrated non-inferiority, and the sponsor terminated the study. Final model-based TCD velocities (mean ± standard error) on Standard versus Alternative Arm were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively, with difference (95% CI) = 4.54 (0.10, 8.98), non-inferiority p=8.82 × 10−16 and post-hoc superiority p=0.023. Among 29 new neurological events adjudicated centrally by masked reviewers, no strokes occurred but there were 3 transient ischaemic attacks per arm. Exit brain MRI/MRA revealed no new cerebral infarcts in either arm, but worse vasculopathy in one participant (Standard Arm). Iron burden decreased more in the Alternative Arm, with ferritin difference −1047 ng/mL (−1524, −570), p<0.001 and liver iron difference −4.3 mg Fe/gm dry weight (−6.1, −2.5), p=0.001. Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities, after four years of transfusions and without severe MRA vasculopathy, hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke.BACKGROUND For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participants maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING National Heart, Lung, and Blood Institute, National Institutes of Health.

Childhood atypical teratoid rhabdoid tumor of the central nervous system: a meta-analysis of observational studies.

Purpose: Therapy for central nervous system (CNS) atypical teratoid rhabdoid tumor (ATRT) is controversial. We describe 4 children treated with sarcoma-like therapy and review the literature to evaluate outcome in relation to treatment modalities. Procedure: Reports from 1995 to 2007, describing clinical features of children (≤18 years) were reviewed for details of demography, therapy, and outcome. Kaplan-Meier survival analyses were used to study the impact of clinical features, demography, and therapy on overall survival (OS). Results: The median OS for patients treated with multiagent chemotherapy (n=79) was 17.3 months (range, 1.5-93 mo); unrelated to age at diagnosis, sex, tumor site, and extent of resection. Overall mortality was 67%. Disease progression (craniospinal spread in 58%) was the major cause of death. Patients (n=30) treated with intrathecal (IT) chemotherapy had significantly higher 2-year OS [64% (95% confidence interval, 46.5-82.0) vs. 17.3% (95% confidence interval, 5.4-29.3); P<0.0001] and lower prevalence of distant CNS metastasis compared with those without IT therapy (n=49) (20% vs. 59.2%; P=0.001). Conclusions: Despite dismal OS, multimodal therapy can induce remission even in metastatic CNS ATRT with partial resection. IT chemotherapy results in higher OS and, because of an overall high rate of distant relapse, should be considered in future trials.

Osteopenia, physical activity and health‐related quality of life in survivors of brain tumors treated in childhood

Osteopenia has been reported in children surviving acute lymphoblastic leukemia and brain tumors, apparently as a consequence of therapy. It has been suggested that cranial irradiation may play a role in the development of this complication. In order to explore that possibility, we examined survivors of brain tumors treated with and without radiation in childhood to investigate associations between radiation, osteopenia, physical activity, health status and overall health‐related quality of life (HRQL).

Pulmonary Langerhans cell histiocytosis: A variable disease in childhood

Pulmonary Langerhans cell histiocytosis (PLCH) is rare in childhood but occurs most commonly in children with multisystem (MS) LCH. In adults, by contrast, the lung is the most common and usually the sole organ affected. This retrospective study describes the clinical manifestation, course, and outcome of PLCH in children consecutively diagnosed at two Canadian institutions.

Carboplatin Hypersensitivity Reaction in Pediatric Patients With Low-grade Glioma : A Canadian Pediatric Brain Tumor Consortium Experience

Carboplatin‐based regimens have demonstrated activity in pediatric patients with low‐grade glioma (LGG). However, carboplatin hypersensitivity reaction (Cb HSR) represents a common and limiting factor for the continuation of therapy.

Chelation use and iron burden in North American and British thalassemia patients: a report from the Thalassemia Longitudinal Cohort

Morbidity and mortality in thalassemia are associated with iron burden. Recent advances in organ-specific iron imaging and the availability of oral deferasirox are expected to improve clinical care, but the extent of use of these resources and current chelation practices have not been well described. In the present study, we studied chelation use and the change in iron measurements in 327 subjects with transfusion-dependent thalassemia (mean entry age, 22.1 ± 2.5 years) from 2002-2011, with a mean follow-up of 8.0 years (range, 4.4-9.0 years). The predominant chelator currently used is deferasirox, followed by deferoxamine and then combination therapies. The use of both hepatic and cardiac magnetic resonance imaging increased more than 5-fold (P < .001) during the study period, leading to an 80% increase in the number of subjects undergoing liver iron concentration (LIC) measurements. Overall, LIC significantly improved (median, 10.7 to 5.1 mg/g dry weight, P < .001) with a nonsignificant improvement in cardiac T2* (median, 23.55 to 34.50 ms, P = .23). The percentage of patients with markers of inadequate chelation (ferritin > 2500 ng/mL, LIC > 15 mg/g dry weight, and/or cardiac T2* < 10 ms) also declined from 33% to 26%. In summary, increasing use of magnetic resonance imaging and oral chelation in thalassemia management has likely contributed to improved iron burden.

Clinical and genetic analysis of unclassifiable inherited bone marrow failure syndromes.

OBJECTIVE. Unclassified inherited bone marrow failure syndromes are a heterogeneous group of genetic disorders that represent either new syndromes or atypical clinical courses of known inherited bone marrow failure syndromes. The relative prevalence of the unclassified inherited bone marrow failure syndromes and their characteristics and the clinical and economic challenges that they create have never been studied. METHODS. We analyzed cases of inherited bone marrow failure syndrome in the Canadian Inherited Marrow Failure Registry that were deemed unclassifiable at study entry. RESULTS. From October 2001 to March 2006, 39 of the 162 patients enrolled in the Canadian Inherited Marrow Failure Registry were registered as having unclassified inherited bone marrow failure syndromes. These patients presented at a significantly older age (median: 9 months) than the patients with classified inherited bone marrow failure syndrome (median: 1 month) and had substantial variation in the clinical presentations. The hematologic phenotype, however, was similar to the classified inherited bone marrow failure syndromes and included single- or multiple-lineage cytopenia, severe aplastic anemia, myelodysplasia, and malignancy. Grouping patients according to the affected blood cell lineage(s) and to the presence of associated physical malformations was not always sufficient to characterize a condition, because affected members from several families fit into different phenotypic groups. Compared with the classified inherited bone marrow failure syndromes, the patients with unclassified inherited bone marrow failure syndromes had 3.2 more specific diagnostic tests at 4.5 times higher cost per evaluated patient to attempt to categorize their syndrome. At last follow-up, only 20% of the unclassified inherited bone marrow failure syndromes were ultimately diagnosed with a specific syndrome on the basis of the development of new clinical findings or positive genetic tests. CONCLUSIONS. Unclassified inherited bone marrow failure syndromes are relatively common among the inherited bone marrow failure syndromes and present a major diagnostic and therapeutic dilemma.

Accurate liver T *2 measurement of iron overload: A simulations investigation and in vivo study

To investigate the accuracy of T  *2 liver iron quantification using different curve‐fitting models under varying acquisition conditions, and to compare in iron‐overloaded patients the reliability of rapid T  *2 measurements against approved and slower T2 protocols.

A global perspective on sickle cell disease

The global burden of sickle cell disease (SCD) is now being increasingly realized. SCD poses a significant public health problem in sub‐Saharan Africa, the Middle East, some regions of India, the Caribbean, and Brazil. In many of these regions, progress in the management of SCD has been slow. Long‐term North–South and South–South partnerships between SCD professionals, funding agencies, governments, and industry are needed to help reduce the high disease burden in developing countries, through widespread SCD education, relevant research and implementation of evidence‐based cost‐effective interventions. A group of SCD professionals have responded with action by forming a global network. Pediatr Blood Cancer 2012;59:386–390.