Carla W. Roberts

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.

Use of Handheld Wireless Technology for a Home-based Sickle Cell Pain Management Protocol

PURPOSE To evaluate use of a handheld electronic wireless device to implement a pain management protocol for participants with sickle cell disease (SCD). METHODS Participants were 19 patients with SCD aged 9-20 who experienced vaso-occlusive pain. A single-session training on the use of cognitive-behavioral coping skills was followed by instruction on how to practice these skills and monitor daily pain experience using the device. Daily pain experience and practice of coping skills were collected for the 8-week intervention period using wireless technology. RESULTS High rates of participation, daily diary completion and consumer satisfaction support the use of handheld wireless devices to implement this protocol. A comparison of the rates of self and device-recorded skills practice provides important information about the use of electronic monitoring for behavioral interventions. CONCLUSION Wireless data transfer technology has significant potential to become a practical method to improve symptom monitoring and communication between patients and providers.

Validity of the Pediatric Quality of Life Inventory for Youth with Sickle Cell Disease

OBJECTIVE Evaluate the validity of the Pediatric Quality of Life Inventory (PedsQL) for sickle cell disease (SCD). METHODS Sixty-eight parent-child dyads (children 5-18 years) completed the PedsQL. Medical record review assessed history of specific morbidities. RESULTS Internal consistency of the scales varied. The strongest reliability was for parent proxy-report for specific domains or for global functioning scores with either informant. Modest internal consistency was found for specific domains with child informants, particularly for younger children. Moderate convergent validity was found between informants. History of neurologic problems or major pain episodes indicated criterion validity for specific scales. CONCLUSIONS The PedsQL appears to validly assess quality of life in youth with SCD. Domain-specific measurement of quality of life was limited by (a) low reliability for youth-report and (b) lack of discriminant validity. Choice of informant may be important when evaluating quality of life effects from pain or neurologic problems in SCD.

Interactions of biomedical and environmental risk factors for cognitive development: a preliminary study of sickle cell disease.

ABSTRACT. Sickle cell disease (SCD) is associated with a number of biopsychosocial risk factors for cognitive development. Understanding how these risk factors may interact is important for developing interventions for cognitive functioning. The authors assessed the cognitive abilities of children with SCD (n = 50) and related their performance to anemia severity, socioeconomic status (SES), and their interaction. Demographically matched peers without SCD (n = 36) served as a comparison group. Four areas of cognitive weakness were identified among children with SCD: general cognitive ability, crystallized ability, short-term memory, and processing speed. Anemia severity predicted general cognitive ability, crystallized ability, and processing speed. Interactions between anemia severity and SES were found for general cognitive ability and short-term memory. Disease effects in SCD appear to vary depending on the childs level of socioenvironmental risk. Biomedical interventions to benefit cognitive functioning may have different effects depending on whether additional socioenvironmental risk factors are present.

The Association of Oral Hydroxyurea Therapy with Improved Cognitive Functioning in Sickle Cell Disease

This study examined potential cognitive benefits of oral hydroxyurea therapy for children with sickle cell disease (SCD). Cognitive abilities of 15 children with SCD on hydroxyurea were compared to 50 other children with SCD, controlling for demographics and hematocrit. Children on hydroxyurea scored significantly higher on tests of verbal comprehension, fluid reasoning, and general cognitive ability than children not on the drug. The data therefore provide preliminary evidence of cognitive benefits of hydroxyurea. Mechanisms for this effect may be improved blood/oxygen supply to the brain or reduced fatigue and illness.

Neurobehavioral impact of sickle cell disease in early childhood.

The physical effects of sickle cell disease (SCD) begin in infancy or early childhood, yet most behavioral studies have focused on school-age children. We evaluated the impact of higher versus lower neurologic risk on language, motor abilities, executive functions, and temperament in toddlers and early preschoolers with SCD. Thirty-nine children with higher risk SCD were compared to 22 children with lower risk SCD. Language and motor abilities were lower in older compared with younger children but were unrelated to sickle cell subgroups. Executive functions, particularly working memory, were poorer in children with higher risk SCD regardless of age. Parent-reported activity level was also lower in children with higher risk. Specific behavioral influences of SCD are evident early in childhood and include working memory decrements. Executive function deficits in SCD can emerge early in life and may be an important context for other areas of cognitive and behavioral development.

Cerebral blood flow velocity and language functioning in pediatric sickle cell disease.

We investigated the association of increased cerebral blood flow velocity with specific language abilities in children with sickle cell disease (SCD). Thirty-nine children ages 5 to 8 years old with high-risk genotypes of SCD underwent cognitive testing, which included tests of language skills, visual motor skills, and attention/working memory as part of a routine hematology health-maintenance visit. Transcranial Doppler (TCD) velocities were obtained from review of medical records, with the velocities that were in closest temporal proximity to the cognitive assessment used in the analysis. TCD velocities predicted scores on tests of syntactical skills, even when controlling for anemia severity. Semantic and phonological ability and other cognitive skills were not strongly related to TCD velocities. Elevated blood flow velocities in children with high-risk SCD may contribute to a specific language impairment or to a broader dysfunction of short-term and/or working memory. This study underscores the need for clinicians to monitor language skills of children with SCD who have elevated TCD velocities, as these cognitive abilities might be particularly sensitive to cerebrovascular disruption related to their disease.

Language Processing Deficits in Sickle Cell Disease in Young School-Age Children

Verbal IQ deficits are frequently reported for school-age children with sickle cell disease (SCD), yet the profile of language abilities in SCD is unclear. We examined semantic, syntactic, and phonological processing in five-to-seven-year-olds at high neurologic risk based on SCD subtype (N = 33), at low neurologic risk with SCD (N = 21), and without SCD (N = 54). Low-risk SCD did not show language processing deficits. High-risk SCD showed deficits in all three language domains. Language processing deficits in SCD at the start of middle childhood are related to neurologic risks and include language skills beyond vocabulary.

Neurodevelopmental screening in toddlers and early preschoolers with sickle cell disease.

Sickle cell disease is associated with an elevated risk for neurologic complications beginning in early childhood. Detecting higher-risk cases with developmental screening instruments may be a cost-effective method for identifying young children in need of more frequent or intensive assessment. We evaluated the validity of the Denver II test as a tool to detect lower levels of developmental attainment and their association with neurologic risk in 50 young children with sickle cell disease. Children with suspect Denver II outcomes showed lower scores for functional communication skills, had lower hematocrit percentage, higher mean velocities on transcranial Doppler ultrasound imaging, and were more likely to have had preterm birth. Validity of age equivalencies from specific Denver II areas was demonstrated for Language and Fine Motor scores, suggesting the instrument could be used to index childrens developmental levels in these domains. The Denver II may be a useful behavioral screening tool for neurodevelopmental risk in sickle cell disease.

Changes in coping, pain, and activity after cognitive-behavioral training: a randomized clinical trial for pediatric sickle cell disease using smartphones.

Objectives:We examined the outcomes of a cognitive-behavioral therapy (CBT) intervention for pain in pediatric sickle cell disease (SCD) using smartphones as a novel delivery method. Materials and Methods:Forty-six children with SCD received CBT coping skills training using a randomized, waitlist control design. The intervention involved a single session of CBT training and home-based practice using smartphones for 8 weeks. Pre-post questionnaires between the randomized groups were used to evaluate changes in active psychological coping and negative thinking using the Coping Strategies Questionnaire. Daily diaries completed by the full sample during the treatment period were used to assess whether CBT skill use was related to reductions in next-day pain intensity and increases in same-day functional activity. Results:The pre-post group comparison suggested that the youth increased active psychological coping attempts with the intervention. Daily diary data indicated that when children used CBT skills on days with higher pain, there were reductions in next-day pain intensity. There was no such association between skill use and functional activity. Discussion:CBT coping skills training supported using smartphones can increase coping and reduce pain intensity for children with SCD; however, additions to the study protocols are recommended in future studies. Advantages and caveats of using smartphones are also discussed.