Voxelotor improves red blood cell functionality in children with sickle cell anaemia: An ancillary study of the HOPE-KIDS 1 trial.

INTRODUCTION: Sickle haemoglobin (HbS) polymerisation perturbs red blood cell (RBC) rheology and drives sickle cell disease (SCD) pathophysiology. Voxelotor is an HbS polymerisation inhibitor that increases haemoglobin (Hb)-oxygen affinity. METHODS/RESULTS: In this 48-week, prospective, single-centre translational study, 10 children aged 4-11 years with SCD were treated with voxelotor. Improvements in RBC deformability were observed using osmotic/oxygen gradient ektacytometry, with increases in minimal and maximal elongation index and reductions in point of sickling. Increased Hb and reduced markers of haemolysis were also observed. CONCLUSION: These findings suggest that voxelotor treatment is associated with reduced RBC sickling and haemolysis in children with SCD.

Taylor's law for exponentially growing local populations linked by migration.

We consider the dynamics of a collection of n>1 populations in which each population has its own rate of growth or decay, fixed in continuous time, and migrants may flow from one population to another over a fixed network, at a rate, fixed over time, times the size of the sending population. This model is represented by an ordinary linear differential equation of dimension n with constant coefficients arrayed in an essentially nonnegative matrix. This paper identifies conditions on the parameters of the model (specifically, conditions on the eigenvalues and eigenvectors) under which the variance of the n population sizes at a given time is asymptotically (as time increases) proportional to a power of the mean of the population sizes at that given time. A power-law variance function is known in ecology as Taylor's Law and in physics as fluctuation scaling. Among other results, we show that Taylor's Law holds asymptotically, with variance asymptotically proportional to the mean squared, on an open dense subset of the class of models considered here.

Patient-Reported Experiences in Voxelotor-Treated Children and Adults with Sickle Cell Disease: A Semistructured Interview Study.

Objective: Voxelotor is a first-in-class sickle hemoglobin-polymerization inhibitor that was approved in 2019 by the US Food and Drug Administration for treatment of patients with sickle cell disease (SCD) aged ≥12 years; in 2021, the approval was extended to children with SCD aged 4 to 11 years. Additionally, both the Ministry of Health and Prevention for the United Arab Emirates and the European Commission granted marketing authorization for voxelotor in September 2021 and February 2022, respectively, for treatment of SCD in adults and pediatric patients aged ≥12 years. Thus, additional information on the patient experience with voxelotor would be useful for patients, caregivers, and healthcare professionals alike. The purpose of this study was to conduct semistructured interviews in an effort to understand the experiences and perspectives of voxelotor-treated patients with SCD. Methods: One-time semistructured interviews with adults, adolescents, and children with SCD and their primary caregivers were conducted in the United States. Twenty-three adults and adolescents were recruited across 4 clinical sites, and 10 children-caregiver dyads were recruited from a single site. The interview was designed to elicit patient perspectives on symptomatic changes with voxelotor and the impact of treatment on patients' perceived health-related quality of life. Individual interview transcripts were analyzed using a thematic analytic approach, and concept saturation was assessed in both cohorts. Results: Most patients reported improvements in their SCD symptoms with voxelotor treatment, specifically regarding pain crises, jaundice, and fatigue. Almost all patients experienced improvements in self-reported health-related quality of life with voxelotor treatment. Conclusions: This study provides patient and caregiver perspectives on the symptomatic benefits of voxelotor treatment. These findings not only highlight the benefits of voxelotor treatment in improving symptoms and increasing health-related quality of life across the entire SCD population but also can inform further research on SCD-specific patient-reported outcomes.

Voxelotor for the treatment of sickle cell disease in pediatric patients.

INTRODUCTION: Sickle cell disease (SCD) describes a group of heritable blood disorders caused by the polymerization of sickle hemoglobin (HbS). HbS polymerization leads to anemia and vaso-occlusion, a process that impedes delivery of oxygen to tissues throughout the body, resulting in end-organ damage (EOD). Given the lifelong complications associated with SCD, identification and treatment of early symptoms in childhood is increasingly important. Voxelotor is an oral therapy that inhibits the polymerization of HbS and offers a unique therapeutic mechanism to reduce the causes of EOD. Voxelotor was approved in December 2021 for the treatment of SCD in patients aged ≥4 years. AREAS COVERED: Clinical data on the use of voxelotor in pediatric patients with SCD is reviewed. Ongoing studies examining the clinical efficacy and safety profile of voxelotor in pediatric patients are compared with similar clinical outcomes in adults with SCD. Planned studies of voxelotor in children are also discussed. EXPERT OPINION: Voxelotor provides a unique therapeutic option to target the root causes of EOD and can potentially be used alongside other SCD therapies. Future studies directly observing the impact of voxelotor on EOD will be important for determining treatment strategies.

Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years.

BACKGROUND: Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6 months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality. PROCEDURE: The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single- and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization inhibitor-in patients aged 6 months to 17 years with SCD. Initial findings from a cohort of 45 patients aged 4 to 11 years who received voxelotor treatment for up to 48 weeks are reported. RESULTS: Hemoglobin (Hb) response, defined as a >1.0 g/dl increase from baseline, was achieved at week 24 by 47% (n = 16/34) of patients with Hb measurements at baseline and week 24. At week 24, 35% (n = 12/34) and 21% (n = 7/34) of patients had a >1.5 g/dl increase and a >2.0 g/dl increase from baseline in Hb concentration, respectively. Concurrent improvements in hemolytic markers were observed. Voxelotor was well tolerated in this young cohort, with no newly emerging safety signals. CONCLUSIONS: Based on its mechanism as an HbS polymerization inhibitor, voxelotor improves Hb levels and markers of hemolysis and has the potential to mitigate SCD-related complications; these results support its use in patients aged ≥4 years.

Towards an Effective Patient Health Engagement System Using Cloud-Based Text Messaging Technology.

Patient and health provider interaction via text messaging (TM) has become an accepted form of communication, often favored by adolescents and young adults. While integration of TM in disease management has aided health interventions and behavior modifications, broader adoption is hindered by expense, fixed reporting schedules, and monotonic communication. A low-cost, flexible TM reporting system (REMOTES) was developed using inexpensive cloud-based services with features of two-way communication, personalized reporting scheduling, and scalable and secured data storage. REMOTES is a template-based reporting tool adaptable to a wide-range of complexity in response formats. In a pilot study, 27 adolescents with sickle cell disease participated to assess feasibility of REMOTES in both inpatient and outpatient settings. Subject compliance with at least one daily self-report pain query was 94.9% (112/118) during inpatient and 91.1% (327/359) during outpatient, with an overall accuracy of 99.2% (970/978). With use of a more complex 8-item questionnaire, 30% (7/21) inpatient and 66.6% (36/54) outpatient responses were reported with 98.1% (51/52) reporting accuracy. All participants expressed high pre-trial expectation (88%) and post-trial satisfaction (89%). The study suggests that cloud-based text messaging is feasible and an easy-of-use solution for low-cost and personalized patient engagement.

Sickle cell disease: current treatment and emerging therapies.

Sickle cell disease (SCD) is among the most common genetic diseases in the United States, affecting approximately 100,000 people. In the United States, SCD is characterized by a shortened life expectancy of only about 50 years in severe subtypes, significant quality-of-life impairments, and increased healthcare utilization and spending. SCD is characterized by chronic hemolytic anemia, vaso-occlusion, and progressive vascular injury affecting multiple organ systems. The pathophysiology is directly related to polymerization of deoxygenated hemoglobin, leading to a cascade of pathologic events including erythrocyte sickling, vaso-occlusion, tissue ischemia, and reperfusion injury as well as hemolysis, abnormal activation of inflammatory and oxidative pathways, endothelial dysfunction, increased oxidative stress, and activation of coagulation pathways. These multifactorial abnormalities have both acute and chronic clinical consequences across multiple organ systems, including acute pain episodes, chronic pain syndromes, acute chest syndrome, anemia, stroke and silent cerebral infarcts, cognitive dysfunction, pulmonary hypertension, and a wide range of other clinical consequences. Hydroxyurea was the only approved treatment for SCD for nearly 2 decades; in 2017, L-glutamine oral powder was approved for the prevention of the acute complications of SCD. During the last several years there has been a dramatic increase in research into treatments that address distinct elements of SCD pathophysiology and even new curative approaches that provide new hope to patients and physicians for a clinically consequential disease that has long been neglected.

Using fludarabine to reduce exposure to alkylating agents in children with sickle cell disease receiving busulfan, cyclophosphamide, and antithymocyte globulin transplant conditioning: results of a dose de-escalation trial.

High-dose busulfan, cyclophosphamide, and antithymocyte globulin (BU-CY-ATG) is the most commonly used conditioning regimen in HLA-matched related hematopoietic cell transplantation for children with sickle cell disease. Disease-free survival with this regimen is now approximately 95%; however, it produces significant morbidity. We hypothesized we could create a less toxic regimen by adding fludarabine (FLU) to BU-CY-ATG and reduce the dosages of busulfan and cyclophosphamide. We conducted a multicenter dose de-escalation trial with the objective of decreasing the doses of busulfan and cyclophosphamide by 50% and 55%, respectively. Using day +28 donor-predominant chimerism as a surrogate endpoint for sustained engraftment, we completed the first 2 of 4 planned levels, enrolling 6 patients at each and reducing the total dose of cyclophosphamide from 200 mg/kg to 90 mg/kg. On the third level, which involved a reduction of i.v. busulfan from 12.8 mg/kg to 9.6 mg/kg, the first 2 patients had host-predominant T cell chimerism, which triggered trial-stopping rules. All 14 patients survive disease-free. No patients suffered severe regimen-related toxicity. Our results suggest BU-FLU-CY-ATG using lower dose CY could be a less toxic yet effective regimen. Further evaluation of this regimen in a full-scale clinical trial is warranted.

Activity and school attendance monitoring system for adolescents with sickle cell disease.

Sickle cell disease, the most common hemoglobin disorder, affects major organ systems with symptoms of pain, anemia and a multitude of chronic conditions. For adolescents, the disease adversely affects school attendance, academic progress and social activity. To effectively study the relationship among school attendance and other factors like demographics and academic performance, studies have relied on self-reporting and school records, all of which have some bias. In this study we design and prototype a system, called SickleSAM (Sickle cell School attendance and Activity Monitoring system), for automatically monitoring school attendance and daily activity of adolescents with sickle cell disease. SickleSAM intends to remove human bias and inaccuracies. The system uses built-in GPS to collect data which will be recorded into a cloud database using Short Messaging Service technology. SickleSAM is developed by Georgia Institute of Technology in conjunction with Children's Healthcare of Atlanta (CHOA). System effectiveness is being evaluated using a trial of 10 adolescents with the disease.

SickleREMOTE: A Two-Way Text Messaging System for Pediatric Sickle Cell Disease Patients.

Sickle cell disease, the most common hemoglobinopathy in the world, affects patient lives from early childhood. Effective care of sickle cell disease requires frequent medical monitoring, such as tracking the frequency, severity, and duration of painful events. Conventional monitoring includes paper- or web-based reporting diaries. These systems require that patients carry forms, which are easily lost, or laptop computers, which are impractical to scale to large populations. Both are prone to sporadic use by older adolescents due to lack of reminders. In this paper, we design and prototype a Sickle cell disease REporting and MOnitoring TElemedicine system (SickleREMOTE), aiming to resolve limitations of conventional monitoring diaries. This monitoring system is configured as automated short message service text (SMS-text) messages that arrive at a mobile phone anywhere on a cellular network. The messages may be reminders to encourage treatment adherence or questionnaires to collect self-assessed clinical data relating to treatment adjustments. Patients respond to the messages using pre-determined templates and a cloud database parses and stores messages automatically. Providers use a web-based interface to view, analyze, and download collected data. SickleREMOTE is developed by Georgia Institute of Technology in conjunction with Children's Healthcare of Atlanta (CHOA). System effectiveness will be evaluated using a trial of 30 adolescents with sickle cell disease and measured by response rate, time to response, error rate, and correspondence with data collected by telephone calls.

The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi-centre CHAMPS trial.

In a phase-II multi-centre double-blinded trial, we evaluated haematological effects of oral hydroxycarbamide (HC) and magnesium (Mg) in patients with HbSC, aged 5-53 years old. Subjects were randomized to HC + placebo, Mg + placebo, HC + Mg, or placebo + placebo. The primary endpoint was the proportion of hyperdense red blood cells after 8 weeks. Thirty-six subjects were evaluable, but the study was terminated early because of slow enrollment. In the combined HC groups, mean cell volume and HbF were increased, but differences were not seen in hyperdense red cells or vaso-occlusive events. Mg had no effects. Further investigation of hydroxycarbamide as monotherapy in HbSC disease is warranted.

Regionally specific cortical thinning in children with sickle cell disease.

Sickle cell disease (SCD) is a chronic disease with a significant rate of neurological complications in the first decade of life. In this retrospective study, cortical thickness was examined in children with SCD who had no detectable abnormalities on conventional magnetic resonance imaging/magnetic resonance angiography. Regional differences in cortical thickness from SCD were explored using age-matched healthy controls as comparison. A comparison analysis was done for SCD (n = 28) and controls (n = 29) based on age (5-11; 12-21 years), due to the age-dependent variation in cortex maturation. Distinct regions of thinning were found in SCD patients in both age groups. The number, spatial extent, and significance (P < 0.001) of these areas of thinning were increased in the older SCD group. Regions of interest (ROIs) were defined on the areas of highly significant thinning in the older group and then mapped onto the younger cohort; a multiparametric linear regression analysis of the ROI data demonstrated significant (P < 0.001) cortical thinning in SCD subjects, with the largest regions of thinning in the precuneus and the posterior cingulate. The regionally specific differences suggest that cortical thickness may serve as a marker for silent insults in SCD and hence may be a useful tool for identifying SCD patients at risk for neurological sequelae.

An efficient and high-throughput approach for experimental validation of novel human gene predictions.

A highly automated RT-PCR-based approach has been established to validate novel human gene predictions with no prior experimental evidence of mRNA splicing (ab initio predictions). Ab initio gene predictions were selected for high-throughput validation using predicted protein classification, sequence similarity to other genomes, colocalization with an MPSS tag, or microarray expression. Initial microarray prioritization followed by RT-PCR validation was the most efficient combination, resulting in approximately 35% of the ab initio predictions being validated by RT-PCR. Of the 7252 novel genes that were prioritized and processed, 796 constituted real transcripts. In addition, high-throughput RACE successfully extended the 5' and/or 3' ends of >60% of RT-PCR-validated genes. Reevaluation of these transcripts produced 574 novel transcripts using RefSeq as a reference. RT-PCR sequencing in combination with RACE on ab initio gene predictions could be used to define the transcriptome across all species.

Model for assessment of proficiency of human immunodeficiency virus type 1 sequencing-based genotypic antiretroviral assays.

Use of sequencing-based genotyping as a diagnostic assay for human immunodeficiency virus (HIV) antiretroviral resistance is increasing. Periodic evaluation of the proficiency of laboratories performing this assay should be established. It is important to identify components of the assay that influence the generation of reliable sequencing data and that should and can be monitored. A model was developed to determine what parameters were reasonable and feasible for assessing the performance of genotyping assays. Ten laboratories using the genotyping platform, HIV-1 Genotyping System (HGS) v. 1 and software versions 1.1 or 2.0, participated in two rounds of testing. For each round, each group was sent a panel consisting of three clinical samples to sequence in real time. Six months later, seven laboratories using the TRUGENE HIV-1 Genotyping Kit participated in a separate round, working with both panels at the same time. Analysis of the data showed that one main indicator of genotyping proficiency was achievement of > or =98% sequence homology of a sample tested to a group consensus sequence for that sample. A second was concordant identification of codons at sites identified with resistance mutations in the sample, although scoring of these criteria is still undetermined from this study. These criteria are applicable to all sequence-based genotyping platforms and have been used as a baseline for assessing the performance of genotyping for the determination of antiretroviral resistance in our ongoing proficiency program.