Jeremie H. Estepp

Improved hydroxyurea effect with the use of text messaging in children with sickle cell anemia

In children with sickle cell anemia (SCA), hydroxyurea reduces morbidity, but adherence is frequently suboptimal. Because most families of children with SCA have access to cellular telephone services, we assessed the impact of text messaged reminders as a tool to improve adherence to hydroxyurea.

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations.

Protection from sickle cell retinopathy is associated with elevated HbF levels and hydroxycarbamide use in children.

Elevated foetal haemoglobin (HbF) levels are protective against some manifestations of sickle cell anaemia but the impact on retinopathy is unknown. We report on 123 children with HbSS, 10·6% of whom developed retinopathy. Independent of hydroxycarbamide, children with a HbF <15% had 7·1‐fold (95% confidence interval, 1·5–33·6) higher odds of developing retinopathy. In children treated with hydroxycarbamide, those with retinopathy had lower HbF levels compared to children without retinopathy (9% vs. 16%; P = 0·005). We report a protective benefit of elevated HbF regarding retinopathy, and our data suggests induction of HbF with hydroxycarbamide may prevent retinopathy in children.

The impact of quality and duration of enoxaparin therapy on recurrent venous thrombosis in children.

Venous thromboembolism (VTE) and recurrent venous thromboembolism (rVTE) are rare, but significant problems in pediatrics. Current recommendations for anticoagulant therapy arise from adult literature, and there is little data on clinical outcomes following therapeutic low‐molecular‐weight heparin in children.

Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off‐label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight‐based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan0thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure‐response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open‐label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight‐based dosing schemes provide consistent drug exposure; and age‐based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA.

A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy

Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose‐dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long‐term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient‐years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow‐up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P < .0001), including vaso‐occlusive pain (P < .01) and acute chest syndrome (ACS) (P < .01), and more than four times the odds of admission for fever (P < .001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1000 × 106/L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.

Future Perspectives for the Treatment of Sickle Cell Anemia

After decades with few treatment options for individuals with sickle cell disease (SCD), we have entered a treatment era of promising new therapeutic agents. These novel approaches target the diverse pathophysiology associated with SCD (e.g., increased blood cell adhesion, activated coagulation system, hyperinflammation, endothelial dysfunction). Potential therapies can be classified according to the “level” of the target intervention and related to the pathophysiology of SCD (upstream versus downstream events). In this chapter, “upstream therapies” refer to those that correct the genetic defect (correction of the sickle mutation in the beta globin gene via hematopoietic stem cell transplantation or gene therapy/gene editing), alter the natural hemoglobin switch phenomenon (enhancement of fetal hemoglobin production via gene therapy/gene editing), or prevent hemoglobin polymerization (e.g., drugs that alter the hemoglobin oxygen affinity or enhance fetal hemoglobin production). “Downstream therapies” are those aimed at quelling the downstream effects of hemolysis and vaso-occlusion (e.g., anti-adhesive, anti-inflammatory, or vaso-dilatory agents). This chapter discusses new therapies both in pre-clinical and clinical stages of investigation, and emphasizes those with the highest likelihood for impact on the disease and translation into clinical use over the next decade.

Hydroxycarbamide in children with sickle cell anaemia after first-dose vs. chronic therapy: pharmacokinetics and predictive models for drug exposure

The purposes of this work were to: (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew) vs. those receiving chronic therapy (HCchronic), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies based on a limited number of HC measurements.

MAGiC: VOC remains but kids with SCA appear

In this issue of Blood, Brousseau et al report results from the Magnesium for Children in Crisis (MAGiC; #NCT01197417) trial. This multicenter, double-blind, placebo-controlled trial compared the effects of intravenous magnesium to saline in children with sickle cell anemia (SCA) admitted to the hospital for acute vaso-occlusive pain (VOC). Although magnesium was found to be ineffective, MAGiC illustrates an effective strategy for rapid and efficient patient accrual in pediatric SCA studies.

Sickle Cell Clinical Research and Intervention Program (SCCRIP): A lifespan cohort study for sickle cell disease progression from the pediatric stage into adulthood

Previous natural history studies have advanced the understanding of sickle cell disease (SCD), but generally have not included sufficient lifespan data or investigation of the role of genetics in clinical outcomes, and have often occurred before the widespread use of disease‐modifying therapies, such as hydroxyurea and chronic erythrocyte transfusions. To further advance knowledge of SCD, St. Jude Childrens Research Hospital established the Sickle Cell Clinical Research and Intervention Program (SCCRIP), to conduct research in a clinically evaluated cohort of individuals with SCD across their lifetime.