A Case of Thrombotic Vasculopathy in the Setting of High-Dose Hydroxyurea Use

This case study describes the presentation of a 76-year-old male with a past medical history that included atrial fibrillation, essential hypertension, coronary artery disease status post cardiac stent placement, heart failure, hyperlipidemia, thyroid cancer (with thyroid resection resulting in hypothyroidism), prostate cancer status post brachytherapy (in remission), and a history of JAK2-positive myeloproliferative disease. He presented with painful areas of hyperpigmentation appearing as purple discoloration to his neck, lower abdominal skinfold, and bilateral groin areas that progressed to painful ulcerations a few weeks after a myocardial infarction. Due to the patient’s multiple medical conditions and uncommon presentation of wounds, a multidisciplinary team was involved in his care. Differential diagnosis included antiphospholipid syndrome, symmetrical drug-related intertriginous and flexural exanthema, warfarin-induced necrosis, cutaneous thrombotic vasculopathy, myeloproliferative disorder, and high-dose hydroxyurea therapy. It was determined by the authors that the high-dose hydroxyurea therapy was the cause of the wounds. Because of the patient’s initial health status, treatment of the wounds included use of collagenase and sodium hypochlorite solution to reduce the risk of infection and attempt to promote autolytic debridement until surgical wound debridement could be done. The patient required multiple hospital stays, but ultimately his health status improved and the wounds resolved with the assistance of the combined efforts of the multidisciplinary team to diagnose and treat this complex patient and his uncommon wound presentation.

Effect of Hydroxyurea Therapy on the Incidence of Infections in Ugandan Children with Sickle Cell Anaemia

Hydroxyurea is efficacious against sickle cell anaemia (SCA)-related complications in African children. Prior studies demonstrated conflicting results on the effect of hydroxyurea on risk of infection, the most common cause of morbidity and mortality in African children with SCA. We evaluated the incidence of infections before and after starting hydroxyurea in 117 children aged 1-5 years with SCA enrolled in the Zinc for Infection Prevention in Sickle cell anaemia (ZIPS) clinical trial that received zinc or placebo treatment for one year (Clinicaltrials.gov, NCT03528434). Children were enrolled between March 2018 and November 2019 and initiated on hydroxyurea (20 mg/kg/day) if they met Uganda SCA guideline criteria for hydroxyurea treatment at any time during the study. We compared the incidence of infections before and after hydroxyurea therapy, adjusting for zinc treatment. Overall, the mean duration on hydroxyurea was 223.8 (85.2) person days. The mean(SD) incidence of any severe/invasive infections (infections meeting strict clinical and laboratory or radiological diagnostic criteria) was 6.2(9.0) vs. 1.9(2.3) infections per child per year before and after hydroxyurea (incidence rate ratio [IRR]: 0.40, 95%CI: 0.29-0.54, p<0.001), including a decrease in the incidence of bacteremia [IRR: 0.05] malaria, [IRR 0.28], cellulitis [IRR: 0.24], gastroenteritis [IRR: 0.41], pharyngitis [IRR: 0.59] and sinusitis [IRR: 0.38] (all p<0.05). Similarly, the incidence of clinically defined infections (infections meeting clinical but not laboratory/radiological criteria) decreased after hydroxyurea, (IRR: 0.49, 0.41-0.59), influenced primarily by large reductions in the incidence of lower and upper respiratory tract infections (p<0.001 for both). As expected, hydroxyurea treatment was also associated with a decrease in complications of SCA, including vaso-occlusive crises, hospitalizations and transfusions (all p<0.001). There was no interaction between zinc and hydroxyurea therapy on risk of infection and SCA-related complications. In Ugandan children with SCA, hydroxyurea therapy not only decreases the incidence of SCA-related complications, but also substantially reduces the incidence of infections. Research to understand the underlying mechanisms of protection from hydroxyurea against infection and exploration of its potential use for infection prevention is warranted. Disclosures Ware: Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Hemex Health: Research Funding; Nova Laboratories: Research Funding; Novartis: Other: DSMB Chair; Editas: Other: DSMB Chair.

In Africa, a High Proportion of Adults with HbSC Meet American Society of Hematology's Eligibility Criteria for Severe Sickle Cell Disease and Starting Hydroxyurea Therapy in a Clinical Trial Setting

Introduction : Sickle cell disease (SCD), HbSC, is the second most frequent hemoglobinopathy after HbSS. Worldwide, an estimated 54,736 babies are delivered annually with HbSC disease, with the highest HbC gene frequency in West Africa (Piel et al.2013). A retrospective study at the Ghana Institute of Clinical Genetics [(GICG), a sickle cell clinic] reported that 40% of the 3,000 SCD patients attending the clinic yearly are HbSC (Asare et al.2018). HbSC disease usually results in a comparatively milder form of SCD. However, rates of maternal-fetal morbidity, retinopathy, avascular necrosis (AVN) of the hip, priapism, and chronic kidney disease are increased (Powars et al.2002; Oppong et al.2018). While microalbuminuria is lower in HbSC than HbSS, it still occurs in >23% of adults (Drawz et al.2016). In addition, thrombosis, silent cerebral infarction, sensorineural hearing loss, and pulmonary hypertension may be higher than previously suspected (Sathi et al.2019). Unlike HbSS, hydroxyurea is not routinely recommended for HbSC patients because they are all perceived to have a milder phenotype, with improved life expectancy. Thus, HbSC individuals are often excluded from randomized controlled trials in children and adults with SCD (Luchtman-Jones et al.2016). Given the high proportion of adults with HbSC in Ghana, who may benefit from hydroxyurea therapy, we tested the hypothesis that at least 5% of adults with HbSC will meet the ASH criteria for severe disease and treatment. Data indicating that a significant proportion of adults with HbSC are eligible for hydroxyurea could potentially support pilot safety trials to determine the optimal hydroxyurea dose to ameliorate symptoms while limiting toxicity. Data can also facilitate government health policy decisions to subsidize hydroxyurea costs. Methodology : We conducted a medical chart review of all adults with HbSC disease (total: 639; 18-45years) who attended the SCD clinic, GICG (January 1, 2019, to December 31, 2019). We identified a comparison group of 639 adults with HbSS, age, and gender-matched to the HbSC patients from the same clinic. Severe complications were defined as a history of ≥3 sickle cell-associated moderate to severe pain episodes/year, a history of severe acute chest syndrome (ACS), and severe symptomatic chronic anemia that interferes with daily activities or quality of life (Hydroxyurea and Transfusion Therapy for the Treatment of Sickle Cell Disease.2014). We defined acute pain episode as new onset of pain that lasts at least 4 hours, for which there is no explanation other than vaso-occlusion, which requires therapy with parenteral opioids in a medical setting (Ballas et al.2010). Severe symptomatic chronic anemia was defined as a drop in hemoglobin by ≥2g/dL below the steady state. Data were analyzed using SPSS version 23 and summarized as simple descriptive statistics. Study endpoints were the proportion of individuals with SCD who met the definition of severe disease and were eligible for hydroxyurea. We also calculated the pain and ACS incidence rates. Results: The 639 HbSC participants had a mean age of 30.8years during the one-year study period, which was identical to that of the HbSS group. At least 8.5% of HbSC adults had ≥three acute pain episodes/ year, while 1.6% had ACS. No HbSC patient had severe symptomatic chronic anemia . In total, 10.0%(64/639) of patients with HbSC disease met the eligibility criteria for hydroxyurea therapy, compared to 24.1%(154/639) of patients with HbSS, p=<0.001. The pain and ACS incidence rates for the HbSC and HbSS individuals were [74.6; 95% CI(67.9-81.3) and 2.3; 95% CI(1.2-3.5)] events per 100 patient-years vs. [123.0; 95% CI(114.4-131.6) and 5.6; 95% CI(3.8-7.5)] events per 100 patient-years respectively. Also, 1.1%(7/639), 7.7%(49/639), 0.5%(4/639), and 4.4%(11/252) of patients with HbSC had papillary necrosis, AVN, stroke, and priapism, respectively while 8.5%(54/639) of patients with HbSS had proteinuria, Table 1. Only 0.9%(HbSC) and 2.3%(HbSS) took hydroxyurea during the study period. Conclusion: Based on ASH's evidence-based guidelines, in a large SCD clinic at an academic medical center in Ghana, 10.0% of HbSC adults meet the criteria for shared decision-making to consider starting hydroxyurea therapy in a clinical trial setting. The optimal dose of hydroxyurea that maximizes benefit and minimizes toxicity in adults with HbSC is yet to be determined. Figure 1 Figure 1. Disclosures Asare: ASH Global Research Award: Research Funding.

Cost Analysis of ACUTE Care Resource Utilization Among Individuals with Sickle Cell Disease in a Middle-Income Country

Background: The costs associated with the treatment of sickle cell disease (SCD) are understudied in low and middle-income countries (LMIC), where resources are scarcer and policy decisions about resource allocation rely on detailed cost data. Few studies have investigated the cost-savings of disease-modifying therapies in SCD in real-world setting. We evaluated the cost of treating SCD-related acute complications and the potential cost-savings of hydroxyurea therapy at HEMORIO, a specialized tertiary hematology center in Brazil. Methods: The costs (US dollars) of emergency department (ED) and hospitalizations from SCD-related complications between 01.01.2018 and 06.30.2018 were ascertained using absorption and micro-costing approaches. ED costs are presented as cost per each ED event and hospital admission costs are presented as cost per each admission event. ED and admission costs (separated and combined) were determined and compartmentalized into several inputs by fixed and variable categories for all patients over the period of the study [Falk JA et al, Atlas 2001]. The cause of ED or hospital admission visit was verified by a physician and abstracted via medical record review. All hospital admissions were evaluated in the ED. If an ED encounter resulted in an admission, the encounter was counted as an admission event only. The causes related to SCD were grouped and classified according to the discharge diagnosis: 1) VOC (acute pain crisis, priapism or dactylitis); 2) Infection (fever, sepsis, or acute chest syndrome); 3) Anemia exacerbation (acute hemolytic crisis, transient aplastic crisis, or acute splenic sequestration); 4) Chronic organ damage (overt stroke, chronic kidney disease, chronic liver disease or organ failure. Hydroxyurea adherence was estimated by medication possession ratio (MPR) during the study period [Shah N, et al. Health and quality of life outcomes. 2019]. The one-sample proportions test with continuity correction compared the differences in frequency of ED or admissions across discharge diagnoses and the Wilcoxon rank sum test with continuity correction was used to compare cost differences across the groups. Results: In total, 1144 patients, median age 17 years (range 0-70), 903 (78.9%) with HbSS/HbSβ 0-thalassemia, 441 (38.5%) prescribed hydroxyurea, visited the ED, of whom 381 (33%) were admitted. VOC accounted for 64% of all ED visits and 60% of all admissions (Table 1). Anemia exacerbation was the most expensive reason for ED visit ($321.87/visit), while chronic organ damage carried the highest admission cost ($2,176.40/visit) (Figure 1). Compared with other genotypes, individuals with HbSS/HbSβ 0-thalassemia were admitted more often (79% versus 21%, p<0.0001), and their admission costs were higher ($1,677.18 versus $1,224.47/visit, p=0.0001). Antibiotics and analgesics accounted for 43% and 42% of the total ED costs, respectively, while housing accounted for 46% of the total admission costs (Figure 2). In a regression tree analysis, costs of ED visits were lower among HbSS/HbSβ 0-thalassemia individuals with hydroxyurea MPR ≥65% compared with those with MPR<65% or untreated ($182.46 versus $98.16/visit, p=0.0007). No difference in admission costs were observed relative to hydroxyurea use. Discussion: It is estimated that between 60,000 to 100,000 individuals live with SCD in Brazil today [Lobo CL, et al. Pediatric blood & cancer. 2014]. In a LMIC hematology-specialized center, VOCs accounted for most acute visits from patients with SCD, but costs were highest due to anemia exacerbation. Analgesics, antibiotics, and housing drove most expenses. Our results confirm the lower acute health care resource utilization with hydroxyurea therapy (fewer ED visits and admissions among those prescribed this medication). Hydroxyurea therapy reduced ED costs among individuals with HbSS/HbSβ 0-thalassemia, however, was dependent on adherence level. A cost analysis of individuals with SCD has never been performed in Brazil previously. Our study will facilitate appropriate planning of allocation of funds and development of health policies for individuals with SCD and may serve as the benchmark against which new SCD disease-modifying therapies may be compared for cost-effectiveness and cost-savings estimation in LMIC, such as Brazil. Figure 1 Figure 1. Disclosures Lobo: Novartis: Consultancy. Hankins: Global Blood Therapeutics: Consultancy; UpToDate: Consultancy; Vindico Medical Education: Consultancy; Bluebird Bio: Consultancy.

Effectiveness of Hydroxyurea in the Management of the Painful Crisis in Sickle Cell Anemia

Background: Sickle cell syndromes are inbred disorders distinguished by the presence of blade (Sickle) hemoglobin in red blood corpuscles. The sickling of red cells in patients with SCA is caused by the polymerization of molecules of non-oxygenated hemoglobin S (α2ß2s) into rigid rod-like polymers. In the open-label study of hydroxyurea therapy, the synthesis of embryo hemoglobin increased in most patients with SCA resulting in a humane myelotoxicity and rise in painful crises. By suppressing the sickling process, increased levels of embryo hemoglobin sinew the less frequency of painful crises.

Longitudinal analysis of cardiac abnormalities in pediatric patients with sickle cell anemia and effect of hydroxyurea therapy

Cardiac abnormalities such as left ventricular hypertrophy, dilation and pulmonary hypertension in sickle cell anemia, have been previously described. Hydroxyurea, a disease modifying therapy for sickle cell anemia, has been used for several decades. Longitudinal assessment of echocardiographic abnormalities in children and young adults with sickle cell anemia on hydroxyurea therapy is lacking. In this retrospective study, we aim to determine the prevalence of echocardiographic abnormalities in children and young adults with sickle cell anemia and to examine the effects of hydroxyurea on reverse cardiac remodeling. We reviewed the records of patients with sickle cell anemia who underwent routine cardiac screening at Cohen Children's Medical Center between 2010 and 2017, followed by retrospective longitudinal analysis of echocardiograms performed on patients receiving treatment with hydroxyurea. Data on a total of 100 patients with sickle cell anemia were analyzed; 60 (60%) were on hydroxyurea. Twenty-five (41.6%) of the patients on hydroxyurea had been treated for less than 1 year; these patients had a significantly greater prevalence of left ventricular dilation compared to those who had been on treatment for more than 1 year. Serial echocardiograms were then analyzed on patients receiving hydroxyurea. Left ventricular dilation and hypertrophy improved significantly with hydroxyurea treatment. Additionally, the left ventricular volume and mass correlated negatively with duration of treatment with hydroxyurea. Our study provides evidence that prolonged hydroxyurea therapy may lead to reverse cardiac remodeling. Future studies should attempt to follow this patient cohort for a longer duration.