Longitudinal Analysis of Hydroxyurea and Fetal Hemoglobin in Adult Patients with Sickle Cell Anemia

Introduction: Hydroxyurea (HU) was the first FDA-approved therapy for sickle cell anemia (SCA) and remains the most well-established disease-modifying therapy, reducing painful crisis and improving morbidity and mortality. HU improves outcomes through the upregulation of fetal hemoglobin (HbF). Dosing is highly variable with doses ranging from <10-35 mg/kg/day. Most dosing strategies escalate with a goal of mild myelosuppression, commonly defined using an absolute neutrophil count (ANC) between 2,000-4,000 and platelets >80,000. Macrocytosis is often used as a surrogate marker for compliance and effect. Despite its well-established effectiveness, clinical use remains limited with only 12% of adults with SCA taking HU. The reasons for this are multifactorial but include skepticism by both providers and patients regarding its effectiveness in the adult population. Some experts suggest up to 30% of adults are non-responders with no significant HbF change, and many believe that the effect of HU fades with time. Dosing strategies are usually quite conservative to prevent excessive myelosuppression, though dose is highly correlated with clinical effect and ultimate %HbF. There is very limited real-world data regarding long term effectiveness of HU in adults with SCA over time. Methods: We retrospectively analyzed the records of the 109 adults with SCA currently treated in our multidisciplinary sickle cell clinic. Data from 1/1/2011-6/30/2021 was collected, including genotype, HU prescription status, current and maximum laboratory values (HbF, MCV, ANC), and number of admissions for painful crisis. We performed Wilcoxon rank sum testing between pts prescribed and not prescribed HU and measures of HbF (peak, average and current) and number of admissions for painful crisis over the study period. Results: Among 106 pts (3 excluded from analysis, 2 for lack of data and 1 for post-transplant status), 79 are currently prescribed HU (75%). Among our 63 pts with HbSS genotype 58 are prescribed HU (92%). Average HbF over time for all pts prescribed HU was 11.9%. Average peak HbF was 18.1% and average current HbF is 12.4%. In the pts not prescribed HU HbF average, peak and current levels were 5.5%, 6.7%, and 5.0% respectively. HU prescription was significantly associated with increased HbF at peak, average, and current levels (p-value <0.001, Figure A). HU prescription was also significantly associated with decreased number of admissions for painful crisis (p-value 0.001). Among pts prescribed HU, MCV levels >100 at time of peak HbF were associated with higher peak levels than pts with MCV <100 (p-value <0.001, Figure B). Larger peak HU doses were also correlated with higher MCVs at the time of peak HbF levels (Figure C). Larger current HU doses were also significantly associated with higher current HbF levels (Figure, D). Doses >9.9m/kg were associated with significantly higher HbF levels however there was no significant difference between dose levels 10-19.9mg/kg and 20-29.9 or 20-29.9 and 30-39.9mg/kg (p-values 0.02, 0.68 and 0.84 respectively). Among pts prescribed HU, 34 obtained ANC levels <4000 at the times of peak HbF and 24 at the current dosing level (43% and 30% respectively). 24 pts obtained both MCV>100 and ANC <4000 at time of peak HbF and only 11 achieved both at current dosing levels (30% and 14% respectively). Conclusion: In our adult multidisciplinary sickle cell clinic prescribing rates are well above current HU usage for adults with SCA. Our data notes that elevated HbF levels can be maintained over long periods of time. HU prescription was significantly associated with increased HbF levels and reduced admissions for painful crisis. This was despite a majority of pts not meeting target prescribing levels of ANC <4000 and MCV >100. While higher peak HbF levels were significantly associated with higher HU doses, this was only true for doses above 9.9 mg/kg. Further investigation is needed to explore the factors contributing to suboptimal HbF and MCV response, including careful assessment with medication adherence and dose selection. Overall, these data illustrate the importance of dosing and suggest that one size dosing of HU for adults with SCA does not fit all. We hypothesize that there may be a role individualized dosing strategies in adults with SCA, incorporating factors such as pharmacokinetics and renal function to achieve the optimal dose for each patient. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

Paediatric sickle cell disease at a tertiary hospital in Malawi: a retrospective cross-sectional study

IntroductionSickle cell disease (SCD) remains a major cause of childhood mortality and morbidity in Malawi. However, literature to comprehensively describe the disease in the paediatric population is lacking.MethodsA retrospective review of clinical files of children with SCD was conducted. Descriptive statistics were performed to summarise the data. χ2 or Fisher’s exact test was used to look for significant associations between predictor variables and outcome variables (case fatality and length of hospital stay). Predictor variables that were significantly associated with outcome variables (p≤0.05) in a χ2 or Fisher’s exact test were carried forward for analysis in a binary logistic regression. A multivariable binary logistic regression was used to identify covariates that independently predicted length of hospital stay.ResultsThere were 16 333 paediatric hospitalisations during the study period. Of these, 512 were patients with SCD representing 3.1% (95% CI: 2.9%- 3.4%). Sixty-eight of the 512 children (13.3%; 95% CI: 10.5% - 16.5%) were newly diagnosed cases. Of these, only 13.2% (95% CI: 6.2% - 23.6%) were diagnosed in infancy. Anaemia (94.1%), sepsis (79.5%) and painful crisis (54.3%) were the most recorded clinical features. The mean values of haematological parameters were as follows: haemoglobin (g/dL) 6.4 (SD=1.9), platelets (×109/L) 358.8 (SD=200.9) while median value for white cell count (×109/L) was 23.5 (IQR: 18.0–31.2). Case fatality was 1.4% (95% CI: 0.6% - 2.8%)and 15.2% (95% CI: 12.2% -18.6%) of the children had a prolonged hospital stay (>5 days). Patients with painful crisis were 1.7 (95% CI: 1.02 - 2.86) times more likely to have prolonged hospital stay than those without the complication.ConclusionAnaemia, sepsis and painful crisis were the most common clinical features paediatric patients with SCD presented with. Patients with painful crisis were more likely to have prolonged hospital stay. Delayed diagnosis of SCD is a problem that needs immediate attention in this setting. Although somewhat encouraging, the relatively low in-hospital mortality among SCD children may under-report the true mortality from the disease considering community deaths and deaths occurring before SCD diagnosis is made.

Opioids and Sickle Cell Disease: From Opium to the Opioid Epidemic

Sickle cell disease (SCD) is an inherited disorder of hemoglobin structure. The clinical effects of the sickle gene are pleiotropic in nature causing multiple phenotypic expressions associated with the various complications of the disease. The hallmark of the disease is pain that could be acute, chronic, nociceptive, or neuropathic that could occur singly or in various combinations. The acute vaso-occlusive painful crisis (VOC) is the most common cause of admissions to the Emergency Department and/or the hospital. Although progress has been made in understanding the pathophysiology of SCD as well as in developing preventive and curative therapies, effective pain management continues to lag behind and depend mostly on the use of opioids. This review describes the history of opioids from the ancient times of opium to the current use of the many controversial opioids. In addition, the major cause of death of patients with SCD is the complications of the disease itself and not the use of opioids. The use of opioids by patients with SCD has been stable over the years. Judicious use of opioids to treat sickle cell pain according to available guidelines could minimize the unnecessary suffering experienced by patients with SCD.

Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study

Background: DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) was a Phase 3, randomized, double-blind, placebo-controlled study conducted in children with sickle cell anemia at 51 sites in 13 countries across four continents. Procedure: Data from DOVE were assessed for regional differences in subject phenotype and treatment. Demographics, baseline clinical and laboratory data, hydroxyurea (HU) use, vaso-occlusive crisis (VOCs; composite endpoint of painful crisis or acute chest syndrome (ACS, Beijing, China)), serious adverse events (SAEs, Florence, Italy), hospitalization, and treatments were compared across the Americas, Europe, North Africa/Middle East, and Sub-Saharan Africa (SSA). Results: Race, body mass index, and blood pressures differed by region. Pre-enrollment VOCs were highest in the Americas. For subjects not on HU, baseline hemoglobin was lowest in SSA; reticulocyte count was lowest in the Americas. Within SSA, Kenya subjects presented higher baseline hemolysis. Painful crisis was the most common SAE, followed by ACS in the Americas and infections in other regions. VOC rate and percentage of VOC hospitalizations were highest in Europe. Regardless of region, most VOCs were treated with analgesics; approximately half were treated with intravenous fluids. The proportion of VOC-related transfusions was greatest in Europe. Lengths of hospital stay were similar across regions. Conclusions: Overall differences in SAEs and hospitalization for VOCs may be due to cultural diversities, resource utilization, disease severity, or a combination of factors. These data are of importance for the planning of future trials in SCA in a multinational setting.

Comparison of Clinical Evolution of Children with Sickle Cell Disease before and after Treatment with Hydroxyurea at Saint Damien Hospital, Tabarre-Haiti,2013-2018

INTRODUCTION Sickle cell disease (SCD), an autosomal recessive hemoglobinopathy, is associated with a high morbidity and mortality rate, especially in low income countries. In Africa, 5% of deaths among children under five are attributable to SCD [59th World Health Assembly, WHO 2006]. This chronic disease greatly alters the quality of life of affected children. However, according to several published studies, SCD clinical course can be improved with the administration of hydroxyurea, an antimetabolite drug. [Nkashama, Pan African Medical Journal,2015] Saint-Damien, a pediatric hospital in Haiti, has a current cohort of 1248 sickle cell children. Forty of them (3 %) benefit from hydroxyurea administration since November 2015. In this hospital, data on how hydroxyurea modifies SCD clinical course are lacking, despite the advantage of this drug described in literature [Charache,New England Journal of Medicine,1995]. This study aims to compare the evolution of children treated at Saint Damien Hospital, before and after receiving hydroxyurea. METHODS A retrospective analytic study was conducted from November 2013 to June 2018 in the Sickle Cell Clinic at Saint-Damien Hospital. We included 40 children aged 2 to 15 years old treated with hydroxyurea. All of them benefit of the same treatment protocol: Initial dose of 10 mg per kg per day increase to maintenance dose of 25 mg per kg per day. Any child whose treatment has been permanently discontinued regardless of the cause was excluded. Epidemiological and clinical data were collected using Excel 2010. We compared children clinical evolution two years before and two years after hydroxyurea administration using these parameters: frequency and duration of hospitalizations, hospitalization frequency for specific complications (pain crisis, stroke and acute chest syndrome), and frequency of blood transfusions. We calculated frequencies, ratios and means using Epi Info. We realized statistical analysis to compare quantitative variables with a p value significant when less than 5%. RESULTS Gender ratio was 1:1. The mean age of children at enrollment on hydroxyurea was 8 years. Thirty-eight children of 40 (95 %) experienced at least one hospitalization before receiving the drug, compared with 17 (42.5%) after, p=0.025. The mean duration of hospitalization was 9 days before and 6 days after, p=0.0319. The average number of hospitalizations per child was decreased by 30 %. Seventy percent of children were hospitalized at least once due to painful crisis 2 years before receiving hydroxyurea, compare to 22.5 % after. Thirty-one children (77.5%) were transfused at least once before receiving the drug and 9 (22.5%) after receiving it. There was no cases of acute chest syndrome or stroke reported after hydroxyurea, unlike before the introduction of the drug. (Table 1) CONCLUSION The percentage of hospitalized children and the average length of hospitalization stay decreased significantly with hydroxyurea intake; as well as the frequency of painful crisis and blood transfusions. Hydroxyurea acts directly on the two main causes of hospitalization in the sickle cell, reducing the morbidity related to this pathology; and demonstrating the direct benefit of this drug at Saint Damien Hospital. Since our cohort is young, we have not been able to follow his evolution over a longer period of time. We plan to continue to observe this cohort. But these first results already allow us to recommend a broader use of hydroxyurea for pediatric patients with SCD in Haiti. Disclosures Alvarez: Forma Therapeutics: Consultancy; Novartis: Consultancy.