Use Of Hydroxyurea Research Articles

An assessment of the frequency of blood transfusion before and after starting hydroxyurea therapy in children of sickle cell anemia

Background: Hydroxyurea therapy is a known effective and safe therapy for the treatmentof sickle cell anemia (SCA). Although it is used worldwide in our Madhya Pradesh basedsetup, it is underutilized due to economic reasons and unaware practitioners about itsuse. Aims and Objectives: The Objective of the study is to assess the frequency ofblood transfusion year before and after starting hydroxyurea therapy in children of SCA. Materials and Methods: An ambispective observational study was performed at MGM Medical College Indore over a period of 1 year 8 months. One hundred and ninety patients were enrolled after taking a complete history, then started on Hydroxyurea and followed up every 2 months till 1 year. On follow-up, frequency of blood transfusion was noted along with routine investigations and for any side effects. Results: Of 190 total recruited patients, 84 were studied at the end because of loss to follow-up due to various reasons. Significant decrease in the need for blood transfusion was observed within 1 year of starting Hydroxyurea (P<0.05). Conclusion: The use of hydroxyurea in our native population at our setup can decrease the need for frequent blood transfusion in sickle cell patients.

Immunogenicity of The BNT162b2 COVID-19 mRNA and ChAdOx1 nCoV-19 Vaccines in Patients with Hemoglobinopathies.

Introduction: Studies assessing immune responses following Pfizer-BioNTech BNT162b2 mRNA COVID-19 (Pfizer) and ChAdOx1 nCoV-19 AZD1222 (AstraZeneca) vaccines in patients with hemoglobinopathy are non-existent in the literature despite being thought at high risk of infection. Methods: Prospectively, we collected serum from patients with hemoglobinopathies at least 14 days post vaccine and measured neutralizing antibodies (nAb) in addition to binding antibodies using in-house assays. Results: All 66 participants mounted a significant binding antibody response (100%), but nAbs were detected in (56/66) post-vaccine with a rate of 84.5%. Age, gender, vaccine type, spleen status, hydroxyurea use, and hyperferritinemia did not affect the rate significantly. While 23/32 (71.8%) patients receiving only one dose of the vaccine were able to mount a positive response, 33/34 (97.05%) of those who had two doses of any vaccine type had a significant nAbs response. Patients who had anti-nucleocapsid (N), signifying asymptomatic infection in the past, were able to produce nAbs (31/31). No nAbs were detected in 10/35 (28.5%) patients with no anti-N antibodies. Conclusion: Our results provide supportive data when advising patients with hemoglobinopathy to receive COVID-19 vaccines and ensure booster doses are available for better immunity. Whenever available, measurement of nAb is recommended.

Barriers to Therapeutic Use of Hydroxyurea for Sickle Cell Disease in Nigeria: A Cross-Sectional Survey.

Background: Sickle cell disease, the inherited blood disorder characterized by anemia, severe pain and other vaso-occlusive complications, acute chest syndrome, disproportionate hospitalization, and early mortality, has significant financial, social, and psychosocial impacts and drains individuals, families, and health systems globally. Hydroxyurea could improve the health of the 300,000 individuals born each year with sickle cell disease in sub-Saharan Africa; however, challenges to adoption and adherence persist. This study assessed the barriers to therapeutic use of hydroxyurea for sickle cell disease within the Nigerian healthcare system, specifically from the level of the patient, provider, and health system. Methods: We used purposive sampling to recruit participants from 13 regions in Nigeria. A cross-sectional survey was administered to physicians (n = 70), nurses or counselors (n = 17), and patients or their caregivers (n = 33) at 13 health centers. Findings were mapped onto the appropriate Consolidated Framework for Implementation Research (CFIR) domains. Results: This study was able to identify factors that mapped onto the inner setting, outer setting, and characteristics of individuals domains of CFIR. The majority of physicians (74.3%) prescribe hydroxyurea, and half stated hydroxyurea is the standard of care. Among clinicians, barriers included limited knowledge of the drug, as well as low self-efficacy to prescribe among physicians and to counsel among nurses; perceived side effects; perceived patient preference for traditional medicine; cost for patient and expense of accompanying laboratory monitoring; and limited availability of the drug and equipment for laboratory monitoring. Among patients and caregivers, barriers included lack of knowledge; perceived side effects; cost; religious beliefs of disease causation; and lack of pediatric formulation. Conclusions: Findings suggest that patient, provider, and health systems-level interventions are needed to improve hydroxyurea uptake among providers and adherence among patients with sickle cell disease in Nigeria. Interventions such as patient education, provider training, and policy change could address the disproportionate burden of sickle cell disease in sub-Saharan Africa and thus improve health equity.

Hydroxyurea and fetal hemoglobin effect on leg ulcers in patients with sickle cell disease.

The presence of leg ulcers in individuals with sickle cell disease often represents an early sign of vasculopathy and future end organ damage. Pathophysiological mechanisms of formation and evolution of leg ulcers are poorly understood; nevertheless, HbF has been associated with lower incidence of leg ulcers, while hydroxyurea has been correlated with high risk of leg ulcers. As a result, there is hesitation regarding hydroxyurea use in patients with SCD and leg ulcers. In this study, we aim to define (1) a target of HbF that offers protection against leg ulcer development and (2) the impact of hydroxyurea therapy on leg ulcer prevalence. Our study demonstrated that in order to reduce leg ulcer incidence by one-third, a HbF > 25% is needed, a threshold not commonly reached and maintained in the adult SCD population. Importantly, leg ulcer incidence appears to be independent of HU use (p = 0.50). Our interpretation of this data is that the use of HU in a patient with SCD and leg ulcers should be guided by a careful assessment of risks and benefits of this therapeutic modality.

Cholelithiasis in children and adolescents with sickle cell disease: Experience in a resource-limited setting.

Background:Sickle cell disease (SCD) remains prevalent in Nigeria and can be complicated by cholelithiasis even in children. There is still a dearth of knowledge about the occurrence of cholelithiasis in these children. The present study is aimed to determine the prevalence of cholelithiasis in pediatric SCD in Lagos and documents relevant socio-demographic and clinical correlates.Subjects and Methods:This was a cross-sectional study of children and adolescents aged 1–19 years with SCD attending the Paediatric Haematology Clinic of the Lagos University Teaching Hospital. One hundred and forty-seven children were consecutively recruited into the study over 3 months and they all had sonographic examination of the gall bladder. The association between cholelithiasis, sociodemographic data, clinical symptoms, laboratory parameters, and the use of hydroxyurea was also documented.Results:The median age (range) of the study participants was 9.0 (1–19) years and majority were males (59.9%). The prevalence of cholelithiasis was 13.6% and the condition was most prevalent in adolescents (21.4%) compared to the younger children (6.5%). All the children with cholelithiasis were asymptomatic. Age and the frequency of crisis were significantly associated with cholelithiasis on multivariate analysis (P = 0.03, 0.045, respectively). The use of hydroxyurea was not significantly related to the occurrence of cholelithiasis.Conclusion:The prevalence of cholelithiasis observed in this study is high. Routine screening of older children and adolescents with SCD, especially with the frequent crisis is suggested. Longitudinal studies to establish the relationship between hydroxyurea and cholelithiasis is also advocated.

Relationship between Genotype Variants and the Age of First Acute Splenic Sequestration in Patients with Sickle Cell Disease in a Tertiary Center of Saudi Arabia

BACKGROUND: Acute splenic sequestration crisis (ASSC) is one of the earliest life-threatening complications of sickle cell disease (SCD). Here, we aimed to identify the relation between the age of the first splenic sequestration episode and SCD variants. Episodes of acute splenic sequestration before 1 year of age are associated with a higher risk of recurrence. METHODS: We carried out a retrospective chart review study from the medical charts of SCD patients ≤12 years admitted to the Department of Pediatric Hematology King Saud Medical City, Riyadh with the first episode of ASSC and no other complications from January 2014 to December 2019. RESULTS: We included 47 patients (46.8% males, 53.2% females) diagnosed with SCD and having experienced their first ASSC in this review. The mean age of the patients at which the first episode of splenic sequestration happened was 3.26 years. The genotype distribution in the population was 74.5% HBSS, 21.3% HBS β0 thalassemia, and 4.3% HBSβ+ thalassemia. The crisis precipitated with fever in 74.5% of patients. Treatment included programmed blood transfusion (46.2%), splenectomy (29.8%). The recurrence rate after the first episode of ASSC was 59.6%. The high rate of recurrence was mainly due to the early age of presentation and poor compliance with suggested treatment. The use of hydroxyurea in 19.1% of patients showed a decrease of recurrence of ASSSC by 66.6% of patients. CONCLUSION: The study concluded that the HBSS variant of SCD had the earliest presentation with the first episode of ASSC but the differences were numerical without any statistical difference. Earlier age of presentation is associated with a higher rate of recurrence, but the difference was numerical not statistically significant. Our study shows hydroxyurea decreased recurrent splenic sequestrations; further research would help in establishing its role

Analysis of Risk Factors of Coagulation Dysfunction and Hemorrhage in Newly Diagnosed Hyperleukocytic Acute Myeloma Leukemia.

Purpose To explore whether and why abnormal coagulation function and hemorrhage can appear in patients with hyperleukocytic acute myeloid leukemia (HAML). Method We retrospectively reviewed the charts of 724 acute myeloid leukemia (AML) patients admitted with a white blood cell count of >100 × 109/L between 2010 and 2019 in order to analyze the coagulation index of patients with HAML and explore the correlation of abnormal coagulation. Result Prothrombin time (PT) was extended in group HAML compared with group non-HAML. Respiratory failure, intracranial hemorrhage, and infection were more common in the HAML group. Among the 76 HAML patients, there were 33 patients who had ≥3 abnormal items of coagulation index, and 51.5% of them had level 2 hemorrhage which was more than level 0 hemorrhage, and the difference is statistically significant (P < 0.01). Similarly, we can discover that 40.9% of patients with 2 abnormal items had level 2 hemorrhage in contrast to 0 abnormal items. The use of hydroxyurea had a significant effect on PT and D-dimer (DD). Survival analysis by the Kaplan–Meier method showed that there were statistically significant differences in white blood cell (WBC) count＞200 × 109//L and DD. Abnormal PT is associated with WBC count＞200 × 109//L, and abnormal activated partial thromboplastin time (APTT) is associated with HLA-DR mutation. Infection and respiratory failure were independent influencing factors for the coagulation of patients. Conclusion DD had a marked effect on the survival rate. Infection and respiratory failure were independent influencing factors for the coagulation of patients.

Idiopathic Intracranial Hypertension: An Unusual Cause of Headache in a Patient With Sickle Cell Disease

Idiopathic intracranial hypertension (IIH) is a rare cause of headache and visual disturbance with no known association with sickle cell disease (SCD). We present a patient with SCD with gradual onset of a severe headache and visual changes. Brain magnetic resonance imaging, angiography, and venography were nondiagnostic. Lumbar puncture established a diagnosis of IIH, and the patient had rapid improvement with large-volume lumbar puncture and acetazolamide. To our knowledge, this is the first case of IIH in a nonobese adult with SCD taking hydroxyurea, suggesting an association between SCD or hydroxyurea use and IIH. Furthermore, her clinical course demonstrates the complexities of treating IIH in patients with SCD.

P107: A PHASE 2/3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF MITAPIVAT IN PATIENTS WITH SICKLE CELL DISEASE

Background: The key pathology in sickle cell disease (SCD), a life-threatening, hereditary hemoglobin (Hb) disorder, is red blood cell (RBC) sickling due to polymerization of deoxygenated sickle Hb (HbS), which can be exacerbated by increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG), and decreased ATP.1–3 Sickled RBCs are rigid, not deformable, and fragile, resulting in vaso-occlusion triggering pain and chronic hemolysis.4–6 SCD treatment options are limited, with an unmet need for safe and effective therapies to improve anemia and reduce pain. Mitapivat is an oral, activator of RBC pyruvate kinase (PKR), a key glycolytic enzyme. PKR activation decreases 2,3-DPG and increases ATP, which may reduce HbS polymerization, RBC sickling, and hemolysis in SCD.3,7–9 Data from the phase (ph) 1 National Institutes of Health multiple ascending dose study of up to 100 mg mitapivat twice daily (BID) in SCD (NCT04000165) showed that mitapivat was safe and tolerable, increased ATP and decreased 2,3-DPG in a dose-dependent manner, and improved anemia and hemolysis.8,10 Aims: To report the study design of RISE UP (NCT05031780, EudraCT: 2021-001674-34), a ph 2/3, double-blind, randomized, placebo-controlled, multicenter study evaluating the efficacy and safety of mitapivat in patients (pts) with SCD. Methods: Eligible: pts aged ≥16 yrs with documented SCD (HbSS, HbSC, HbSβ0/HbSβ+ thalassemia, other SCD variants), 2–10 sickle cell pain crises (SCPCs; acute pain needing medical contact, acute chest syndrome, priapism, hepatic or splenic sequestration) in the prior 12 months, and Hb 5.5–10.5 g/dL. If taking hydroxyurea (HU), the dose must be stable for ≥90 days before starting study drug. Ineligible: pts receiving regularly scheduled blood transfusions, with severe kidney disease or hepatobiliary disorders, currently receiving SCD therapies (excluding HU) or who have received gene therapy, bone marrow or stem cell transplantation. In the double-blind ph 2 part, 69 pts will be randomized (1:1:1) to 50 mg or 100 mg mitapivat, or placebo BID for 12 weeks (wks). The primary objective of ph 2 is to determine the recommended ph 3 mitapivat dose by evaluating anemia and safety vs placebo via the following endpoints: Hb response (≥1.0 g/dL increase in average Hb concentration over Wks 10–12 vs baseline [BL]), and type, severity, and relationship of adverse events and serious AEs. In the double-blind ph 3 part, 198 pts who did not participate in ph 2 will be randomized (2:1) to the selected ph 3 mitapivat dose or placebo BID for 52 wks, stratified by number of SCPCs in the prior yr (<5, ≥5) and HU use. The primary objectives of ph 3 are to determine the effect of mitapivat vs placebo on anemia, measured by Hb response (≥1.0 g/dL increase in average Hb concentration over Wks 24–52 vs BL), and the effect of mitapivat vs placebo on SCPC, measured by annualized rate of SCPCs. Key secondary endpoints include average change from BL in Hb concentration, indirect bilirubin, percent reticulocyte, and Pt-Reported Outcomes Measurement Information System® Fatigue 13a Short Form score over Wks 24–52; and annualized frequency of hospitalizations for SCPC. Pts who complete the double-blind period will be eligible to receive mitapivat in the open-label extension period in each ph. Results: Not yet available. Conclusion: This ph 2/3 study will investigate the efficacy and safety of mitapivat in pts aged ≥16 yrs with SCD. Enrollment is currently ongoing.

Barriers and Facilitators of Use of Hydroxyurea among Children with Sickle Cell Disease: Experiences of Stakeholders in Tanzania.

Factors contributing to low use of HU among SCD patients exist in high-income countries. The latter leaves a drift of literature on factors for low utilization of HU in developing countries. This study aimed to explore the factors influencing the use of HU in the management of SCD in Tanzania. A qualitative study was employed to interview purposively selected participants for this study. The in-depth interviews were conducted with 11 parents of children with SCD, four medical doctors working at sickle cell clinics, and two representatives of the national health insurance fund (NHIF). Interviews were audio-recorded, transcribed, and thematically analysed. Barriers identified were misconception of parents on SCD, financial constraints, regulatory restrictions, worries and fears of medical doctors on the acceptability of HU, shortages of laboratory equipment and consumables, and limited availability of HU. Adequate knowledge of the parents and medical doctors on SCD and HU and opportunities for HU accessibility were the facilitators identified. The utilization of HU by the individual with SCD is affected by several factors, from individual to policy level. Nevertheless, parents of children with SCD and medical doctors working in sickle cell clinics demonstrated good knowledge of the diseases and HU.

A call to start hydroxyurea by 6months of age and before the advent of sickle cell disease complications.

A call to start hydroxyurea by 6months of age and before the advent of sickle cell disease complications.

Prognostic factors associated with COVID-19 related severity in sickle cell disease

BackgroundEquipoise exists regarding sickle cell disease (SCD) as a risk factor for COVID-19 disease severity and variables that increase risk of COVID-19 severity in SCD. Given our health system's large SCD patient catchment, we analyzed our own experience in this regard. Study methodsRetrospective analysis of the clinical course and factors associated with need for hospitalization and ICU admission of SCD patients diagnosed with COVID-19 through the Northwell Health system from March 1 to Dec 31, 2020. ResultsOf 1098 patients with SCD, 3.3% were diagnosed with COVID-19. Overall rates of hospitalization, ICU admission, cohort mortality, and in-hospital mortality were 80%, 19%, 2.5%,and 3.1%, respectively. By multivariable analysis, hospitalization risk was decreased by 60% for every 1 g/dL increase in admission Hb. ICU admission risk was increased by 84% as a health care worker; increased by 45% for every 1000/uL increase in admission immature granulocyte count; and decreased by 17% with hydroxyurea use. DiscussionHigh hospitalization rates are compatible with worsened severity upon COVID-19 infection in SCD compared to the general population. Patients should be placed on hydroxyurea to increase their Hb and perhaps lower their neutrophil counts. Health care workers with SCD may warrant special safety precautions.

Benefits of a Disease Management Program for SCD in Germany 2011 - 2019: The Increased Use of Hydroxyurea Correlates with a Reduced Frequency of Acute Chest Syndrome

BackgroundWorldwide, Sickle Cell Disease (SCD) is the most common single gene disorder affecting >250,000 newborns annually. In Germany, SCD qualifies as a rare disease and almost exclusively affects immigrants from endemic countries and their descendants. The recent surge of immigration from high-prevalence countries increased the numbers of patients with SCD in Germany and raised awareness for the need of specialized care.In 2012, the German Society for Pediatric Oncology and Hematology (GPOH) mandated a consortium of five university hospitals to develop a disease management program for patients with SCD. This consortium issued treatment guidelines for SCD that strongly favor the use of hydroxyurea, initiated patient and physician education events, prepared for a universal newborn screening program that will start 09/2021, moderated a consensus on the indication of allogeneic stem cell transplantation for patients with SCD, and established a national patient registry.MethodsIn order to quantify the effect of these activities, we made use of claims data that were collected by the research institute (WIdO) of the major German insurance company, the Allgemeine Ortskrankenkasse (AOK), and of publicly accessible data collected by the Federal Statistical Office (Statistisches Bundesamt, Destatis). ICD10 codes were used to identify patients with SCD and their comorbidities. Pharmacologic treatments were quantified using the German Anatomical Therapeutic Chemical (ATC)-Classification with defined daily doses.ResultsWe estimate that the number of patients with SCD in Germany increased from approximately 2,200 in 2011 to approximately 3,200 in 2019. Analyses of administered treatments illustrate that important components of recently issued national treatment guidelines have been largely implemented. Specifically, the use of hydroxyurea has more than doubled, resulting in a proportion of approximately 45% of all patients with SCD being treated with hydroxyurea in 2019 (Figure 1A). In strong negative correlation with the use of hydroxyurea, the frequency of acute chest syndromes decreased (Figure 1B). While before the widespread use of hydroxyurea (2011-2013) 8.1% of patients with SCD were admitted at least once per year for ACS, this proportion dropped to 6.6% in the period 2017 to 2019. Similarly, the proportion of patients who required analgesics, red blood cell transfusions and hospitals admissions declined from 2011 to 2019, indicating a reduced burden of SCD with the increased use of hydroxyurea.ConclusionIn sum, these data demonstrate an association between the dissemination of nationwide treatment guidelines and changes in clinical practice in particular relating to the use of hydroxyurea. These changes translate into a remarkable improvement of key measures of disease activity in a representative population based analysis. [Display omitted] DisclosuresLobitz: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kulozik: BioMedX: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Pediatric Hydroxyurea Treatment Patterns, Sickle Cell Disease-Related Complication Rates, and Costs in a Large US Administrative Claims Database: A Retrospective Analysis

Introduction: Sickle cell disease (SCD) is an inherited blood disorder and hydroxyurea (HU) is the only pharmaceutical treatment approved for pediatric patients aged 9 months and older. In 2014, the National Heart, Lung, and Blood Institute (NHLBI) recommended that infants, children, and adolescents be offered treatment with HU regardless of disease severity to reduce SCD-related complications, such as pain and anemia. In 2017, the FDA approved HU in pediatric patients aged 2 and older to reduce the frequency of painful crises and the need for blood transfusions. This study aimed to describe SCD treatment patterns, SCD-related complications rates, and health care resource utilization and costs in pediatric patients with SCD using HU to identify gaps in care.Methods: This retrospective analysis of a large US commercial claims database included health plan enrollees aged 0-17 years old with 1+ SCD diagnosis code from July 1, 2013-March 31, 2020 (study period) and 1+ HU pharmacy claim from January 1, 2014-September 30, 2019 (identification period) in the Optum Research Database. Index date was defined as the first date with a HU claim. Patients were continuously enrolled for 6 months before (baseline period) and 6+ months after the index date (fixed 6-month and variable follow-up periods) and excluded if they had evidence of clinical trial participation or pregnancy amongst females. Demographics and the top five Agency for Healthcare Research and Quality (AHRQ) comorbidities were captured during baseline. Fixed 6-month follow-up treatment patterns included use of HU, short-acting opioids, and red blood cell transfusions. Follow-up rates of priapism among males, acute kidney injury (AKI), chronic kidney disease (CKD), stroke, and transient ischemic attack (TIA) per 1,000 person-years (PY), excluding those with baseline evidence, were calculated. Fixed 6-month follow-up all-cause health care resource utilization included ambulatory, emergency department (ED), and inpatient hospitalizations. Total all-cause health care costs included health plan- and patient-paid amounts and were calculated as per-patient-per-month (PPPM) to account for the variable follow-up period.Results: 160 pediatric patients met the selection criteria (mean [SD] age: 10 [4.5] years, 58.1% male, 53.13% HB-SS). Mean (SD) follow-up was 2.7 (1.7) years. Top five 6-month baseline AHRQ comorbidities were anemia: 154 (96.3%); respiratory infections: 65 (40.6%); asthma: 40 (25.0%); heart disease: 37 (23.1%), and other gastrointestinal disease 34 (21.3%). Nearly a third (32.5%) had baseline HU use and 74 (46.2%) continued HU use for 6+ months. Among 86 (53.8%) with < 6 months of HU use, 34 (39.5%) never restarted HU during the fixed 6-month follow-up period. Short-acting opioid use was observed in 65 (40.6%) of pediatric patients, with a median of 2 fills, and 25 (15.6%) had at least one red blood cell transfusion during the fixed 6-month follow-up period. SCD-complication rates per 1,000 PY for priapism among males, AKI, CKD, stroke and TIA were 16.4, 2.3, 11.9, 19.7, and 4.7, respectively. SCD-complication rates by age groups are shown in Table 1. In the first 6 months of HU treatment, 154 (96.3%), 59 (36.9%), and 37 (23.1%) had at least one ambulatory, ED, and inpatient hospitalization, respectively. Mean (SD) total all-cause health care costs in the first 6 months of HU treatment were $24,446 ($108,930), driven primarily by inpatient hospitalizations $17,467 ($103,639). Mean (SD) total PPPM costs in total follow-up were $2,703 ($5,028), attributed mostly to medical care $2,511 ($4,866).Conclusions: Despite a recommendation for HU use in pediatric patients with SCD, less than half of this large commercial claims study cohort had consistent HU use. Pediatric patients with recent or current HU use were noted to have SCD-related complications. Among patients with SCD less than 18 years old, health care costs were high. Notably, short acting opioid use and blood transfusions typically prescribed to alleviate pain and treat SCD-related complications were observed, demonstrating significant burden of disease. Alternative or concomitant SCD treatments for the pediatric population could potentially reduce SCD-related complications and associated health care costs when HU use alone may not be sufficient. [Display omitted] DisclosuresManwani: Novartis: Consultancy. Paulose: Novartis Pharmaceuticals Corporation: Current Employment. Yen: Novartis Pharmaceuticals: Current Employment; Merck & Co., Inc.: Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Lee: Novartis Pharmaceuticals Corporation: Current Employment. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Early Evaluation of the Use of Crizanlizumab in Sickle Cell Disease: A National Alliance of Sickle Cell Centers Study

Early Evaluation of the Use of Crizanlizumab in Sickle Cell Disease: A National Alliance of Sickle Cell Centers Study

Excess All-Cause Mortality in 2020 for People Living with Sickle Cell Disease in New York City

BackgroundThe COVID pandemic resulted in excess all-cause mortality in 2020 in the United States, especially among people who identify as Black and/or Latino. While many of these deaths were due to COVID-19 infection, others have been attributed to strain on the overburdened health care system and delays in patients seeking medical care due to the pandemic. We sought to examine the overall mortality in individuals with sickle cell disease (SCD) who received their care at our Sickle Cell Center in Bronx New York in 2020 and investigated whether the number and causes of death in 2020 differed from the previous 3 years.Methods:Death date was collected from electronic medical records (EMR) and death certificates. Clinical variables collected from EMR included age, gender, race, genotype, history of comorbidities, hydroxyurea use, and health care utilization in the 12 months prior to death date. To determine cause of death, two hematologists performed manual review of the EMR blinded from each other and deaths were categorized as due to: sudden death, cardiovascular causes, sepsis, stroke, acute organ failure (including multi organ failure syndrome), chronic organ failure, hemorrhage, and unknown when records of the death event were not available. A third hematologist served as a tie breaker in cases of disagreement. Patients were also categorized as having: 1) sepsis present or absent during the death event, 2) acute (new or newly worsened) renal or liver failure present or absent during the death event, and 3) COVID status at death (acute COVID, past COVID, no COVID, or unknown COVID status). Acute COVID infection was defined by a positive PCR swab during the hospitalization leading to death or in the prior two weeks. Past COVID infection was defined by a negative PCR swab during the hospitalization and a positive PCR swab and/or antibody test more than two weeks before the death event with documented resolution of symptoms. No COVID infection was defined by a negative PCR swab or antibody test documented in the EMR and no positive tests present or noted per patient report. Unknown COVID status was unknown if no testing was present in the EMR. To examine how 2020 decedents differed from decedents in the prior 3 years, we compared clinical variables using the Kruskal Wallis test for continuous variables and chi 2 tests for dichotomous variables. To examine differences between 2020 decedents between known COVID (acute or chronic) vs. no COVID, we repeated similar tests among the 2020 decedents only.Results:In the years 2017, 2018, 2019, and 2020, there were 9, 10, 8, and 22 patient deaths respectively. Compared with decedents in the prior 3 years, patients who died in 2020 were more likely to have acute liver failure during the hospitalization, were more likely to have history of stroke, and had more heme clinic visits in the prior 12 months. Otherwise, there was no difference in age, gender, genotype, hydroxyurea use, history of disease morbidity, hospital utilization in the prior 12 months, or sepsis before death (Table 1). Among the 22 who died in 2020, 3 had an acute COVID infection, five had past COVID, 8 had no COVID, and 6 had unknown COVID status. Among 2020 decedents, acute or past covid was associated with acute organ failure (p=0.02) and less hydroxyurea use (p=0.04). (Table 2).Conclusions:SCD deaths at our center more than doubled in 2020 compared to prior years, but fewer than half of the decedents had acute or prior COVID. Compared with prior years, 2020 decedents were more likely to have acute organ failure. This could be explained by COVID infection, delays in seeking care, or changes in care delivery during the COVID pandemic. This study emphasizes the need for further studies on the impact the pandemic had on the health of adults with SCD, as well as the need for prospective studies of patients with SCD who recover from COVID. [Display omitted] DisclosuresCurtis: GBT: Consultancy. Minniti: Forma: Consultancy; GBT: Consultancy; Novartis: Consultancy; Novo Nordisk: Consultancy; Chiesi: Consultancy; F. Hoffmann-La Roche: Consultancy; Bluebird Bio: Other: Endpoint adjudicator; CSL Behring: Other: Endpoint adjudicator.

Early Hydroxyurea Use May be Neuroprotective in Children with Sickle Cell Anemia

Introduction: The neurologic changes of sickle cell anemia (SCA) are particularly devastating and include acute stroke, silent infarctions, and cerebral hypoxemia that together result in cumulative damage and significant neurocognitive deficits. Executive functioning and attention are the most commonly reported deficits with individuals with SCA scoring on average ten points lower on measures of full scale intelligence compared to matched unaffected controls, translating to poor academic achievement and later job attainment. Hydroxyurea is the standard-of-care in patients with SCA with a growing body of evidence suggesting a role in neuroprotection. However, although encouraging, until now, the only studies have involved children who began hydroxyurea in grade school, well after the onset of SCA-related neurocognitive decline. Beginning in 2014, Cincinnati Children's Hospital Medical Center (CCHMC) began treating children with SCA as young as six months with hydroxyurea; these children have had few SCA-related complications and offer a unique population to evaluate the effects of the early introduction of hydroxyurea on neurocognition.Methods: We completed a cross-sectional analysis of the neurocognitive status of our SCA population. Children at least three years old with SCA were enrolled in two cohorts: 1) children with SCA (HbSS and HbS-B 0thalassemia genotypes) who began hydroxyurea before age five years and 2) children with SCA who did not qualify for the first cohort (either on hydroxyurea or chronic transfusions (CTT)). Unaffected controls (siblings of patients with SCA or children seen in the CCHMC primary care clinic) were matched to each patient with early hydroxyurea use by age, race, and sex. All participants completed the NIH Toolbox: Cognition Battery, a shortened neuropsychological evaluation administered using a handheld tablet in the clinical setting, requiring 15-30 minutes. The mean score is 100 and standard deviation 15. We also obtained academic history, demographic variables, and laboratory values for SCA patients.Our overall objective was to compare the neurocognitive status of children with SCA who initiated hydroxyurea before age five years to an unaffected, matched sibling and community control cohort and to historically treated patients followed at the CCHMC sickle cell clinic in order to assess whether the beneficial effects of hydroxyurea extend to neuroprotection.Results: We enrolled 29 patients into the early hydroxyurea SCA group with 24 matched unaffected controls (early hydroxyurea group: mean age 7.2 +/-3.2 years, 52% female). The SCA cohort who initiated disease modifying treatment later in life included 20 patients (mean age 16 +/-5.1 years, 70% female) (Table 1). There were no differences in age, gender, patient education, maternal education, and Area Deprivation Index (ADI, a marker of socioeconomic status) between the early hydroxyurea SCA and control cohorts (Table 1). In the SCA cohort initiating treatment later in life, 5 patients received hydroxyurea, 13 were on CTT for reasons other than for stroke prophylaxis, and 2 received no therapy. The early hydroxyurea use patients and controls scored no differently on the composite cognition score (86 +/-13 versus 88 +/-12, p = 0.6), while the early hydroxyurea patients scored significantly higher than the SCA cohort treated later in life on the composite cognition (versus 77 +/-14, p = 0.03) (Table 2). On a linear regression model, age (p = 0.004) and patient years of education (p = 0.04) were significantly correlated with the composite cognition score when considering all cohorts. When limited to only patients with SCA on hydroxyurea, age (p = 0.005) and patient education (p = 0.002) remained significant, while maternal educational attainment below high school (p = 0.07), hemoglobin (p = 0.07), and fetal hemoglobin (p = 0.07) approached significance.Conclusions: Due to challenges with social determinants of health, children with SCA are already at risk for poor academic performance with early and recurrent “silent” hypoxic events further exacerbating these challenges. If started early in life and maintained through the important early years of brain development, hydroxyurea may be neuroprotective for children with SCA. These data provide further evidence to support the universal prescription of hydroxyurea beginning in the first years of life for all children with SCA. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Vitamin D Levels: Associations with Acute Pain Events and Self-Reported Pain in Children with Sickle Cell Disease

Background/Aims: Individuals with sickle cell disease (SCD) are at high risk for vitamin D deficiency due to dark skin color, limited physical activity, poor nutrition, and renal dysfunction. In smaller retrospective studies, vitamin D deficiency in SCD was associated with increased frequency of acute pain events and higher opioid use, however the impact of vitamin D deficiency on pain related patient reported outcomes has not been described . Supplementation with high dose vitamin D is shown to be associated with fewer pain days per week and higher physical activity scores in patients with chronic pain. Thus, the objective of our study was to evaluate relationship between vitamin D levels, acute health care utilization and self-reported pain among children with SCD. We hypothesized that vitamin D deficiency is associated with increase health care utilization for pain and patient-reported outcomes for pain.Methods: Patients with SCD (1 to 18 years of age), enrolled in Sickle Cell Clinical Research and Intervention Program (SCCRIP), at St. Jude Children's Research Hospital were included in the study (Hankins et.al., Pediatric Blood and Cancer, 2018). Demographic, clinical and laboratory data were extracted from SCCRIP database. Prospective pain event leading to a hospital visit was analyzed. We analyzed pain-related hospitalizations in two ways: the number of pain-related hospitalizations within 2 years prior to and after vitamin D measurement in a cross-sectional design and longitudinally. Generalized linear regression model was used to examine associations between vitamin D and cross-sectional pain events with adjusting for hydroxyurea use. Generalized linear mixed effect model was used to assess the associations between vitamin D and longitudinal pain events, with adjusting for SCD genotype, sex, age, hydroxyurea use and interaction between age and hydroxyurea use.Pediatric Quality of Life Inventory™ Sickle Cell Disease Module (PedsQL™ SCD) was used to measure pain and pain interference using 1) Pain and Hurt and 2) Pain Impact scales. PedsQL™ SCD assessments include a Likert response scale. Items are reverse -scored and transformed to a 0-100 scale where higher scores indicate better health related quality of life in that scale. Two sample t-test or Wilcoxon rank sum test was used to compare mean scores between the two groups.Results: A total of 799 patients (females, n=398; males, n=401) were included in the study. Mean age (Standard Deviation [SD]), range at time of first vitamin D measurement for entire cohort was 8.7 (4.7), (0.8-18 years). Mean (SD) initial vitamin D level for entire cohort was 19.0 (9.4) ng/dl. Mean (SD) number of pain-related hospitalizations within two years of first vitamin D measurement was higher in the vitamin D deficient group as compared to non deficient group [0.81(1.97) vs 0.66 (1.2), (p=0.0034)]. Longitudinal data analyses showed vitamin D deficiency was associated with increased number of pain related hospitalizations (p=0.0091), after adjusting for covariates listed above (Figure 1a).Mean (SD) scores for Pain and Hurt in vitamin D deficient versus non deficient group were [74.5.7(18.2) versus 83.5(15.6), p < 0.001]. Mean (SD) scores for Pain Impact in vitamin D deficient group as compared to non deficient group were [(66.7 (22.7) versus 75.5 (22.3), p <0.001] (Figure 1b)Conclusion: Results indicated that low vitamin D levels predicted higher frequency of painful events leading to a hospital visit and were associated with higher prevalence of self-reported pain and pain interference. Further studies evaluating mechanisms by which vitamin D influences sickle cell pain are warranted and larger controlled trials can help evaluate the therapeutic efficacy of vitamin D for sickle cell pain. [Display omitted] DisclosuresHankins: UpToDate: Consultancy; Bluebird Bio: Consultancy; Vindico Medical Education: Consultancy; Global Blood Therapeutics: Consultancy.

Defining and Predicting Rapid Egfr Decline in Sickle Cell Disease

Chronic kidney disease is observed in up to 50% of adults with sickle cell disease (SCD) and is a consistent predictor for increased morbidity and early mortality. Progression of kidney disease can be manifested by a rapid decline in estimated glomerular filtration rate (eGFR). In retrospective studies, up to 38% of SCD patients have a rapid decline in kidney function, defined from the non-SCD literature as an eGFR slope < -3.0 mL/min/1.73m 2. Clinical and genetic predictors and the appropriate cutoff for rapid eGFR decline in SCD are unclear, but are paramount for guiding intervention studies in sickle cell nephropathy.We investigated 1) genetic, laboratory, and clinical risk factors for eGFR decline and 2) the rate of eGFR decline that best predicted mortality risk in a longitudinal cohort of SCD patients enrolled in a prospective registry at our institution. Between 10/2009 and 2/2018, 439 SCD patients were recruited. Blood samples, clinical and laboratory data were collected after obtaining consent at the time of enrolment during a clinic visit without the patient being in a vaso-occlusive crisis. 352 SCD patients with > 6 months of outpatient eGFR assessments were included in this analysis. The eGFR slope was calculated for each patient by linear regression of eGFR by time. Genotyping for the APOL1 G1 and G2 kidney risk variants and alpha thalassemia were performed by PCR. High-risk APOL1 status was defined as being either homozygous or compound heterozygous for the G1 and/or G2 variants. The statistical analyses for predictors of eGFR decline were conducted using linear regression, adjusting for age, sex, SCD genotype, hydroxyurea use, angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) use, and baseline eGFR. Median and interquartile ranges (IQR) are provided.The median age of the cohort was 32 years old (IQR, 24 - 43 years), 60% were female, 76% had Hb SS or Sβ 0-thalassemia genotype, 47% were on hydroxyurea, and 12% were on ACEi or ARB therapy. With a median follow up of 6.7 (IQR, 3.8 - 8.5) years, the median annual eGFR slope was -0.9 (IQR, -3.6 to 1.1) mL/min/1.73m 2. A faster rate of eGFR decline was observed in SCD patients with the Hb SS or Sβ 0-thalassemia genotype, with high-risk APOL1 status, and in those without coinheritance of α-thalassemia (Figure 1A). The urine albumin concentration, based on the average of two consecutive values from the time of enrolment, was significantly associated with a more rapid eGFR decline (β -0.63, P < 0.0001). An albuminuria cutoff of ≥ 100 mg/g creatinine was a stronger predictor for eGFR decline than cutoffs of ≥ 30 or ≥ 300 mg/g (Figure 1B). During the follow up period, we observed 26 deaths (7.4% mortality). An annual eGFR slope of < -6 mL/min/1.73m 2 was independently associated with a greater risk for mortality, after adjusting for age, sex, SCD genotype, hydroxyurea use, ACEi or ARB use, and baseline eGFR (Figure 1C). Using receiver operating curves, this cutoff was also associated with the largest area under the curve for predicting mortality.Our data highlights genetic risk factors and supports albuminuria as an independent predictor of eGFR decline in a longitudinal cohort of SCD patients. We also demonstrate that an annual eGFR slope of < -6 mL/min/1.73m 2 is the strongest predictor for mortality in our cohort. This threshold will need to be validated in other longitudinal SCD cohorts. The association of urine albumin ≥ 100 mg/g creatinine with eGFR decline supports using this cutoff as a clinical biomarker to identify high risk patients for kidney disease progression and for initiating disease modifying and reno-protective therapies. [Display omitted] DisclosuresSaraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy.

The Burden of Atrial Fibrillation in Sickle Cell Disease

▪IntroductionLife expectancy amongst individuals with sickle cell disease (SCD) has plateaued, with cardiopulmonary complications now becoming a leading cause of death (Fitzhugh et al. Am. J. Hematology 2010). Indeed, SCD is associated with increased rates of pulmonary hypertension (pHTN) and diastolic dysfunction (Sachdev et al. Blood 2005). In the general population, atrial fibrillation (AF) is associated with an increased mortality in the setting of either pHTN or diastolic dysfunction. Although cardiac structural and biochemical changes likely create an electrophysiological substrate for AF in SCD, the prevalence and risk factors for AF in SCD remain unclear. We determined the prevalence, incidence, and clinical characteristics of AF in a large cohort of patients with SCD.MethodsWe conducted a retrospective, longitudinal cohort study of all adult patients with SCD seen at our large, urban single center from January 2008 to December 2017. SCD patients were identified using a previously described semi-automated system with a subset with direct chart review (Srisuwananukorn et al. Blood Advances 2020). We performed manual review of ~17,000 available electrocardiograms of all enrolled subjects to look for AF. For univariate analyses, the associations of linear and categorical variables with AF were assessed using the Kruskal-Wallis test and Pearson's χ 2 test, respectively. We used Bonferroni correction for categorical variables with greater than two groups. Logistic regression analysis with stepwise addition of variables (p>0.15) was used to evaluate for the effects of previously described AF risk factors, degree of anemia, hydroxyurea use, and genotype on AF development.ResultsOur cohort consisted of 763 adult SCD patients with a median age of 27.95 years, 59.50% female, 72.4% with Hb SS or Sβ 0-thalassemia genotype, and 61.2% were prescribed hydroxyurea. Mean observation time for the cohort was 8.3 ± 6.3 yrs. We identified AF in 30 out of 763 adult SCD individuals with a mean age onset of 51 ± 10 years (median age 52 years). The period prevalence of AF was 3.93% and the incidence density was 3.02 per 1000 patient years observed. Individuals with AF tended to be older at initial (40 vs. 25 years, p<0.0001) and follow-up (53 vs. 35 years, p<0.0001) visits and were observed for a longer period (13.3 vs. 9.5 years, p=0.0014). There was no difference in gender (p=0.7), ethnicity (p=0.5), or SCD genotype (p=0.03) between groups (see Table 1). Those with AF were more likely to carry diagnoses of chronic obstructive pulmonary disease (p=0.0004), hypertension (p<0.0001), chronic kidney disease (p<0.0001), type 2 diabetes (p<0.0001), and any cancer (p=0.04). However, hydroxyurea use was not associated with AF development (p=0.3). SCD patients with AF were more likely to receive diuretics, atrioventricular nodal blocking agents, antihypertensives, antiplatelets, and statin therapies (see Table 1). AF was associated with worse anemia and reduced renal function. Regression analysis identified significant odds ratios (ORs) for age at initial visit (OR 1.06, p=0.03), serum creatinine per 1 mg/dL increase (OR 2.34, p=0.02), hemoglobin level per 1 g/dL increase (OR 0.52, p=0.0009), fetal hemoglobin level per 1% increment (OR 0.81, p=0.008), and total observation time per year follow up (OR 1.26, p=0.0006).ConclusionWe showed that the prevalence and incidence of AF is high in patients with SCD with the median age of onset occurring 1-2 decades earlier than in the general populace (Feinberg et al. JAMA Internal Medicine 1995). AF in patients with SCD is associated with advanced age, worse renal function, a higher degree of anemia, and greater usage of cardio- and nephro-active medications. The high incidence of AF in patients with SCD may contribute to the plateauing of life expectancy and identifying the causative risk factors and the underlying mechanisms may not only improve life expectancy but also the quality of life. Further study is warranted. [Display omitted] DisclosuresSaraf: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding.