Hydroxyurea Exposure in Lactation—a Pharmacokinetics Study (HELPS)

Abstract Hydroxyurea is a potent and safe disease-modifying therapy for both children and adults with sickle cell anemia (SCA). Several decades of research data have documented clinical efficacy characterized by fewer acute complications, improved organ function, and reduced mortality. Relatively sparse data exist, however, regarding the risks and benefits of hydroxyurea for mothers with SCA during pregnancy and lactation. Mothers with SCA who wish to breastfeed their babies are discouraged from taking hydroxyurea, due to mostly theoretical concerns about transfer of the drug into breast milk. Determination of the pharmacokinetics (PK) of hydroxyurea in breast milk, along with accurate measurement of the amounts transferred to infants during lactation, are warranted since hydroxyurea is now commonly prescribed to women of child-bearing years. We designed the prospective HELPS trial (Hydroxyurea Exposure in Lactation: a Pharmacokinetics Study, NCT02990598) with the following objectives: (1) determine the PK profile of hydroxyurea in blood and breast milk; (2) calculate the distribution of hydroxyurea between plasma and milk compartments; (3) measure the amount of hydroxyurea excreted into the milk and urine; and (4) create population PK profiles to estimate infant drug exposure. Lactating women were recruited to receive a single oral dose of hydroxyurea (two 500mg capsules). Breast milk, blood, and urine were collected before the dose and then at scheduled timepoints, including 15, 30, 60, 120, 180, 240, 360, 480, 720, and 1440 minutes. Hydroxyurea concentrations were measured using a validated HPLC assay. A total of 16 women (14 healthy volunteers and 2 with SCA; 11 white and 5 black) were recruited into HELPS; the median age was 31 years (range 26-38 years) and the median weight was 76.3 kg (range 48.8-115.9 kg). All women were currently lactating and breastfeeding their infants for a median duration of 6 months (range 2-22 months). After the 1000mg dose, peak plasma hydroxyurea concentrations ranged from 10-40 µg/mL, typically at 60-120 minutes after dosing although absorption varied among participants. Hydroxyurea was measured in breast milk at ~80% of the plasma concentration, with both compartments having a similar PK profile for each participant, from absorption through distribution and clearance. No hydroxyurea was detected in either plasma or breast milk 24 hours after the dose. With this frequent collection schedule, an average of 2.2 ± 1.0 mg of hydroxyurea transferred into breast milk over the 24-hour timeframe, with the majority transferred in the first 3-6 hours. Most of the drug was excreted into the urine, with an average of 542 ± 178 mg (range 295-876 mg) measured over the 24-hour timeframe; over 90% of urinary excretion occurred in the first 9 hours after the dose. The collection schedule was then modified to assess drug accumulation and equilibrium in more physiologically relevant 3-hour intervals, which reduced the average amount of hydroxyurea transfer to 1.1 mg; this 50% reduction in drug transfer indicated a rapid equilibrium between milk and plasma compartments. Two lactating women with SCA had similar hydroxyurea PK curves for plasma and milk to the 14 healthy volunteers. PK analysis based on the frequent milk collection schedule and a standard 150 mL/kg intake per 24 hours concluded that 0.41 ± 0.14 mg hydroxyurea will transfer per kg of infant weight per day. Using the World Health Organization definition of Relative Infant Dosage (RID), defined as the infant dose (mg/kg/day) compared to the maternal dose (mg/kg/day), this infant hydroxyurea exposure is 3.1%, where <5% is generally considered safe and acceptable. However, since 48% of the drug transfers in the first 3 hours, the RID would be 1.6% if the mother fed her baby before the dose and waited 3 hours before the next feeding, and <1% when using a single "pump and dump" process. The HELPS trial provides definitive measurements and PK data regarding hydroxyurea in human breast milk, confirming that drug does transfer but has a rapid equilibrium between plasma and milk. Breastfeeding mothers will transfer only a small amount of hydroxyurea to their infants, so lactation during hydroxyurea therapy should not be contraindicated. These data are relevant for expanded access to hydroxyurea as a disease-modifying therapy to lactating women around the world. Disclosures Ware: Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: advisory board; Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Agios: Other: advisory board; Nova Laboratories: Consultancy; Biomedomics: Research Funding.

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T-MDS Is a Distinct Clinical and Pathological Entity Characterized By Better Survival Compared to t-AML

Blood ◽

10.1182/blood-2021-152380 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3377-3377

Author(s):

Mithun V. Shah ◽

Rakchha Chhetri ◽

Urshila Durani ◽

Monika Kutyna ◽

Hassan B. Alkhateeb ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

World Health ◽

Advisory Committees ◽

Disease Modifying Therapies ◽

The World ◽

Blast Count ◽

Disease Modifying ◽

Health Organization

Abstract Introduction: Therapy-related myeloid neoplasm (t-MN) includes acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) that occur as a complication of DNA-damaging therapies. The World Health Organization recommends considering t-MN as a single entity. Whether t-MDS and t-AML have distinct characteristics and outcomes is not known. The aim of this study was to compare clinicopathological characteristics and outcomes of t-MDS and t-AML. Methods: All patients diagnosed with t-MN based on the World Health Organization criteria were identified. Bone marrow biopsies, cytogenetic, and next-generation sequencing (NGS) were obtained at the treating physician's discretion. Pathogenic/likely pathogenic variants (PV) were called based on the standard criteria. Overall survival (OS) was calculated from the time of t-MN diagnosis until the last follow up using Kaplan-Meier analysis using Wilcoxon test. For survival analysis comparing chemotherapy to best supportive care (BSC) only, patients were censored at the time of allogeneic stem cell transplant (SCT). Multivariate analysis was performed using Cox proportional hazard method and corrected using false discovery rate (FDR). Statistical analysis was performed using JMP (v14.1, SAS Institute) and significance was defined as P<0.05. Results: We identified 554 patients, of which 180 (32.4%), 365 (65.8%), and 9 (1.6%) presented as t-AML, t-MDS, and t-MDS/MPN respectively. t-MDS/MPN patients were excluded from further analysis due to a small number. Clinical and laboratory characteristics of the t-AML and t-MDS cohorts is shown in Table 1. t-AML patients were significantly more anemic and thrombocytopenic at presentation. As expected, t-AML had a higher peripheral blood and BM blast count. There was no difference in proportion of patients with chromosomal abnormalities, though a statistically significantly higher proportion of t-MDS patients had chromosome 5 abnormality, 5q deletion, monosomy 5, chromosome 7 abnormality, monosomy 7 compared to t-AML patients. On other hand, 11q23 (mixed lineage leukemia, MLL) rearrangement was more common in t-AML compared to t-MDS (9.3% vs. 2.8%, P=0.005). A higher proportion of t-MDS patients had PV detected by NGS compared to t-AML (92.9% vs. 85.6%, P=0.038). A higher proportion of t-MDS patients had PV in TP53 (37.6% vs. 21.4%, P=0.004) and ASXL1 (23% vs. 11.7%, P=0.016) genes; whereas a higher proportion of t-AML patients had PV in RAS (18.9% vs. 9.1%, P=0.013) and WT1 (8.1% vs. 2.9%, P=0.05) genes. One hundred twenty-eight (35%) of 365 t-MDS patients progressed to t-AML. The presence of any chromosomal abnormality at t-MDS diagnosis predicted a higher risk of transformation to t-AML (χ 2 3.9, P=0.03). t-AML patients had a significantly shorter OS compared to t-MDS (9.2 vs. 19.7 months, P<0.0001, Figure A). This difference persisted when stratified by no disease modifying therapies (BSC only) 2 vs. 17 months (P<0.0001, Figure B), as well as among those who received at least one line of chemotherapy (14 vs. 24.6 months, P<0.001). Finally, a higher proportion of patients with t-AML underwent SCT and there was a trend towards improved survival for t-AML patients (vs. t-MDS 52.9 vs. 20.7 months, P=0.07) from the time of transplant. Multivariate analysis for OS performed to control for all the variables that were different at presentation (except for blast count), showed that t-MDS (as opposed to t-AML) phenotype at diagnosis, and undergoing SCT were independent predictors of improved survival (Table 2). Conclusion: t-MDS and t-AML have distinct clinical, cytogenetic, and genetic features at presentation. In the absence of disease modifying therapies, t-AML is a more aggressive phenotype, consistently associated with a shorter survival. Even after controlling adverse risk features, t-AML phenotype had a shorter survival compared to t-MDS. Figure 1 Figure 1. Disclosures Litzow: AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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Study of the influence of anxiety on the parameters of hand tapping in patients with postoperative epilepsy in comparison with the group of healthy volunteers

Vestnik nevrologii, psihiatrii i nejrohirurgii (Bulletin of Neurology, Psychiatry and Neurosurgery) ◽

10.33920/med-01-2004-06 ◽

2020 ◽

pp. 49-56

Author(s):

E. Narodova ◽

N. Shnayder ◽

A. Narodov ◽

D. Dmitrenko

Keyword(s):

Healthy Volunteers ◽

Theoretical Basis ◽

Focal Epilepsy ◽

Disease Modifying Therapy ◽

Hand Tapping ◽

Disease Modifying

The presented work devoted to hand tapping is intended to lay foundations in a theoretical basis for the development of a new direction of non-drug disease-modifying therapy for structural focal epilepsy, implemented through the formation of a new dominant “healthy system” based on the distraction of the patient and switching of attention.

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The Grndad Registry: Contemporary Natural History Data and an Analysis of Real-World Patterns of Use and Limitations of Disease Modifying Therapy in Adults with SCD

Blood ◽

10.1182/blood-2020-138895 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-36

Author(s):

Alexandra Boye-Doe ◽

Elizabeth Brown ◽

Charu Puri-Sharma ◽

Anjulika Chawla ◽

Joshua J Field ◽

...

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Clinical Characteristics ◽

Reticulocyte Count ◽

Principal Investigator ◽

Advisory Committees ◽

Disease Modifying Therapy ◽

Disease Modifying ◽

The Impact

Incremental improvement in care for children with sickle cell disease (SCD), arising from government-funded research over the last 4 decades, resulted in a dramatically reduced childhood mortality. However, the impact of iterative research and disease modifying therapy (DMT) on adults with SCD has not been as strong. Until now, there has been no coordinated, longitudinal, generalizable, natural history study of SCD that allowed for an assessment of the contemporary adult population. Here, we describe demographics at enrollment and cross-sectional clinical characteristics of 570 adults with SCD (SCA, homozygous HbSS or HbSb0 N=387, 68%, and compound heterozygous SCD variant, HbSC or HbSb+ N=183, 32%, Table I) on whom we have evaluable data. These data are from the multi-site REDCap-based prospective Globin Research Network for Data and Discovery (GRNDaD) registry, comprising 11 centers with over 1100 consented adults and children. The objective of this work was to evaluate the cohort at year of entry, including the use and clinical associations with DMT, and to explore indicators of disease progression as patients age. 16% of adults with SCA and 9.6% with variant disease stroke; 60.9% of adults with SCA and 41% with variant disease had a history of acute chest syndrome. Albuminuria was prevalent in both SCA (39.5%) and variant disease (19.4%). 185 adults (185/387, 47.8%) with SCA, previously referred for symptoms in clinic, had recorded tricuspid regurgitant jet velocity measurements, with a significantly abnormal result (>2.7 m/s), in 92 (92/185, 49.7%). At enrollment, 45% of adults with SCA (175/387) and 14% of adults with variant disease (25/183) were on hydroxyurea (HU); 20.4% of adults with SCA were on chronic transfusions (79/387) compared with 7% of adults with variant disease (13/183). One third of all adults with SCA were not on or were not consistently on DMT, and had laboratory evidence for increased hemolysis (Table 1). Adults with SCA who were on HU had a higher MCV and higher HbF than other treatment states (Table 1). However, only 34% (60/175) of adults with SCA on HU were at maximally tolerated dose (MTD), per guideline-based recommendations, i.e. ANC ≤4.0 x109/L. On HU, those in the lowest quartile for ANC (<3.2 x109/L) were older (mean age 35.9 years (95% Confidence Limit (CL) 32.5-39.3) vs. 31.2 (95% CL 28.2 to 34.4) years, P=0.04), had a lower mean reticulocyte count (119 x109/L (95% CL 76-162) vs. 203 (95% CL 129-278), P=0.05), and a higher mean MCV (104.4 fL (95% CL 100.2-108.7) vs. 92.5 (95% CL 87.2-97.8), P=0.0007), compared to those in the highest quartile for ANC (>5.7 x109/L, N=34), but did not otherwise differ (including mean HbF, which was not measured in a standardized way). In older adults with SCD (Table 2), fewer people with SCA than with variant disease were >54 years old, (26/387 HbSS, 7%, vs. 34/183, 19%, respectively). The older adult with SCA had a depressed reticulocyte count and a trend towards a higher creatinine. 45% of adults with SCA were on HU, and only a minority were at MTD, highlighting the challenges to optimal long-term therapy in chronic illness. Those patients not stably on DMT had laboratory evidence for worse anemia and hemolysis, without an evident increase in hospital admissions, perhaps due to a hyper hemolytic phenotype. Despite a more intensive regimen, SCA patients on transfusions had a higher Hgb but did not have hemolysis labs that differed from SCA patients on HU. Further, there was no difference in hospitalizations amongst treatments for SCA, although a decrease in hospitalizations was detectable in variant disease (Table 1). Successful use of DMTs in SCA was challenging even in academic centers, and there was evidence for ongoing hemolysis in treated and untreated patients. These real world data provide useful information about adults (>17 years) with SCD. These data highlight opportunities to improve adherence to therapy (patient-centered) and to prescribing guidelines (provider-centered), and to consider less-burdensome alternatives. Importantly, we found that a large proportion of people with SCA were not on DMT, and with HU often not at MTD. In future, the GRNDaD registry will enable prospective longitudinal real-world analyses of the impact of DMTs and/or newer therapies on clinical outcomes, will enhance quality improvement, and will allow us to more fully explore clinical characteristics, of SCA and variant disease, in the aging adult. Disclosures Puri-Sharma: Bluebird Bio: Current Employment. Chawla:Bluebird Bio: Current Employment. Field:Shires: Research Funding; Ironwood: Research Funding. Neumayr:Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other. Desai:Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ironwood Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Rockpointe Continuing Medical Education Company: Consultancy. Lanzkron:GBT: Research Funding; HRSA: Research Funding; Ironwood: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; Pfizer: Research Funding; Pharmacy Times Continuing Education: Honoraria; Prolong: Research Funding. Little:Hemex Health, Inc.: Patents & Royalties: Microfluidic electropheresis (patent, no royalties); BioChip Labs: Patents & Royalties: SCD Biochip (patent, no royalties); GBT: Research Funding; GBT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding; NHLBI: Research Funding.

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Application of Interferon Beta-1b in Multiple Sclerosis

US Neurology ◽

10.17925/usn.2011.07.01.46 ◽

2011 ◽

Vol 07 (01) ◽

pp. 46 ◽

Cited By ~ 1

Author(s):

Francesca Bagnato ◽

Keyword(s):

Multiple Sclerosis ◽

Side Effects ◽

Interferon Beta ◽

Regulatory Agencies ◽

Recombinant Interferon ◽

Beneficial Effects ◽

Disease Modifying Therapy ◽

The World ◽

Disease Modifying ◽

Inflammatory Component

Recombinant interferon beta-1b (IFNβ-1b) was the first approved disease-modifying therapy for patients with multiple sclerosis (MS) by the world regulatory agencies for medical drugs and devices. IFNβ-1b significantly decreases the inflammatory component of MS but still has doubtable effect on the neurodegenerative component. This article appraises the beneficial effects of IFNβ-1b on clinical and imaging measures of disease. Upon only briefly discussing the side effects of the drug, it will conclude with some crucial scientific aspects warranting urgent investigations to precisely address the potentials of IFNβ-1b in MS patients.

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Application of Interferon Beta-1b in Multiple Sclerosis

European Neurological Review ◽

10.17925/enr.2011.06.01.36 ◽

2011 ◽

Vol 6 (1) ◽

pp. 36 ◽

Cited By ~ 1

Author(s):

Francesca Bagnato ◽

Keyword(s):

Multiple Sclerosis ◽

Side Effects ◽

Interferon Beta ◽

Regulatory Agencies ◽

Recombinant Interferon ◽

Beneficial Effects ◽

Disease Modifying Therapy ◽

The World ◽

Disease Modifying ◽

Inflammatory Component

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Immunogenicity of Covid-19 Vaccination in Subjects with Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2021-152401 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3696-3696

Author(s):

Jennifer Vidler ◽

Thanussuyah Alaguthurai ◽

Sultan Abdul-Jawad ◽

Sivalekha Viramuthu ◽

Richard Beatson ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Severe Disease ◽

Booster Vaccination ◽

Cellular Responses ◽

Post Vaccination ◽

Disease Modifying Therapy ◽

Disease Modifying

Abstract Myelodysplastic syndromes (MDS) represent a spectrum of clonal bone marrow neoplasms from low risk disease through to those transforming into acute myeloid leukaemia. The COVID-19 pandemic has presented a great risk to those with hematological malignancies who are at higher risk of severe disease and death than the general population. Previous studies looking at the immune response to influenza vaccination in those with MDS had shown promising results, with immune responses not differing from those of healthy family members. Whilst some data exist to reassure the MDS community that majority of patients show seroconversion following Covid-19 vaccination, little data exists on their neutralizing capacity or post vaccination T-cell responses in this cohort. In addition, the majority of patients in these studies received BNT162b2 and there is little published data on vaccine response to the ChAdOx1 nCoV-19 vaccine. We have investigated the humoral and T-cell response of 39 patients with MDS two to four weeks following Covid-19 booster vaccination with BNT162b2 or ChAdOx1 nCoV-19 through the SOAP study (Sars-cov-2 fOr cAncer Patients, IRAS project ID:282337). Plasma and PBMCs from MDS cases and healthy controls have been collected, and are being assessed for both humoral and cellular responses to SARS_CoV_2, the alpha (B.1.1.7) and delta (B.1.617.2) variants. Humoral responses will be assessed using ELISA (peptide binding) and functional viral neutralization assays. Cellular responses will be assessed using IFNy ELISPOT and flow cytometry (CD25 and CD69 expression) after 24h peptide stimulation. All data at time point 1 (2 - 4 weeks following booster vaccination) have been collected and will subsequently be collected at 6 months and 12 months post-vaccination. We also report on the safety data for these vaccines within this patient population. Of this cohort 64% were male with a median age of 65 years (range 21-84). 54% received vaccination with ChAdOx1 nCoV-19 and 44% received BNT162b2 (2% unrecorded). The vaccines were well tolerated with no serious adverse events to date. The mean interval between doses was 70.7 days (range 50 - 90 days). 71% of the cohort were receiving no disease modifying therapy at the time of vaccination, half of whom were receiving supportive therapy and the other half no intervention for their MDS. Of those receiving disease modifying therapy; 5 were receiving azacitidine, (1 in conjunction with low-dose cytarabine) and 3 ciclosporin. We will report the largest study of the humoral and T-cell mediated response to the Covid-19 vaccine in MDS patients to date. This will include cellular response to the delta variant and immunogenicity of both the BNT162b2 and ChAdOx1 nCoV-19 vaccines. Given the vulnerability of these patients to severe disease, investigating the immune response to the vaccines begins to build an evidence base for advising MDS patients on their ongoing risk of infection during the pandemic and going forward. The SOAP study will reassess the immune response at 6 and 12 months post-vaccination to continue to investigate post-vaccine immunity in this cohort. Disclosures Kulasekararaj: F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Akari: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support. Patten: JANSSEN: Honoraria; NOVARTIS: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding; ROCHE: Research Funding; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria.

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Increased Hydroxyurea Prescribing Practices over Ten Years with Improved Clinical Outcomes in Children with Sickle Cell Anemia: A Single Center's Experience

Blood ◽

10.1182/blood-2020-138754 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-34

Author(s):

Kristine Anne Karkoska ◽

Kevin E Todd ◽

Kelly Clapp ◽

Lynette Fenchel ◽

Theodosia A. Kalfa ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Group Versus ◽

First Year ◽

Prescribing Practices ◽

Clinical Complications ◽

Disease Modifying Therapy ◽

Disease Modifying ◽

First Year Of Life

Introduction: Sickle cell anemia (SCA) is a severe and life-threatening disorder that requires treatment to prevent short- and long-term complications and prolong life. The primary disease-modifying therapy for SCA remains hydroxyurea (HU). Due to 30 years of evidence demonstrating safety and efficacy culminating with BABY HUG, the 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines recommended offering HU to all children with the severe sickle cell genotypes (HbSS, HbS-0thalassemia) beginning at 9 months of age. Despite these recommendations, HU utilization in pediatric patients in the US remains with rates reported as low as 38-47% among the most severe genotypes as recently as 2017. Providers have identified a number of barriers to more widespread use, including the inability to identify which patients may benefit, concern for possible side effects, uncertainties regarding dose, and concerns regarding possible nonadherence. As complications begin as early as the first year of life, it is a disservice to withhold a proven therapy. Here, we describe the effective and nearly universal uptake of HU in our pediatric SCA population at Cincinnati Children's Hospital Medical Center (CCHMC). Methods: We performed an IRB-approved retrospective review to assess the hydroxyurea prescribing practices and clinical complications of patients with SCA treated at CCHMC from 2010-2019. Following the NHLBI guidelines' release in 2014, we changed the recommended age of HU initiation to be within the first year of life. Corresponding with this change, we have initiated HU for most young children with an individualized, pharmacokinetics (PK)-guided dosing strategy through both the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT03789591) and the Hydroxyurea Optimization through Precision Study (HOPS, NCT03789591). Due to the onset of symptoms for some patients before 9 months, we have offered HU initiation as early as 6 months of age since 2015. Our objective was to compare the rates of HU utilization, age of initiation, and hospitalization rate before (2010-13) and after (2014-19) the release of the NHLBI guidelines and the start of the TREAT study in 2014. Demographic and clinical data, including sickle cell genotype, prior/alternative therapy, SCA-related complications, HU dosing, and laboratory values were abstracted from each patient's electronic medical record (EMR). Patients were identified using the EMR's sickle cell registry. Results: We identified 439 patients with sickle cell disease followed at CCHMC from 2010-2019 (47% female, age range: 0-22 years); 275 had SCA (HbSS, HbS-0-thalassemia, or HbSD). The proportion of patients with SCA prescribed HU increased from 2010-19, from 35% in 2010 to 80% in 2019 with significantly more patients initiating HU during 2014-19 versus 2010-13 (average 20 versus 12 patients/yr, p = 0.0028, Figure 1A). The age of HU initiation was significantly lower during 2014-19 compared to 2010-13 (median = 2 y vs 6 y, p = 0.00028). Of 35 patients with SCA not on HU in 2019, 28 received chronic transfusions and the remaining 7 received no disease-modifying therapy with 3/7 patients not yet at the age to start HU. Ninety-six percent (53/55) of children with SCA born during 2014-19 were on treatment, including 52 on HU (median starting age = 10 months) and 1 on chronic transfusions; 45/52 (87%) were enrolled on TREAT or HOPS. With increased HU utilization during this study period, the number of admissions for sickle-related events was significantly lower in the 2014-19 group versus 2010-13 (2.8 vs 6.9 admissions/pt, p = 9.0 x 10-10) with no change in non-SCA related admissions, most commonly for fever (3.8 vs 4.0 admissions/pt, p = 0.8, Figure 1B). Conclusions: HU has become the standard of care for children with SCA, beginning at 6-9 months of age, prior to the onset of acute and chronic complications. Despite widespread concerns that HU will not be accepted by patients and national trends demonstrating low rates of utilization, we have shown that a deliberate, systematic, and preventive approach to HU is possible and results in nearly universal acceptance of HU for young patients with SCA. This has translated to excellent laboratory responses and significantly fewer SCA-related clinical complications in our population. Our approach and improved patient outcomes can serve as a model for other programs to expand their HU treatment for more children with SCA. Figure 1 Disclosures Kalfa: Agios Pharmaceuticals, Inc: Consultancy, Research Funding; Forma Therapeutics, Inc: Research Funding. Malik:Aruvant Sciences, CSL Behring: Patents & Royalties; Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy.

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