Efficacy Of Hydroxyurea Research Articles

Therapeutics for sickle cell disease intravascular hemolysis.

Sickle cell disease (SCD) is a genetic disorder predominantly affecting individuals of African descent, with a significant global health burden. SCD is characterized by intravascular hemolysis, driven by the polymerization of mutated hemoglobin within red blood cells (RBCs), leading to vascular inflammation, organ damage, and heme toxicity. Clinical manifestations include acute pain crises, hemolytic anemia, and multi-organ dysfunction, imposing substantial morbidity and mortality challenges. Current therapeutic strategies mitigate these complications by increasing the concentration of RBCs with normal hemoglobin via transfusion, inducing fetal hemoglobin, restoring nitric oxide signaling, inhibiting platelet-endothelium interaction, and stabilizing hemoglobin in its oxygenated state. While hydroxyurea and gene therapies show promise, each faces distinct challenges. Hydroxyurea's efficacy varies among patients, and gene therapies, though effective, are limited by issues of accessibility and affordability. An emerging frontier in SCD management involves harnessing endogenous clearance mechanisms for hemolysis products. A recent work by Heggland et al. showed that CD-36-like proteins mediate heme absorption in hematophagous ectoparasite, a type of parasite that feeds on the blood of its host. This discovery underscores the need for further investigation into scavenger receptors (e.g., CD36, SR-BI, SR-BII) for their possible role in heme uptake and detoxification in mammalian species. In this review, we discussed current SCD therapeutics and the specific stages of pathophysiology they target. We identified the limitations of existing treatments and explored potential future developments for novel SCD therapies. Novel therapeutic targets, including heme scavenging pathways, hold the potential for improving outcomes and reducing the global burden of SCD.

ELN Criteria for Cytoreduction Start Identify Patients with Polycythemia Vera at Higher Thrombotic Risk

Introduction Recently, the European Leukemia Net (ELN) recommended cytoreduction in patients (pts) with Polycythemia Vera (PV) at low risk (LR) (age <60 yrs & no previous thromboses) but carrying additional criteria for therapy start (CTS) ( Marchetti M et al, Lancet Haematol 2022). Little is known about: 1] efficacy of hydroxyurea (HU) in LR pts, high risk due to age >60 yrs (HR-AGE) or high risk due to previous thrombosis regardless of age (HR-THRO); 2] impact of CTS on thrombotic risk. Aims In a large cohort of HU-treated PV pts, we investigated if thrombotic risk was influenced by: 1] conventional risk factors for thrombosis; 2] ELN-defined complete response (CR) at 12 mos; 3] presence of CTS. Methods After IRB approval, data of 961 WHO2016-defined PV pts were retrospectively collected by 21 Hematology Centers. In April 2023, an update was performed in 10 participating Centers with specific focus on CTS at diagnosis and HU start; 504 HU-treated pts resulted eligible for this analysis. Therapy was at discretion of the treating hematologist. Pts were followed until death or data cut-off date. CTS evaluated for association with thrombosis included: persistent/progressive leukocytosis (100% increase if white blood cells (WBC) <10 x10 9/L or 50% increase if WBC>10 or WBC>15 at diagnosis and HU start); extreme persistent thrombocytosis (>1000 x10 9/L platelets (PLT) at diagnosis and HU start); progressive splenomegaly (increase of >5 cm from diagnosis); inadequate hematocrit (Hct) control (>6 PHL/yr; HCT >53% at diagnosis and HU start; PHL intolerance); uncontrolled cardiovascular risk factors (CVRF). Symptoms were present as the only ELN criterion in 40 patients, of whom none had thrombosis; therefore, they were not included in the analysis. Results 504 pts received HU: 81 pts were at LR and 423 (83.9%) were at HR (HR-AGE, no. 290, 57.5%; HR-THRO, no. 133, 26.4%). Median time on HU was 11.6 yrs (0.1-23.1). During HU, 53 pts had 69 thromboses (35 arterial) for an incidence rate of thrombosis (IR-thro) of 1.5 %p-y, comparably in LR and HR ( Table 1). Notably, IR-thro was equal in LR and HR-AGE (p=0.94), but significantly higher in HR-THRO pts (p=0.005 vs LR and p=0.009 vs HR-AGE). At 12 months, CR was achieved by 8.2%, 23% and 25% of LR, HR-AGE and HR-THRO pts, respectively (LR vs HR-AGE and HR-THRO, p<0.001 and p=0.003). Thrombosis-free survival (TFS) by landmark analysis at 12 months was significantly better in CR pts (p=0.01). Specifically, best TFS was observed in LR and HR-AGE pts with CR, while HR-THRO pts without CR had the worst TFR (p=0.009). CTS were observed in 255 (50.6%) pts: 48 LR (59.3%), 139 HR-AGE (47.9%) and 68 HR-THRO (51.1%). In the remaining LR pts, HU was triggered by mild thrombocytosis (<1000 x10 9/L) and/or mild leukocytosis (<15 x10 9/L) and/or mild splenomegaly (<5 cm from costal margin) and/or persistent systemic symptoms. CTS were associated to significantly increased of IR-thro in the overall cohort (p<0.001), in LR pts (p=0.04), in HR-AGE pts (p=0.02) and in HR-THRO pts (p=0.03) ( Table 1) . The impact of CTS was confirmed in the overall cohort both for arterial (1.30 vs 0.44 %p-y, p=0.01) and venous thrombosis (1.37 vs 0.44 %p-y, p=0.007). TFS at 5 yrs was 87% and 95% in pts with or without CTS (p<0.001) ( Fig.1a). In presence of CTS, TFS of LR and HR-AGE pts were comparable to HR-THRO pts without CTS ( Fig. 1b). In multivariate Cox analysis considering age>60 yrs, previous thrombosis, CTS, and CR to HU at 12 months, CTS and previous thrombosis remained associated with thrombotic risk (HR: 2.7, 95% CI: 1.4-5, p =0.002; HR: 2.4, 95% CI: 1.4-4.2, p =0.001). Finally, in 59 additional LR pts untreated with HU, IR-thro was 0.78 in absence of CTS, and 1.57 %p-y in presence of such criteria. Conclusions Albeit retrospective, this study shows for the first time that ELN criteria for therapy start including splenomegaly, leukocytosis, thrombocytosis, uncontrolled Hct and CVRF, identified an increased risk phenotype either in LR and HR pts treated with HU. This was confirmed also in HU-untreated pts. Also, lack of CR at 12 months was detrimental on TFS particularly in HR-THRO pts, and less significantly than CTS. These findings, that complement data from the Majic-PV trial ( Harrison CN et al, J Clin Oncol 2023), dictate better management of HU therapy, and call for greater attention to CTS and their integration into prognostic models that go beyond the two categories related only to age and thrombotic history.

Barriers to medication adherence in sickle cell disease: A comprehensive theory-based evaluation using the COM-B model.

Sickle cell disease (SCD) affects more than 100,000 Americans, with complications such as pain episodes and acute chest syndrome. Despite the efficacy of hydroxyurea in reducing these complications, adherence remains low. Study objectives were to examine barriers to hydroxyurea adherence, and to evaluate the relationship between barriers and their impact on adherence. In this cross-sectional study, patients with SCD and their caregivers were enrolled if they were taking hydroxyurea. Study measures included demographics, self-report of adherence using visual analog scale (VAS), and the Disease Management and Barriers Interview (DMI)-SCD. The DMI-SCD was mapped to the Capability, Opportunity, Motivation, and Behavior (COM-B) model. Forty-eight caregivers (females 83%, median age 38 [34-43]) and 19 patients (male 53%, median age 15 [13.5-18]) participated. Using VAS, many patients (63%) reported low hydroxyurea adherence, while most caregivers (75%) reported high adherence. Caregivers endorsed barriers across multiple COM-B components, with physical opportunity (e.g., cost) and reflective motivation (e.g., SCD perceptions) being the most identified categories (48% and 42%), respectively. Patients' most identified barriers included psychological capability (e.g., forgetfulness) and reflective motivation (84% and 68%), respectively. Patients' and caregivers' VAS scores negatively correlated with the number of barriers (rs =-.53, p=.01; rs =-.28, p=.05) and COM-B categories (rs =-.51, p=.02; rs =-.35, p=.01), respectively, suggesting lower adherence with more endorsed barriers. Fewer barriers to hydroxyurea adherence were associated with higher adherence. Understanding barriers to adherence is essential to develop tailored interventions aimed at improving adherence.

P-007: HYDROXYUREA FOR THE MANAGEMENT OF SICKLE CELL DISEASE IN LOW- AND MIDDLE-INCOME COUNTRIES: A SYSTEMATIC REVIEW (2000–2022)

Purpose: Hydroxyurea (HU) is a disease modifying oral therapy with demonstrated clinical efficacy and safety in patients with sickle cell disease (SCD) for over 30 years. In low- and middle-income countries (LMICs) where the disease burden is high, universal HU treatment is limited. Our aim for this systematic literature review was to summarise the available evidence conducted in low-resource settings on HU efficacy, safety and real-world effectiveness to demonstrate the need for wider access to HU for SCD patients in LMICs. The preliminary observations from clinical studies are presented here. Materials and methods: Articles published in Embase, PubMed, OVID and Web of Science between January 2000–2022 were reviewed; studies assessing the impact of HU in patients with SCD were considered. Results: Out of 3709 screened articles, 124 unique studies were included (Figure) with 20 clinical trials. Majority of the studies are from sub-Saharan Africa (SSA) and Latin America. The initial dose of HU ranged from 10–25 mg/kg/day and the most common initial dose was 15–20 mg/kg/day; the maximum tolerated dose (MTD) was 25–35 mg/kg/day. Across various age groups, as anticipated, a significant increase in haemoglobin, foetal haemoglobin and mean corpuscular volume levels with HU at both fixed (20 mg/kg/day) and escalated dose (≤35 mg/kg/day). HU at doses 15–30 mg/kg/day reduced the need for transfusions during the treatment period. HU treatment initiation reduced VOC-related pain, and reduction was better with escalated (30 mg/kg/day) versus fixed dosing (20–25 mg/kg/day). Similar reductions across various age groups were observed for atherosclerotic events. Initial low-dose HU therapy of 10 mg/kg/day and a 12-month MTD of 24.1±6.0 mg/kg/day reduced the primary stroke risk. Secondary strokes were prevented with HU (3 years; initial dose: 15–20 mg/kg/day; MTD: 30–35 mg/kg/day), and long-term treatment (3.5–9.3 years; 30–40 mg/kg/day) prevented recurrent strokes. HU treatment showed a reduction in the rates of hospitalisation, and this was?50% lower with escalated dose (29.0±3.5 mg/kg/day) when compared to fixed dose (19.3±1.7 mg/kg/day). Treatment with HU was also associated with significant reduction in malaria events and related hospitalisations. Significant reduction in the risk of mortality was observed after treatment with HU, assessed as events per 100 patients/person years, which can be attributed to fewer SCD–related clinical complications, infections, malaria and possibly transfusions. Various dosing of HU was well tolerated in children and adults, and the reported events of myelosuppression were mostly transient. Conclusion: Our preliminary observations suggest that clinical use of HU in low-resource settings is effective in improving haematological outcomes, reducing the risk of VOCs and primary and recurrent strokes, and reduction of malaria-related events. Need for transfusion, rates of hospitalisation and mortality were also reduced with HU treatment. These findings are in line with current consensus guidelines to initiate HU therapy to SCD patients starting as early as 9 months of age. We expect that the complete analysis of this systematic review will enable us to compile sufficient evidence for optimising the use of HU in LMICs.K. MARFO declares a conflict of interest: Stock shareholder: Novartis Other: Employee of Novartis S. KHAN declares a conflict of interest: Other: I am an employee of Novartis

How Hydroxyurea Alters the Gut Microbiome: A Longitudinal Study Involving Angolan Children with Sickle Cell Anemia.

Sickle cell anemia (SCA) is an inherited hematological disorder and a serious global health problem, especially in Sub-Saharan Africa. Although hydroxyurea (HU) is the leading treatment for patients with SCA, its effects on the gut microbiome have not yet been explored. In this context, the aim of this study was to investigate this association by characterizing the gut microbiome of an Angolan SCA pediatric population before and after 6 months of HU treatment. A total of 66 stool samples were obtained and sequenced for the 16S rRNA gene (V3-V4 regions). Significant associations were observed in alpha and beta-diversity, with higher values of species richness for the children naïve for HU. We also noticed that children after HU had higher proportions of several beneficial bacteria, mostly short-chain fatty acids (SCFAs) producing species, such as Blautia luti, Roseburia inulinivorans, Eubacterium halli, Faecalibacterium, Ruminococcus, Lactobacillus rogosae, among others. In addition, before HU there was a higher abundance of Clostridium_g24, which includes C. bolteae and C. clostridioforme, both considered pathogenic. This study provides the first evidence of the HU effect on the gut microbiome and unravels several microorganisms that could be considered candidate biomarkers for disease severity and HU efficacy.

Efficacy of hydroxyurea in β-thalassemia major patients

Efficacy of hydroxyurea in β-thalassemia major patients

A study of efficacy of Hydroxyurea in Non-Transfusion Dependent Thalassemia (NTDT)

A study of efficacy of Hydroxyurea in Non-Transfusion Dependent Thalassemia (NTDT)

Long-term safety and efficacy of hydroxyurea in patients with non-transfusion-dependent β-thalassemia: a comprehensive single-center experience.

Over the past 20years, hydroxyurea (HU) has emerged as an effective therapeutic agent in thalassemic patients to improve anemia and decrease the transfusion dependency. We evaluated long-term safety and clinical response to HU in patients with non-transfusion-dependent β-thalassemia (NTDT). In this retrospective study, medical records of 181 patients with NTDT were evaluated during October to December 2020 in Southern Iran. No requirement to blood transfusion was considered as sustained transfusion independence response. All patients were regularly examined and monitored for the occurrence of any adverse event (AE) of HU. The mean duration of HU consumption ± SD was 18.2 ± 4.0 (8-22) years. Overall, 149 patients (82.3%) had sustained transfusion independence response. β-globin gene mutations and XmnI polymorphisms were not significantly associated with clinical response (P > 0.05). Mild and transient AEs were reported in 60 patients (33%) with no requirement to drug interruption. Hydroxyurea with the dose of 8-15mg/kg can be used as a safe and effective treatment in NTDT patients. It was well tolerated in long term without any serious complication or secondary malignancy. No relationship between XmnI or β-globin gene mutations with HU response was observed in this geographic area of the world.

The Influence of the Age of Adults with Sickle Cell Disease on the Uptake, Utilization and Efficacy of Hydroxyurea

BackgroundDespite the efficacy of Hydroxyurea (HU) in decreasing morbidity and mortality in adults with sickle cell disease (SCD) the uptake of and adherence with HU is poor, probably as the result of a combination of both physician and patient related factors. Lack of knowledge about HU, doubts regarding effectiveness, concerns over side effects and unrealistic expectations from HU treatment have been previously identified as barriers to the wider uptake of HU by the patient. Since approval of HU for SCD by the FDA in 1998, there has been a progressive increase of the use of HU in SCD. Changes in approach and practice over this time may have impacted the attitude towards HU of patients of different ages differently. The impact of patients' age on the uptake and utilization of HU has not been studied. We investigated the impact of age on the attitudes of adult patients towards the purpose, side effects, associated risks and benefits of taking HU.MethodsWe conducted qualitative interviews with adult SCD patients from a geographically diverse population recruited from national conferences and local SCD clinics. Data were gathered as part of a larger study of decision making regarding disease modifying therapies for SCD and development of a decision- aid tool for patients involving these disease-modifying therapies. We used a semi-structured open-ended interview guide to collect data. Audio recordings were transcribed verbatim. Transcripts were coded using qualitative content analysis with NVivo 11. We sought to understand attitudes of adult patients with SCD towards available treatment options. We then focused our analyses specifically on attitudes towards HU as a model for how SCD patients viewed their disease and treatment options. We also sought to interrogate differences in attitudes among patients who reached adulthood, before and after the general adoption of hydroxyurea as a treatment option for SCD.ResultsAge of the 95 participants ranged from 18 years to 67 years old. Female = 71. While approximately 50% of all participants reported that they were currently taking HU, younger participants were more likely to be currently taking HU than the older participants (p = .05). Seventy percent of the younger adults (Age 18-30) reported they were currently taking HU as compared to 41% of the older adults (Age 31-67) [table 1]. Younger participants were more likely to report that the decision to accept a physician recommendation to start HU was made by their parent, though some participants decided to start HU as a young adult. Younger participants understood the purpose of HU as intended to improve “blood counts” thereby decreasing crises and hospital stays. They were hopeful that HU would help and thus focused on the potential for successfully managing SCD complications rather than on the side effects from HU. For those who decided to start as young adults, they offered positive accounts in regards to the decision to start HU and maintain the treatment.In contrast, the older participants were not well informed about HU and reported a concern about taking a chemotherapy drug. Older adults currently taking HU were more likely to be skeptical about whether they were receiving any benefits from staying on the treatment. They were also less trusting than the younger participants, that all of the side effects from HU are known or that healthcare providers divulged them. Older participants were more likely than the younger participants to report advanced complications from SCD. They were also more likely to report an aversion to taking medications. Six older participants reported they tried HU past, but stopped taking the drug because of either bad side effects, lack of efficacy, or the belief that HU caused more crises.ConclusionThe younger adults with SCD are more likely to have started HU as children and are more likely to be taking HU and believe in its efficacy while older adults were more skeptical about the efficacy of HU and the information they are provided by their healthcare providers. That so many older adults are concerned about the efficacy of HU also raises the question whether it HU is effective in the face of multi-organ complications. These data provide the rationale for a larger prospective study of the impact of age on both the attitudes and efficacy of HU. We believe that the data from this study will help tailor healthcare provider approaches to HU amongst older adults. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Use of trans‐3′5'4‐trihydroxystilbene (Resveratrol) as an adjunct in the treatment of Sickle Cell Disease

Sickle Cell Disease (SCD) and □-thalassemia are among the most common forms of hemoglobinopathy and life-threatening genetic diseases worldwide. So far, the only approved drug for these disorders is the ribonucleotide reductase inhibitor hydroxyurea (HU) falls short of being curative. The efficacy of HU in the management of thalassemia and SCD is generally attributed to its limited ability to boost the levels of fetal hemoglobin (Hb F,α2γ2), which decreases sickling by interfering with the polymerization of hemoglobin in patients with SCD and can partially correct the globin chain imbalance in □-thalassemia patients, while at the same time facilitating O2 transport to myoglobin in peripheral tissues. The naturally occurring dietary polyphenol resveratrol (trans-3′5'4-trihydroxystilbene, RV), has also been postulated to induce Hb F production via a biochemical mechanism like HU. Preclinical studies using the human erythroleukemic K562 cell line suggested RV can induce Hb F production in a more robust manner than HU. However, clinical studies on the efficacy and effectiveness of RV are limited and conflicting. This study sought to evaluate the clinical efficacy and safety of RV in managing SCD compared to HU. A systematic literature review was conducted in peer-reviewed, published full-text articles investigating RV in the management of SCD. Eligible studies were required to report explicitly, including participants diagnosed with β-thalassemia or SCD anemia or cultured cells with the SCD or thalassemia disease and where HU was included as a control. The analysis included thalassemia, RV type, RV dosage, duration of treatment, and outcome, Hb F induction and antioxidant activity. Additionally, a pilot study of RV in the management of adults with SCD who received treatment at National Hospital Abuja, Nigeria, was attempted but discontinued due to the COVID 19 pandemic. A case study of a single 23-year-old female SCD patient who had been taking RV [1000mg daily p.o.] for more than 6 years was included. Outcome variables evaluated include number of hospitalization episodes of pain crisis, need for blood transfusion, possible side effects and RBC indices. The early results of this metanalysis show that RV was as effective as HU in inducing production of Hb F in adult SCD patients and reducing hospital treatment days post RV treatment. Four primary treatment and curative therapies that have shown great potential and are currently used to prevent and treat acute and chronic complications in SCD, HU and blood transfusions, are the most well-established disease-modifying therapies used to prevent and treat complications associated with SCD. Other lesser used therapies include stem cell transplantation or the allogeneic hematopoietic stem cell transplant (HSCT), and the investigational gene therapy is the only known curative therapy that exists regarding SCD. The results of this study indicate that RV is an effective inducer of Hb F production in adults and shows promise as a cost effective and useful adjunct for the treatment of hemoglobinopathies including SCD and thalassemia.

Sickle Cell Anemia: Variants in the CYP2D6, CAT, and SLC14A1 Genes Are Associated With Improved Hydroxyurea Response.

Differences in hydroxyurea response in sickle cell anemia may arise due to a series of factors with genetic factors appearing to be predominant. This study aims to investigate the effects of single nucleotide polymorphisms in genes encoding drug-metabolizing enzymes and solute carriers on hydroxyurea response, in patients with sickle cell anemia. For that purpose, a total number of 90 patients with sickle cell anemia were recruited, 45 were undergoing hydroxyurea treatment, while 45 were not under the treatment. Association analyses were performed between CYP3A4 (rs2740574), CYP2D6 (rs3892097), CAT (rs7943316 and rs1001179), and SLC14A1 (rs2298720) variants and laboratory parameters. According to our findings, patients with hydroxyurea treatment demonstrated higher HbF levels and a significant improvement in hemolytic, hepatic, inflammatory, and lipid parameters in comparison to those without the treatment. We also found significant associations between the CYP2D6 (rs3892097), CAT (rs7943316 and rs1001179), and SLC14A1 (rs2298720) variants and an improvement of the therapeutic effects, specifically the hemolytic, hepatic, inflammatory, lipid, and renal parameters. In conclusion, our results highlight the importance of the investigated variants, and their strong association with hydroxyurea efficacy in patients with sickle cell anemia, which may be considered in the future as genetic markers.

Safety and efficacy of hydroxyurea and eflornithine against most blood parasites Babesia and Theileria.

BackgroundThe plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug targets for both prophylaxis and chemotherapy. Hydroxyurea (HYD) is an antineoplastic agent with antitrypanosomal activity. Eflornithine (α-difluoro-methyl ornithine, DFMO) is the best choice therapy for the treatment of late-stage Gambian human African trypanosomiasis.MethodsIn this study, the inhibitory and combination efficacy of HYD and DFMO with existing babesicidal drugs (diminazene aceturate (DA), atovaquone (ATV), and clofazimine (CLF)) deoxyribonucleotide in vitro against the multiplication of Babesia and Theileria. As well as, their chemotherapeutic effects were assessed on B. microti strain that infects rodents. The Cell Counting Kits-8 (CCK-8) test was used to examine their cytotoxicity on human foreskin fibroblast (HFF), mouse embryonic fibroblast (NIH/3T3), and Madin–Darby bovine kidney (MDBK) cells.FindingsHYD and DFMO suppressed the multiplication of all tested species (B. bigemina, B. bovis, B. caballi, B. divergens, and T. equi) in a dose-related manner. HFF, NIH/3T3, or MDBK cell viability was not influenced by DFMO at 1000 μM, while HYD affected the MDBK cell viability at EC50 value of 887.5±14.4 μM. The in vitro combination treatments of DFMO and HYD with CLF, DA, and ATV exhibited synergistic and additive efficacy toward all tested species. The in vivo experiment revealed that HYD and DFMO oral administration at 100 and 50 mg/kg inhibited B. microti multiplication in mice by 60.1% and 78.2%, respectively. HYD-DA and DFMO-DA combined treatments showed higher chemotherapeutic efficacy than their monotherapies.ConclusionThese results indicate the prospects of HYD and DFMO as drug candidates for piroplasmosis treatment, when combined mainly with DA, ATV, and CLF. Therefore, further studies are needed to combine HYD or DFMO with either ATV or CLF and examine their impact on B. microti infection in mice.

Efficacy of hydroxyurea in a hypereosinophilic syndrome patient with significant eosinophilia

Efficacy of hydroxyurea in a hypereosinophilic syndrome patient with significant eosinophilia

Anti-Mullerian Hormone, a Measure of Ovarian Reserve, Is Low in Female Subjects in the Multi-Center Study of Hydroxyurea

Introduction: Whether sickle cell disease (SCD) or its primary treatment, hydroxyurea (HU), limits reproductive potential in affected women is unknown. Females are born with a finite number of eggs. Anti-Mullerian Hormone (AMH), produced by immature ovarian follicles, is an established method to measure ovarian reserve. Two studies of AMH, one in adolescents with SCD and another in adult women with SCD exist, but neither normal AMH values nor the effect of HU on AMH are established in girls and women with SCD. The purpose of this study is to evaluate AMH levels in women who participated in the seminal study that led to FDA-approval for HU in adults with SCD, the Multi-Center Study of Hydroxyurea (MSH). Methods: The MSH was a randomized placebo-controlled trial (RCT) of HU. The RCT demonstrated HU's efficacy, so a 10-year MSH extension study was conducted to assess HU's potential for "mutagenesis, teratogenesis and oncogenesis". Although no samples from the RCT remain, serum samples (n=285) were available for many women in the follow-up study (n=93). We measured AMH in these samples using the CLIA-certified electrochemiluminescence assay in clinical use at our institution (Esoterix Labs, Calabasas Hills, CA). The assay's reference median AMH in women ages 26 - 30 years is 4.20 ng/mL, and in women 36 - 40 years is 1.69 ng/mL. The assay's lower limit of detection is 0.015ng/mL. Samples with AMH levels beneath the detection limit were run in duplicate when sufficient sample existed; this did not change any results. Here, we report AMH levels in female subjects (n=57) with a serum sample from the first annual follow-up visit (AV01). Descriptive statistics with median values reported for non-parametric variables (Mann Whitney U Test) were performed. AMH < 1 is associated with diminished ovarian reserve, a risk factor for shortened reproductive lifespan, infertility and poor outcomes with assisted reproductive technology. Therefore, we categorized AMH as normal (>/= 1 ng/ml) and low (<1 ng/ml). We initially evaluated factors associated with low AMH using the chi-squared and Mann Whitney U test for categorical and continuous variables, respectively. We then performed logistic regression analysis to evaluate the independent association of age, BMI, absolute neutrophil count (ANC), mean corpuscular volume (MCV) and months of HU exposure with AMH levels. Results: Samples from the first post-study visit were available for 57 women; the median time to first post-study visit was 31 months (IQR 6.5) after RCT closure. Median values for the cohort were: AMH, 0.306ng/ml (IQR 1.162), age, 32.50 years (IQR 11), MCV, 102.0 fl (IQR 15.8), and HU exposure, 23.92 months (IQR 30.72). Figure 1 shows AMH distribution in the cohort. AMH levels were low in 77% (44 of 57) of the cohort. Table 1 compares patient characteristics of subjects with low AMH (n=44) versus normal AMH (n=13). In univariate analysis, subjects with low AMH were older (34.5 vs 24.5, p<0.001) and had larger MCV (105.55 vs 95.80, p=0.002). Median HU exposure time did not reach significance between low and normal AMH groups (33 months vs 17 months, p=0.055). In a logistic regression model, age [OR 1.252, (95% CI 1.066, 1.014), p=0.006] and MCV [OR 1.139, (95% CI 1.014, 1.279), p=0.028] were associated with low AMH while duration of exposure to HU [OR 1.01 (95% CI 0.91, 1.09), p=0.364], body mass index [OR 1.07 (95% CI 0.91, 1.25), P=0.442] and ANC [OR 1.39 (95% CI 0.91, 2.13), p=0.127) were not associated with low AMH. Conclusions: Most women (77%) in this cohort had low AMH, associated with older age and higher MCV. This preliminary analysis raises concerns about diminished ovarian reserve in women with SCD. Although months of HU exposure was not associated with low AMH, HU exposure does not account for adherence, which is a major limitation in most sickle cell studies. MCV which increases with consistent HU use and is a biological proxy measure of the last 3-months of HU adherence, was associated with low AMH. Ovarian reserve was not a planned endpoint in the MSH. A prospective study of ovarian reserve in women with SCD is needed to understand how the physiology of SCD itself or exposure to HU may influence multiple fertility endpoints. Disclosures Chaturvedi: Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Lanzkron:PCORI: Research Funding; NIH: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Research Funding; Ironwood: Research Funding; HRSA: Research Funding.

Prospective longitudinal follow‐up of children with sickle cell disease treated with hydroxyurea since infancy

Hydroxyurea (HU) increases fetal hemoglobin (HgbF) and ameliorates sickle cell disease (SCD) symptoms. Studies have demonstrated the safety and efficacy of HU in infants and children. Initiation of HU in infancy for children with SCD needs to be implemented in community practice. Starting in 2011, the Pediatric Sickle Cell Program of Northern Virginia initiated HU in infants with SCD. A prospective longitudinal database tracked the clinical course and outcomes. Twenty-four children with HgbSS who started HU by age 1 were continuously followed for a total of 95 person-years. Age at the time of analysis ranged from 2 to 7 years. Average hemoglobin at 6-month intervals ranged from 9.5 + 1.9 to 10.7 + 0.8g/dL, and average HgbF ranged from 27.8 + 5.0% to 34.1 + 6.6%. Twenty-seven hospitalizations occurred (0.28/person-year), all before age 3, including 19 (70%) for fever or infection, five (19%) for splenic sequestration, and one (4%) for pain in an infant prior to starting HU. The treat-and-release emergency department visits totaled 68 (0.72/person-year), including 62 visits (91%) for fever, infection, or viral illness, and two visits (3%) for pain/dactylitis in infants before HU initiation. Splenic sequestration accounted for all five transfusions. No pain episodes requiring medical attention were documented after HU initiation. No complicated acute chest syndrome, no abnormal or conditional transcranial Doppler ultrasound, and no overt strokes occurred. Implementation of HU in infancy for patients with SCD in community practice is feasible and is highly effective in preventing disease complications.

Outcome of Initiating Hydroxyurea in Infancy for Patients with Sickle Cell Disease 2011-2018

IntroductionApproximately 2000 babies are born with sickle cell disease annually in the US. Children with severe forms of sickle cell disease (SCD), such as Hemoglobin SS and Hemoglobin S beta 0 thalassemia (Sbeta0), are at risk for severe anemia, vasoocclusive pain crisis, acute chest syndrome, splenic sequestration, central nervous system ischemia, and shortened life expectancy. The drug Hydroxyurea (HU) increases Hgb F, is effective in ameliorating many sickle cell symptoms, and improves survival. Safety and efficacy of HU in children and infants have been demonstrated.MethodsFollowing publication of the BABY HUG trial results in 2011, the Comprehensive Pediatric Sickle Cell Program of Northern Virginia implemented HU initiation for all infants with Hgb SS or Hgb Sbeta0. HU was prescribed at age 6-7 months for 2 patients and at 9-12 months of age for 22 patients. HU dosage was diligently adjusted at clinic visits to maximize Hgb F. An IRB-approved prospective, longitudinal database was launched to follow each patient's clinical course and outcome in 6-month increments. Data are reported for children born after January 2011 who were started on HU by 12 months of age, followed on HU therapy continuously in this clinic, and were at least 2 years of age by June 2018.ResultsAll 24 children in the analysis have Hgb SS. Sixteen children have been followed for 3 years or more, 11 children have been followed for 4 years or more, 7 children have been followed for 5 years or more, 4 children have been followed for 6 years or more, and 3 children have been followed for 7 years. Average Hgb at 6 months of age was 9.5 g/dL, and ranged between 9.5 and 10.7 g/dL for age 1-7. Average Hgb F was 34.1% at 6 months of age and dipped to 29.1% at 1 year of age, but was maintained above 30% from age 1.5 - 3 years and at 27.8% - 30.5% for age 3.5 - 7 years. For a total of 92 person-years, there were 27 hospitalizations, all within the first 3 years of life. 20/27 (74%) hospitalizations were for fever, pneumonia without hypoxia or need for transfusion, or other infections, 5/27 (19%) were for splenic sequestration, and only 1/27 (4%) hospitalization was for pain that occurred before HU initiation. ED visits totaled 68, 53/68 (78%) were for fever and 47/68 (69%) occurred in the first 3 years of life. Only 2/68 (3%) ED visits were attributed to dactylitis/pain, occurring prior to HU initiation. ED visits after age 3 were all for fevers. The most common complication specific to sickle cell disease was splenic sequestration, which is not preventable by HU. All 4 transfusions given were for splenic sequestration.ConclusionContinuous tracking in a single center observational study demonstrated that continuous HU therapy starting in infancy maintained Hgb and Hgb F at or above pre-HU levels into childhood, is associated with no hospitalizations after age 3 and no ED visits for pain after HU initiation by age 1. No acute chest syndrome requiring oxygen or transfusion, no abnormal or conditional TCD, and no overt strokes occurred in this cohort. Implementation of HU for children with sickle cell disease starting in infancy is feasible in the community and is effective in maintaining high fetal hemoglobin and preventing disease complications. DisclosuresNo relevant conflicts of interest to declare.

The Role of Hydroxyurea to Prevent Silent Stroke in Sickle Cell Disease: Systematic Review and Meta-Analysis

Chronic blood transfusions are standard of care for stroke prevention in sickle cell disease. We evaluated hydroxyurea's efficacy in preventing silent stroke. We searched for randomized controlled trials (RCTs) and observational studies on Pubmed, CENTRAL, Embase, and Web of Science without using language/time limits. Eligible studies compared hydroxyurea with transfusions or observation to prevent silent stroke. This systematic review adheres to the Cochrane guidelines. Data were pooled using random effects model using STATA to perform meta-analysis. Methodological quality of RCTs was investigated using the Cochrane risk of bias assessment tool, while observational studies were assessed using the Downs & Black Checklist for Study Quality. One RCT enrolling 121 participants was included. There were no strokes, silent strokes, or deaths reported in either arm. There was no difference between hydroxyurea versus chronic blood transfusions (RR 1.52, 95% CI 0.57 to 4.02, P = 0.39) for adverse events. We included 10 observational studies, with 361 participants receiving hydroxyurea. There were no deaths attributed to hydroxyurea. Approximately 1% (I2 = 48.67%, 95% CI 0.0 to 0.05, 314 participants, seven comparisons) of patients receiving hydroxyurea had stroke. Approximately 18% (I2 = 91.37%, 95% CI 0.03 to 0.4, 266 participants, six comparisons) of the hydroxyurea patients had silent stroke. Approximately 24% (I2 = 88.54%, 95% CI 0.02 to 0.57, 91 participants, four comparisons) of the hydroxyurea patients had adverse events attributed to hydroxyurea. Our findings suggest that hydroxyurea is safe and may prevent silent stroke and stroke. More high-quality studies are needed. DisclosuresNo relevant conflicts of interest to declare.

Evidence of hydroxyurea activity in children with pretreated desmoid-type fibromatosis: A new option in the armamentarium of systemic therapies.

The treatment paradigm in desmoid-type fibromatosis (DF) has changed in recent years from a surgery-based strategy to a multidisciplinary approach that includes systemic therapies. Among various medical therapies, hydroxyurea has been considered of potential interest. This case series summarizes the experience gained at four centers using hydroxyurea in relapsing DF. Eligibility requirements were age<21 years, histologically confirmed DF, and progressive or recurrent disease after at least one line of systemic therapy. Hydroxyurea was given orally at an initial dose of 20mg/kg/day (escalated up to 30mg/kg/day as necessary, if well tolerated). The series included 16 patients treated between 2008 and 2016. Hydroxyurea was the second systemic therapy in nine cases, and the third (at least) in seven. There was no reported G3-G4 hematological toxicity, and one case of G3 diarrhea. Dose reductions were reported in three cases (due to G2 neutropenia). The response rate was 18.7% major partial remissions, 37.5% considering any amount of shrinkage, 68.7% considering symptom response or signs of tissue response as well. In patients with no progression, the treatment was continued for 9-24 months. This is the first published series on the efficacy of hydroxyurea in pediatric DF. The response rate was moderate, but similar to that reported for other medical therapies currently considered as treatment options in this disease. Though further, larger series are needed to confirm as much, hydroxyurea has potential as an effective alternative therapy for DF.

Minireview: Prognostic factors and the response to hydroxurea treatment in sickle cell disease.

This review describes current considerations in the use of hydroxyurea for the management of sickle cell disease in the context of clinical severity. Randomized trials of hydroxyurea have generally enrolled subjects with increased severity based on frequent vaso-occlusive events. An exception was the BABY HUG study in infants which documented substantial benefit even for asymptomatic subjects. Increasing data indicate that hydroxyurea has a substantial effect on reducing mortality in both adults and children-perhaps the most compelling reason for advocating the drug's widespread use. Although the efficacy of hydroxyurea is mediated primarily through increased erythrocyte fetal hemoglobin and much has been learned about the genomic influences on fetal hemoglobin levels in sickle cell disease, our ability to predict the fetal hemoglobin response to hydroxyurea remains limited; much more work in this area is indicated. The review is concluded with the recommendations of the 2014 NIH Evidence-Based Management of Sickle Cell Disease Expert Panel Report.

Original Research: Use of hydroxyurea and phlebotomy in pediatric patients with hemoglobin SC disease.

Hydroxyurea is an excellent therapeutic agent for the pharmacological induction of HbF in patients with sickle cell disease (SCD). However, all completed clinical trials of hydroxyurea have excluded patients with hemoglobin SC (HbSC) disease. HbSC differs significantly in pathophysiology from HbSS, as HbC does not sickle, but instead causes cellular dehydration which potentiates sickling of HbS. Many severely affected HbSC patients have been placed on hydroxyurea on a case by case basis, but there are no large scale prospective data on safety or efficacy of hydroxyurea in this subset of patients with SCD. Here, we report a case series of 14 pediatric patients with HbSC treated to maximum tolerated dose (MTD) with hydroxyurea. Those who failed to show clinical improvement after at least six months at MTD were offered phlebotomy in addition to hydroxyurea. Five out of 11 patients with HbSC who achieved MTD failed to demonstrate clinical improvement on hydroxyurea. Of the four placed on dual hydroxyurea and phlebotomy therapy, all showed at least partial clinical improvement. Percent dense red blood cells (%DRBC) were measured via an ADVIA hematology analyzer. A marked rise in percent dense cells preceded clinical complications in three patients. Dual therapy with hydroxyurea and phlebotomy may be an effective approach to patients with HbSC that do not experience improvement with hydroxyurea alone. Monitoring of %DRBC may predict adverse events and aid in assessing hydroxyurea compliance. Large scale clinical trials are needed to evaluate the safety and efficacy of hydroxyurea and hydroxyurea with phlebotomy in patients with HbSC disease.