Dose Of Hydroxyurea Research Articles

Do Genetic Polymorphisms Affect Fetal Hemoglobin (HbF) Levels in Patients With Sickle Cell Anemia Treated With Hydroxyurea? A Systematic Review and Pathway Analysis.

Hydroxyurea has long been used for the treatment of sickle cell anemia (SCA), and its clinical effectiveness is related to the induction of fetal hemoglobin (HbF), a major modifier of SCA phenotypes. However, there is substantial variability in response to hydroxyurea among patients with SCA. While some patients show an increase in HbF levels and an ameliorated clinical condition under low doses of hydroxyurea, other patients present a poor effect or even develop toxicity. However, the effects of genetic polymorphisms on increasing HbF levels in response to hydroxyurea in patients with SCA (Hb SS) have been less explored. Therefore, we performed a systematic review to assess whether single-nucleotide polymorphisms (SNPs) affect HbF levels in patients with SCA treated with hydroxyurea. Moreover, we performed pathway analysis using the set of genes with SNPs found to be associated with changes in HbF levels in response to hydroxyurea among the included studies. The systematic literature search was conducted on Medline/PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Web of Science. Seven cohort studies were included following our inclusion and exclusion criteria. From the 728 genetic polymorphisms examined in the included studies, 50 different SNPs of 17 genes were found to be associated with HbF changes in patients with SCA treated with hydroxyurea, which are known to affect baseline HbF but are not restricted to them. Enrichment analysis of this gene set revealed reactome pathways with the lowest adjusted p-values and highest combined scores related to VEGF ligand–receptor interactions (R-HSA-194313; R-HSA-195399) and the urea cycle (R-HSA-70635). Pharmacogenetic studies of response to hydroxyurea therapy in patients with SCA are still scarce and markedly heterogeneous regarding candidate genes and SNPs examined for association with HbF changes and outcomes, suggesting that further studies are needed. The reviewed findings highlighted that similar to baseline HbF, changes in HbF levels upon hydroxyurea therapy are likely to be regulated by multiple loci. There is evidence that SNPs in intron 2 of BCL11A affect HbF changes in response to hydroxyurea therapy, a potential application that might improve the clinical management of SCA. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=208790).

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.

Factors Influencing Change in MCV and Age at Transplantation in the Belgian Sickle Cell Disease Registry

The Belgian sickle cell disease registry (BCR) was initiated in 2008 and aims to evaluate mortality, morbidity as well as clinicals practices in participating centers. The current analysis focuses on criteria influencing age at transplantation (HSCT) and on the management of Hydroxyurea (HU) therapy across centers.The methodology of the registry has already been published (Le PQ et al., Pediatric Blood and Cancer, 2015) . Data are recorded prospectively from neonatal screening or first contact until last annual follow-up (FU) or death. The data collected included diagnosis, demography, treatment and outcome data as well as a minimal set of biological values. Data were extracted from the database in May 2021.There are 1029 patients registered by 14 different centers (2 centers exclusively treating adult patients). The median FU is 9 y (1-53 y). Median age at last FU is 13 y (0-61 y). 890 patients (86,5%) have a severe phenotype (SS or Sβ°) and 52% are female. Among them, 561 (55%) are born in Belgium of whom 379 (68%) are diagnosed by neonatal screening. In the absence of neonatal screening, median age at diagnosis is 1 year (range 0-18). 131 patients have been transplanted (126 successfully), 68 HSCT were performed before 2005. At last FU, 646 patients (76%) received at least 1 disease-modifying treatment (DMT) : 598 patients receive HU, 65 are chronically transfused, 8 participate in a study with crizanlizumab. The prescribed HU dose is known for 572 patients. 179 patients (31.3%) receive less than 20 mg/kg/day, 217 (37.9%) less than 25 mg/kg/day, 148 (25.9%) less than 30 mg/kg/day and 28 (4.9%) were prescribed more than 30 mg/kg/day.The majority of HSCT were performed in two centers (68 and 59, respectively). Median age at HSCT was significantly different between both centers (8y (2-15) versus 5y (0-19); p=0.002) (figure 1).Variables associated with a lower age at HSCT are detailed in table 1.In a linear multivariate regression model, birth in Belgium (p=0.002), no treatment with HU (p=0.009) and shorter duration of FU (p<0.001) but not the center are independent factors correlated with younger age at transplantation. This linear model explains 90.60% of the variance (adjusted R²) of age at HSCT.Among not transplanted patients, the proportion of those receiving HU is different between centers (50% to 91%; p=0.050). The median age at which HU was initiated was also significantly different between centers (4y to 21y; p<0.001) as was the management of HU treatment in a multiple comparison model measured by ΔMCV (difference in MCV before start of HU versus at last FU). In a linear univariate regression model, other variables are significant predictors for the variance of ΔMCV (table 2). In the linear multivariate regression model, the variance of ΔMCV between centers is controlled by the duration of FU (p<0.001), neonatal screening (p=0.046), HU dose between 25-30mg/kg/day (p<0.001), all resulting in a higher ΔMCV, while patients not born in Belgium (p=0.033) have a lower ΔMCV. Age at diagnosis, severity of the disease (assessed by the number of VOC/FU year) and HU dose <20 mg/kg/day are not correlated with the variance in ΔMCV.Twenty-seven (2.6%) patients died which accounted for a mortality rate of 0.24/100 patients-years (PY) which increases significantly with age (0.18/100PY <18 years, 0.35/100PY 18-40 years and 1.43/100PY >40 years; p=0.001).Conclusions:BSR has an excellent registration activity from participating centers and represents a reliable tool to evaluate the Belgian SCD population. Mortality remains low with a significant trend to increase with age.Regarding treatment practices, the age at start of HU is significantly different between centers as the approach to further HU treatment, evaluated by ΔMCV. A higher dose of HU resulted in a higher ΔMCV. However, the policy to increase HU to maximal tolerated dose seems not implemented in most centers, as 2/3 of the patients are prescribed less than 25 mg/kg/day.Being born in Belgium and no treatment with HU are associated with younger age at HSCT. Nevertheless since 2005, almost all patients were treated with HU prior HSCT, reflecting the wider implementation of HU in SCD patients living in Belgium. [Display omitted] DisclosuresBenghiat: Novartis: Consultancy; BMS: Consultancy. Labarque: Bayer: Consultancy; Sobi: Consultancy; NovoNordisk: Consultancy; Octapharma: Consultancy; Novartis: Consultancy.

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

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

A Pharmacist-Managed Hydroxyurea Prescribing Protocol Improves Uptake and Optimization Among Patients with Sickle Cell Disease within the Southern Alberta Rare Blood and Bleeding Disorders (SARBBD) Comprehensive Care Program

Introduction: Sickle cell disease (SCD) is associated with major morbidity and mortality and yet many of our patients are not using the available disease modifying medication, hydroxyurea (HU). Furthermore, dose-titration of HU is required in order to achieve the maximum therapeutic benefit. Certain challenges can limit HU acceptance, such as misconceptions about safety, frequency of monitoring, and ease of access (i.e. insurance). Incorporating a pharmacist-managed HU hydroxyurea prescribing protocol into the SARBBD Comprehensive Care Program will help to address many of the barriers responsible for poor HU uptake among SCD patients and improve HU utilization.Objectives: To improve the uptake and optimization of HU among patients with Sickle Cell Disease within the SARBBD Comprehensive Care Program.Methods: Commencing in January 2020, clinic pharmacist support of 0.2 full-time equivalents (FTEs) was made available to the SARBBD program, and a pharmacist-led comprehensive HU prescribing protocol was adapted from the current CanHaem and National Heart, Lung, and Blood Institute guidelines. The clinical pharmacist was available for all Sickle Cell Disease clinic appointments, and was responsible for all aspects of HU management, including educating, counselling, and prescribing (titrating and monitoring as outlined in the prescribing protocol). It is worth noting that independent pharmacist prescribing is permitted in Alberta (Alberta College of Pharmacists, 2021).Patients were initiated on HU at a low dose of 500 mg daily to limit gastrointestinal sensitivities, and then increased to 1000 mg daily after one week. Thereafter the dose was titrated every 2-4 weeks as permitted by the patient's tolerance and laboratory parameters (i.e., CBC, liver and renal function, reticulocyte count) up to their maximum tolerated dose (MTD), defined as the maximum dose that maintains neutrophils ≥ 1.5 x 10 9/L, platelets > 80 x 10 9/L, and hemoglobin > 50 x 10 9/L. Following HU initiation and after every laboratory visit, the clinical pharmacist followed-up with patients via telephone to discuss HU tolerance, adherence, and dosing. Perceived benefits (i.e., pain episodes), medication supply, drug access (insurance), and planning for future follow-ups were also addressed as necessary.Results: As of January 2020, the SARBBD program provided care to 119 patients with SCD. Of those patients, 7 patients were managed with a transfusion exchange protocol, and therefore were not considered HU candidates. Of the 112 eligible SCD patients, 39 (34.8%) were already on HU therapy, 15 of whom were at MTD (38.4% of HU patients, 13.4% of 112 eligible SCD population). By June 2021 (18 months of pharmacist managed HU), there were 123 eligible SCD patients, of whom 71 were on HU (57.7%), with 37 at MTD (52.1% of HU patients, 30.1% of total eligible SCD population). Every month on average the pharmacist; has 27 interactions (phone, email) with SCD patients, reviews 18 lab reports, initiates HU for 2 patients, and will make over 4 dose adjustments.A majority of patient interactions involved educating patients on HU, and addressing common misconceptions about HU adverse effects and risks. Further, a significant proportion of HU initiations required pharmacist assistance with insurance authorization. Overall, patient acceptance of the pharmacist-managed HU prescribing was positive. One patient commented, “Working with [the pharmacist] has been great as he diligently has been able to keep a close eye on my blood results while making adjustments to my dosage of HU, without requiring a visit to the doctor. This was great as it didn't tie the doctors up, but also I was able to communicate with [the pharmacist] and get the same information at a convenient time. [The pharmacist] has also been extremely supportive, open and positive while answering questions”.Conclusion: Incorporating a pharmacist into the SARBBD program, as well as implementing a pharmacist-managed HU prescribing protocol has led to improved HU uptake and optimization. In addition, a greater proportion of patients have been able to reach MTD. The most common barriers to HU utilization, such as miseducation, frequency of laboratory monitoring, and medication access, can be overcome with dedicated pharmacist involvement.Funding: Sickle Cell Disease Association of Canada (SCDAC) grant and Novo Nordisk Investigator Initiated Grant DisclosuresPoon: University of Calgary: Current Employment; Bayer: Honoraria, Research Funding; CSL-Behring: Honoraria, Research Funding; Bioverativ/Sanofi: Honoraria; Novo Nordisk: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Takeda: Honoraria. Lee: Bayer: Research Funding, Speakers Bureau; Biovertiv/Sanofi: Honoraria, Research Funding; CSL Behring: Honoraria; Novo Nordisk: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Roche: Honoraria; Takeda: Honoraria.

Hydroxyurea Reduces the Transfusion Burden in Children with Sickle Cell Anemia: The Reach Experience

▪Introduction: Many children with sickle cell anemia (SCA) require blood transfusions, which carry risks and utilize a scarce resource globally, particularly in Africa. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) has documented the safety, feasibility, and benefits of hydroxyurea for children with SCA living in sub-Saharan Africa. In REACH, hydroxyurea escalated to maximum tolerated dose (MTD) significantly decreased vaso-occlusive events, malaria, and death; transfusions were decreased by ~70% over 30 months of treatment when compared to the 2-month screening period. Characterizing how hydroxyurea reduces transfusion needs in REACH could contribute to improved clinical understanding and lead to better outcomes, a decreased transfusion burden, and preservation of the blood supply in these limited-resource settings.Methods: Transfusions were recorded prospectively in the REACH REDCap electronic database. Using time-varying predictors and landmark analysis, transfusions during screening and treatment were analyzed by clinical site, calendar month, age, gender, splenomegaly, hydroxyurea dose, MTD status, baseline and latest laboratory values (Hemoglobin, MCV, HbF, absolute neutrophil count, and platelets, all measured at least 30 days prior to the transfusion), alpha thalassemia trait, and G6PD deficiency. Incidence rate ratios (IRR) were calculated for treatment periods compared to screening. Univariate relationships were assessed using the Anderson-Gill model, plus multiple regression to estimate Hazard Ratios (HR) with 95% confidence intervals (CI's).Results: A total of 635 children with SCA enrolled in REACH, and 606 started hydroxyurea treatment. During screening, 48 transfusions were given to 43 children, and during the treatment phase 405 transfusions were administered to 214 children over an average treatment time of 5.2 ± 1.3 years. The transfusion rate was 43.3 per 100 patient-years during screening, which decreased to 22.0 per 100 patient-years during the initial fixed dose treatment period (IRR = 0.50; 95%CI = 0.35-0.74, p<0.001 compared to screening) and then decreased further to 12.1 per 100 patient-years during the dose escalation period (IRR = 0.28; 95%CI = 0.21-0.39, p<0.001 compared to screening; IRR = 0.54; 95%CI = 0.43-0.73, p<0.001 compared to fixed-dose). For every 100 children treated for a year with hydroxyurea during dose escalation, there were 31.4 fewer transfusions compared to the untreated screening period. Comparison of the indications for transfusion between the screening and treatment periods revealed transfusions administered for anemia decreased from a rate of 26.1 to 5.1 per 100 patient-years (p<0.001), while transfusions for malaria trended toward a decrease from 7.2 to 3.8 per 100 patient-years (p=0.08). Lower transfusion rates on hydroxyurea were associated with higher hemoglobin concentration (HR = 0.72 per 1g/dL increase; 95%CI = 0.65-0.78, p <0.0001) and higher HbF levels (HR = 0.80 per 10% increase, 95%CI = 0.69-0.92, p=0.0071). Those with palpable splenomegaly had higher transfusion rates (HR = 1.58, 95%CI = 1.22-2.03, p=0.0094). Age, gender, alpha thalassemia trait, G6PD deficiency, and neutrophil count were not associated with differences in transfusion rates.Conclusion: Hydroxyurea significantly reduces blood transfusion administration in children with SCA in sub-Saharan Africa, especially when escalated to MTD. Transfusions for the sole indication of anemia decreased significantly on hydroxyurea treatment, likely due to higher treatment-associated hemoglobin levels and decreased hemolysis, and transfusions for malaria also trended toward a decrease. Splenomegaly remains a risk factor for transfusions despite hydroxyurea treatment. Overall, increased access to and implementation of hydroxyurea treatment for children with SCA across sub-Saharan Africa may not only improve individual patient outcomes through reduction in anemia, transfusion burden, and transfusion-associated complications including infections, but may also to help preserve the scarce blood supply for the benefit of the larger population. DisclosuresAygun: Global Blood Therapeutics: Consultancy; Patient Centered Outcomes Research Institute: Research Funding; National Heart, Lung, Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stuber: ASH Research Collaborative: Consultancy. Ware: Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Hemex Health: Research Funding; Nova Laboratories: Research Funding; Novartis: Other: DSMB Chair; Editas: Other: DSMB Chair.

A Method to Measure Voxelotor Exposure in People with Sickle Cell Disease Using Capillary Zone Electrophoresis

Background:Voxelotor (Oxbryta®) is a small molecule that binds to the alpha chain of hemoglobin (Hb) and increases the affinity of Hb for oxygen which reduces sickle Hb polymerization. It was approved by the FDA in 2019 for the treatment of sickle cell disease (SCD). Currently, the only method available to estimate the concentration of voxelotor in the blood is to obtain exposure measurements which are only available in select research laboratories. A method to measure voxelotor at a standard laboratory would allow clinicians to assess compliance and may be useful in determining optimal dosing. Case studies have reported that voxelotor binding to Hb interferes with capillary zone electrophoresis (CZE). As previously reported, in CZE the characteristic peaks of hemoglobin A2 (HbA2) and hemoglobin F (HbF) split in the presence of voxelotor. Interestingly, it does not cause the hemoglobin S peak to split. We posited that we could use this split to estimate the presence of voxelotor and whole blood concentration. Biophysical measurements of voxelotor binding to Hb were also measured in these samples.Methods:Patients were enrolled prospectively in an IRB approved protocol. Voxelotor was initiated at 1500 mg daily on day 0 and samples were taken at day 0 (pre-dose), 14, 30, and 60. Samples had Hb variants quantified by CZE using the Capillarys 2 FlexPiercing Instrument (Sebia, Georgia). Hematology parameters were measured with the Sysmex XN-1000 automated analyzer (Sysmex, Illinois).To determine whole blood concentration of voxelotor, samples were sent to Worldwide Clinical Trials where a validated liquid chromatography-tandem mass spectrometry method was used.Voxelotor's interference with HbA2 on CZE is dependent on the HbF percentage, therefore samples from patients with SCD were combined into three pooled samples (5-10 samples per pool) of HbF percentages spanning 5-30%. Three hundred µL aliquots of each pool were spiked with voxelotor in DMSO in triplicate to different concentrations between 0 and 600 µMol/L and were incubated at room temperature for 1 hour before being tested with CZE. Samples were then analyzed for voxelotor interference resulting in split peaks of HbF and HbA2. HbA2 interference percent (%VarA2) was calculated as the reported value of the HbA2 split peak over the total HbA2 value (both split and parent peak) times 100. F% was used as directly reported by the instrument without consideration of voxelotor interference. Results were then analyzed in Excel (Data Analytics package) using a multiparameter regression to generate a line of best fit. To allow for logarithmic fit when examining the correlation of calculated concentration with increase in Hb due to voxelotor, samples with negative Hb rises were excluded and concentrations which resulted as negative values were changed to 0.01 µM.Results:Of 20 patients which have been enrolled to date, 9 patients have completed the study and their data was used for these analyses. Using the CZE method described above the concentration of voxelotor was quantifiable using the following equation.Equation 1: uM voxelotor = -99.13 + 7.10*%HbF +12.52*%VarA2The calculated concentrations of voxelotor based on CZE results had a strong correlation with whole blood concentration (R 2 = 0.85, p <0.001). (Figure 1)When calculated concentration was compared to change in Hb at days 14, 30, and 60 there was a significant positive logarithmic correlation between concentration and change in Hb (R 2=.56, p<0.01). (Figure 2)Conclusions:Using equation 1, CZE can be used to detect the presence of voxelotor and estimate its whole blood concentration. This will allow clinicians to have a better understanding of how their patients are using voxelotor. Additionally, higher calculated whole blood concentrations correlated with higher increases in Hb. It was previously shown that patients who receive higher doses of voxelotor have on average larger increases in Hb. If it could be shown that increasing concentration in an individual on voxelotor is associated with an increased Hb for that individual, then our method could also be used to help clinicians select and adjust doses of voxelotor in a similar manner to how HbF is used in hydroxyurea dosing. [Display omitted] DisclosuresCurtis: GBT: Consultancy. Minniti: CSL Behring: Other: Endpoint adjudicator; Bluebird Bio: Other: Endpoint adjudicator; F. Hoffmann-La Roche: Consultancy; Chiesi: Consultancy; Novo Nordisk: Consultancy; Forma: Consultancy; Novartis: Consultancy; GBT: Consultancy. Ngyuen Dang: GBT: Current Employment. Pochron: GBT: Current Employment. Campbell: GBT: Research Funding; Sebia: Research Funding.

Severe Acute Complications of Sickle Cell Disease in Two Expert Referral Centers (UK and Italy): Natural History Studies Highlight Ongoing Unmet Need for Effective Disease Modifying or Curative Therapies

Severe Acute Complications of Sickle Cell Disease in Two Expert Referral Centers (UK and Italy): Natural History Studies Highlight Ongoing Unmet Need for Effective Disease Modifying or Curative Therapies

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

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

Recombinant ADAMTS13 for Patients with Sickle Cell Disease: Design of a Phase 1 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study

BackgroundSickle cell disease (SCD) is an autosomal recessive hemoglobinopathy associated with chronic hemolysis and vaso-occlusive crises (VOCs) resulting in pain, organ damage, and a shortened lifespan. Current treatment options are limited, and many individuals with SCD continue to experience VOCs despite receiving therapy. Although the precise cause of VOCs is not clear, evidence suggests that cell adhesion is involved. Von Willebrand factor (VWF) is a multimeric glycoprotein that mediates the adhesion of platelets to each other and to other cell types, including vascular endothelium and leukocytes. An emerging hypothesis is that VWF contributes to the pathophysiology of VOCs through the formation of hyper-adhesive ultra-large VWF multimers. VWF activity is regulated by the metalloprotease ADAMTS13, which specifically cleaves ultra-large VWF multimers in an extended conformation. Patients with SCD have been shown to have higher levels of VWF multimers and lower levels of ADAMTS13 activity during VOCs. This imbalance could be caused either by the increased generation and release of ultra-large VWF multimers or by the inhibition of ADAMTS13 activity by plasma free hemoglobin or thrombospondin-1. Increasing the plasma concentration of ADAMTS13 using a recombinant ADAMTS13 (rADAMTS13; TAK-755, Takeda Development Center Americas, Inc., Lexington, MA, USA) may be therapeutically beneficial by enhancing cleavage of ultra-large VWF multimers. Here, we report the design and enrollment status of the Recombinant ADAMTS13 In Sickle Cell Disease (RAISE-UP) study (NCT03997760), the first clinical study of a recombinant ADAMTS13 in patients with SCD.Study Design and MethodsThis phase 1, randomized, double-blind, placebo-controlled, multicenter, ascending single dose study will assess the safety (including immunogenicity), tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of rADAMTS13 in patients with SCD. This study is planned to be conducted in 2 parts (part A and part B). Here we present the study design for part A which is being conducted initially and will enroll approximately 20 patients aged between 18 and 65 years with a documented history of SCD (HbSS or HbSβ 0 thalassemia). Concurrent treatment with a stable dose of hydroxyurea is allowed. Exclusion criteria include an acute VOC in the preceding 21 days and a blood transfusion either within the last 30 days or on ≥2 occasions in the last 90 days. Ethics committee approval and patient consent were obtained. Patients will be randomized 3:1 to receive a single intravenous infusion of either rADAMTS13 or placebo in 3 sequential dose cohorts. Patients in cohort 1 (n=4) will receive a 40 IU/kg dose, cohort 2 (n=8) will receive an 80 IU/kg dose, and cohort 3 (n=8) will receive a 160 IU/kg dose (Figure). In cohorts 2 and 3, 6 patients will receive rADAMTS13 and 2 patients will receive placebo. The first 3 patients enrolled in each cohort will be dosed with a separation time of at least 14 days. Enrollment into the next higher dose cohort will only be allowed following review of safety data and authorization by a dose escalation committee. Enrollment will be paused if anaphylaxis, binding or inhibitory antibodies, a life-threatening condition, or death are reported. All patients will complete an end-of-study visit on day 28 following infusion. Primary safety endpoints include adverse events, serious adverse events (SAEs), adverse changes in vital signs and laboratory parameters, and incidence of binding and inhibitory antibodies against rADAMTS13 occurring during the study. A secondary objective is to assess the PK of single-dose rADAMTS13 in each dose cohort, including an assessment of ADAMTS13 antigen and ADAMTS13 activity. Secondary PD objectives are to assess the effect of rADAMTS13 on VWF and platelet count and to study the correlation of plasma free hemoglobin and thrombospondin-1 with rADAMTS13 activity and VWF. Enrollment has been completed for cohort 1. In the review of safety data by the dose escalation committee, no drug-related SAEs were reported and no binding or inhibitory antibodies to ADAMTS13 were observed. On the basis of these findings, cohort 2 has been opened for enrollment. [Display omitted] DisclosuresPatwari: Takeda Development Center Americas, Inc.,: Current Employment. Nguyen: Takeda Development Center Americas, Inc.,: Current Employment. Bhattacharya: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.: Current Employment. Jain: Takeda Development Center Americas, Inc.,: Current Employment; Takeda: Current equity holder in publicly-traded company.

European Leukemianet (ELN) Response Predicts Disease Progression but Not Thrombosis or Death in Polycythemia Vera (PV): An Analysis of a Multicenter Database

European Leukemianet (ELN) Response Predicts Disease Progression but Not Thrombosis or Death in Polycythemia Vera (PV): An Analysis of a Multicenter Database

BCL11A POLYMORPHISMS ASSOCIATED WITH INCREASED FETAL HEMOGLOBIN IN RESPONSE TO HYDROXYUREA TREATMENT IN A COHORT OF PEDIATRIC PATIENTS WITH SICKLE CELL ANEMIA

Fetal Hemoglobin (HbF) is a major modifier of clinical events in patients with sickle cell anemia (SCA). Hydroxyurea (HU) improves their clinical course by raising HbF level. There is variability in the response to HU treatment among SCA patients. Genome-wide association studies (GWAS) have identified the BCL11A gene and HBS1L-MYB intergenic region (HMIP-2) as the main regulators of baseline HbF production, and polymorphisms in both loci have been associated with HbF levels. However, it is unknown whether genetic polymorphisms involved in regulation of baseline HbF can modulate HbF in response to HU treatment. Therefore, we examined whether polymorphisms in BCL11A (rs11886868, rs766432, rs4671393, rs1427407, rs7557939 and rs7599488) and HMIP-2 (rs9399137, rs9402686, rs4895441 and rs9494145) were associated with HbF changes in a retrospective cohort of 110 pediatric patients diagnosed with SCA (HbSS) by the Newborn Screening Program of Minas Gerais, and followed up at Center of Hematology and Hemotherapy of Minas Gerais (HEMOMINAS), Belo Horizonte. Participants have been on HU treatment for at least one year. We assessed “delta HbF”for each patient as the “final HbF relative concentration”(last available test during HU treatment and at least three months after blood transfusion) “minus baseline HbF”(last available test before HU treatment and after the age of 5 years, and at least 3 months after blood transfusion). Genotypes were assessed by Taqman assays and real-time PCR or PCR-RFLP. Univariate associations were performed using Mann-Whitney U Test. For the 110 enrolled SCA patients (59/53.6% were females), we calculated the average age at start of HU (10.0±2.8 years), average HU dose (24.40±4.41 mg/kg/day) and the average HU treatment time (4.23±2.01 years). Mean of baseline HbF was 12.01±6.05% and final HbF concentration 18.97±8.75%. While we found no significant differences at final HbF or delta HbF among genotypes of HMIP-2 polymorphisms, carriers of the minor alleles of rs9402686, rs4895441 and rs9494145 showed higher baseline HbF when compared to wild-type homozygous patients (all p 0.05). Moreover, carriers of the minor allele T (GT or TT genotypes) of rs1427407 showed higher baseline HbF (p = 0.002) and delta HbF (p = 0.049) when compared to GG homozygous patients. Similarly, carriers of the minor allele C (AC or CC genotypes) of rs766432 showed higher delta HbF when compared to AA homozygous patients (p = 0.009). Finally, carriers of the minor allele T (CT or TT genotypes) of rs7599488 showed higher final HbF (p = 0.003) and delta HbF (p = 0.002) when compared to CC homozygous patients. BCL11A is a negative regulator of HbF expression. BCL11A polymorphisms were associated with increased HbF after HU treatment in pediatric patients with SCA, suggesting they modulate HbF levels in response to HU. Understanding genetic factors underlying HU response may clarify the interpatient variability on HbF induction upon HU treatment and help to guide therapy.

Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a dismal prognosis. Here, we show how an inhibition of de novo dNTP synthesis by the ribonucleotide reductase (RNR) inhibitor hydroxyurea and an inhibition of epigenetic modifiers of the histone deacetylase (HDAC) family affect short-term cultured primary murine PDAC cells. We used clinically relevant doses of hydroxyurea and the class 1 HDAC inhibitor entinostat. We analyzed the cells by flow cytometry and immunoblot. Regarding the induction of apoptosis and DNA replication stress, hydroxyurea and the novel RNR inhibitor COH29 are superior to the topoisomerase-1 inhibitor irinotecan which is used to treat PDAC. Entinostat promotes the induction of DNA replication stress by hydroxyurea. This is associated with an increase in the PP2A subunit PR130/PPP2R3A and a reduction of the ribonucleotide reductase subunit RRM2 and the DNA repair protein RAD51. We further show that class 1 HDAC activity promotes the hydroxyurea-induced activation of the checkpoint kinase ataxia-telangiectasia mutated (ATM). Unlike in other cell systems, ATM is pro-apoptotic in hydroxyurea-treated murine PDAC cells. These data reveal novel insights into a cytotoxic, ATM-regulated, and HDAC-dependent replication stress program in PDAC cells.

Impact of telehealth visits on hydroxyurea response in sickle cell anemia.

It is important to ensure access to hydroxyurea (HU) for patients with sickle cell anemia (SCA) living in rural areas. The University of Alabama at Birmingham (UAB) Pediatric Sickle Cell program's satellite clinics reduce the barrier of transportation to the university-based clinic. However, as compared with the university clinic, these satellite clinics do not offer immediate access to HU dosing laboratory results and a nurse clinician calls families with HU dose adjustments after the clinic visit. This study evaluated the impact of telehealth dosing adjustments on HU laboratory and clinical response as compared with university-based patients. A one-year retrospective chart review was performed to evaluate HU laboratory and clinical response based on clinic location and socioeconomic status for patients with SCA. We identified the number of clinic and acute care visits for one year and calculated the mean complete blood count and fetal hemoglobin (HbF) values for each patient. We identified 107 academic center participants with SCA-prescribed HU and 65 satellite clinic participants. The mean age of participants was 11 ± 5 years. We identified no difference in HbF (13.3 ± 0.7vs 11.7 ± 0.8, P=0.13), Hb (8.46 ± 1.1vs 8.55 ± 1.1, P=0.59), mean corpuscular volume (91.0 ± 10.6vs 91.7 ± 9.5, P=0.67), or absolute neutrophil count (4.85 ± 2.3vs 4.87 ± 2.3, P=0.95) when comparing Birmingham versus satellite clinics. We also identified no difference in hospital admissions (0.99 ± 0.1versus 0.85 ± 0.2, P=0.49), based on clinic location. The use of telehealth did not negatively impact laboratory response to HU. Future studies should identify novel approaches to improve access to HU among patients with SCA living in rural areas.

A PHARMacist led Initiative for the Management of Hydroxyurea Therapy in Pediatric Sickle Cell Anemia patients attending a Multidisciplinary Tertiary Hemoglobinopathy Clinic: A retrospective cohort study (PHARMIT‐SCA)

AbstractBackgroundThe pharmacological treatment of choice for sickle cell anemia (SCA) is hydroxyurea (HU). The therapeutic effect of HU is believed to be dose‐dependent and titration to maximum tolerated dose (MTD) is the standard of care. Clinical pharmacists took an active role in managing HU therapy through patient assessment and prescribing as part of a multidisciplinary team in a pediatric Hemoglobinopathy Clinic.ObjectivesTo identify the proportion of pediatric patients with SCA achieving MTD within 6 months of initiating HU therapy with traditional or pharmacist‐led management. Secondary objectives included quantifying and characterizing pharmacist interventions, and comparing the rate of dose change, dose assessments secondary to laboratory visits and number of acute care visits between cohorts in the 6 months post therapy initiation.MethodsFor this retrospective single center cohort study, 46 patients with SCA on treatment for six consecutive months between January 3, 2013 and February 28, 2019 were included and analyzed. Both groups were allocated 23 patients. Data were collected using electronic and paper medical records. SPSS version 25 was used for all statistical analyses. A P‐value &lt;.05 was used for statistical significance.ResultsMean HU dose at 6 months was significantly higher in the pharmacist cohort (19.1 vs 22.2, P = .038). No patients achieved MTD in either cohort. More acute care visits occurred in the traditional cohort (20 vs 6, P = .01), and dose assessments secondary to laboratory visits occurred more in the pharmacist cohort (1 vs 3 per patient, P = .002). Pharmacists completed 82 follow‐ups and 175 interventions. Most follow‐ups were by phone (53.7%) to assess HU therapy for dose assessments secondary to laboratory visits (58.5%). Thirty‐eight percent of pharmacist interventions were related to HU dose and medication adherence was assessed in 76.8% of follow‐ups.ConclusionPharmacist‐led HU dose management resulted in a significantly higher mean dose of HU at 6 months, more frequent dose assessments secondary to laboratory work, and a reduced number of acute care visits.

Hydroxyurea-The Good, the Bad and the Ugly.

Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the cycle by inducing replication stress. It is a well-known and widely used drug, one which has proved to be effective in treating chronic myeloproliferative disorders and which is considered a staple agent in sickle anemia therapy and—recently—a promising factor in preventing cognitive decline in Alzheimer’s disease. The reversibility of HU-induced replication inhibition also makes it a common laboratory ingredient used to synchronize cell cycles. On the other hand, prolonged treatment or higher dosage of hydroxyurea causes cell death due to accumulation of DNA damage and oxidative stress. Hydroxyurea treatments are also still far from perfect and it has been suggested that it facilitates skin cancer progression. Also, recent studies have shown that hydroxyurea may affect a larger number of enzymes due to its less specific interaction mechanism, which may contribute to further as-yet unspecified factors affecting cell response. In this review, we examine the actual state of knowledge about hydroxyurea and the mechanisms behind its cytotoxic effects. The practical applications of the recent findings may prove to enhance the already existing use of the drug in new and promising ways.

Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition.

Simple SummaryLeukemic cells show differential sensitivity to apoptosis induction by the clinically relevant drug hydroxyurea. Since resistance to hydroxyurea can pose a therapeutic problem, we searched for mechanisms that protect such cells from the toxic effects of hydroxyurea. We used proteomics followed by mass spectrometry to accomplish this task and noted a loss of the RAF1 kinase in cells that are killed by hydroxyurea. Pharmacological inhibition of RAF1 and its target BCL-XL show that these proteins suppress apoptosis induction. Furthermore, inhibition of their upstream regulators BCR-ABL1 (in chronic myeloid leukemia cells) and FLT3-ITD (in acute myeloid leukemia cells) plus hydroxyurea produced favorable results. This approach may benefit patients that are not successfully treated with tyrosine kinase inhibitors. Taken together, we provide novel insights into strategies that eliminate chronic and acute myeloid leukemia cells with combinations of clinically established and currently tested pharmaceutical agents.The ribonucleotide reductase inhibitor hydroxyurea suppresses de novo dNTP synthesis and attenuates the hyperproliferation of leukemic blasts. Mechanisms that determine whether cells undergo apoptosis in response to hydroxyurea are ill-defined. We used unbiased proteomics to uncover which pathways control the transition of the hydroxyurea-induced replication stress into an apoptotic program in chronic and acute myeloid leukemia cells. We noted a decrease in the serine/threonine kinase RAF1/c-RAF in cells that undergo apoptosis in response to clinically relevant doses of hydroxyurea. Using the RAF inhibitor LY3009120, we show that RAF activity determines the sensitivity of leukemic cells toward hydroxyurea. We further disclose that pharmacological inhibition of the RAF downstream target BCL-XL with the drug navitoclax and RNAi combine favorably with hydroxyurea against leukemic cells. BCR-ABL1 and hyperactive FLT3 are tyrosine kinases that causally contribute to the development of leukemia and induce RAF1 and BCL-XL. Accordingly, the ABL inhibitor imatinib and the FLT3 inhibitor quizartinib sensitize leukemic cells to pro-apoptotic effects of hydroxyurea. Moreover, hydroxyurea and navitoclax kill leukemic cells with mutant FLT3 that are resistant to quizartinib. These data reveal cellular susceptibility factors toward hydroxyurea and how they can be exploited to eliminate difficult-to-treat leukemic cells with clinically relevant drug combinations.

Therapeutic Dose of Hydroxyurea-Induced Synaptic Abnormalities on the Mouse Spermatocyte.

Hydroxyurea (HU) is a widely used pharmacological therapy for sickle cell disease (SCD). However, replication stress caused by HU has been shown to inhibit premeiotic S-phase DNA, leading to reproductive toxicity in germ cells. In this study, we administered the therapeutic doses of HU (i.e., 25 and 50 mg/kg) to male mice to explore whether replication stress by HU affects pachytene spermatocytes and causes the abnormalities of homologous chromosomes pairing and recombination during prophase I of meiosis. In comparison with the control group, the proportions of spermatocyte gaps were significantly different in the experimental groups injected with 25 mg/kg (p < 0.05) and 50 mg/kg of HU (p < 0.05). Moreover, the proportions of unrepaired double-stranded breaks (DSBs) observed by γH2AX staining also corresponded to a higher HU dose with a greater number of breaks. Additionally, a reduction in the counts of recombination foci on the autosomal SCs was observed in the pachytene spermatocytes. Our results reveal that HU has some effects on synaptonemal complex (SC) formation and DSB repair which suggest possible problems in fertility. Therefore, this study provides new evidence of the mechanisms underlying HU reproductive toxicity.

Abstract 1443: CHKing melanoma: CHK1 inhibitor +low dose hydroxyurea triggers immunogenic cell death and immunostimulatory cytokine expression to drive an anti-tumor immune response

Abstract About half of melanomas respond to immunotherapy, but we currently lack reliable markers to identify likely responders. Therefore, a large number of patients receive this expensive therapy for no benefit. We have previously shown that inhibition of the cell cycle regulator, Checkpoint kinase 1 (CHK1), with subclinical dose of the replication stress inducer hydroxyurea is cytotoxic in a high proportion of melanomas tested. We now report that CHK1 inhibitor + low dose hydroxyurea (LDHU) treatment triggers immunostimulatory cytokine and chemokine expression, and an immunogenic form of cell death. In xenograft models, the drug combination blocks tumor growth for extended periods after the completion of treatment. In syngeneic mouse melanoma models, the drug combination also effectively controls tumor growth and induces regression in a proportion of cases. It also increases immune cell infiltration and activation of a tumor directed cytotoxic T cell response. We also demonstrate that the drug combination does not adversely affect an adaptive immune response or rapidly proliferating human T cells. The mechanism by which drug treatment promotes cytokine expression is unlikely to involve the cGAS-STING signalling pathway which is commonly defective in melanomas. Using two engineered mouse melanoma models we have found that CHK1 inhibitor + LDHU increases cytotoxic CD8+ T cells and NK cell infiltration and activation, but we have also found increased CD4+ Treg tumor infiltration and increased CD8+ T cell PD-1 expression. We have also found increased expression of other immune checkpoint regulators. This indicates a strong anti-tumor immune response is initiated but immune suppression and T cell exhaustion have limited the extent of the response of the tumor infiltrating T cells. However, circulating T cells retained strong anti-tumor activity. The harvested tumors from the drug combination treated mice that do increase in size after treatment show strong evidence of cytotoxic activity. These data provide evidence that CHK1 inhibitors + LDHU is well tolerated and triggers a strong anti-cancer immune response that should combine with immune therapy, although the selection of the target of the immunotherapy will be critical for successfully overcoming the immune suppression triggered. Citation Format: Brian G. Gabrielli, Martina Proctor, Jazmina Gonzalez Cruz, Bijun Zeng, Riccardo Dolcetti, Colm Keane, Nikolas Haass, James Wells. CHKing melanoma: CHK1 inhibitor +low dose hydroxyurea triggers immunogenic cell death and immunostimulatory cytokine expression to drive an anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1443.

Examining the Treatment Patterns and Blood Counts Among Patients with Polycythemia Vera Treated with Hydroxyurea in the United States: An Analysis from the Reveal Study

Abstract Introduction: Polycythemia vera (PV) is associated with erythrocytosis (with or without thrombocytosis/leukocytosis), increased risk of thrombosis, and symptoms including fatigue, early satiety, and abdominal discomfort. Hydroxyurea (HU) is a common cytoreductive strategy used to control blood counts and splenomegaly in patients with PV. Although blood counts in many patients with PV are effectively controlled with HU, a proportion of patients fail to achieve controlled blood counts. The European LeukemiaNet (ELN) has defined response criteria for blood count control as well as HU resistance and intolerance in patients with PV; 1 criterion for HU resistance includes a lack of blood count control at a minimum dose of ≥ 2 g/day HU for ≥ 3 months. The REVEAL observational study (ClinicalTrials.gov, NCT02252159) is being conducted to describe contemporary demographics, burden of disease, clinical management, patient-reported outcomes, and healthcare resource utilization among patients with PV in the United States. The objective of this analysis is to describe HU treatment patterns, blood count control, and HU intolerance among patients enrolled in REVEAL. Methods: REVEAL is a multicenter, noninterventional, nonrandomized, prospective, observational study of adult patients with PV. Patients with high-risk PV were defined as being ≥ 60 years of age or having a history of thrombosis. Patients who had ever been treated with or were currently receiving HU were included in this analysis. HU treatment patterns were assessed by evaluating dose modifications and discontinuations. HU interruptions were defined as gaps of > 14 days or complete discontinuation of HU treatment. Toxicities were assessed following initiation of HU. Components of the ELN response criteria for PV (hematocrit [HCT] Results: Among the 2510 patients enrolled in REVEAL, 1432 (57.1%) were treated with HU at some point during their course of treatment. In this cohort, the median age was 69.0 years (range, 26.0-95.0 years), median duration of disease was 4.2 years (range, 0-36.5 years), 49.7% of patients were male, 89.5% were white, and 84.1% were high risk. Median exposure to HU was 35.7 months (range, 0.1-448.6 months). The 2 most common maximum total daily HU doses were 500 mg (30.8%) and 1000 mg (30.6%). Approximately one-third of patients (34.50%) had ≥ 1 HU dose adjustment, 14.53% had both dose increases and decreases, and 16.56% interrupted treatment with HU. Patients experienced as many as 11 HU dose changes over the course of treatment. At data cutoff, 90.4% of patients exposed to HU continued on treatment. Among the 1390 patients receiving HU for ≥ 3 months, more than half (57.1% [n = 632]) of the evaluable patients (n = 1106) had an HCT value > 45% after the 3-month mark; more than one-quarter (27.4% [n = 303]) had uncontrolled myeloproliferation (44.9% with an elevated WBC count and 49.2% with an elevated PLT count). HU-related nonhematologic toxicities, including leg ulcers, were observed in 7.4% (106/1432) of patients during HU treatment. Cytopenias were observed in 15.0% (201/1342) of patients during the treatment period. Conclusions: In REVEAL, HU is a commonly used therapy for PV, but over half (57%) of patients treated with HU for ≥ 3 months still had not achieved HCT control (HCT Disclosures Grunwald: Genentech: Research Funding; Cardinal Health: Consultancy; Pfizer: Consultancy; Janssen: Research Funding; Celgene: Consultancy; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; ARIAD: Consultancy; Forma Therapeutics: Research Funding; Alexion: Consultancy. Altomare: Incyte: Consultancy, Honoraria. Burke: Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Gerds: Incyte: Consultancy; CTI BioPharma: Consultancy. Savona: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Equity Ownership; Sunesis: Research Funding; Takeda: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kuter: Rigel: Consultancy, Research Funding; Amgen: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Research Funding; Syntimmune: Consultancy, Research Funding; Zafgen: Consultancy; Genzyme: Consultancy; Alexion: Consultancy, Research Funding; Fujifilm: Consultancy; Argenx: Consultancy; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees; ONO: Consultancy; 3SBIO: Consultancy; Shire: Consultancy, Research Funding; Protalex: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Merck: Consultancy; Novartis: Consultancy. Stein: Incyte: Consultancy. Oh: Incyte: Honoraria. Colucci: Incyte Corporation: Employment, Equity Ownership. Naim: Incyte Corporation: Employment, Equity Ownership. Paranagama: Incyte Corporation: Employment, Equity Ownership. Mesa: Gilead Sciences, Inc.: Research Funding; Galena Biopharma, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; CTI BioPharma Corp.: Research Funding; Ariad: Consultancy; Promedico: Research Funding.