Successful Quality Improvement Projects to Maximize Prescription Rates and Acceptance of Hydroxyurea Among Patients with Sickle Cell Anemia

Abstract Background: "Education and Mentoring to Bring Access to Care for SCD (EMBRACE SCD)"--U1EMC31108-- is a multicenter study sponsored by HRSA in the US southeastern region, which focuses on extending knowledge about sickle cell disease (SCD) to hematology and primary care providers and to improve the care of children and adults with SCD. In Florida we aimed to improve access by increasing prescription (RX) rates of hydroxyurea (HU), by at least 10% from baseline in patients with sickle cell anemia. Methods: Three SCD centers, assisted by three community-based organizations and with the support of two pediatricians with expertise in quality improvement (QI), were engaged in this QI project. The SCD centers are the University of Miami (UM), Salah Foundation at Broward Health and Johns Hopkins All Children's Hospital (JH). Data were abstracted locally and entered into REDCap by a central data manager. Run charts were created to assess data improvement. UM also assessed barriers using a parent/caregiver questionnaire administered at least 6 months after offering HU with the purpose of improving patient education and desire to take HU. Results: Beginning in June 2019 until June 2021, center clinicians concentrated in identifying all patients who were eligible for HU (namely, children 9 months and older with hemoglobin SS and hemoglobin SB 0thalassemia who were not on chronic transfusions). As a group, 50.2% (N=263) of patients were on hydroxyurea at entry (range 35.4-62.4 % among the sites) from a total of 524 eligible patients. The main organizing activities which allowed for higher percent were having a center patient database (done March 2019), educating all providers in the centers about the importance of HU as disease-modifying therapy, having a unified protocol for the education of parents and/or patients about HU benefits, and using visual aids (pictures) of erythrocytes pre and post HU treatment. The QI consultants met virtually with the Florida EMBRACE team monthly beginning June 2020 to increase engagement and interest in participating in this QI activity. We implemented a data collection sheet to track medical records every month to determine whether we were capturing all eligible patients. As depicted in the run chart, we surpassed the QI goal by ending with 64.8% (N=343) prescription rate (range 48.0-85.0 %) from a total of 529 eligible patients. From the 76 barrier assessment questionnaires given at UM, we identified 12 (15.8%) refusals. Seven of 12 refused because of fear of taking "chemotherapy", one because of fear of side effects, and four because their children's disease was considered mild. With further education, we decreased the refusals from 12 to 9. Conclusion: A unified approach to a QI project was successful among several centers in Florida, increasing the prescription rate of hydroxyurea by 14.6% among patients with sickle cell anemia. Acknowledgment: We acknowledge HRSA and region principal investigators for EMBRACE SCD Drs. Ify Osunkwo, Julie Kanter and John J. Strouse for their support in this work. Figure 1 Figure 1. Disclosures Alvarez: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; GBT: Membership on an entity's Board of Directors or advisory committees. Clay: Novartis: Honoraria; GBT: Membership on an entity's Board of Directors or advisory committees.

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Results from the Displace Consortium: Practice Patterns on the Use of Transcranial Doppler Screening for Risk of Stroke in Children with Sickle Cell Anemia

Blood ◽

10.1182/blood-2018-99-116709 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4697-4697

Author(s):

Shannon Phillips ◽

Martina Mueller ◽

Alyssa M Schlenz ◽

Cathy Melvin ◽

Robert J. Adams ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Cerebral Artery ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Research Funding ◽

Practice Patterns ◽

The United States ◽

Care Providers ◽

Advisory Committees

Abstract Introduction: Stroke is one of the most devastating complications of sickle cell anemia (SCA). The STOP (Stroke Prevention Trial in Sickle Cell Anemia) protocol has been adopted by National Heart Lung and Blood Institute (NHLBI) as the guideline for stroke screening using transcranial Doppler ultrasound (TCD) and prevention with chronic red cell transfusion therapy (CRCT). Evidence from the STOP I/II studies indicates the protocol is highly effective, yet wide scale implementation has not been achieved. The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI funded consortium of 28 sites across the United States whose purpose is to identify barriers to the implementation of the STOP protocol and test novel methods for overcoming barriers. The purpose of this study was to use data on practice patterns to evaluate current measurement and practice standards at DISPLACE consortia sites. This abstract presents reported TCD screening and CRCT practices. Methods: A practice patterns survey was sent to the principal investigator (PI) for each DISPLACE site via RedCap ©. PIs were hematology/oncology specialty care providers for children with SCA. Sites represent urban and rural regions, large and small academic institutions, and community-based institutions. The survey was developed by the study investigators; questions were predominantly in a multiple-choice format. Items pertaining to TCD screening included: screening technique (including type of TCD); screening frequency; follow-up for abnormal, conditional, and inadequate results; standard value ranges. Results: All 28 PIs completed the survey. About half of the respondents were female (53.5%). Most identified as White (77.8%), followed by Asian (11.1%) and Black or African American (7.4%). Two identified as Hispanic or Latino (7.4%). Slightly more sites reported using standard TCD (57.1%) versus imaging TCD (TCDi) (42.9%). To calculate the time-averaged mean of the maximum (TAMM) velocities and characterize TCD results, nearly all sites use the middle cerebral artery (96.4%); a majority also use the anterior cerebral artery and/or the terminal internal cerebral artery or distal internal cerebral artery (71.4%). Fewer sites use the posterior cerebral artery (35.7%) or the basilar artery (14.3%). In 7.1% of sites, the radiologist determines which vessels to use during the exam. TCD screening is ordered for children with SCA annually in 92.9% of sites and every 6 months in 7.1% of sites. When TCD screening indicates abnormal TAMM velocities, 85.7% of sites initiate CRCT, 7.1% initiate hydroxyurea (HU) therapy, and 3.6% initiate both HU and CRCT. For additional evaluation, an MRI/MRA is obtained at 64.3% of sites. For high conditional results, the most common action is to initiate HU (67.9%). Other responses include obtaining an MRI/MRA (46.4%) and/or repeating the TCD in 2-4 weeks (25.0%), 6-8 weeks (35.7%), or 12-16 weeks (7.1%). Results deemed inadequate led to repeating the TCD in 2-12 weeks (57.1%) or in one year (3.6%), obtaining an MRI/MRA (57.1%), beginning HU therapy (7.1%), or no repeat TCD or change in management (3.6%). Actions for low conditional results include repeating the TCD (71.4%), obtaining an MRI/MRA (32.3%), and/or initiating HU therapy (57.1%). Surprisingly, sites use different TAMM ranges to characterize the normal/abnormal findings (Table 1). Conclusions: Nearly all DISPLACE sites order TCD screening annually, as recommended in the guidelines, with some ordering screening more frequently. A few sites did not report initiation of CRCT per STOP protocol for abnormal TCD results; however, over half of the sites reported following up with an MRI/MRA, which may suggest evaluating for vasculopathy prior to CRCT. Some sites reported beginning HU therapy for abnormal results; this may reflect consideration of patients for whom CRCT is not possible, but data were not collected for confirmation. Interestingly, results suggest a reliance on MRI/MRA since sites commonly reported ordering neuroradiology studies for abnormal, conditional, and inadequate TCD results. This may suggest an unclear pathway for children with borderline TCD results, and an area for future study. While reported value ranges closely approximated those in the STOP protocol, results indicate sites conducting screening with TCDi may use more conservative values than the validated protocol. Disclosures Phillips: NHLBI: Research Funding. Mueller:NHLBI: Research Funding. Schlenz:NHLBI: Research Funding. Melvin:NHLBI: Research Funding. Adams:NHLBI: Research Funding. Kanter:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sancilio: Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Apopharma: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees.

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Splenomegaly in Children with Sickle Cell Anemia Receiving Hydroxyurea in Sub-Saharan Africa

Blood ◽

10.1182/blood-2019-129937 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 993-993

Author(s):

Leon Tshilolo ◽

George A. Tomlinson ◽

Patrick T. McGann ◽

Teresa S. Latham ◽

Peter Olupot-Olupot ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Growth Parameters ◽

Sub Saharan Africa ◽

Advisory Committees ◽

Splenic Enlargement ◽

Hydroxyurea Treatment ◽

Lower Blood ◽

Sub Saharan

Introduction. Children with sickle cell anemia enrolled in Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) received open-label hydroxyurea at maximum tolerated dose (MTD) in four countries within sub-Saharan Africa (Tshilolo et al, NEJM 2019;380:121-131). Unlike children in the United States or Europe, a substantial proportion of REACH participants had splenomegaly at enrollment, and more developed splenomegaly while receiving hydroxyurea. Splenic enlargement in association with hydroxyurea treatment in sub-Saharan Africa is previously unrecognized, and its causes and consequences remain unclear. Methods. Palpable splenomegaly was evaluated at both the mid-clavicular and mid-axillary lines at each scheduled and unscheduled sick visit. The size of the spleen, defined as the greatest distance (cm) below the subcostal margin, was recorded in the REDCap trial database at all four clinical sites. Cross-sectional analysis was performed at baseline enrollment using four spleen categories (Not Palpable, 1-4 cm, ≥5 cm, or Splenectomy) with correlations for age, sex, site, growth parameters, alpha-thalassemia trait and G6PD deficiency. This analysis was repeated using the largest spleen size over the first two years on hydroxyurea, but examining two-year laboratory values and also the hydroxyurea dose at MTD, time to MTD, dose-limiting toxicities, and clinical outcomes including acute splenic sequestration, malaria infections, and sepsis. Results. A total of 606 children started hydroxyurea study treatment, including 6 (1.0%) with previous splenectomy, 59 (9.7%) with previous splenic sequestration, and 99 (16.3%) with palpable splenomegaly at enrollment (52 children with 1-4 cm and 47 with ≥5 cm). Large spleens (≥5 cm) were commonly observed at baseline at all clinical sites except Uganda, which identified only 1 child. Compared to those with no palpable spleen, children with large spleens at baseline had similar age and growth parameters, but were significantly more likely to have alpha-thalassemia (78.7% versus 56.2%, P=0.004) and also G6PD deficiency among males (28.0% versus 17.6%, P=0.32). Children with large spleens at enrollment also had a lower hemoglobin (Hb = 6.5 versus 7.3 g/dL, P<0.001) and lower platelet count (platelets = 227 versus 410 x 109/L, P<0.001), but equivalent fetal hemoglobin (HbF = 10.2 versus 9.4%, P=0.82). On hydroxyurea treatment with escalation to MTD, 262 children (43.7%) had palpable splenomegaly recorded, including 120 (20.0%) with spleens ≥5 cm. These large spleens were observed at all four clinical sites, with DRC having the most (52) and Uganda with the least (14). After 24 months of hydroxyurea treatment, laboratory differences were noted according to the cumulative occurrence of splenomegaly including a significantly lower hemoglobin and platelet count, higher absolute reticulocyte count, and lower hydroxyurea dose at MTD (Table). Large spleens were associated with a high cumulative incidence of laboratory dose-limiting toxicities, as well as a significantly higher risk of having clinically symptomatic malaria and receiving blood transfusions (Table). A total of 31 children (5.2%) on hydroxyurea treatment received elective splenectomy, including one partial splenectomy using arterial embolization. Conclusion. Children with sickle cell anemia living in sub-Saharan Africa have an increased risk of having palpable splenomegaly, which is further increased while receiving hydroxyurea treatment. Large spleen at baseline were associated with lower blood counts, consistent with hypersplenism. On hydroxyurea treatment, children with large spleens had significantly lower blood counts and more dose-limiting toxicities, which lowered their eventual hydroxyurea dose at MTD but still led to robust HbF responses. Children with large spleens were also at higher risk of developing malaria infections, receiving transfusions, and requiring surgical splenectomy. Splenic enlargement in association with hydroxyurea treatment was common in children with sickle cell anemia in the REACH trial; its cause remains unclear but the consequences include substantial laboratory toxicity and clinical morbidity. Investigating the etiologies and management of children with chronically enlarged spleens is crucial before expanding hydroxyurea access across Africa for sickle cell anemia. Disclosures Ware: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Other: Research Drug Donation; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; Agios: Membership on an entity's Board of Directors or advisory committees; Addmedica: Other: Research Drug Donation.

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Sickle Stroke Screen: A Patient-Centered Educational Initiative for Children with Sickle Cell Anemia in the Displace Consortium

Blood ◽

10.1182/blood-2020-141963 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Alyssa M Schlenz ◽

Shannon Phillips ◽

Martina Mueller ◽

Cathy L Melvin ◽

Robert J Adams ◽

...

Keyword(s):

Needs Assessment ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

Stroke Risk ◽

Advisory Board ◽

Educational Initiative ◽

Advisory Committees ◽

Board Membership

Introduction: The NHLBI funded Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE) study was designed to improve implementation of stroke prevention guidelines in children with sickle cell anemia (SCA), particularly implementation of transcranial Doppler (TCD) ultrasound for identifying individuals at risk of stroke. The study consists of 3 phases: 1) evaluating current stroke risk screening practices, 2) exploring barriers and facilitators to guideline implementation (needs assessment), and 3) designing and implementing interventions to improve stroke risk screening. A key barrier identified through qualitative methods during the needs assessment was a gap in education, including an overall lack of understanding among patients and caregivers of the purpose of TCD screening. This abstract describes the process of developing one of the interventions for phase 3, a rebranding and educational initiative. Methods: During the needs assessment, 27 key informant interviews and 173 complete surveys were conducted with individuals with SCA and their caregivers. Transcripts from the interviews and survey responses were reviewed to better understand the extent of educational gaps described by families as well as to guide initial rebranding prototypes. Prototypes were developed by the study team, including a new name and logo for TCD as well as an infographic. An interview guide was then created to obtain feedback on the prototypes from individuals with SCA and/or the parent or primary caregiver from two sites in the consortium. Cue cards with prototypes were included with prompts for the "think aloud" method to be applied during interviews. Cue cards were presented first with prototypes for the new name in black font on a white background to solicit feedback on the wording alone. Then, cue cards included various layouts, fonts, and graphics with the prototype names for in-depth feedback on the logo appearance. Finally, participants were asked questions pertaining to the infographic. Results: Twenty interviews were conducted with individuals with SCA and/or the parent/caregiver at two DISPLACE sites. Almost all participants (95%) made the connection between the wording prototypes and TCD without prompting. Many participants expressed that the word "stroke" in both options was "scary," and sometimes chose the option that was "less scary to them." However, many participants also felt that the word "stroke" was necessary to explain the reason for the procedure and would prompt families to ask about the screening as opposed to making them more fearful. The majority of participants (60%) chose "Sickle Stroke Screen" over "Stroke Risk Screen." Participants reported preferring this wording because it is specific to SCA, was easier to remember and represented a less "scary" option. The most commonly preferred logo is presented in Figure 1. Participant reasons for selecting this option were: it is easier to read; they preferred the stacked layout; it is less spread out; they liked the bold letters; it is more eye catching; and it includes the words "sickle cell" in the logo. When asked about preferences for an infographic, the majority described including a picture of a brain. Nearly all participants believed a reassuring message was needed to balance out the fear of the word "stroke." The message, "knowledge is power" provided this balance and resonated with nearly all participants (95%). Figure 2 presents the infographic developed based on participant feedback. Conclusions: Results from this educational rebranding effort highlight the importance of understanding patient and family educational gaps and incorporating their perspective and feedback into educational campaigns. The new logo and infographic were integrated into an educational pamphlet, informative posters and other material designed by the DISPLACE site principal investigators. Part 3 of the study is underway including implementation of the educational initiative at the DISPLACE sites. The new terminology and logo have also been broadly distributed throughout the US through community-based organizations to other patients, families, and stakeholders. Disclosures Kanter: AGIOS: Membership on an entity's Board of Directors or advisory committees; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; Wells Fargo: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; BEAM: Membership on an entity's Board of Directors or advisory committees.

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Iron Unloading By Therapeutic Phlebotomy in Previously Transfused Children with Sickle Cell Anemia: The Twitch Experience

Blood ◽

10.1182/blood.v128.22.1018.1018 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1018-1018 ◽

Cited By ~ 1

Author(s):

Banu Aygun ◽

Nicole Mortier ◽

Zora R. Rogers ◽

William Owen ◽

Beng Fuh ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Chelation Therapy ◽

Venous Access ◽

Study Entry ◽

Iron Loading ◽

Advisory Committees

Abstract Background: TCD With Transfusions Changing to Hydroxyurea (TWiTCH, ClinicalTrials.gov NCT01425307), an NHLBI-sponsored Phase III multicenter trial, compared transfusions to hydroxyurea for maintaining TCD velocities in children with sickle cell anemia who previously received transfusions for abnormal TCD velocities. Iron overload was treated with serial phlebotomy in children randomized to hydroxyurea. At the first scheduled interim analysis, non-inferiority of hydroxyurea was demonstrated and the study was terminated prematurely. Methods: Participants randomized to hydroxyurea received decreasing volumes of monthly transfusions during hydroxyurea dose escalation to maximum tolerated dose (MTD), averaging 6-7 months. During this transfusion overlap period, no chelation therapy was given. After hydroxyurea MTD was reached, transfusions were discontinued and children started monthly phlebotomy if their entry liver iron concentration (LIC) by MRI-R2 (FerriScan®) was ≥2 mg Fe/g dry weight liver (DWL). The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) with adjustments for anemia (5 mL/kg for Hb 8.0-8.5 g/dL and held if Hb <8.0 g/dL). Phlebotomy was performed over 30 minutes with immediate equal volume normal saline replacement, typically using peripheral venous access. LIC was assessed at study entry, midpoint (12 months), and exit (24 months/early closure). Ferritin was monitored monthly using a centralized laboratory. Iron loading calculations were based on actual transfusion and phlebotomy volumes. Results: Sixty children (mean age 9.7±3.2 years; range 5.2-19.0 years; 48% male) were randomized to the Hydroxyurea Treatment Arm. The average duration of previous transfusions was 4.5±2.8 years. Almost all (51/60, 85%) had previously received chelation, primarily deferasirox, and 48 (80%) were on chelation therapy at study enrollment. Hydroxyurea MTD was achieved in 57 children (95%), and 54 commenced phlebotomy (two had low iron burden with LIC <2 and one had Hb <8.0 g/dL). A total of 914 phlebotomy procedures were scheduled per protocol for these 54 children and 756 (83%) were fully completed. There were 77 procedures cancelled due to anemia and another 81 procedures cancelled due to planned anesthesia (16), provider preference (14), hydroxyurea-related cytopenia (13), intercurrent illness (11), inadequate iv access (9), family request (5) or other (13). In 94% of phlebotomy procedures that were initiated, the full volume was removed; for the remaining 6% (47 procedures), a reduced volume was removed due to loss of venous access (37), symptoms such as headache or lightheadedness (7), or other reasons (3). A total of 18 Adverse Events (17 Grade 2 and one Grade 3) occurred in 14 participants in association with phlebotomy (2.3% prevalence). The most common complication was light headedness/near-syncope (6) followed by anemia (4), hypotension (3), headache (3), and pain at the venous access site (1). One subject had a syncopal episode followed by transient weakness, which was centrally adjudicated as TIA. An average of 53.6±21.8 mL/kg blood was administered in the hydroxyurea-treated arm, which calculates to an average iron loading of 40.1±16.3 mg Fe/kg, while an average of 112 mL/kg of venous blood was removed by phlebotomy, which calculates to an average iron unloading of 36.1±15.7 mg Fe/kg. For the 54 children who received phlebotomy, the average LIC was 12.0± 9.7 mg/g at study entry, 13.4±10.3 at midpoint reflecting overlap transfusions without chelation, and 9.7±8.9 at study exit reflecting serial phlebotomy, for an average net LIC decrease of 2.3±4.1 mg/g. Average serum ferritin at study entry was 3105±741 ng/mL and 1392±1542 ng/mL at study exit. For 39 children who completed all 24 months of treatment before study closure, the overall average LIC decrease was 3.2±3.8 mg/gram DWL and 10 had final LIC measurements <3 mg Fe/g. Calculated net iron loading was not significantly associated with measured changes in LIC or ferritin. Conclusions: In the TWiTCH trial, phlebotomy was a feasible, safe, well-tolerated, and effective treatment for transfusional iron overload in children with sickle cell anemia. Although initial overlap transfusions without chelation limited the phlebotomy effects, in children who reached hydroxyurea MTD and discontinued chronic transfusions, monthly phlebotomy led to net iron unloading and lower LIC, and significantly reduced iron burden. Disclosures Rogers: Apopharma: Consultancy. Kalfa:Baxter/Baxalta/Shire: Research Funding. Kwiatkowski:Sideris Pharmaceuticals: Consultancy; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Apopharma: Research Funding; Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy. Wood:World Care Clinical: Consultancy; Biomed Informatics: Consultancy; Biomed Informatics: Consultancy; Celgene: Consultancy; Celgene: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; AMAG: Consultancy; World Care Clinical: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy. Ware:Global Blood Therapeutics: Consultancy; Biomedomics: Research Funding; Bayer Pharmaceuticals: Consultancy; Addmedica: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding.

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Outcomes in Children with Severe Vasculopathy from Sickle Cell Anemia after Treatment with Chronic Transfusion, Surgical Revascularization and/or Allogenic Hematopoetic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-118693 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1098-1098

Author(s):

Courtney W. Johnson ◽

Suvankar Majumdar ◽

Andrew D. Campbell ◽

Suresh Magge ◽

Deepika S. Darbari ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Moyamoya Syndrome ◽

Surgical Revascularization ◽

Advisory Committees ◽

Time Of Intervention

Abstract Background: Cerebral vasculopathy is a frequent complication of sickle cell anemia (SCA) and is associated with a high risk for stroke. This vasculopathy seen in SCA can be progressive and severe. Sickle cell patients with severe vasculopathy, including Moyamoya syndrome are at increased risk for neurological disabilities and death. While chronic transfusions decrease the risk of stroke in SCA; unfortunately, progression of vasculopathy can occur despite treatment. Limited data exists regarding long term outcomes for this population. We evaluated effectiveness of three treatment approaches at our center, namely chronic transfusions, surgical revascularization plus chronic transfusions and allogenic hematopoietic stem cell transplant (HSCT). Methods: A retrospective chart review was preformed to identify patients with SCA (hemoglobin SS, Sβ0) and severe vasculopathy including Moyamoya syndrome between 1986 to 2017. Severe vasculopathy was defined as having at least one cerebral artery with > 70% stenosis and/or occlusion as seen on MR angiogram (MRA), CT angiogram (CTA) or conventional angiogram (DSA) as determined by a neuroradiologist at our institution. Patients were identified from an institutional stroke database. Patients were included for analysis if they received at least one of the following: chronic transfusions, surgical revascularization (i.e. encephalo-duro-arterio-synagiosis (EDAS) plus chronic transfusions or HSCT. For HSCT, all graft types (bone marrow, peripheral blood stem cells, umbilical cord blood), conditioning regimens and donor types (related, unrelated and haploidentical) were included. Time to event analyses were performed from the time of intervention (transfusion, HSCT, EDAS/chronic transfusions) using overt clinical stroke, new silent infarcts, progression of vasculopathy or new vasculopathy. Survival curves were analyzed using the log-rank (Mantel-Cox) test. Results: Of 35 patients identified, 54% (n =19) underwent chronic transfusions, 23% (n=8) of patients underwent HSCT after being on chronic transfusions, 23% (n=8) underwent EDAS with chronic transfusions and 1 patient underwent each of the above three modalities (Table 1). Median age at time of intervention was similar for all three cohorts (Table 1). Males were overrepresented in all treatment arms (62.5-79% of patients). Average hemoglobin level prior to intervention was also similar: 7.6 g/dL (IQR 7.1-8.3) for the chronic transfusion cohort, 7.3 gm/dL (IQR 6.3-8.2) for the HSCT cohort, and 7.5 gm/dL (IQR 7.2-8) for the EDAS/chronic transfusion cohort. Absolute reticulocyte count was 492.9 K/ul (IQR 358.4-550) for the chronic transfusion group, 389.4 (IQR 174.3-449) for HSCT, and 250.2 (IQR 107.3-393) for EDAS/chronic transfusions (p=0.08). One patient died of overt stroke in the chronic transfusion cohort. The median follow-up times for the transfusion, HSCT and EDAS plus transfusion groups were 4.4, 2.4 and 6 years respectively. Time from date of intervention (transfusion, HSCT, EDAS) to overt clinical or silent stroke was evaluated (Fig 1). Two of the nineteen patients in the chronic transfusion cohort suffered an overt stroke, while one of eight and two of eight had strokes in the post-HSCT and EDAS plus chronic transfusion cohorts respectively. Fourteen of nineteen (74%) in the chronic transfusion cohort had progression of severe vasculopathy after being on transfusions while two of eight (25%) in the HSCT and four of the eight (50%) patients in the EDAS plus chronic transfusion cohorts had progression. The one patient with all three different interventions did not have additional infarction (clinical or silent) or vasculopathy progression during 1.5 years of follow-up. Conclusions: The risk for cerebral infarction and/or vasculopathy progression after initiation of treatment with either chronic transfusion, HSCT or EDAS is still a major concern. Our data suggest HSCT and surgical revascularization with chronic transfusion provide the greatest benefit in reducing stroke risk and HSCT reduces risk for progression of a severe vasculopathy. Additional, large population studies are needed to clarify the risk. Disclosures Majumdar: NIMHD: Research Funding. Campbell:Functional Fluitics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Maximum Tolerated Dose Versus Fixed Low-Dose Hydroxyurea for Treatment of Adults with Sickle Cell Anemia - Retrospective Comparison of Two Studies

Blood ◽

10.1182/blood-2018-99-114990 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3656-3656

Author(s):

Titilola S. Akingbola ◽

Bamidele Tayo ◽

Chinedu A Ezekekwu ◽

Omowunmi Sonubi ◽

Santosh L. Saraf ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Multicenter Study ◽

Research Funding ◽

Low Dose ◽

Primary Care Providers ◽

Maximum Tolerated Dose ◽

Acute Chest Syndrome ◽

Care Providers ◽

Hemoglobin F

Abstract Background. Despite a large body of evidence that hydroxyurea is effective for sickle cell anemia (SCA), utilization with the "maximum tolerated dose" regimen has been low.1 Hydroxyurea therapy for SCA increases hemoglobin F, reduces pain crises, acute chest syndrome and blood transfusions, and possibly increases survival.2 The increase in hemoglobin F with hydroxyurea is related to the plasma level achieved, which depends on the dose.3 Hydroxyurea is typically initiated at 15 mg/kg/day followed by dose escalations up to 35 mg/kg/day if tolerated - the "maximum tolerated dose" approach used in the seminal Multicenter Study of Hydroxyurea (MSH) in the 1990's.4 With this approach, neutropenia and thrombocytopenia are limitations to achieving maximal dose and frequent blood count monitoring is required.These considerations limit the use of hydroxyurea in areas of the world where frequent blood monitoring is not feasible, and they also cause primary care providers in the US to hesitate to prescribe the medication. Methods. We recently reported a trial of hydroxyurea (500 mg/day orally) in 48 adults with SCA in Ibadan, Nigeria - a "fixed low-dose" approach.5 In the present report, we compare hematologic responses in 38 per protocol patients from the Ibadan study (received at least five of the planned six 4-weekly supplies of hydroxyurea)5 to the responses in 152 patients in the MSH study.6 Results. Baseline hematologic values for the two studies are shown in Table 1. Over the first 12 to 14 weeks of hydroxyurea, responses in hemoglobin, mean corpuscular volume (MCV), and platelets were similar in the two studies (Figure 1). At end-of-study (24 weeks Ibadan and 104 weeks MSH) responses in hemoglobin F and complete blood count were similar, except that the decline in neutrophil count in the Ibadan cohort was significantly less than the decline in MSH after the Bonferroni correction for multiple comparisons (Table 1and Figure 2). At this time the median (range) dose of hydroxyurea per body weight was 10 (7-14) mg/kg per day in the 38 Ibadan patients versus 20 (2.5-35) mg/kg per day in the 119 patients who remained on hydroxyurea in the MSH study.6 We performed a review of the medical records in the Ibadan patients. There were seven acute non-infectious complications in the 38 patients while taking fixed low-dose hydroxyurea for 24 weeks (admission for pain or acute chest syndrome) versus 17 while being observed off hydroxyurea for 24 weeks (pain, acute chest syndrome, need for blood transfusion, heart failure or death) (Table 2). Incidence of infections was similar during 24 weeks of fixed low-dose hydroxyurea and during 24 weeks of observation off hydroxyurea (Table 2). Discussion. These findings suggest that a "fixed low-dose" regimen may have substantial clinical benefit. Such a regimen would have a low chance of inducing cytopenias, would be straightforward for primary care providers to prescribe and would be ideal to test in combination therapy regimens for SCA. It would also be cost-efficient and affordable, especially for patients in low and middle-income countries where access to health insurance is lacking. We propose that the clinical efficacy of "fixed low-dose" hydroxyurea for SCA should be investigated further. We believe that a randomized comparison of the efficacy and safety of the "fixed low-dose" and "maximum tolerated dose" regimens should be a high priority. References Stettler N, McKiernan CM, Melin CQ, Adejoro OO, Walczak NB. Proportion of adults with sickle cell anemia and pain crises receiving hydroxyurea. JAMA 2015;313:1671-2. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med 2008;358:1362-9. Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 1992;79:2555-65. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995;332:1317-22. Tayo BO, Akingbola TS, Saraf SL, et al. Fixed Low-Dose Hydroxyurea for the Treatment of Adults with Sickle Cell Anemia in Nigeria. Am J Hematol 2018. Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996;75:300-26. Disclosures Hsu: Global Blood Therapeutics: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ironwood: Research Funding; Emmi: Consultancy; Hilton Publishing: Consultancy; Gerson Lehman Group: Consultancy; Guidepoint: Consultancy.

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Transcranial Doppler Screening in Children with Sickle Cell Anemia Is Feasible in Central India and Reveals High Risk of Stroke

Blood ◽

10.1182/blood-2019-131416 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2279-2279

Author(s):

Dipty Jain ◽

Kavitha Ganesan ◽

Sati Sahota ◽

Deepika S. Darbari ◽

Lakshmanan Krishnamurti ◽

...

Keyword(s):

High Risk ◽

Oxygen Saturation ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Central India ◽

Normal Range ◽

Advisory Committees ◽

Tribal Populations

Introduction: India has been identified as having the second largest number of births with sickle cell anemia (SCA) in the world after Africa, with estimated 44,400 new-borns affected per year. SCD was previously reported to have a milder course in children from India, with less severe disease among aboriginal tribal populations than in non-tribal populations. Recent reports indicate the occurrence of severe manifestations of SCD in both tribal and non-tribal populations in India. Stroke is one of the serious complications of SCD, but there are no data on transcranial Doppler (TCD) screening for evaluating children with SCD in India who may be at high risk for strokes. The objective of this study was to assess the feasibility of using TCD to measure time averaged maximum of the mean velocities (TAMMV) in the intracranial arteries in children attending a tertiary centre in central India. Methods: STUDY DESIGN: A cross sectional study was conducted in consecutively recruited stable children of either sex with homozygous SCA proven by electrophoresis and high performance liquid chromatography in the age group of 1-26 years. Patients who were febrile, acutely ill, hypoxic or asleep were not included in the study as these conditions can falsely elevate the intracranial blood flow velocities. Patients with hemoglobinopathies other than HbSS or S/b0 Thalassemia and those with a history of congenital neurological illness were excluded. DETERMINATION OF TCD VELOCITY: TCD was performed in a tertiary care center in Nagpur using either an imaging machine (Lasiq s8) in the department of radiology or a portable non-imaging TCD (Compumedics); for both a probe of frequency 2Mhz was used. Maximum values for TAMMV in the Middle (MCA) and Anterior (ACA) cerebral arteries were measured in all; for the non-imaging TCD values for posterior cerebral artery (PCA) and basilar artery were also obtained. The results of the first scan performed on these individuals were included in this study. Using values similar to the STOP trial, TAMMV of each of these vessels were categorized as follows: Normal <= 170cm/s; Conditional - between 170 and 199 cm/s; Abnormal >= 200 cm/s; Low <50 cm/s and unobtainable. MEASUREMENT OF HAEMATOLOGICAL VALUES: Laboratory parameters such as Hemoglobin, white blood cell count (WBC), Mean corpuscular volume (MCV) and hemoglobin F (HbF) levels of the patients in the study were also included if the parameters were available on the day of TCD or within 90 days of TCD study. MEASUREMENT OF HEIGHT, WEIGHT AND BMI: The height and weight of each of the patients on the day of TCD or within a period of 60 days from the TCD were measured and the body mass index (BMI) was calculated. Results One hundred and twenty children and youth aged 1-26 (median 7) years, 67 male (56%), were recruited. Of the 120 patients, 106 (88.5%) belonged to the Scheduled Caste category, 3 (2.5%) to the Scheduled Tribe category and 11 (9.1%) to the Other Classes category. Three (2.5%) had had a clinical stroke and 8 (7%) had had seizures, one of whom also had a stroke. Twenty-seven (23%) children had TAMMV outside the normal range. Five had abnormal TAMMV in the MCA (n=4) and/or ACA (n=1), 8 had conditional TAMMV in the MCA (n=7) and/or ACA (n=1) while 14 patients had low (n=12) or unobtainable (n=2) TAMMV in the MCA. One child with stroke had low TAMMV and one had conditional TAMMV while the third had normal TAMMV. Of the 7 with isolated seizures, one had low TAMMV and one had conditional TAMMV while the remaining 5 were normal. BMI was 8.6-25.3 (median 14.1), height/weight was 3.4-10.3 (median 6.5), hemoglobin was 43-134 (median 81) g/L, oxygen saturation 87-100 (median 99)%, HbF was 1.9-60 (median 21) g/dL, MCV was 59.1-96.7 (median 83.2) fl, WBC was 2.3-35.9 (median 10.1)*109. Those with TAMMV outside the normal range were not different from those with normal TAMMV in terms of age, BMI, Height/weight, or recent hemoglobin, oxygen saturation, HbF, MCV, or WBC. Discussion This study demonstrates the feasibility and importance of TCD screening in Indian SCD population. TAMMV on TCD was outside the normal range in nearly a quarter of children with SCD, as has been reported in studies in other populations. The findings of this study may not be representative of stroke risk in tribal populations since they were underrepresented in this study. These data provide the rationale for implementing systematic screening with TCD to reduce the risk of stroke in children affected by SCD in India. Disclosures Darbari: Novartis: Membership on an entity's Board of Directors or advisory committees; Hilton Publishing: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: one day advisory board meeting .

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Characteristics of Children with Abnormal TCD in the Modern Era: Results from the Displace Consortium

Blood ◽

10.1182/blood-2019-129951 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2270-2270

Author(s):

Julie Kanter ◽

Mary Dooley ◽

Logan P Sirline ◽

Martina Mueller ◽

Shannon Phillips ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

High Risk Group ◽

Phase Iii ◽

Dissemination And Implementation ◽

Advisory Committees ◽

Transfusion Therapy ◽

The Mean

Background: Stroke is one of the most devastating complications of sickle cell anemia (SCA). In 1998, the Stroke Prevention Trial in Sickle Cell Anemia (STOP), demonstrated that a high-risk group of children with SCA could be identified using Transcranial Doppler ultrasound(TCD) and that chronic red cell transfusion therapy (CRCT) could reduce the risk of first ischemic stroke in this group by over 90% (Adams, et al NEJM 1998).At STOP studyenrollment, 9.7% of children with SCA were identified as having an abnormal TCD. Baby HUG, (NCT00006400), an NHLBI supported phase III trial showed that severe anemia in SCA was associated with elevated white blood cell (WBC) and higher TCD velocities (Lebensburger, et al Blood 2010 ). It is unclear if lower hemoglobin (Hb) and/or higher WBC are causative of elevated TCD velocities or correlative biomarkers. As new disease therapies become available, it is important to know the current rate of abnormal TCD and characteristics of those patients. The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI-funded study whose primary purpose is to identify barriers to implementation of stroke screening in SCA and test novel methods for improving outcomes. DISPLACE is a 3-part study: retrospective assessment of current practice, qualitative review of barriers and facilitators to screening and a cluster-randomized intervention implementation project to improve stroke screening. Part 1 of the study showedthat TCD screening rates varied widely among institutions ranging from 30-75.2% (mean 48.4%, median 47%). We are now reporting on the rate of abnormal TCD and the characteristics and outcomes of patients with abnormal TCD. Methods: DISPLACE is a consortium of 28 US centers. Each site performed a rigorous retrospective chart review of children with SCA aged 2-16 years from 2012-2016. To be eligible for inclusion, children must have been seen at their institution at least 2x during the study period and have confirmation of SCA. A custom electronic data capture (EDC) system facilitated entry of de-identified data including demographics, TCD and MRI results, medications, transfusions, and laboratory values. For children with SCA who had TCD or central nervous system imaging prior to 2012, these results were also entered into the EDC. TCD results were recorded in the EDC as normal, conditional or abnormal based on their institutional interpretation. Labs and vitals were entered for each patient in closest proximity to each TCD. Confirmation and adjudication of each abnormal TCD and associated outcomes were performed. Stroke status was also recorded as well as presence or absence of CRCT. Results: In total, 5247 children with SCA are included in the database of whom 5225 should have received a TCD. Of this cohort, 4210 children (80.6%) had at least one TCD recorded in the database. Within this group, 207 (4.9%) of children had an abnormal TCD and 816 (19.4%) had a conditional TCD. For those children who underwent TCD during the study (2012-2016) period, there were 105 (2.9%) abnormal TCD and 501 (13.6%) conditional TCD (Table 1). The mean age of children at the time of abnormal TCD was 6.6 years (range 2-16 yr). The majority of children were <10 yr at first abnormal TCD. Over 30% of patients with an abnormal TCD were identified as receiving hydroxyurea.The mean Hb associated with an abnormal TCD was 7.8 +/- 1.1g/dl (range 5.7-10.6) and the mean WBC was 13 x109/L+/- 3.6 (range 3.9-23.4) (Table 2). Of the 105 patients with abn TCD during the study period, 18% had a stroke. Of the total 5247 patients in the database, 3093 (59%) had been prescribed hydroxyurea (HU) and 999 (19%) were prescribed CRCT. CRCT was prescribed most often for abnormal TCD (37%) or secondary stroke prevention (31%). Discussion: DISPLACE is the largest contemporary cohort of children with SCA. The incidence of abnormal TCD in the DISPLACE cohort is significantly lower than at randomization in the STOP study. The number of children receiving CRCT is higher than expected which may partly account for the decrease in frequency of abnormal TCD. Many patients with abnormal TCD were receiving HU when their TCD was abnormal and were started on CRCT. Additionally, while the outcomes of children with conditional TCD are still being evaluated, many of those children reverted to normal TCD without intervention. These data may also help us redefine the use and interventions needed for abnormal TCD. Disclosures Kanter: NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; SCDAA: Membership on an entity's Board of Directors or advisory committees; Guidepoint Global: Consultancy; GLG: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria. Adams:GBT: Consultancy, Other: consultancy to companies GBT and Blueburd Bio; Bluebird: Consultancy.

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Progression of Albuminuria in Sickle Cell Anemia: A Multicenter, Longitudinal Study

Blood ◽

10.1182/blood-2019-125860 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1004-1004

Author(s):

Omar Niss ◽

Adam Lane ◽

Monika Asnani ◽

Marianne McPherson Yee ◽

Ashok Raj ◽

...

Keyword(s):

Blood Pressure ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Multicenter Study ◽

Univariate Analysis ◽

Prospective Multicenter Study ◽

Advisory Committees ◽

Sickle Cell Nephropathy ◽

Clinic Visits

Introduction Chronic kidney disease (CKD) is a significant cause of morbidity and mortality in patients with sickle cell anemia (SCA). Albuminuria quantified by urinary albumin-to-creatinine ratio (ACR) is predictive of CKD and end-stage renal disease in other settings (non-SCA). As most sickle cell nephropathy studies are retrospective and cross-sectional, little is known about the natural progression of albuminuria in SCA and its correlation with glomerular filtration rate (GFR) decline and development of CKD. Methods We conducted a prospective, multicenter study (between 2009 and 2017) to investigate the longitudinal progression of sickle cell nephropathy (NCT02239016). Participants with SCA (HbSS or HbSb0 thalassemia) of all ages from 11 centers in the United States and the Caribbean were enrolled and provided urine and blood samples during routine clinic visits at steady-state. Urine ACR, cystatin C-estimated GFR (eGFR), and standard biomarkers of SCA and nephropathy in addition to kidney injury molecule (KIM-1) and N-acetyl-b-D-glucosaminidase (NAG) were followed longitudinally. Participants with albuminuria for ≥ 2 annual measurements were considered to have persistent albuminuria. Results A total of 303 participants with SCA were enrolled and followed for a median of 2 years. Participants were 1.6-64 years old (mean 21 years), and 46% were females. Participants provided annual samples (average 14.5-month interval between sample collections) and contributed to 644 patient-years on the study. 175 participants provided at least three annual samples and were included in a longitudinal analysis. The prevalence of albuminuria (ACR>30mg/g) at baseline was 32% (97/303) of which 26% (80/303) had microalbuminuria (UACR 30-300 mg/g) and 6% (17/303) had macroalbuminuria (UACR>300 mg/g). At study entry, 45% of patients were prescribed hydroxyurea, and 20% received chronic transfusion therapy. In univariate analysis, baseline ACR was significantly associated with older age (P<0.0001), sex (P=0.009), higher systolic and diastolic blood pressure (P<0.0001 and P=0.005), lower hemoglobin (P=0.01) and HbF (P=0.0005), higher bilirubin (P=0.001), and higher NAG (P<0.0001) and KIM-1 (P<0.0001). In a longitudinal multivariate analysis (years 0-3) that included the statistically significant variables from univariate analysis in addition to age-adjusted eGFR, only age (P=0.03), female sex (P=0.009), hemoglobin (P=0.01), bilirubin (P=0.002) and KIM-1 (P<0.0001) were significantly associated with ACR. In participants who had at least 3 annual samples, a baseline ACR ≥100mg/g was predictive of persistent albuminuria (ACR>30mg/g for ≥2 annual measurements): 81% of participants with baseline ACR ≥100 mg/g had persistent albuminuria compared to 19% of participants with baseline ACR<100 mg/g. Participants with persistent albuminuria had significantly higher age, blood pressure, and serum creatinine, but were less likely to be on disease-modifying therapy (hydroxyurea or chronic transfusions), and had significantly lower HbF compared to those with non-persistent albuminuria. eGFR correlated with age (P<0.0001) and persistent albuminuria (P=0.002), but not with baseline ACR. Participants with persistent albuminuria were also more likely to have a rapid decline in eGFR (a decline by >3 ml/min/1.73m2 per year) compared to those with non-persistent albuminuria (48% vs 31%, P=0.03). Conclusion In this longitudinal, prospective, multicenter study of sickle nephropathy, albuminuria was strongly associated with age and progressed over time (figure 1). Despite variability in spot urine ACR measurements, high baseline ACR ( ≥100mg/g) was associated with persistent albuminuria. Patients with persistent albuminuria were more likely to have rapid eGFR decline, a high-risk factor for CKD progression. Use of hydroxyurea and chronic transfusions was associated with less incidence of persistent albuminuria. Our results demonstrate that persistent albuminuria and high ACR at baseline predict kidney function decline in SCA. These findings show the feasibility of determining ACR and monitoring sickle nephropathy at routine clinic visits and have important implications for clinical decision-making and the design of future controlled therapeutic trials. Disclosures Saraf: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Quinn:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Research Support.

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Optimizing Hydroxyurea Dosing in Sickle Cell Anemia: The Uganda MTD Study

Blood ◽

10.1182/blood-2019-125128 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 520-520 ◽

Cited By ~ 2

Author(s):

Chandy C. John ◽

Robert Opoka ◽

Teresa Latham ◽

Heather Hume ◽

Maria Nakafeero ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Dose Escalation ◽

Fixed Dose ◽

Primary Study ◽

Advisory Committees ◽

Low Resource Settings ◽

Low Resource

Introduction. Hydroxyurea treatment has proven safety, feasibility, and efficacy for children with sickle cell anemia living in sub-Saharan Africa. Even in malaria endemic regions, hydroxyurea is safe and has been shown to reduce vaso-occlusive events and lower mortality. The optimal dosing regimen is not known, however, and specifically whether a fixed dose at 15-20 mg/kg/day is better than escalation to maximum tolerated dose (MTD) at 25-30 mg/kg/day. Particularly in low-resource settings, additional drug-related toxicities and monitoring costs associated with dose escalation could outweigh potential laboratory and clinical benefits. Methods. Children with sickle cell anemia previously enrolled in NOHARM (NCT01976416) received hydroxyurea at ~20 mg/kg/day during the open-label portion of that trial, after which they transitioned to commercial supply at that same daily dose. All were then offered enrollment in the NOHARM MTD trial (NCT03128515), a double-blinded trial with 1:1 randomization between continuing fixed-dose oral hydroxyurea (20 ± 2.5 mg/kg/day) versus dose-escalation to MTD (30 ± 2.5 mg/kg/day), using hydroxyurea tablets donated by Addmedica. The primary study outcome was the proportion of study participants who achieved either hemoglobin ≥9.0 g/dL or fetal hemoglobin ≥20% after 24 months of treatment. Secondary outcomes included sickle-related clinical adverse events, malaria events, and laboratory toxicities. We now present the main results of the NOHARM MTD trial. Results. A total of 187 children enrolled and began study treatment: 94 children (4.8 ± 0.9 years, 55 males) received hydroxyurea at fixed dose versus 93 who received hydroxyurea with dose escalation (4.6 ± 1.0 years, 47 males). At Month 6 of study treatment the average doses were 19.3 ± 1.7 mg/kg/day and 29.0 ± 3.5 mg/kg/day, respectively, and these dose differences were continued through Month 12 and Month 18. The trial was terminated prematurely by the independent Data Safety Monitoring Board after 146 children had reached Month 18, when the clinical complications and interventions were significantly fewer among children randomized to MTD compared to fixed-dose. The incidence rate ratio (IRR) with 95% confidence intervals (CI) included the following: all sickle-related Adverse Events [IRR = 0.43, CI = (0.34, 0.56), P<0.00001]; vaso-occlusive crises [IRR = 0.43, CI = (0.33, 0.56), P<0.00001]; acute chest syndrome/pneumonia [IRR = 0.27, CI = (0.11, 0.55), P=0.001]; transfusions [IRR = 0.29, CI = (0.20, 0.43), P<0.00001]; and hospitalizations [IRR = 0.21, CI = (0.13, 0.34), P<0.00001]. The rates of Laboratory Adverse Events were similar between treatment arms [IRR = 0.83, CI = (0.60, 1.15), P=NS] and dose-limiting toxicities were equivalent [IRR = 1.01, CI = (0.66, 1.54), P=NS] without any episodes of severe neutropenia or thrombocytopenia. Superior laboratory benefits were observed in the dose-escalation arm, with higher hemoglobin (8.7 versus 8.3 g/dL, P=0.006) and fetal hemoglobin (30.5 versus 18.2%, P<0.0001), and lower reticulocyte counts (157 versus 261 x 109/L, P<0.0001) and neutrophil counts (3.4 versus 5.1 x 109/L, P<0.0001). At the time of study closure, more children on the dose-escalation arm had achieved the primary study endpoint compared to those on fixed-dose hydroxyurea (86% versus 37%, P<0.0001). Conclusion. NOHARM MTD is the first randomized controlled clinical trial to compare hydroxyurea at fixed-dose versus escalation to MTD in either high- or low-resource settings. Hydroxyurea escalated to MTD at ~30 mg/kg/day had superior clinical and laboratory efficacy compared to fixed-dose treatment at ~20 mg/kg/day in this high-risk population, without any increase in toxicity. Optimal hydroxyurea dosing to MTD at ~30 mg/kg/day is therefore recommended for children with sickle cell anemia living in sub-Saharan Africa, which represents an important paradigm shift from the concept of low-dose daily treatment. Increasing access to hydroxyurea at optimal doses will require concerted efforts that include training and implementation strategies, to enable safe and effective hydroxyurea dose escalation for children in low-resource settings. Disclosures Ware: Bristol Myers Squibb: Other: Research Drug Donation; Addmedica: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB.

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