Randomized Controlled Trial of Fixed Low-Vs Moderate-Dose Hydroxyurea for Primary Stroke Prevention in Sub-Saharan Africa: Final Results of the Spring Trial

Introduction: In children with sickle cell anemia (SCA) without transcranial Doppler (TCD) screening, the incidence rates of ischemic strokes is approximately the same among children living in low- and high- low-resource settings (Pediatr Neurol. 2019;95:73-78.) with a prevalence of ~ 11%. However, in high-income settings, the standard use of TCD ultrasonography, coupled initially with monthly blood transfusion therapy has dropped the stroke prevalence to < 1%. In a low-income setting, such as Nigeria, where 50% of children in the world with SCA are born (150,000 per year), initial monthly blood transfusion therapy is not practical for most children. In the Stroke Prevention in Nigeria (SPIN) Feasibility Trial (NCT01801423), fixed moderate-dose hydroxyurea was associated with a decreased rate of strokes in children with SCA and abnormal time-averaged mean of the maximum velocity (TAMMV) TCD measurements (≥200cm/sec) when compared to no treatment in the STOP Trial, 0.76 and 10.7 strokes per 100 person-years, repsectively (Am J Hematol. 2020). Based on the success of the SPIN trial, plus the challenges of real-world implementation of a government-supported primary stroke prevention programs for estimated 40,0000 children with SCA in three states in Nigeria, we tested the hypothesis that fixed-moderate dose (~20 mg/kg/day) hydroxyurea therapy for primary stroke prevention results in a 66% relative risk reduction (9 to 3 events per 100 person-years) when compared to fixed low-dose hydroxyurea (~10 mg/kg/day) therapy in a randomized controlled trial (The SPRING Trial; NCT02560935). Methods: In this partial-blind controlled phase III trial, we randomly assigned children between 5 and 12 years of age with SCA and a TCD time-averaged mean of the maximum velocity (TAMMV) ≥ 200 cm/sec measured independently twice or TAMMV ≥220 cm/sec once at study screening to receive fixed low-dose or fixed moderate-dose hydroxyurea. The primary endpoint was a clinical stroke or a transient ischemic attack (TIA). Myelosuppression was assessed with monthly complete blood counts (CBCs). Adherence to hydroxyurea was primarily based on an increase in MCV from baseline and monthly pill count return as a percent of dispensed pills. Hemoglobin F levels were measured at baseline, annually and upon trial exit. To evaluate the safety of hydroxyurea in the trial, children attending the same SCA clinics with TCD (TAMMV) <200 cm/sec at study screening were prospectively followed with biweekly phone calls and annual research visits. Results: A total of 220 children (mean age: 7.5 years, 51.8% female) were randomly assigned to fixed low- (10 mg/kg/day) or moderate- (20 mg/kg/day) dose hydroxyurea, and were followed for a median of 2.4 years (IQR 2.0-2.8). NINDS Clinical Trials leaders stopped the trial early because of futility for the primary outcome. In the fixed low- and moderate-dose hydroxyurea groups, the incidence rates of strokes per 100 person-years were 1.19 and 1.92 respectively, with an incidence rate ratio of 1.60 (95% CI: 0.31-10.34), p = 0.768. The incidence rate ratio of mortality when comparing the children treated with low- and moderate- fixed-dose hydroxyurea to the non-elevated TCD group (no hydroxyurea therapy, n= 211) was 1.97 (95% CI: 0.64-6.02) and 0.47 (95% CI: 0.05-2.38), p = 0.265 and 0.545, respectively. Returned pills during the trial was 5.4% and 4.8% in the fixed low- and moderate-dose groups, respectively, p= 0.144. MCV from baseline to endpoint increased 1.5fl and 7.2 fl in the fixed low- and moderate-dose groups, respectively, p<0.001. Upon exit from the trial 29.4% and 66.7% of the fixed- low and moderate -dose groups, respectively, had either hemoglobin level ≥ 9.0 g/dl, or a fetal hemoglobin level ≥ 20%. Conclusions: For primary stroke prevention in children with SCA, fixed low-dose, when compared to fixed moderate-dose hydroxyurea therapy, demonstrated no difference in the incidence rate of strokes. Both fixed low- and moderate -dose hydroxyurea doses are superior to no treatment for primary stroke prevention with abnormal TCD values. In partnership with Katsina, Kano, and Kaduna health department's leaders in Nigeria, 9 distinct SCA and primary stroke prevention clinics have been established, with the provision of free fixed low-dose hydroxyurea therapy (Bond Chemical, Nigeria; $0.15 per 500 mg) for abnormal TCD values, and biannual CBCs as standard care ,for over 40,000 children with SCA. Disclosures DeBaun: Global Blood Therapeutics (GBT): Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: fixed low and moderate dose hydroxyurea for primary stroke prevention in sickle cell

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Low- Versus Moderate-Dose Hydroxyurea for Secondary Stroke Prevention in Children with Sickle Cell Disease in Sub-Saharan Africa: Final Results of a Randomized Controlled Trial, Sprint Trial

Blood ◽

10.1182/blood-2020-142896 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Shehu Umar Abdullahi ◽

Surayya M. Sunusi ◽

Mohammed Sani Abba ◽

Saifuddeen Sani ◽

Aisha Galadanci ◽

...

Keyword(s):

Randomized Controlled Trial ◽

Blood Transfusion ◽

Incidence Rate ◽

Stroke Prevention ◽

Low Dose ◽

Controlled Trial ◽

Secondary Stroke Prevention ◽

Moderate Dose ◽

Transfusion Therapy ◽

Randomized Controlled

Introduction Strokes are a preventable cause of neurological morbidity and premature death, particularly in children with sickle cell anemia (SCA) living in low-resource countries. If untreated, 50% of children with SCA their first overt ischemic stroke will have a recurrent stroke within two years of the event. In high-income countries, ASH 2020 guidelines recommend indefinite regular blood transfusion therapy for secondary stroke prevention (Blood Adv. 2020). Unfortunately, regular blood transfusion therapy is not a feasible option for children with SCA in sub-Saharan Africa due to the high cost of monthly blood transfusion, limited blood supply, and unsafe transfusion practices. Also, children who receive regular blood transfusions will ultimately require daily iron chelation at a cost that is prohibitive to most families in low-income settings. One randomized controlled trial provided evidence that HU therapy may be an effective therapy for secondary prevention of strokes when compared to no therapy (Blood. 2012;119(17):3925-3932). In the SWiTCH trial, the incidence rate of stroke recurrence in the group randomly allocated to receive maximum tolerated dose HU therapy was significantly higher than the group randomly assigned to receive blood transfusion therapy (5.6 and 0 events per 100 person-years, respectively, but considerably lower when compared to children not treated with any treatment, approximately 28 events per 100 person-years (Niger Postgrad Med J. 2013;20(3):181-187). Given the practical limitations for regular blood transfusion therapy, we tested the hypothesis that for secondary stroke prevention among children with SCA and acute overt ischemic stroke, fixed moderated dose HU therapy (~20 mg/kg/day) results in 80% relative risk reduction when compared to fixed low-dose HU therapy (10 mg/kg/day) in a randomized controlled trial (SPRINT Trial; NCT02675790). Methodology In phase III controlled trial, partially blind d controlled trial, we randomly assigned children 1 - 16 years of age with SCA and a new-onset of ischemic stroke (within 1 month) to receive fixed moderate-dose HU therapy at 20 mg/kg/day or fixed-low dose HU therapy at 10 mg/kg/day) with a monthly follow-up for at least 36 months. The primary endpoint was a recurrence of overt stroke or transient ischemic attack. Myelosuppression was assessed with monthly CBCs. Adherence to hydroxyurea was based on an increase in MCV from baseline and monthly pill count return, as a percent of dispensed pills. Results A total of 101 children with SCA were randomly assigned to fixed low- (~10 mg/kg/day) or moderate- (~20 mg/kg/day) dose hydroxyurea. The mean age was 6.6 years; 55.4% were males, and the median follow up was 1.6 years (IQR 1.0 - 2.3). The DSMB stopped the trial early due to the futility of the primary endpoint. In the fixed low- and moderate-dose groups, the incidence rates of recurrent strokes per 100 person-years were 7.1 and 6.0, respectively, incidence rate ratio of 0.85 (95% CI: 0.20 - 3.34), p=0.999. The incidence rates of mortality per 100 person-years in the fixed low dose and moderate- fixed-dose groups were 2.38 and 3.63, respectively, with an incidence rate ratio of 1.53 (95% CI: 0.18 - 18.30), p=0.98. No participant had hydroxyurea therapy stopped because of myelosuppression. As a measure of adherence, MCV from baseline to endpoint increased 6.2 fl and 13.3 fl in the fixed low- and moderate-dose groups, respectively, p=0.025; returned pills during the trial were 3.3% and 3.5% in the fixed low- and moderate-dose groups, respectively, p= 0.76. Conclusion For secondary stroke prevention, in a randomized controlled trial in children with SCA and new onset of ischemic strokes, fixed low-dose, when compared to fixed moderate-dose hydroxyurea therapy, demonstrated no difference in the incidence rate of stroke recurrence. Fixed low-dose hydroxyurea for secondary prevention of strokes in Nigeria provided similar stroke recurrence rate, when compared to the SWiTCH Trial (Blood. 2012;119(17):3925-3932) with the maximum tolerated dose of hydroxyurea of 7.0 and 5.7 events per 100 person-years, respectively. For secondary stroke prevention, in low-income settings without access to indefinite regular blood transfusion therapy, fixed low-dose hydroxyurea of at least 10 mg/kg/day with biannual CBC is a new evidence-based strategy to prevent strokes and minimize unnecessary laboratory testing. Disclosures DeBaun: Global Blood Therapeutics (GBT): Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: fixed low and moderate dose hydroxyurea for primary stroke prevention in sickle cell

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Feasibility Trial for Primary Stroke Prevention in Children with Sickle Cell Anemia in Nigeria (SPIN Trial)

Blood ◽

10.1182/blood.v128.22.122.122 ◽

2016 ◽

Vol 128 (22) ◽

pp. 122-122 ◽

Cited By ~ 1

Author(s):

Najibah Aliyu Galadanci ◽

Shehu Umar Abdullahi ◽

Leah Danielle Vance ◽

Musa Tabari ◽

Shehi Abubakar ◽

...

Keyword(s):

Treatment Group ◽

Sickle Cell ◽

Stroke Prevention ◽

Comparison Group ◽

Controlled Trial ◽

Preliminary Evidence ◽

Feasibility Trial ◽

Transfusion Therapy ◽

Comparison Groups ◽

Hydroxyurea Therapy

Abstract Background: In children with sickle cell anemia (SCA), the routine use of transcranial Doppler (TCD) measurements and regular blood transfusion therapy for those with elevated velocities > 200 cm/sec, has dramatically decreased the rate of strokes. However, blood transfusion therapy for primary stroke prevention is not an option for most children in Africa. In preparation for a phase III trial of hydroxyurea therapy (20 mg/kg/day vs 10 mg/kg/day) for primary prevention of strokesin children with SCA in Africa, we conducted a single site, single-arm feasibility trial of hydroxyurea therapy for primary stroke prevention in children with SCA. Participants were between 5 and 12 years of age, attending the pediatric sickle cell disease clinic of Aminu Kano Teaching Hospital, in Kano, Nigeria. The main objectives of the feasibility trial were to determine the acceptability rate of a hydroxyurea therapy trial to families, and to obtain preliminary evidence of hydroxyurea safety in Africa. Methods: All eligible participants were screened with TCD, non-imaging technique, to determine increased stroke risk; defined as time-averaged maximum velocity (TAMV) greater than or equal to 200cm/sec in the middle cerebral artery (MCA). Families were offered moderate fixed dose hydroxyurea (~20mg/kg/day) for initially 2 years. Primary outcome measures of acceptability were based on three key components required for phase II randomized controlled trial: recruitment rate, retention rate and adherence to the study medication. To determine the expected background rate of adverse events and serious adverse events in this population, children with TCD velocities less than 200cm/sec who were not on hydroxyurea therapy were enrolled. Results: A total of 375 families were approached to be screened for elevated TCD measurements, of which 90% (330 of 375) enrolled; 8% (27 of 330) had two consecutive elevated TCD measurements; and 92% (25 of 27) participated in the trial. A total of 210 participants were identified with TCD velocities less than 200 cm, signed informed consents, and agreed to be followed prospectively in a comparison group. The median age for the trial participants and comparison group were 8 and 6.8 years, respectively. No statistically significant difference was observed in age, sex, ethnicity, height and weight of the treatment and comparison groups. The median time on therapy was 2.1 years (range: 0 to 2.8 years), and the average mean cell volume increased from 85 fl at baseline to 101.3 fl at 2 years. As per protocol, all patients were expected to attend monthly research visits and none were missed (n=total 603 visits). No participant in the treatment group dropped voluntarily from the trial, though one participant was withdrawn due to development of progressive renal failure. After follow up visits, participants in the comparison group with subsequent TCD measurements, were given the option to receive hydroxyurea therapy, and the only 2 with elevated TCD values elected to do so. No stroke occurred in the treatment group and 1 stroke occurred in the comparison group. Hospitalization rates in treatment and comparison groups were 35.1 and 48.0 per 100 patient years respectively, (p=0.06). A total of 9 deaths occurred, 1 death in the treatment group, but after participant withdrew from the trial because of progressive renal disease (1.76 per 100 patient-years) and 8 deaths in the comparison group (1·88 per 100 patient-years) p = 0.94. No participants that died received any PCV-13 vaccinations and only 2 received Hib vaccinations. At the time of death, all participants were prescribed malaria prophylaxis, and 8 of 9 participants were prescribed penicillin prophylaxis. Conclusion: In Nigeria, participants in SPIN Trial with elevated TCD measurements treated with moderate dose of hydroxyurea, showed high rates of successful recruitment, retention and adherence rates to trial medication. Importantly hydroxyurea therapy did not reveal any evidence of excessive toxicity when compared to those not treated with hydroxyurea. Our results provide strong preliminary evidence supporting the current multi-center randomized controlled trial comparing hydroxyurea therapy (20 mg/kg/day vs 10 mg/kg/day) for preventing primary strokes in children with SCA living in Nigeria (1R01NS094041-01;clinical trials.gov NCT 02560935). Disclosures No relevant conflicts of interest to declare.

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Avascular Necrosis in Untreated Patients with Type 1 Gaucher Disease.

Blood ◽

10.1182/blood.v114.22.1353.1353 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1353-1353

Author(s):

Pramod K Mistry ◽

Patrick Deegan ◽

Ashok Vellodi ◽

J. Alexander Cole ◽

Michael Yeh ◽

...

Keyword(s):

Incidence Rate ◽

Avascular Necrosis ◽

Gaucher Disease ◽

Incidence Rates ◽

Advisory Committees ◽

Type 1 Gaucher Disease ◽

Receive Treatment ◽

To Receive

Abstract Abstract 1353 Poster Board I-375 Objective To determine the incidence of avascular necrosis (AVN) in untreated patients with type 1 Gaucher disease (GD1). Methods All patients with GD1 enrolled in the ICGG Gaucher Registry as of July 2007 were included in this analysis. All GD1 patients who either never received treatment or eventually went on to receive treatment were identified. Follow-up began on each patient's date of earliest reported assessment in the Registry. Among patients who never received treatment, follow-up continued until the last recorded assessment date in the Registry. For patients who eventually went on to receive treatment, follow-up continued until the date of initiation of therapy. Incidence rates (and Poisson exact 95% confidence intervals) of AVN were determined for both groups of patients. AVN was typically ascertained from X-Ray or MRI results. Results As of July 2007, the inclusion criteria were met by 3,497 patients. The incidence rate of AVN among untreated patients was 22.8 per 1,000 person years (95% CI 20.2 to 25.7). Patients with antecedent splenectomy (total or partial) had a higher incidence rate of AVN (46.6 per 1,000 person-years, 95% CI 38.4 to 56.1) compared to patients without a splenectomy (incidence rate 17.0 per 1,000 person-years, 95% CI 14.5 to 19.8). The primary sites where AVN was identified in both groups were the hip and femur. Conclusion This is the first epidemiologic analysis to estimate incidence rates of AVN among untreated patients with GD1. Splenectomy appears to be a risk factor for GD1-associated AVN. Based on the incidence results above and presupposing equal risk distribution, without therapeutic intervention, most patients should theoretically experience at least one episode of AVN at some point in their life. However, because the GD1 population is genotypically and phenotypically heterogeneous, further analyses will attempt to identify characteristics that distinguish untreated patients at high risk of developing AVN from those who are less likely to develop this serious complication. Disclosures Mistry: Genzyme Corporation: Honoraria, Research Funding. Deegan:Genzyme Corporation: Honoraria. Vellodi:Genzyme Corporation: Honoraria, Speakers Bureau. Cole:Genzyme Corporation: Employment. Yeh:Genzyme Corporation: Employment. Weinreb:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Initiating adjunct low-dose hydroxyurea therapy for stroke prevention in children with SCA during the COVID-19 pandemic

Blood ◽

10.1182/blood.2020005992 ◽

2020 ◽

Vol 135 (22) ◽

pp. 1997-1999 ◽

Cited By ~ 10

Author(s):

Michael R. DeBaun

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

Low Dose ◽

Hydroxyurea Therapy

In anticipation of possible blood shortages during the current COVID-19 pandemic, DeBaun proposes rapid initiation of administration of low, fixed doses of hydroxyurea for children with sickle cell anemia (SCA) who receive regular prophylactic transfusions for stroke prevention.

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Editorial Comment: Low-Dose or Moderate-Dose Anticoagulation: Dream or Hope for Stroke Prevention?

Stroke ◽

10.1161/01.str.0000072821.77040.fd ◽

2003 ◽

Vol 34 (6) ◽

Cited By ~ 1

Author(s):

M.G. Hennerici

Keyword(s):

Editorial Comment ◽

Stroke Prevention ◽

Low Dose ◽

Moderate Dose

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Low Dose Apixaban As Secondary Prophylaxis for Venous Thromboembolism in Cancer Patients, 30 Months Follow-up

Blood ◽

10.1182/blood-2021-148105 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3231-3231

Author(s):

Trine-Lise Hannevik ◽

Herish Garresori ◽

Jorunn Brekke ◽

Tone Ronnaug Enden ◽

Hege Froen ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Cancer Patients ◽

Incidence Rate ◽

Major Bleeding ◽

Low Dose ◽

Advisory Committees ◽

Full Dose ◽

Kaplan Meier ◽

Recurrent Vte

Abstract Background: Apixaban is a treatment option for venous thromboembolism (VTE) in cancer patients. There are no data on the effect of low dose apixaban after 6 months treatment. We wanted to assess the efficacy and safety of apixaban 2.5 mg twice daily as prophylaxis for recurrent VTE after 6 months initial treatment with full-dose apixaban. Patients and methods: We included 298 patients with cancer and any type of VTE. All patients were treated with full dose apixaban for the first 6 months. After 6 months, all patients with active cancer continued with apixaban 2.5 mg twice daily and were followed for the next 30 months. The primary endpoint of efficacy was recurrent VTE, the primary safety endpoint was major bleedings. Clinically relevant non-major bleedings was a secondary endpoint. The endpoints are reported as incidence rates or fractions with 95% confidence intervals, and as Kaplan-Meier plots. Results: During the first 6 months of full-dose anticoagulation 12 of 298 patients had recurrent VTE (4.0%, 95% confidence interval 2.1-6.9), 16 experienced major bleeding (5.4%, 95% CI 2.8-7.9%), and 26 patients experienced one or more episodes of CRNMB (8.9%, 95% CI 5.5-12) as previously reported. 1 Of the 298 patients included, 196 continued with apixaban 2.5 mg twice daily after 6 months. During treatment from 6 to 36 months with low-dose apixaban 15 of 196 (7.6%, 95% CI: 4.4-12) patients had recurrent VTE, 7 (3.6%, CI: 1.5-7.2) patients experienced major bleeding and 16 (8.2%, 95% CI: 4.7-13) patients experienced CRNMB. The highest incidence rate of both recurrent VTE and major bleedings were seen during the first month of full-dose apixaban (Table 1). After the dose reduction of apixaban, the incidence rate of recurrent VTE increased slightly during 6 to 12 months while the incidence rate of major bleeding decreased during the same time-period. After 12 months the incidence rate of both recurrent VTE and major bleeding was low and remained low during the entire 30 months follow-up (Table 1 and Figure 1). The Kaplan-Meier plot of the composite endpoint of recurrent VTE or major bleeding did not change after dose-reduction. After about 9 months treatment (i.e. 3 months on low dose apixaban) the Kaplan-Meier curve of the composite endpoint flattened out. Conclusion: Dose reduction of apixaban to 2.5 mg twice daily after 6 months of full dose anticoagulation resulted in a small increase in recurrent VTE, but a marked decrease in major bleedings during the 6-12 months period. After approximately 9 months the frequency of recurrent VTE and major bleedings remained low compared with the first 6 months of full-dose treatment. Reducing the dose of apixaban to 2.5 mg twice daily after 6 months of full-dose treatment appears safe and effective. References 1. Hannevik TL, Brekke J, Enden T, et al: Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism. Thromb Res, 2020 Figure 1 Figure 1. Disclosures Hannevik: Pfizer/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Garresori: Pfizer: Honoraria; Amgen: Honoraria; Bayer: Honoraria. Froen: Bristol-Myers Squibb: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees. Porojnicu: Bristol-Myers Squibb: Honoraria. Ghanima: Bayer, BMS/Pﬁzer: Research Funding; Amgen, Novartis, Pﬁzer, Bristol Myers Squibb, SOBI, Griffols, Sanoﬁ: Honoraria; Amgen, Novartis, Pﬁzer, Principia Biopharma Inc- a Sanoﬁ Company, Sanoﬁ, SOBI, Griffols, UCB, Argenx: Consultancy. Dahm: Pfizer: Honoraria; Novartis: Honoraria; Pfizer/Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

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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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Primary Prevention of Strokes in Nigerian Children with Sickle Cell Disease (SPIN Trial): Final Results

Blood ◽

10.1182/blood-2019-126474 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 521-521

Author(s):

Najibah Aliyu Galadanci ◽

Shehu Umar Abdullahi ◽

Shehi Abubakar ◽

Aisha Amal Galadanci ◽

Halima Bello-Manga ◽

...

Keyword(s):

Treatment Group ◽

Blood Transfusion ◽

Incidence Rate ◽

Stroke Prevention ◽

Death Rate ◽

Comparison Group ◽

Fixed Dose ◽

Transfusion Therapy ◽

Significant Difference ◽

Comparison Groups

Introduction: In children with sickle cell anemia (SCA) living in high-income settings, the routine use of transcranial Doppler (TCD) measurements, coupled with regular blood transfusion therapy for those with abnormal velocities (> 200 cm/sec) dramatically decreased the rate of strokes. Despite evidence of its beneficial effects in preventing strokes, regular blood transfusion therapy is not feasible for 99% of the children that are born with SCA living in low- and middle-income countries. To address this gap in care, we tested the hypothesis that moderate fixed dose of hydroxyurea (20 mg/kg/day) for primary stroke prevention was feasible in a low-income setting, Kano, Nigeria. Specifically, we previously demonstrated that families were willing to enroll at a 92% recruitment rate and were adherent to the study protocol with no missed monthly research visits (603 of 603 visits). We have extended the trial for approximately five years to test the hypotheses that moderate fixed dose hydroxyurea will: 1) not result in excess incidence rate of severe adverse events (death or stroke) when compared to a group of children with SCA and TCD measurements less than 200 cm/sec; 2) decrease the incidence rate of strokes to the level of children receiving regular blood transfusion for primary stroke prevention in the STOP Trial. We report the final results of the primary Stroke Prevention Feasibility Trial in Nigeria (SPIN Trial (NCT01801423). Methods: At trial entry, all eligible participants were screened with non imaging TCD to determine increased stroke risk; defined as two independent measurements of time-averaged maximum velocity (TAMV) ≥ 200cm/sec in the middle cerebral artery (MCA) or one measurement >219cm/sec. Families were offered moderate fixed dose hydroxyurea (~20mg/kg/day). The comparison group included individuals with SCA that have a TCD measurement less than 200 cm/sec and agreed to be followed as routine medical care. Serious adverse events including death or stroke in the treatment and comparison groups were defined based on WHO criteria. Results: A total of 29 children treated with hydroxyurea for primary stroke prevention, and 206 children in the comparison group, were included. The median age for the treatment and comparison groups were 7.0 and 8.2 years, respectively. No statistically significant difference was observed in age, sex, ethnicity, height and weight of the treatment and comparison groups. Table 1 The median time on therapy (follow up time) was 4.9years (IQR- 4.60, 5.2). After 3 months of starting hydroxyurea therapy, 65.5% of the participants had a drop in TCD measurement to below 200cm/sec, which was sustained through 12months of therapy (61.5% had a TCD measurement below 200cm/sec at 12 months). Figure 1 The stroke incidence rate among the participants on hydroxyurea was 0.76 per 100 person-years (95% confidence interval 0.11 to 5.24), which was not significantly different from the incidence rate of 0.32 per 100 person-years (95% confidence interval 0.10 to 0.99) for participants in the comparison arm (P = 0.489), and significantly lower than the reported rate of stroke in the standard care group for the STOP study (10.7 per 100 person-years, total of 102 patient years). A total of 20 deaths occurred, with no death in the treatment group. One death occurred in a child that was originally in the treatment group, but after the patient was withdrawn from the trial due to progressive renal disease unrelated to treatment. The death rate in the comparison group was 2.05 per 100 patient-years. There was no statistically significant difference in the death rate between treatment and comparison group (p = 0.082). The leading cause of death was suspected malaria occurring in 79% (15 of 19). As expected, we found a statistically significant higher incidence rate of pain in the comparison group (30.04 per 100 person-years) compared to the treatment group (15.28 per 100 person-years) (P <0.001). No difference in incidence rates of anemia, infection, malaria and transfusion rates between the two groups. Conclusion: The extended results of the SPIN trial provide clear evidence that initial treatment with fixed moderate dose hydroxyurea (20 mg/kg/day) will prevent strokes in children with abnormal TCD measurements in a low-resource setting. The results of the extended SPIN trial have established the first evidence based stand care strategy for primary stroke prevention for children with SCA in Africa. Disclosures No relevant conflicts of interest to declare.

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Effect of Sickle Cell Related Therapies on Growth in Children with Sickle Cell Disease: Evidence from the Displace Study

Blood ◽

10.1182/blood-2020-140582 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-21

Author(s):

Najibah Aliyu Galadanci ◽

Maira Sohail ◽

Oluwasegun Philip Akinyelure ◽

Akinyemi I. Ojesina ◽

Julie Kanter

Keyword(s):

Blood Transfusion ◽

Board Of Directors ◽

Sickle Cell ◽

Vital Signs ◽

Advisory Committees ◽

Cross Sectional ◽

Transfusion Therapy ◽

The Us ◽

Hydroxyurea Therapy ◽

Baseline Hemoglobin

Introduction Reduced growth and delayed maturation have been previously described in children with sickle cell disease (SCD) due to multifactorial causes including chronic anemia and increased hemolysis. Interventions that decrease anemia and inflammation may have a beneficial effect on growth in children with SCD. Previous studies have demonstrated that children with SCD treated with hydroxyurea (HU) and chronic red cell transfusion therapy (CRCT) experience linear growth and increase in body mass index (BMI) compared to their counterparts not on therapy. Unfortunately, most of these studies were limited due to small sample size, cross-sectional study design or were conducted from single or a few center(s). DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) is a large, NHLBI (National Heart, Lung, and Blood Institute) funded consortium to improve stroke prevention implementation in SCD. DISPLACE includes the largest database of children with SCD from 28 different centers in the US. These data allow for an optimal assessment of growth in children with SCD on different disease modifying therapies. Using the DISPLACE database, we conducted a cross-sectional sub-study to evaluate how HU and CRCT affect growth in children over time. Methods The DISPLACE study collected data on 5,247 children aged 2-19 years with SCD from 28 centers in the US between 2012-2016. The majority of children have data collected from at least five years of continuous care. At baseline and annually thereafter, all children had routine standard of care anthropometric measurements including height and weight, vital signs, laboratory tests including complete blood count and chemistries and SCD-related therapies including chronic blood transfusion therapy and hydroxyurea therapy. Body mass index was converted to z-scores (zBMI) based on the Centers for Disease Control guide for age and sex. Children were categorized based on the zBMI score as underweight, normal, and overweight/obese. Our inclusion criteria included children with documented results of weight, height, vital signs, clinical and laboratory tests at baseline. Children who do not have sufficient data for evaluation (at least one missing anthropometric measurement or laboratory value) were excluded. Results Of the 3,305 children included in the study, 19.8%, 66.1%, 14.2% were underweight, normal, and overweight/obese at their initial (baseline) visit respectively. Children who were overweight/obese had a significantly higher hemoglobin level (p<0.0001) and significantly lower reticulocyte count (p = 0.0334) at baseline than normal and underweight children. Children who are overweight/obese had a significantly higher systolic and diastolic blood pressure compared to those who are normal or underweight (p = 0.0079 and p = 0.0003 respectively). A higher proportion of children who were overweight/obese were on CRCT at baseline compared to children with normal or underweight zBMI (p = 0.0002). The proportion of children on HU therapy at baseline was similar across zBMI categories (p = 0.2412). The multivariable adjusted model showed that the baseline hemoglobin levels were associated with the odds of being underweight (OR 0.93, 95% CI: 0.86 - 0.99), or overweight/obese (OR: 1.26, 95% CI: 1.17 - 1.36) compared with normal zBMI. At baseline, blood transfusion was associated with being overweight/obese versus normal (OR: 1.85, 95% CI: 1.31 - 2.60). After two years of therapy, there was a statistically significant increase in median zBMI from baseline among children initiating blood transfusion versus controls, (p = 0.0481), but the zBMI difference in hydroxyurea therapy versus controls remain same. (p=0.3925). Conclusion In our US-based study, the majority of children with SCD (70%) had normal zBMI. As baseline hemoglobin is associated with zBMI, that may predict who is at risk for being underweight or overweight. In addition, patients treated with CRCT are more likely to be overweight and have higher blood pressure. These findings suggest that individuals on CRCT should be monitored and may need lower calories than those not on disease modifying therapies. Disclosures Kanter: bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; 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; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees.

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Practice Patterns in the Use of MRI/MRA and Chronic Transfusion Therapy for Monitoring and Treatment of Stroke in Pediatric Patients with Sickle Cell Anemia

Blood ◽

10.1182/blood-2018-99-116968 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4716-4716

Author(s):

Alyssa M Schlenz ◽

Martina Mueller ◽

Shannon Phillips ◽

Cathy Melvin ◽

Robert J. Adams ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

Research Funding ◽

Pediatric Patients ◽

Practice Patterns ◽

Advisory Committees ◽

Transfusion Therapy ◽

Hemoglobin S ◽

Prevention Guidelines

Abstract Introduction: Current stroke prevention guidelines in pediatric sickle cell anemia (SCA) specify the use of transcranial Doppler (TCD) and chronic red cell transfusion therapy (CRCT) for detection and prevention of stroke. Guidance on the use of MRI/MRA in the context of stroke prevention, screening, and monitoring is less clear. While overt stroke is able to be identified clinically, silent stroke can be more difficult to diagnose and screening guidelines have not been developed. The DISPLACE Consortium (Dissemination and Implementation Looking at the Care Environment) is a multi-center study funded to evaluate optimal implementation of stroke prevention guidelines. The purpose of the present study was to provide information on practice patterns across the DISPLACE Consortium as they relate to the use of MRI/MRA and CRCT for monitoring and treating stroke in pediatric patients with SCA. Methods: DISPLACE is a multi-site study in SCA including 28 centers across the United States. A practice patterns survey was sent to the principal investigator (PI) for each DISPLACE site through RedCap. All PIs are specialty care providers in hematology/oncology who provide care to pediatric patients with SCA. The sites were chosen to represent a range of characteristics, including both urban and rural regions, large and small academic institutions, and community-based institutions. The survey was developed by the study investigators and questions were provided predominantly in a multiple choice format. The following types of questions were asked about MRI/MRA: indication for pediatric patients with SCA in general and for those on CRCT for stroke prevention. The following types of questions were asked about CRCT: indication and frequency of CRCT and target hemoglobin S level. Results: All 28 providers completed the survey (100%). About half of providers were female (53.5%). Most providers 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%). MRI was used for the following indications: abnormal TCD (85.7%), conditional TCD (46.4%), recurrent headaches (78.6%), and behavior issues (53.6%). A few sites also reported obtaining an MRI if a child has had poor school performance (10.7%) or if there was concern for developmental delay (3.7%). Indications for MRA were similar. Notably, many sites reported the use of a screening or baseline MRI in the absence of other indications (25.0%). The most common indications for initiating CRCT were abnormal TCD (96.4%) and overt stroke (92.9%), followed by silent stroke (53.6%) and abnormal MRA (50.0%). The majority of sites reported scheduling CRCT at a frequency of every 4 weeks (63.0%), though many (37.0%) described other more frequent transfusions intended to either more rapidly reduce hemoglobin S levels or maintain a level under 30%. Most sites used a target of 30% hemoglobin S, though a few sites noted alternatives including 40% (3.7%) and 50% (3.7%). The frequency of MRI for patients receiving CRCT for stroke prevention was as follows: annually (44.4%), every 2 years (14.8%), and every 5 years (3.7%). Several sites reported obtaining MRIs only if there were new changes or concerns (14.8%) or reported alternative practices (14.8%) that depended on patient characteristics. Frequency for MRA was similar for patients on CRCT. Conclusions: The results of the DISPLACE practice patterns survey suggested nearly universal adoption of CRCT for children with abnormal TCD and prior overt stroke across sites. The use of MRI/MRA in detecting potential cerebrovascular abnormalities in the absence of clinical neurologic symptoms and for monitoring patients on CRCT was much more variable, which likely reflects the minimal amount of guidance for the use of MRI/MRA in SCA. Notably, a number of sites were using MRI/MRA to screen pediatric patients for cerebrovascular abnormalities and to monitor patients on CRCT. The variability in responses for MRI/MRA highlights the importance of future studies evaluating best neuroimaging practices for detecting cerebrovascular abnormalities (apart from TCD) and for using MRI/MRA to monitor patients on CRCT. Disclosures Schlenz: NHLBI: Research Funding. Mueller:NHLBI: Research Funding. Phillips:NHLBI: Research Funding. Melvin:NHLBI: Research Funding. Adams:NHLBI: Research Funding. Kanter:bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Apopharma: Research Funding; Sancilio: Research Funding; Global Blood Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees.

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