• Similarly, the longitudinal relationship of change in Hb level and change in TCD velocity was negatively correlated (Figure 2; r=–0.59), and a Hb increase of 1 g/dL from baseline was associated with an 11.6 cm/s decrease in TCD velocity (95% CI: 9.4-13.8 cm/s; P<0.0001).

– The effect of Hb change on TCD velocity remained statistically significant after adjusting for gender, baseline age, baseline Hb, baseline TCD, and time since baseline.

Figure 2. Correlation Between Change in TCD Flow Velocity and Change in Hb

Patients with multiple pairs of change-from-baseline observations were included.Hb, hemoglobin; TCD, transcranial Doppler ultrasound.

• Consistent results were found with an alternative analysis method.

– After reducing each patient’s multiple post-baseline observations to a single measure of overall mean change for that patient, changes in TCD velocity remained negatively correlated with changes in Hb levels (Figure 3; r=–0.57), and a Hb increase of 1 g/dL was associated with an average decrease of 13.4 cm/s in TCD velocity (95% CI: 8.7-18.2 cm/s; P<0.0001).

Figure 3. Correlation Between Patient-Level Mean Change in TCD Flow Velocity and Patient-Level Mean Change in Hb

Hb, hemoglobin; TCD, transcranial Doppler ultrasound.

Jenifer H. Voeks, PhD1; Sarah Gray, PhD2; Josh Lehrer-Graiwer, MD, MPhil, FACC2; Robert J. Adams, MD1

1Medical University of South Carolina, Charleston, SC, USA; 2Global Blood Therapeutics, South San Francisco, CA, USA

BACKGROUND• Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by

sickle hemoglobin (HbS) polymerization and erythrocyte sickling, leading to chronic hemolytic anemia and episodic vaso-occlusive crises (VOC).1

• Transcranial Doppler ultrasound (TCD) measurement of intracranial blood flow velocities can be used to identify children at an increased risk of developing overt stroke and silent cerebral infarcts, which may result in physical andneurocognitive deficits.2,3

• Children with abnormal blood-flow velocities (≥200 cm/s) are at the highest risk of developing a stroke compared to those with conditional (170 to 199 cm/s) and normal (<170 cm/s) TCD velocities.3,4

• Prophylactic transfusions can reduce the risk of stroke in children with SCD, and the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) trial demonstrated that the discontinuation of transfusions for stroke prevention results in reversion to abnormal TCD velocities.5,6

• While transfusion therapy is used to prevent strokes in children with SCD, this work further characterizes the relationship between hemoglobin (Hb) andTCD velocities.

CONCLUSIONS

• A retrospective analysis of STOP 2 data demonstrated that higher Hb levels were associated with decreased TCD velocities in children with SCD.

• An increase in Hb level likely conveys a reduction in stroke risk and highlights the need for alternative therapies that improve Hb level to potentially prevent strokes in this population.

RESULTSBaseline Characteristics

• Of the 79 patients randomized to continue or discontinue transfusions in STOP 2, 57 patients with time-matched Hb and TCD assessments were included in the baseline evaluation, and 47 patients with time-matched Hb and TCD assessments over time were included in the longitudinal evaluation.

• Baseline characteristics of the 47 patients included in the longitudinal analysis are shown by study arm in Table 1.

Table 1. Baseline Characteristics of Patients Included in theLongitudinal Analysis

Hb, hemoglobin; HbS, sickle hemoglobin; SD, standard deviation; TCD, transcranial Doppler ultrasound; WBC, white blood cell.

Increased Hb Levels Were Associated With Lower TCD Velocities

• At baseline, TCD velocities were negatively correlated with Hb levels (r=–0.30), and a 1 g/dL higher Hb level was associated with a 12.5 cm/s lower TCD velocity (95% CI: 6.1-18.9 cm/s; P=0.0002; data not shown).

– The effect of Hb level on TCD velocity remained significant after adjusting for age and gender.

METHODSStudy Design• The randomized, controlled STOP 2 trial assessed whether transfusions can be

safely discontinued in children with SCD who converted from high to low stroke risk while receiving transfusions, as assessed by TCD velocities.6

• Patients who reached TCD normalization after transfusions for 30 or more months were randomized 1:1 to continue or discontinue transfusions and had their TCD velocities and Hb levels monitored every 3 months (Figure 1).

Figure 1. STOP 2 Study Design

Hb, hemoglobin; HbSβ0, sickle beta zero thalassemia; HbSS, sickle cell anemia; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; SCD, sickle cell disease; TCD, transcranial Doppler ultrasound.

ACKNOWLEDGEMENTS• This study was supported by grants (U01 HL 052193 and U01 HL 052016) from the

National Heart, Lung, and Blood Institute.

• We are indebted to the patients and their families for their contribution tothis research.

OBJECTIVE• To evaluate the relationship between Hb levels and TCD velocities collected

longitudinally in children with SCD from STOP 2 in a retrospective analysis.

REFERENCES1. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers.

2018;4:18010.

2. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet. 2017;390(10091):311-323.

3. Estcourt LJ, Fortin PM, Hopewell S, et al. Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease. Cochrane Database Syst Rev. 2017;1:CD003146.

4. Adams RJ, McKie VC, Carl EM, et al. Long-term stroke risk in children with sickle cell disease screened with transcranial Doppler. Ann Neurol. 1997;42(5):699-704.

5. National Heart, Lung, and Blood Institute (NHLBI). Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014.

6. Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005;353(26):2769-2778.

Correlation Between Hemoglobin Levels and Transcranial Doppler Velocities: A Retrospective STOP 2 Analysis in Children With Sickle Cell Disease

DISCLOSURES• Jenifer H. Voeks: Nothing to disclose. Sarah Gray: Global Blood Therapeutics,

employee and stockholder; Josh Lehrer-Graiwer: Global Blood Therapeutics, former employee and former stockholder. Robert J. Adams: National Institutes of Health, research investigator; Global Blood Therapeutics, consultant.

• Nelson Jen, PhD (Healthcare Consultancy Group, with funding from Global Blood Therapeutics) provided editorial assistance in the preparation of this report.

• This retrospective study was sponsored by Global Blood Therapeutics.

ContinueTransfusion

(n=23)

DiscontinueTransfusion

(n=24)

Age, median (range), years 11.4 (6.8-16.2) 10.4 (5.9-19.2)

Female, n (%) 10 (43.5) 17 (70.8)

Hb level, mean (SD), g/dL 9.5 (0.8) 9.8 (1.0)

TCD flow velocity, mean (SD), cm/s 147.7 (20.7) 149.4 (19.8)

TCD flow velocity group, n (%)

<170 cm/s 21 (91.3) 22 (91.7)

≥170 to <185 cm/s 1 (4.3) 1 (4.2)

≥185 to <200 cm/s 1 (4.3) 1 (4.2)

Indirect bilirubin, mean (SD), mg/dL 1.9 (0.8) 1.9 (1.0)

WBC count, mean (SD), 109/L 12.9 (4.2) 11.9 (3.4)

HbS, mean (SD), % 22.8 (10.1) 23.5 (7.2)

• The primary objective of this retrospective analysis was to evaluate the relationship between changes in Hb level and changes in TCD flow velocity.

– STOP 2-randomized subjects with time-matched assessments of Hb level and TCD flow velocity were included in the analysis.

– The relationship between changes in Hb level and TCD velocity from baseline was assessed using a mixed-effects model for repeated measures (MMRM) analysis.

– To assess consistency of results, analysis using each patient’s average change from baseline in Hb and average change from baseline in TCD velocitywas undertaken.

• The relationship between baseline Hb levels and baseline TCD velocities was also examined.

Chan

ge in

TCD

Flo

w V

eloc

ity (c

m/s

)

100

50

0

–50

–100

–4 –2 0 2

Change in Hb (g/dL)

Continue Transfusion Discontinue Transfusion

N=47 unique patients

Chan

ge in

TCD

Flo

w V

eloc

ity (c

m/s

)

100

50

0

–50

–100

–4 –2 0 2

Change in Hb (g/dL)

Continue Transfusion Discontinue Transfusion

N=47

© 2020 Global Blood TherapeuticsPresented at the 25th Congress of the European Hematology Association; June, 2020