How Have Clinical Trials Altered Treatment of Stroke Due to Sickle Cell Disease?

1. How Have Clinical Trials Altered Treatment of Stroke Due to Sickle Cell Disease? E. Steve Roach, M. D. Robert & Edgar Wolfe Foundation Chair in Child Neurology Ohio State University College of Medicine Nationwide Children’s Hospital Columbus, Ohio

2. STROKE & SICKLE CELL DISEASE • No conflicts of interest • No off label clinical uses except in the context of research • This presentation is fully HIPPA compliant

3. TODAY’S CONSIDERATIONS • What is the stroke risk from SCD? • Mechanisms of stroke due to SCD? • Have clinical trials altered treatment?

4. Milestones in Sickle Cell Disease • African literature “ogbanjes” -“children who come and go” • James B. Herrick (1910) first published - Intern Ernest Edward Irons (1877-1959) - Chicago Presbyterian Hospital - Walter C. Noel – Grenadian dental student • Vernon Mason (1922) coined “sickle cell anemia” • Linus Pauling (1949) - abnormal hemoglobin – First genetic disease to specific protein • Robert Adams et al (1998) – publication of STOP trial Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch Intern Med 6: 517-521, 1910

5. SICKLE CELL DISEASE • Autosomal recessive trait • Gene: 11p.15.5 (Hgb Beta) • Mutation: A-to-T in sixth codon • Heterozygous: 1:10 African Americans • Homozygous: 1:400 African Americans • Carrier & prenatal detection possible

6. SICKLE CELL STROKE RISK • Medical center: 40% • Cohort studies: 5 -15% • Abnormal TCD: 10% /year • Based on MRI: 25-50% • After 1st stroke: > 65%

7. SCD: OVERLAPPING STROKE PHENOTYPES Roach, Lo, Heyer. Pediatric Stroke and Cerebrovascular Disorders, New York, 2011 • Small vessel occlusion • Large vessel ischemic stroke • Watershed (“border zone”) infarction • Brain and subarachnoid hemorrhage

8. Obstruction by sickled cells? No increased stroke risk during crises Most are asymptomatic (“silent”) Cumulative effects? Small Vessel Occlusion Roach, Lo, Heyer. Pediatric Stroke and Cerebrovascular Disorders, New York, 2011

9. Progressive endothelial proliferation Artery to artery embolism Border zone (“watershed”) infarctions SCD: Large Vessel Occlusion Roach, Lo, Heyer. Pediatric Stroke and Cerebrovascular Disorders, New York, 2011

10. Hemorrhage & Hemorrhagic Infarction • Hemorrhage much less than infarction • SCD responsible for 4-5% of spontaneous brain hemorrhages (3 of 68 in one report)

11. SICKLE TRAIT & STROKE? • Mostly case reports of SCT & stroke • Younger patients, no other risk factors • Consider the odds: - If a city population is 1 million - And 20% are African-American - Then about 20K have SCT • Need better data

12. RISK FROM SICKLE TRAIT? • Symptoms in high altitudes* • Death among US military recruits** > All recruits: 0.7 /100 000 > Black recruits: 1.0 per 100,000 > With SCT: 32.2 per 100,000 • Stroke risk from SCT is still very low *Lane et al. JAMA, 253:2251-4, 1985 **Kark et al. NEJM 317:781-7, 1987

13. Research: Challenges & Opportunities Challenges for stroke research in children • Heterogeneous stroke pathophysiology • Stroke still relatively uncommon Unique opportunities with SCD • SCD more common than other risk factors • Diagnosis (& thus risk) known in advance • Transfusions prevent recurrent stroke • Development of TCD

14. SCD: Transcranial Doppler • TCD & infarction risk • Time averaged mean velocity, not peak • 10%/ year infarction risk if TAM >200cm/sec • Predicts large vessel Adams et al. N Eng J Med, 326:605-10, 1992

15. Stroke Prevention Trial in Sickle Cell Anemia (“STOP”) • Age: 2-16 years • TCD TAM velocity > 200 cm/sec • TCD abnormal x 2 • TCD confirmed by central interpreter • Standardized neurological exam • Periodic MRI and MRA • Transfusion versus standard care Adams et al. N Eng J Med 1998, 339:5-11

16. STOP RESULTS 1934 children screened in 14 centers 2941 TCDs in 21 months 206 patients with 2 TCDs > 200 cm/sec 130 patients randomized Transfusions N =63 Standard care N =67 11 strokes 1 stroke Adams et al. N Eng J Med 1998, 339:5-11

17. STOP RESULTS • Trial halted at interim analysis • All patients offered transfusion # with stroke

18. Transfusions work! Iron overload > Liver & heart failure Chelation helps Is it possible to lessen intensity of transfusions? - Transfusion duration - Transfusion frequency TOO MUCH OF A GOOD THING:AN ELEMENTAL IRONY

19. STOP II: Duration of Transfusion • Re-randomization of STOP I patients • Continued transfusion or standard care • STOP II also halted - 2 ischemic strokes with standard care - 14 TCDs reverted to high risk Adams et al. N Eng J Med 2005; 353:2769-2778

20. STOP2: TRANSFUSION WITHDRAWALAdams et al. N Eng J Med 2005; 353:2769-2778 Children transfused > 30 months With normal TCD x 2 (n=79) Continued versus halt transfusions Transfusions (n =38) No transfusions (n =41) 2 strokes 14 Doppler conversions 0 Strokes 0 Doppler conversions

21. Stroke With Transfusions Changing to Hydroxyurea (SWITCH) Transfusions & chelation versus Hydroxyurea & phlebotomy • Age 5-18 years • Documented stroke after age 1 • > 8 months transfusions & iron overload • Non-inferiority trial

22. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) Transfusions & chelation Stroke in 0/66 Hydroxyurea & Phlebotomy Stroke in 7/67 (10%) SCD, stroke, iron overload Transfusions > 18 months (n = 133) Also no improvement in iron toxicity in drug arm. Ware et al. Blood. 119:3925-32, 2012

23. Silent Infarction Transfusion Trial (SITT) • MRI with one or more infarction • No clinical stroke or focal lesions • Transfusion vs no transfusion • Periodic transfusions lower risk of new infarctions (6% vs 14%) DeBaun MR, et al. N Engl J Med 2014; 371:699-710

24. Silent Infarct Transfusion Trial (SITT) • Recurrent headaches in 317 of 872 (36.4%) • 132 of 872 (15.1%) met criteria for migraine • Multivariable logistic regression analysis: - No association with silent infarction - Lower steady state Hgb (p = < 0.001) - More pain episodes (p = < 0.001) • Only 6/317 (1.9%) on headache prophylaxis Dowling MM, et al. J. Pediatr 2014; 164: 1175-1180

25. AHSA Guidelines for SCD • Class I Recommendations • Optimize hydration, oxygenation & blood pressure • Periodic RBC transfusions for abnormal TCD • Periodic RBC transfusions after confirmed infarct • Reduce SS Hgb to < 30% before catheter angiogram Roach et al. Stroke. 39: 2644, 2008

26. AHSA Guidelines for SCD • Class II Recommendations • Evaluate SCD for causes of hemorrhage • Annual TCD if normal; if abnormal, q 3-6 months • Hydroxyurea if transfusion not feasible • Revascularization for symptomatic large vessel stenosis Roach et al. Stroke. 39: 2644, 2008

27. California: 1991-1998 = 0.88 strokes/100 person-years 1999 = 0.05 strokes/100 person-years 2000 = 0.17 strokes/100 person-years KIDS Analysis: 1993-1998: 0.51/ 100 patient years 1999-2009: 0.28/ 100 patient years (p = 0.008) McCavit et al. Pediatr Blood Cancer 2013; 60:823 FEWER STROKES DUE TO SCD?

28. SCD: Future Directions • Altered RBC function or structure - L-glutamine – lessen RBC deformity? - MP4CO – sickling occurs at lower PaO2 - Zinc sulphate – minimizes RCB dehydration • Increase % fetal HgB - Hydroxyurea - Valproic acid? • Hematopoietic stem cell transplantation – works • Gene therapy – starting to see initial reports Ribeil, et al. N Engl J Med, 2017; 376:848-855