1. The Many Faces of Hydroxyurea Soheir Adam, MD

2. Sickle Cell Disease The commonest genetic disorder in the US Affects about 75,000 individuals Single genetic mutation Variable clinical presentation

3. Hydroxyurea Chemotherapeutic agent First reports in the 1980s Promising enough to start the MSH ( Multicenter Study of Hydroxyurea in Sickle Cell Anemia)

4. MSH January 1992- June 1994 Double blind, randomized control study of 299 severe SS patients HU at a dose of 15mg/kg/day and escalated gradually

5. MSH Terminated Early Reduced annual rate of crisis Increased median time to first crisis Reduced incidence of ACS Reduced transfusion requirements WBC count was better associated with lower crisis rate than Hb F level

6. MSH Nine year follow- up revealed a 40% reduction in mortality in the HU group Study was not randomized any more Patients who had good clinical response had improved survival Better medical care and follow- up

7. CSSCD found correlation between leucocyte count and mortality Not true in MSH

8. MSH No correlation between neutropenia and effect of HU Individuals with Retics < 250,000 and Hb < 9 g/dl and low Hb F had increased mortality They received lower doses of HU( lower BM reserve) Anemia & reticulocytopenia may indicate renal disease

9. Copyright restrictions may apply. Steinberg, M. H. et al. JAMA 2003;289:1645-1651. Cumulative Mortality in Patients With Sickle Cell Anemia in the MSH and in Follow-up

10. Pharmacokinetics Readily absorbed orally Peak level in 1 to 4 hours Metabolized in the liver Excreted through kidneys No data on dose adjustment in liver disease In renal disease if creatinine clearance > 60ml/min 15 mg/kg/day creatinine clearance<60 ml/min 7.5 mg/kg/day

11. Hydroxyurea Mechanism of action 1. Increases Hb F levels 2.Reduces red cell- endothelial interactions 3.Improved red cell rheology 4.Myelosuppression 5.Nitric oxide release vasodilatation

12. Hydroxyurea 1.Increases Hb F production: Kills rapidly- dividing late progenitor red cell and stimulates release of primitive F red cells.

13. Hb F Fetal hemoglobin Switched off soon after birth Individuals with HPFH function normally with high Hb F levels Better than Hb A at preventing red cell polymerization Clinical effect of Hb F is variable Can be up to 20% in severe disease

15. Hydroxyurea 2. Red cell- endothelial interactions: Reduces adhesion and down- regulates endothelial adhesion molecules

16. Hydroxyurea 3. Effect on red cell rheology Improves red cell hydration Increases cell deformability Reduces red cell density

17. Hydroxyurea 4. Myelosuppression Reduces neutrophil count Reduces pro- inflammatory mediators

18. Implication of Inflammation in SC Vaso-occlusion Inflammation markers are elevated in patients with SCD even in steady- state White blood cell counts ≥2x normal is a predictor of death Multivariate analysis showed that neutrophil counts were a predictor of clinical response to Hydroxyurea (better than HbF) in one trial

20. S/E of Hydroxyurea Non- hematological G.I: nausea, vomiting, dairrhoea, stomatitis, constipation Skin: pigmentation, ulceration, rash Hair loss :uncommon Teratogeneticity: no controlled trials in humans, proven in male & female rats Excreted in breast milk

21. Hydroxyurea Hematological : Neutropenia is the earliest & commonest Thrombocytopenia & anemia less common Close monitoring required Cessation may be necessary Usually reversible Macrocytosis : can mask folate defficiency

22. Hydroxyurea in SCD Indications Recurrent severe painful crisis Recurrent Acute Chest Syndrome Severe anemia Severe vaso-occlusive complications

23. HU in SCD Before starting Counseling Compliance Prescription Contraception Regular follow up

24. Hydroxyurea in SCD Base- line Labs: Blood counts MCV Hb F Chemistry ( hepatic & renal) Pregnancy test

25. HU Follow- Up Start at 500 mg / day for 6 to 8 weeks Monitor counts every 2 weeks If counts are acceptable Increase dose in 500 mg increments every 6-8 weeks until 1500 mg/ d Continue to monitor counts regularly

26. HU Follow - Up Neutrophils > 2000X 10 9 Platelets > 80,000 x 10 9 Hb usually increases If Hb or retics drop evaluate carefully An initial Hb of 5.5 g/ dl is not a contraindication

27. The Future in SCD Comprehensive care Early diagnosis and access to medical care Patient and family education Prophylaxis: antibiotics and vaccines HU started early in life Follow up

28. The Future in SCD Other Hb F inducers Modifiers of sickle cell hydration Bone Marrow Transplantation Gene therapy