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2 nd July 2008 Annette Gilmore RN BSc MSc

Ten Years Longitudinal Follow-up Study of Sickle Cell Disease Patients Treated with Hydroxyurea in Four English Centres. 2 nd July 2008 Annette Gilmore RN BSc MSc G Cho MD, M Layton MD, J Howard MD, I Dokal MD, G Hughes MD,

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2 nd July 2008 Annette Gilmore RN BSc MSc

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  1. Ten Years Longitudinal Follow-up Study of Sickle Cell Disease Patients Treated with Hydroxyureain Four English Centres 2nd July 2008 Annette Gilmore RN BSc MSc G Cho MD, M Layton MD, J Howard MD, I Dokal MD, G Hughes MD, N J Philpott MD, C A Michie MD, G Abrahamson MD, A E Davies MD, M Sekhar MD, S C Davies MD

  2. History of Hydroxyurea • Only drug available that ameliorates the symptoms of Sickle Cell Disease (SCD). • Hydroxyurea (HU) has a long history in medicine • 1869 – Developed in Germany • 1960’s – Developed as anticancer drug • 1984 – First tested for SCD • 1990’s – First used to treat SCD patients in early 1990’s • 1998 – Granted USA marketing licence for adult SS patients • 2007 – Granted European marketing licence for SCD adults and children • 1995 – Multicenter Study of Hydroxyurea in Sickle Cell Anaemia(MSH) stopped early as it showed conclusively that HU benefited adult scd patients • No ‘gold standard research’ studies conducted with children so less strong evidence of benefit. Smaller studies and emerging data support results found in adults 2

  3. MSH Trial Results (1995) • Double-blinded randomised controlled trial (RCT) of 299 SCD adult patients – half treated with HU and half with placebo. • Trial stopped early as patients on HU showed significant benefit over patients not taking it. • Clinical benefits from HU: • 44% reduction in no. of pain crises • ↓ Acute chest syndrome events • ↓ Transfusions given • ↓ no. hospitalizations and inpatient days • Haematological benefits derived: • ↑ Hb level, ↑ Hb F%, ↑ MCV, ↓ WBC • Two yr follow-up only: – ? benefit sustained long-term – ? long-term side effects 3

  4. Other research study results Belgian Clinical Trial of HU (1996): Pilot study of 25 children and adults on HU for 6 months ↓ no. inpatient days and ↓ no. hospitalizations 70% of patients had no events Belgian Registry of sickle patients on HU (2001): 93 children and adults followed for up to 5 yrs 55% chance of no hospitalization for pain crisis in 5 yrs 47% chance of not having any event (requiring hospitalization) ↓ no. annual hospitalizations and inpatient days No serious side effects reported MSH 9 year follow-up of SS adults (2003): 233 of original cohort followed for 9 yrs (patients on HU and those not on HU) ↓ in mortality of 40% for patients on HU No serious side effects from HU

  5. NWL Haemoglobinopathy Registry • The Registry was initiated in 1998, as a collaborative effort between 10 European countries, with the aim of addressing the long-term effectiveness and toxicity of Hydroxyurea therapy in Sickle Cell Disease. • Later developed into the North West London Sector Haemoglobinopathy Registry – collecting clinical data for all SCD patients attending 4 local hospitals. • UK Data Protection Act Registration[Registration No. Z5730583] • REC [Approval - MREC/99/2/4] • Patient Informed Consent for research

  6. Aim To evaluate the long-term benefit and side effects of hydroxyurea treatment for sickle cell disease patients managed in their usual clinical care settings (in local haematology or paediatric outpatient department)

  7. Methods • Compare the change in various clinical and laboratory variables over time • Analysis examined changes from baseline to each of the years 1,2,5,7 and 9 • Baseline = data collected for 12 months pre HU • Clinical outcomes – annual no. IP days, no. Pain Crisis, ACS and Tx events • Incidence of side effects (toxicities) • Appropriate tests for paired data used (Paired t-tests, Wilcoxen matched pairs test and paired exact test)

  8. Sample Patient Graph 8

  9. Patient Cohort

  10. Patient Characteristics

  11. Health Improvements over time(Median/Average no. of events per year on HU) 11

  12. Improvements in Blood Markers(Changes over time - Average values per year on HU) 12

  13. Adverse event ratesduring treatment • Transient toxicity common at start of treatment due to raising the dose to find the patient’s maximum tolerated dose (MTD) • Annual survey revealed: ≈ ½ patients (12 of 27 at 12mths – 4 of 7 at 9yrs) developed mild/moderate nail discoloration. Some already had nail discoloration prior to starting HU. • Annual survey revealed: 1-3 patients had mild skin darkening. 1 patient experienced severe skin darkening on a higher then average dose of HU. • No patient developed cancer or leukaemia due to HU.

  14. HU Treatment Statusat End of the Study Period

  15. Summary • Significant improvement in health status maintained over time (up to nine years) • Short term side effects are dose related and predictable. No serious long-term side effects occurred • Results are same as found in other small studies monitoring longer term HU treatment in scd • Demonstrates problems with long-term follow-up of patients

  16. Contact Details Annette Gilmore Central Middlesex Hospital Haematology Department Acton Lane London, NW10 7NS United Kingdom Tel: +44(0)20 8453 2135 Fax: +44(0)20 8965 1115 Email:annette.gilmore@nhs.net www: www.hbregistry.org.uk

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