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, N J Philpott MD, C A Michie MD, G Abrahamson MD, A E Davies MD, M Sekhar MD, S C Davies MD 1

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

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

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

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. Z ] REC [Approval - MREC/99/2/4] Patient Informed Consent for research 5

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)

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)

Sample Patient Graph 8

Patient Cohort 9

Patient Characteristics 10

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

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

Adverse event rates during 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.

HU Treatment Status at End of the Study Period 14

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 15

Contact Details Annette Gilmore Central Middlesex Hospital Haematology Department Acton Lane London, NW10 7NS United Kingdom Tel:+44(0) Fax:+44(0) www: 16