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Ten Years Longitudinal Follow-up Study of Sickle Cell Disease Patients Treated with
Hydroxyureain Four English Centres
22ndnd July 2008 July 2008Annette 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
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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
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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
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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. Z5730583]
• REC [Approval - MREC/99/2/4]
• Patient Informed Consent for research
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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
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1 1 2Toxic Episodes
3
11 3 1 4 2 IP Days
0
5
10
15
20
25
30
35
0
20
40
60
80
100
120
140
HU
Do
se (m
g/k
g/d
ay)
MC
V (f
l) an
d H
b F
(%
)
MCV and Hb F & HU Dose - (13 years Follow-up)
Calculated dose (mg/kg/day) MCV (fl) Hb F (%) HU Toxic Episodes IP Days
Patient Cohort
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TotalPatients Started HU, No. 80Patients Excluded:
< 1 Year of Data 14SC and SβThal+ 4
Total, No. 62Person-years 263Follow-up, median (IQR) 3 (1-6)
Patient Characteristics
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Total Children AdultsTotal, No. 62 11 51
Diagnosis:SS, No. (%) 55 (88.7) 10 45SβThal0, No. (%) 6 (9.7) 1 5SD-Punjab, No. (%) 1 (1.6) 0 1
Gender:Male, No. (%) 38(61.3) 7 31Female, No. (%) 24(38.7) 4 20
Age at Start of Treatment, mean (SD) 10 (4) 28 (7)Range 1 - 14 16 - 44
Health Improvements over time(Median/Average no. of events per year on HU)
11
0
2
4
6
8
10
12
14
16
18
20
0
0.5
1
1.5
2
2.5
Pain Crisis (Ave.) Chest Syndrome Blood Tx IP Days
Med
ian/
Ave
rage
No.
43 31 17 13 8
Baseline Yr 1 Yr 2 Yr 5 Yr 7 Yr 9
Improvements in Blood Markers(Changes over time - Average values per year on HU)
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Baseline Yr 1 Yr 2 Yr 5 Yr 7 Yr 9Year:
0
20
40
60
80
100
120
0
2
4
6
8
10
12
14
16
18
20
Hb Hb F (%) Neutrophils MCV
Ave
rage
valu
es
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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.
HU Treatment Statusat End of the Study Period
14
On HU, 20
On HU - Lost to Follow-up, 6
On HU - Care Transferred, 5
On HU - Incomplete Data, 2
On HU - Data Collection Ended, 6
Stopped, 23
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
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Contact Details
Annette GilmoreCentral Middlesex HospitalHaematology DepartmentActon LaneLondon, NW10 7NSUnited KingdomTel: +44(0)20 8453 2135Fax: +44(0)20 8965 1115Email: [email protected]: www.hbregistry.org.uk
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