Ten Years Longitudinal Follow-up Study of Sickle Cell Disease Patients Treated with Hydroxyurea in Four English Centres 2 nd July 2008 Annette Gilmore.

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

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11 3 1 4 2 IP Days

0

5

10

15

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25

30

35

0

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HU

Do

se (m

g/k

g/d

ay)

MC

V (f

l) an

d H

b F

(%

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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)

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0

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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:

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Hb Hb F (%) Neutrophils MCV

Ave

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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

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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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