Iron Chelation Policy statement for NW London sector*
*Agreed by the NW London Haemoglobinopathy Managed Clinical Network Board Meeting on 3rd March 2008, c/o Director Public Health Department, Brent Teaching Primary Care Trust.
Background
Thalassaemia & Sickle Cell Disease are amongst the commonest inherited anaemias in the UK. Chronic red blood cell transfusion can prevent many of the manifestations of Sickle Cell Disease, whilst initiation of blood transfusion therapy significantly increases life expectancy in thalassaemia by controlling anaemia, and its sequelae, but this treatment also leads to progressive deposition of iron in the tissues, posing significant risk of severe cardiac, endocrinological and hepatic complications, which are fatal if not prevented.
For nearly 30 years, patients with transfusional iron overload have depended on nightly Desferrioxamine (Desferal, DFO) infusions for iron chelation, and despite some gains in life expectancy for patients the leading cause of death for young adults with thalassaemia major and related disorders has been cardiac disease from myocardial iron deposition. Parenteral administration and the daily nuisance of an infusion pump hinder optimal compliance, The development of new oral iron chelators to improve compliance and reduce cardiac events and mortality came ten years ago with Deferiprone (Ferriprox,DFP)) and more recently in the last year with Deferasirox (ICL670, Exjade, DFX))
PCT cost implications
The up-front price of the new drug Exjade is much more than the price of
Desferal simply as a drug. But the true cost of Desferal must be computed to
include the delivery system: balloon pumps or syringe pumps, insertion and
maintenance of Hickman lines for some patients, the homecare third party
suppliers that some patients need etc.
Furthermore, Desferal has large hidden costs related to partial or non-compliance. The prolonged sc infusion regime is very hard to bear for all but the most self-controlled of adult patients. It is estimated that complete compliance with the regimen is seen in fewer than 30% of those supposedly on it. This entails both wastage of vials of Desferal and considerable loss in cost-effectiveness, with ferritins staying up and iron toxicity progressing despite investment in Desferal and its delivery systems.
The main issue around Exjade (the new drug) is that PCTs have not identified the true cost of Desferal (the old drug). This is because the hidden cost surrounding Desferal is harder to prove and quantify, and so it appears to be cheaper. The cost of Exjade (around £15,500 per 70kg adult) is midway between cost of Desferal using graseby’s pump and cost of Desferal using Baxter’s pump.( based on communications with thalassaemia expert Dr Farrukh Shah Whittington Hospital). Cost calculations for graseby’s on average dose of 2.5 g 5x/week is £111 per week for drug only, annual cost £5772, cost of thalaset needles £697, cost of water for injection, syringes, needles, dressings, emla etc per annum £800 total cost around £7,500. Baxter’s cost around £80 each but less drug, less cost. Most patients on 5 days a week but some on 7 days as well. Average cost is between £16,000 to 22,000 per annum based on cost of manufacture and cost of health care at home delivery costs. The actual true costs per patient with the use of deferiprone will make the combination treatment more expensive.
Incidence, prevalence and survival from SC & T
SCD is now the most common genetic condition in England, affecting more than 1 in 2,000 live births. The birth prevalence in urban areas like NW London may be as high as 1 in 300. (1).
During the past three months alone (i.e. Oct-Dec 2006), in NW London, 29 infants with Sickle Cell Disease & Thalassaemia were diagnosed by the NHS New Born Screening Programme who would potentially benefit from the availability of an effective oral chelator. Out of these 29 babies, 18 (60%) were of African origin, 3 Caribbean, 1 White and Black African, 1 any other ethnic category and 6 ethnicity not stated. During the same period, 842 infants were carriers, out of which 5% (39) were British White or any other white and 10% (83) were mixed White & any other mixed background.
Using data from the CMH haemoglobinopathy register, it is projected from the network baseline audit carried in 2002 that as of Jan 2007 there are 1436 adults & children affected by SC & T in NW London ( CMH - 676 patients; H H -178; CXH – 70; Ealing Hospital -90; West MIddx Univ Hosp – 40; SMH -146; Hillingdon Hospital -31; NPH -138). This is a 15% increase over the 1291 patients identified in 2002 whose names & clinical details were to be entered in the NW London haemoglobinopathy register. Work was stopped on the register pilot in 2004 due to financial constraints. (2, 3)
Life expectancy has improved considerably over the last decades due to improved recognition and better management of acute episodes. However, in the USA there is a marked geographic difference in mortality of young children with sickle cell which greatly exceeds mortality of black children without the disease. This highlights the importance of having a robust follow-up programme and access to high-quality care wherever a child with SCD lives.
Life expectancy will considerably increase with access to better treatment. The median life expectancy of SS men & women in the UK is mid forties and likely to increase.
Policy statement
The NW London Haemoglobinopathy Network Board has reviewed the evidence(4-9) about oral chelators Deferasirox and Deferiprone for transfusional iron overload in Thalassaemia major, Sickle Cell Disease, Myelodysplastic Syndromes (MDS) etc
The network board also looked at an initial cost-effectiveness analysis (10-13), which showed that the extra cost of the new oral chelator Deferasirox weighed favourably against the cost of illness and death from noncompliance and iron overload for the injectable Deferoxamine. The economic analysis work by David Lawrence at Brent Teaching Primary Care Trust suggested there was overall increase in cost effectiveness using Deferasirox. For example, at compliance difference of 20% and extra mortality due to lack of compliance, of 1 year loss of life, Deferasirox (new) treatment cost per QALY is less than Deferoxamine (old)
The NW London haemoglobinopathy Network board supports that:
Every new transfusion – dependent patient, not on chelation before, will be requesting to start with oral chelation treatment with Deferasirox (Exjade) which is licensed as first line treatment for iron overload in Thalassaemia Major children above the age of 6 and adults. In children between ages 2 and 5 the licence is as second line where Desferal has been found to be ineffective or intolerable as with the other iron overload anaemias. However, because in NW London the largest groups of patients requiring chelation are those with sickle cell disease who mostly do not develop cardiac iron overload, in the end only about 80% of patients would be eligible and wanting to take Deferasirox.
All patients receiving oral chelation with Deferiprone, either alone or in combination with Desferrioxamine are monitored carefully for side effects of Deferiprone. This should include mandatory weekly full blood count. Patients should understand that if they develop fever or symptoms of infection they should stop the medication and immediately attend for a blood count.
All patients receiving Deferiprone should be issued “adverse effect” warning cards
Patients previously on Desferrioxamine , or combination with Deferiprone, and doing well, should continue with this regimen. A ferritin level of 1500 to higher than 2500 to be used as a guide to adequacy of chelation. Ferritin level of 2500 is too high as a reflection of good control in Thalassaemia Major as many patients with ferritin of greater than 2000 have high liver irons and evidence of cardiac iron deposition. If ferritin is 1500 to higher > 2500ng/ml, or desferrioxamine sensitivity, then should switch to Deferasirox. In patients with cardiac decompensation (low ejection fraction), then Deferasirox should not be used until the ejection fraction has improved.
Patients on Desferrioxamine, and with high ferritin => 2500ng/ml, and /or difficulty adhering to desferrioxamine injection pump treatment should switch to Deferasirox.
PCTs will need to consider offering Deferasirox to patients who have been
on the Exjade trial after the trial ends. The experience of the NW London
adult Thalassaemia patients who managed to get on the pre-licensing
Exjade Programme is of utter amazement. There are currently 9 patients
on the trial at UCLH (Westminster PCT- 2 patients; Brent -2; Harrow-4;
Hillingdon -1) and 5 at the Whittington Hospital (Ealing -2 patients; H &F-
1; Harrow-2) To replace the endless grinding unpleasantness of
subcutaneous infusions of Desferal these 14 patients now take one dose
per day of a well-tolerated tablet and their ferritin is reducing for the first
time in years. There is a potentially huge QoL gulf between oral Exjade
and injectable Desferal therapies.
7. Patients who have adhered to a very burdensome treatment in the form of desferrioxamine should not be penalised and denied access to a treatment that confers major quality of life benefits. If they express a strong preference to convert to deferasirox (Exjade) after discussion of the efficacy and safety issues this should be made available.
8. The specific indications for deferasirox may change as data from ongoing clinical trials becomes available.
9. Through its protocol group the network is developing a guideline for management of iron overload which reflects proposed national recommendations by the UK Forum on Haemoglobin Disorders.
10. The London New Drugs Group (LNDG) have looked at deferasirox use in England for SC & T and have considered deferasirox to be a first line treatment for iron overload. The Scottish Medicines Consortium (SMC) has accepted the use of deferasirox in Scotland for the management of transfusional iron overload associated with the treatment of rare acquired or inherited anaemias like Sickle Cell disease & Thalassaemia.
References1. Standards and guidelines for clinical care of sickle cell disease in childhood. NHS Antenatal and Newborn Screening Programmes. First Edition September 2006
2. NW London haemoglobinopathy registry pilot data for Hammersmith Hospital, Ealing Hospital & West Middx Univ Hospital, 2002. Priscilla Plocki, Mark Layton, Nicki Philpott, George Hughes.
3. EHR- European Haemoglobinopathy Registry data, CMH, 2003-4. Annette Gilmore, Jo Howard, Sally Davies.
4. Neufeld Ellis J. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassaemia major: new data, new questions. Blood 1 may 2006, vol 107, no 9, p 3436-41, 42 refs.
5. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once daily-oral iron chelator, in patients with beta-thalassaemia. Blood.2005; 107:3455-3462
6. Borgna-Pignatti C, Cappellini MD, De Stefano P, etal Cardiac morbidity and mortality in deferoxamine -or - deferiprone - treated patients with thalassaemia major. Blood. 2005; 107: 3733-3737
7. Pennell DJ. Berdoukas V, Karagiorga M, et al. Randomised controlled trial of deferiprone or deferoxamine in beta thalassaemia major patients with asymptomatic myocardial siderosis. Blood 2005; 107:3738-3744
8. Porter JB, Tanner MA, Pennell DJ, Eleftheriou P. Improved myocardial T2* in transfusion dependent anaemias receiving ICL670 (Deferasirox) (abstract). Blood. 2005:106:1003a. Abstract 3600
9. Porter J, Borgna-Pignatti C, Baccarani M, et al. Iron chelation efficiency of deferasirox (Exjade®, ICL670) in patients with transfusional hemosiderosis (abstract). Blood. 2005; 106: 755a. Abstract 2690
10. Cost Utility analysis of deferasirox versus deferoxamine for patients requiring iron chelation in the UK. J.Kamai, RL Akehurst, NL Papo. Haematologica 2006; 91 (supplement)
11. Estimated total annual costs of infused iron chelation treatment in the UK. MP Desrosiers, K Payne, I Proskorovsky' K Ishak, JF Balad. Haematologica 2006; 91 (supplement1)
12. Deferasirox model: treatment costs per QALY compared between deferasirox and deferoxamine for Central Middlesex Hospital. David Lawrence, Public Health Department Brent PCT, December 2006
13. Financial Analysis of chronic transfusion for stroke prevention in sickle cell disease. Alan S Wayne, Steve E Schoenike, and Charles H Pegelow. Blood, 1 October 2000. Volume 96, Number7
14. UK Forum on Haemoglobin Disorders Feb 2007. Iron Chelation Consensus v7.
www.haemoglobin.org.uk15. London New Drugs Group. October 2007. Review of Iron Chelators (deferasirox, deferiprone & desferrioxamine) for Iron Overload