Deferasirox (Exjade) access in MDS – Myelodysplastic Syndromes Overview of a UK wide postcode lottery – 2015 to 202118 Nov. 2021
Below you'll find excerpts of the document and explanations for:
- Patients (and families) affected by MDS, Myelodysplastic Syndromes and on regular blood transfusions
- MPs representing these patients in parliament
- Clinicians needing support to obtain access to deferasirox (Exjade) for their MDS patients
- MDS patients on regular transfusions?
- Ferritin levels increasing?
- Discussions about iron chelation?
- Difficulties accessing the oral version of the iron chelation treatment?
If you, or a patient you know are living in a region which STILL denies access to deferasirox (Exjade), the oral iron chelation treatment, please read on.
In the absence of a NICE decision, some pockets of the UK still will not grant funding to this drug, effectively creating a postcode lottery.
We first reported on this anomaly in 2015: https://mdspatientsupport.org.uk/mds-patients-achieve-access-to-vital-new-treatment-option/
2021 - and we still have reports of patients denied access, despite special circumstances:
- Bournemouth area, a half-blind elderly MDS patient who could not handle needles, was denied Exjade. He since passed away.
- Exeter area, an MDS patient, AND main carer for his wife with a degenerative condition, has been forced to use the cumbersome pump option to reduce his ferritin levels.
- Cornwall, further reports from consultants, who have given up on applying for IFR’s Individual Funding Requests, as all are rejected.
Below, you will find:
Part 1 - The current national BSH Guidelines for the use of iron chelation in MDS patients
Part 2 – A selection of regional decisions regarding the funding of deferasirox (Exjade), in chronological order
Part 3 – The latest clinical paper supporting the use of deferasirox as the most beneficial treatment option in this group of MDS patients.
Request: As the national patient support group for MDS, we request an end to this postcode lottery.
In the absence of a NICE submission/decision, access should be aligned to the positive SMC decision.
It is simply not ethical to deny access to a drug based on a post-code, for patients who are clearly struggling with quality of life issues, or elderly, or suffering with additional sight or manual dexterity issues.
NOTE: Clinical commissioning groups will be subsumed into integrated care systems by the end of 2021, and will be statutorily dissolved into ICS in April 2022 if the government’s planned health bill goes ahead.
Part 1 - BSH Guidelines for MDS – June 2021 revision
- Expert opinion is that deferasirox is the drug of choice for transfusion-related iron overload in patients with MDS
Iron chelation in MDS
Patients with MDS are at risk of developing iron overload from transfusion of red cells where iron build-up is inevitable (one unit of red blood cells delivers 200–250 mg iron), and there is also increased intestinal absorption of iron driven by ineffective erythropoiesis,48 mostly relevant to MDS-RS. Excessive iron ultimately leads to secondary end organ damage and cardiac disease remains the main non-leukaemic cause of death in MDS.49, 50
Iron overload is associated with adverse outcome in MDS
Retrospective studies have shown that OS is significantly shorter in transfusion-dependent MDS patients either through cardiac deaths, hepatic cirrhosis50, 51 or increased leukaemic progression.50 The European LeukemiaNet MDS Registry showed that the risk of death in transfusion-dependent patients with detectable labile plasma iron levels is independent of risk of disease progression.52 Iron overload also increases transplant-related mortality in haematopoietic stem cell transplantation (HSCT) in MDS patients53 and total transfusion burden implied a worse prognosis in a European Society for Blood and Marrow Transplantation (EBMT) study.54
Measuring iron loading
Routine estimations of iron loading can be made by serial monitoring of ferritin and tracking of red cell units transfused. However, there is little correlation between units transfused, or serum ferritin, and the degree of organ iron deposition.
Magnetic resonance imaging (MRI) for R2 (liver proton relaxation rate),55 or cardiac and liver T2* assessments56 can be used to help quantify hepatic and cardiac iron loading and its impact on organ function.
Iron chelation can improve natural history
Effective iron chelation may improve haemopoiesis. The EPIC study57 and the GIMEMA group58 showed an International Working Group (IWG) erythroid response in 15–25% of patients although median response duration was only eight weeks in the EPIC study. Platelet and neutrophil responses were also reported.
Desferrioxamine has been shown to lower cardiac iron assessed by MRI measurements59 and deferasirox has been shown to improve alanine transaminase (ALT) levels.60 A German registry study showed that chelation therapy improved survival in almost 200 transfused lower-risk MDS patients,61 supported by prospective data from the EUMDS registry.62 Furthermore, it is now accepted that iron chelation prior to HSCT in congenital anaemia can improve transplant-related mortality.53 Although this is not yet proven to be the case in haematological neoplasms including MDS, a recent EBMT joint expert panel recommended chelation in patients who have received more than 20 units of blood prior to HSCT.63
Choice of iron chelator
Desferrioxamine remains the most efficient iron chelator available and is given subcutaneously in overnight infusions, which may decrease the labile iron pool. However, many patients find it uncomfortable and cumbersome, reporting QoL issues. Deferasirox and deferiprone are given orally and are generally well tolerated, although deferiprone is associated with agranulocytosis in around 4% of patients. Deferiprone should not be used routinely in patients with MDS, and only after careful consideration with a haematologist experienced in treating MDS. It should be undertaken with very careful monitoring (weekly blood counts), and should not be used where the baseline neutrophils are <1·5 × 109/l. Deferasirox is the only iron chelator currently licensed for use in MDS patients with proven reduction in labile iron and improved haemopoiesis in some patients.57, 64
Discussion of recommendations
Iron chelation in lower-risk MDS patients
It is recommended that all suitable lower-risk patients (IPSS low and intermediate-1; IPSS-R low and very low) should be considered for iron chelation therapy around the time they have received 20 units of red cells, or when the ferritin is more than 1 000 μg/l. Patients should have ferritin levels measured every 12 weeks and have ophthalmological and auditory examinations before commencing therapy and annually while on treatment. Iron chelation with deferasirox should be stopped if the ferritin falls below 500 μg/l and desferrioxamine should be stopped if the ferritin falls below 1 000 μg/l.
Iron chelation in higher-risk MDS patients
Patients who are considered suitable for HSCT should have iron levels monitored and iron chelation therapy given prior to transplant, if time allows.
Deferasirox is only licensed second line (after desferrioxamine) for the treatment of chronic iron overload due to blood transfusions in patients with anaemia, such as MDS. However, real-world experience is that deferasirox is better tolerated, compliance is far superior and safety data are now mature. For these reasons, expert opinion is that deferasirox is the drug of choice for transfusion-related iron overload in patients with MDS. Desferrioxamine remains an option in those resistant to or intolerant of deferasirox. The two drugs may be combined in exceptional circumstances with heavy cardiac iron overload, but only under the supervision of a haematologist experienced in MDS treatment, although there are no data to support the combination.
There is no contraindication to the use of iron chelation in combination with other disease-modulating treatments such as lenalidomide or azacitidine.
- All suitable lower-risk patients (IPSS low and intermediate-1; IPSS-R low and very low) should be considered for iron chelation therapy at the time they have received 20 units of red cells, or when the ferritin is more than 1 000 μg/l (1B).
- Iron chelation therapy should be considered in patients prior to stem cell transplant, if time allows (2C).
- Expert opinion is that deferasirox (although only licensed second line in MDS) is the drug of choice based on tolerability, compliance and mature safety data (2C).
- Deferiprone is not routinely recommended in MDS (2C).
- Iron chelation therapy with deferasirox should be stopped if the ferritin falls below 500 μg/l and desferrioxamine should be stopped if the ferritin falls below 1 000 μg/l (2C).
Part 2 - Selection of regional decisions regarding the funding of deferasirox (Exjade), in chronological order
SMC HTA – January 2017
- Deferasirox accepted for use
“In the base case analysis, deferasirox was considered to dominate desferrioxamine ie was cheaper and more effective. Compared to desferrioxamine, deferasirox resulted in savings of -£6,783 and a QALY gain of 0.58.
Although deferasirox was associated with a relatively large incremental drug cost (£27,890) compared to desferrioxamine, this was offset by the lack of iron chelation therapy equipment costs; these were £28,847 for desferrioxamine. In addition, deferasirox resulted in fewer transfusion-related costs, treatment-related monitoring costs and complication costs.
At the PACE meeting, it was said that transfusion requirements appear to decrease in some MDS patient treated with deferasirox. Additionally, the use of an oral treatment may reduce risk of infection as patients no longer need to use needles.
Patient and clinician engagement (PACE)
A PACE meeting with patient group and clinical specialist representation was held to consider the added value of deferasirox, as an ultra-orphan medicine, in the context of treatments currently available in NHS Scotland.
The key points expressed by the group were:
· Around half of patients with MDS will develop severe anaemia and the resultant need for regular transfusions. The associated iron overload can cause iron accumulation in vital organs causing potentially life threatening problems such as liver, heart and renal dysfunction. Full compliance with chelation therapy is essential to minimise the impact of iron overload.
· Deferasirox is the only chelation treatment option available for those low to intermediate risk MDS patients who cannot tolerate administration of the desferrioxamine subcutaneous infusion or where this treatment is contra-indicated. It is of particular benefit for patients with sight or dexterity issues or those with a needle phobia.
· Existing chelation treatment involves subcutaneous infusion administered 5-7 days per week. Patients usually use the pump overnight or wear it underneath clothes for eight hours during the day, which may cause pain and discomfort. As such, current treatment is generally associated with an inferior quality of life for the patients.
· PACE participants highlighted their experience that compliance with the oral treatment is greater than that seen with the infusion and consequently deferasirox is a more effective chelation therapy option.
Deferasirox offers a vastly improved quality of life for patients with MDS and their families/carers by reducing the physical, psychological and emotional burden associated with desferrioxamine infusion therapy.”
Thames Valley – July 2017
- Subcut infusion not well tolerated, not advisable in MDS
- Deferasirox ‘safe and effective
East of England data – June 2021
- Routine funding not recommended
- IFR’s or group approval via business case submission
Herts Valley – Sept 2017
- Not routinely commissioned, despite SMC cost-effectiveness acknowledged
Thames Valley – Sept 2018
- Deferasirox to be used when subcut ICT contraindicated or inadequate
London data – Jan 2020
- Clinical judgement should define choice of chelator
Greater Manchester – May 2020 (revised)
- Deferasirox mentioned on its own
General recommendations are primarily based on studies in thalassemia, in which there is strong evidence for iron chelation (15). There is no doubt that heavily transfused MDS patients accumulate iron to potentially harmful effect.
There is evidence that iron chelation reduces iron overload in MDS, and even data suggesting reduced risk of leukaemic transformation. Iron chelation may also improve outcome after transplantation. However, there are currently no good quality controlled studies proving a survival or other long-term outcome advantage for iron chelation in MDS (16).
On balance, it is recommended that patients who satisfy the following criteria be considered for iron chelation:
• Where long-term transfusion therapy is likely (eg MDS-SLD, MDS-RS, 5q- patients; unless very high age or severe concomitant disease)
• In more advanced MDS (MDS-MLD, MDS-EB), iron chelation should be considered if life expectancy exceeds 2 years from time of iron overload (ferritin >1500 μg/l, or after 24 units of RBC).
• Candidates for allogeneic transplantation
Deferasirox (Exjade®) is an oral agent with now many years’ experience that is broadly well tolerated. Iron excretion occurs almost entirely in the faeces and is dose dependent. Caution is advised in renal and liver impairment. A film-coated preparation (FCT) is now available with better side effect profile. It is licenced but not NICE assessed (recommended by Scottish Medicines Consortium in first-line for Low/INT-1 risk MDS). Recommended starting dose is 10-30 mg/kg; starting at lower doses may improve tolerance; for FCT recommended dose is 7-21mg/kg.
Somerset – March 2021
- Deferasirox recommended for specialist prescribing only
Part 3 – Latest clinical paper supporting the use of deferasirox as the most beneficial treatment option in this group of MDS patients
From Biology to Clinical Practice: Iron Chelation Therapy With Deferasirox – October 2021
In patients with MF and MDS, but also with AA and hemolytic anemias, the prognosis is not merely associated with individual factors such as age, comorbidities, or underlying condition, but also with complications associated with the degree of cytopenia present (severity of anemia, hemorrhages, and infections) and the treatment that they receive (blood transfusions, allogeneic transplants, etc.). In these patients, any therapeutic interventions should also face not only the management of comorbidities but also complications caused by the evolution of disease and adverse effects of primary treatments.
The excess iron, associated with direct and indirect toxicity on the various tissues, leads to a worsening in age-related comorbidities, ultimately resulting in cumulative organ damage. Iron-induced toxicity also affects the evolution of the MDS or MF, by increasing cellular genomic instability and altering the bone marrow stroma through the oxidative stress, thus favoring progression to acute leukemia (15, 65).
The performance of a multidisciplinary evaluation of patients treated with deferasirox, at baseline and during follow-up, makes it possible to improve the therapeutic approach and optimally manage elderly patients with MF and MDS, consequently avoiding the need to discontinue specific therapy and reducing the risk of developing organ damage.”