Take part! An international survey to understand your needs and quality of life

• 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 cirrhosis^{50, 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. 

Drug recommendations

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.

Recommendations

• 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.”

https://www.scottishmedicines.org.uk/medicines-advice/deferasirox-exjade-resubmission-34707/

Thames Valley – July 2017

• Subcut infusion not well tolerated, not advisable in MDS
• Deferasirox ‘safe and effective

http://nssg.oxford-haematology.org.uk/myeloid/guidelines/ML-25-guidelines-for-oral-iron-chelation-in-mds.pdf

East of England data – June 2021

• Routine funding not recommended
• IFR’s or group approval via business case submission

https://medicines.blmkccg.nhs.uk/wp-content/uploads/2020/06/iron-chelators-for-iron-overload-in-myelodysplastic-syndromeMERGED.pdf

Herts Valley – Sept 2017

• Not routinely commissioned, despite SMC cost-effectiveness acknowledged

https://hertsvalleysccg.nhs.uk/application/files/5515/3633/5366/FINAL_Iron_chelators_in_MDS_PAC_decision_document_201709_HMMC.pdf

Thames Valley – Sept 2018

• Deferasirox to be used when subcut ICT contraindicated or inadequate

http://fundingrequests.nhsdigital.org.uk/wp-content/uploads/2018/12/26-09-18-Minutes-TVPC-Final.pdf

London data – Jan 2020

• Clinical judgement should define choice of chelator

https://www.kingshealthpartners.org/assets/000/003/347/Pan_London_MDS_Guideline_Jan_2020_original.pdf

Greater Manchester – May 2020 (revised)

• Deferasirox mentioned on its own

Iron Chelation
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.

https://gmcancerorguk.files.wordpress.com/2019/08/mds-guidelines-july-2019.pdf 

Somerset – March 2021

• Deferasirox recommended for specialist prescribing only

https://www.somersetccg.nhs.uk/wp-content/uploads/2021/03/Somerset-Traffic-Light-System-39th-Edition-March-2021.pdf

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

“Conclusions

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.”
https://www.frontiersin.org/articles/10.3389/fonc.2021.752192/full

The UK’s blood cancer patient community are clinically extremely vulnerable to COVID-19. Several studies showed that about 60% of blood cancer patients failed to develop effective antibodies for an immune response to the virus after their second jab.

The growing spread of the virus is causing concern and fear within blood cancer patients and it is imperative the Government does more to support them.

The Blood Cancer Alliance Policy Group, which includes ACLT, Anthony Nolan, Blood Cancer UK, CLL Support, CML Support, DKMS, Leukaemia Care, Leukaemia and Lymphoma Northern Ireland, Leukaemia Cancer Society, Leukaemia UK, Lymphoma Action, MDS UK, Myeloma UK, Race Against Blood Cancer and WMUK, have recently sent two open letters to Sajid Javid, Health Secretary, requesting more support for blood cancer patients.

Read the open letter here >

Dr. Rob Swanda gives a brief overview of how the Pfizer/BioNTech or Moderna mRNA vaccines work.

He says in his YouTube Channel

There is a lot more information I wanted to cover, such as the immunity length over time, side effects, and non-mRNA vaccine technologies. We could discuss this for hours. But, the focus here is on the technology itself.

I do use some technical terms, please find them defined below. Im happy to hear questions and comments. Thank you for taking a little time to learn about RNA! ?

(technical terms: 3’UTR/5’UTR = untranslated regions of the mRNA that do not code for the protein but aid in stability. Lipid = fat molecule. Ribosome = cell machinery that makes proteins from mRNA. Macrophage = a white blood cell in our body that responds to infection. Antigen = foreign protein that antibodies detect.)

Learn more about COVID-19 Vaccines and how effective they are on MDS Patients >

Additional reference links:

• 2020: https://mdspatientsupport.org.uk/trial-to-test-existing-drugs-against-rare-blood-cancer/
• 2020: https://www.birminghamhealthpartners.co.uk/trial-to-test-existing-drugs-against-rare-blood-cancer/
• 2020: https://warwick.ac.uk/newsandevents/pressreleases/trial_will_test/
• Oct 2021: https://bloodcancer.org.uk/news/how-re-purposing-drugs-could-revolutionise-blood-cancer-treatment/
• Oct 2021: https://www.birminghamhealthpartners.co.uk/triple-drug-combo-could-prove-key-weapon-in-fight-against-cancer/

From a practical side, I live in Cumbria and my specialist consultants are in London. This has meant i have not been able to go to face to face appointments for nearly two years, because of the risk of covid with travelling and staying overnight in a hotel.

This makes it so difficult when different hospitals don't have access to other hospitals' patient information, results or the means to get tests or specialist appointments booked quickly. I only see the risk as getting greater with rising cases and people being less cautious.

As someone who is now 5 years post stem cell transplant, with multiple health issues that put me at risk until vaccine efficiency is better known, I feel stuck: unable to see friends and loved ones unless outside at unbusy places, unable to go to social or leisure events, unable to go shopping anywhere busy such as supermarkets or clothing stores, the list goes on but I will be 'shielding' until we know more.”

Rebecca contacted her MP, Tim Farron, who then raised the issue with the then Secretary of State.

Disappointedly, Mr. NADHIM ZAHAWI MP, Minister for COVID Vaccine Deployment, responded with just a standard answer:
"The Government has advised that, from 1 April, those who are clinically extremely vulnerable do not need to shield. This is because, since the national restrictions and shielding measures were introduced, the number of COVID-19 cases has fallen considerably across all parts of the country and prevalence rates are now significantly lower.”

MDS-EB: Stephen Andrews’s Story

“Since then – says Stephen – I’ve had one or two minor issues, but the doctors have generally been extremely pleased with my progress, and I’m looking forward to the future with considerable optimism, thanks to the extraordinary team at King’s and my anonymous donor.

I joined the MDS Support Group almost as soon as I was diagnosed. I find it incredibly helpful, both as a source of comradeship, friendship and support via the network of fellow-patients (with both similar and different MDS sub-types) but also as a way of accessing the most expert and up-to-date advice and information about our condition and important related issues, such as Covid and vaccinations.

I would wholeheartedly recommend anyone who has been diagnosed themselves or who has a loved one with MDS to join our network.“

MDS-RS: Simon Wilkes’ Story

MDS-MLD: Suzanne McWilliams’ Story

Regarding antibodies, all healthy volunteers produced antibodies as a result of having been vaccinated.

Among MDS patients, all those vaccinated with the Pfizer vaccine generated antibodies, whereas 5 MDS patients vaccinated with the Oxford vaccine didn't. The specific results for each brand of the vaccines, however, are not conclusive due to the small numbers of patients in each vaccine group.

Were these antibodies effective against the different variants of the COVID-19 virus?

In other words, when people created antibodies, whether by way of the Pfizer or the Oxford vaccine, were these able to neutralise the virus?

In the case of some MDS patients, these antibodies did not seem as effective as in healthy volunteers, in particular to offer protection against the Delta variant.

One of our members (we’ll call him Daniel), who wrote to us this week on this issue, would very much like some answers. In his own words:

“I am a 56-year-old unemployed blood cancer patient from Brighton registered as CEV, living with, and part time carer for, my 86-year-old father who is also vulnerable and has health issues.

Me and my father have shielded as much as possible throughout the Covid pandemic. I have been claiming Universal Credit since June 2020.

However, as government shielding has now ended, I am being pressed by the DWP to make myself available for work again immediately or lose my benefit. They have said that the only thing that can take the pressure off is to be declared unfit for work by my GP, which is difficult as I am a watch and wait patient who is currently not physically unwell with my condition. But myself and my father are still extremely vulnerable to Covid.

I am very worried about potentially returning to a workplace and mixing amongst people who no longer have to compulsorily wear a face mask or social distance.”

We urged Daniel to contact his MP, Caroline Lucas, in the first instance, who responded immediately to his call for help: “I am dismayed at what the Government is putting you and so many other people through and am raising my concerns with Ministers.

It is unfair of the Government to effectively push you into asking your GP to say you are unfit for work when that is not the case – and when the reality is you are vulnerable to Covid.”