EPO (Erythropoietin) & other Erythropoiesis Stimulating Agents (ESAs) in the Treatment of MDS

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In this article Dr Chris Dalley, Consultant Haematologist University Hospital Southampton (NHS Foundation Trust), looks at the use of conventional and new Erythropoiesis Stimulating Agents (ESAs) in the treatment of MDS.

What are Erythropoiesis Stimulating Agents (ESAs)?

Erythropoiesis (from Greek 'erythro' meaning "red" and 'poiesis' meaning "to make") is the process which produces red blood cells.

More than two thirds of patients with Myelodysplastic Syndromes (MDS) are anaemic at the time of diagnosis and about the same proportion of patients are known to have lower-risk disease as defined by the International Prognostic Scoring System criteria1 (IPSS).

Anaemia is a significant burden to many patients with MDS. It may impair a person’s ability to perform normal tasks due to exhaustion or fatigue and may exacerbate coexisting medical conditions like heart disease or respiratory conditions. Measures taken to optimise or improve haemoglobin levels are vitally important, particularly in patients with low-risk MDS who may have to live with the anaemia for many years.

Red cell transfusions remain the most frequent way in which anaemia is managed in patients with MDS. Although safe, regular transfusions may cause iron overload which may then need to be controlled. Also, regular red cell transfusions schedules are time consuming and carry the inconvenience and burden of travel to and fro from the hospital for the patient.

Erythropoieis stimulating agents (ESAs) are therapeutic drugs that improve haemoglobin levels. They have the potential to reduce the frequency or the need for red cell transfusions and may improve or maintain a patient’s quality of life.

Clinical guideline groups have defined the role of these agents in the management of MDS including those published by the British Society of Haematology, the European LeukemiaNet and the National Comprehensive Cancer Network. Recent clinical trials have highlighted the effectiveness and safety of new ESAs and this article will highlight the salient points relating to the use of conventional and novel ESAs in the setting of MDS.

How do Erythropoiesis Stimulating Agents work?

1. Erythropoietin (EPO)

Erythropoietin (EPO) is a naturally occurring hormone produced by specific cells in the kidneys in response to low levels of oxygen in the blood. It plays a vital role in promoting and controlling red cell the production (erythropoiesis) by the bone marrow.

Pharmaceutical companies have manufactured recombinant EPO (rEPO) including erythropoietin-alpha, erythropoietin-beta and Darbopoietin using DNA technology since the late 1980s. When rEPO is administered by a simple injection under the skin (subcutaneous injection) it leads to an increase in haemoglobin levels which may result in therapeutic benefit to the patient.

Since the 1990s clinical trials demonstrated that rEPO can be safely used to improve haemoglobin levels in patients with low-risk MDS. Numerous clinical research groups have confirmed the clinical efficacy of rEPO in patients with low- risk MDS. Better responses to rEPO have been reported in patients with baseline EPO levels of less than 200U/L, and a MDS diagnosis other than refractory anaemia with ring sideroblasts (RARS)2.

Other factors influence response to rEPO in patients with MDS. These include shorter time from MDS diagnosis to treatment, a low transfusion requirement prior to commencing rEPO treatment and a low risk disease defined as IPSS low and intermediate-1, and fixed dosing of rEPO3.

Recombinant human erythropoietin (rhEpo) is used to treat anemia by stimulating the bone marrow to produce more red blood cells. rhEpo is structurally identical to native Epo, a hormone produced primarily in the kidney. Figure courtesy of Dr. H. Franklin Bunn.

2. Erythropoietin and granulocyte colony-stimulating factor

Granulocyte colony-stimulating factor (G-CSF) is a growth protein that stimulates the production of neutrophils (a type of white blood cell) in the bone marrow. Like rEPO, it is manufactured using DNA technology and has to be administered as a subcutaneous injection.

A number of clinical studies have demonstrated that rEPO and G-CSF work together to improve haemoglobin levels in patients with MDS, with response rates of approximately 50%! The combination may be particularly beneficial in patients with RARS, or patients who fail to respond, or have only a temporary response to rEPO alone.

How will my haematologist decide if I need an ESA?

Patients with low-risk MDS (IPSS low or intermediate 1, IPSS-R very low, low or intermediate) with symptoms of anaemia with haemoglobin level of less than 100g/L may be candidates for ESA therapy.

A validated predictive score which takes into account monthly red cell transfusion requirement, and baseline serum EPO levels of patients before starting an ESA treatment can be used to establish if a patient is likely to respond to ESA therapy7.

Haematologists use this metric to aid their decision making. Patients with predictive scores of 0 to 1.0 have a relatively high chance of responding to ESAs (predictive responses of 74% and 23% respectively) and should be offered rEPO if they are anaemic. However, patients with a score of 2.0 generally have a relatively low chance of responding to ESA (less than 10%), and rEPO is generally not recommended for patients with this predictive score.

What is the optimal dosis of erythropoiesis stimulating agents for each patient?

Typically, patients with low-risk MDS with the exception of RARS (refractory anaemia with ring sideroblasts) should initially start rEPO at 30,000 units/week but lower doses may be recommended in patients with impaired kidney function.

If a response is not achieved after 8 weeks the dose should be increased to 30,000 units twice weekly or 60,000 units/week for a further 8 weeks.

For patients treated with Darbopoietin the starting dose should be 150 micrograms/week or 300 micrograms every 2 weeks. The dose can be increased after 8 weeks in non-responding patients to 300 micrograms/week.

Patients with RARS, and patients who fail to respond to single agent rEPO should be considered for rEPO and G-CSF. The typical starting dose of G-CSF in this setting is 300 micrograms once weekly with the aim of increasing the neutrophils count to no more than 6 to 10x109/L. Doses of G-CSF should generally not exceed 300 micrograms three times per week.

How will my haematologist assess my response to erythropoiesis stimulating agents?

Patients receiving ESA should have their response to erythropoiesis stimulating agents assessed after a maximum period of 4 months of therapy. Clinical responses are usually assessed by documenting improvement in haemoglobin levels, and or reduction in red cell transfusion requirement. Defined criteria for response include:

I. Partial response

  1. In red-cell transfusion dependent patients: Stable anaemia without need for transfusions.
  2. In patients with stable anaemia: Increase in haemoglobin of at least 15g/L but haemoglobin less than 115g/L.

II. Complete response

1. Stable haemoglobin of at least 115g/L and transfusion independence.

Patients who achieve a sustained complete response may have their ESA dose slowly tapered down by their treating haematologist to the lowest dose that sustains the response.

Patients who lose their response to ESA may require reassessment of their MDS disease status with a bone marrow biopsy, full blood count and blood film examination in order to exclude the possibility of progression of their disease.

New Erythropoiesis Stimulating Agents

Luspatercept and Sotatercept

Luspatercept and its analogue Sotatercept are two new ESAs. Both drugs are manufactured using DNA technology, and like rEPO they have to be administered by subcutaneous injection.

However, they both work in a distinctly different way to rEPO and both drugs promote late-stage red cell production in the bone marrow by binding to proteins from the transforming growth factor β family.

Promising efficacy and safety data from phase 2 clinical trials has recently reported and both drugs appear to be particularly effective in patients with RARS, MDS with SF3B1 mutation or both. In the PACE-MDS trial, patients with low-risk MDS and anaemia, (with or without the need for red cell transfusion) received Luspatercept at various doses every 3 weeks. Although the total number of patients in the study was relatively small, 63% of 51 patients who received Luspatercept at higher doses experienced improvement in their haemoglobin and 38% of 42 patients achieved transfusion independence as measured by trial criteria9. A randomised placebo-controlled phase 3 multicentre clinical trial to determine the safety and efficacy of Luspatercept was initiated in 2016 and is ongoing.

In a recent phase 2 study Sotatercept was administered to 74 patients with low-risk MDS who were red cell transfusion dependent. Patients recruited to the study had either lost response, had no response, or were predicted to have low chance of response to EPO. The investigators reported improvement in haemoglobin in nearly 50% of patients, and responses were sustained without the need for red cell transfusion for at least 56 days in 7 out of 12 patients (58%) with low transfusion requirements.

In Sum:

  1. Anaemia is the central clinical problem for patients with low- risk MDS.
  2. Red cell transfusions play a central role in managing anaemia, but ESAs also play an important role and national and international MDS clinical guideline groups have defined when ESAs should be used in patients with low-risk MDS.
  3. In general, only patients predicted to have a high chance of responding to an ESA should be prescribed rEPO, either as single drug, or in combination with G-CSF11.
  4. Haematologists may change the dose of ESA depending on a patient’s response to treatment, aiming at maintaining the lowest possible dose of rEPO in those patients to achieve a complete response.
  5. There are data to suggest that an early start with ESA may delay the need regular red cell transfusion and improve quality of life.
  6. A low response may require an increase in ESA dose
  7. Patients who lose a response to their ESA may need to have their MDS reevaluated because loss of response may be due to progression of their MDS.
  8. Luspatercept and Sotatercept are new ESAs that work in a different way to rEPO to increase red cell production.
  9. Both drugs have been investigated in clinical trials and have been shown to improve haemoglobin levels in patients with low-risk MDS, with relatively few adverse effects.
  10. These new ESAs have not yet found their way onto MDS guidelines
  11. More extensive clinical outcome trial data is required before we can understand their true clinical utility in MDS anaemia.
  12. However, in the future a more extensive repertoire of ESAs will hopefully be available to clinical haematologists and their patients.

MDS UK May 2018 Newsletter

This article was first published in the 8th Edition of the MDS UK Newsletter. If you haven't received it, please contact us.
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Erythropoiesis Stimulating Agents and other Growth Factors in Low-risk MDS

The Basics: Understanding Blood Formation: Blood Cells & Blood Structure


MDS UK Patient Support Group Newsletter – May 2018

Our 8th edition of the MDS UK Newsletter is now out!

Read all about:
Patient's Stories: Reginald Hall, Reverend Kes Grant and Bergit Kuhle.
MDS Research: Azacitidine Latest News, Personalised Medicine and EPO Treatments.
Advocacy, Fundraising, Local News and much more.
CLICK ON THE IMAGE TO DOWNLOAD


We’ve got seven amazing people riding the Prudential Ride London for MDS UK

Great News: MDS UK is taking part in this year’s Prudential Ride London

MDS UK is delighted to announce that we've got seven amazing fundraisers taking part in this year’s Prudential Ride London, on Sunday 29th July 2018. This is one of the legacies of the 2012 London Olympic Games and will give us an opportunity to both raise awareness of MDS as well as a fantastic opportunity to raise money.

Prudential Ride London provides a fantastic platform to help fulfil The Mayor of London and Transport for London’s goal of encouraging more people to cycle more safely, more often. TfL anticipates tens of thousands of spectators and participants every year will take up regular cycling after each event. There is no other closed-road event like it that combines the fun and accessible element of a free family ride in central London with the excitement of watching the world’s best professional cyclists race.

Here is our team of SUPER RIDERS!!!

Clare Fraser
I am an indoor cycling instructor and I have my own studio in Weybridge. I am also planning on doing an 8 hour spin-a -thon where people can come and join in on the hour for 1 hour at a time and donate money for my fund raising in payment for the class.

Peter Southey
I was told I needed to get fit and this seemed a good idea, well it did at the time, as I was helping a good cause as well as me. Cycling experience almost none.

Team Cashew and Ginger: Caitlin Limmer and Moni Lau
Caitlin: I have no riding experience, am doing it purely to raise money and awareness of MDS and make a big noise with my great, great friend Moni on the back. Clare Fraser is also a great mate of ours and she is a very good cyclist. All 3 of us have been in sport for years, but Moni and I are defo a liability on the bike - however we are going to try very hard!

Please Donate on Team Cashew and Ginger Virgin Money Giving Page!

Steve Richardson
My experience is that have been riding since my teens and now I am 67. I completed Ride London 2015 and 2016. I have been an MDS patient since 2011 but have been lucky to maintain my levels on EPO

Darren Laverty
I work with Russell and have known him for too long!! Around 30 years now. I have just started cycling but I always like to have a challenge to focus on and keep my fitness levels up and keep me out of the pub. I have seen Russell’s journey with MDS and cannot think of a better cause to raise a few pounds for.

Alex Myers
I'm a fairly regular cyclist, though have never done Ride London. I'm now mostly into triathlons, but last year did the Granfondo Stelvio in Italy which is a similar bike ride to this in distance. My father in law Don Barrett, who is Treasurer of MDS Patient Support, is very passionate about the work the charity is doing so I wanted to try and support with fundraising along with giving Ride London a go.

We would love more supporters to come on the day to be on the course and look out for our #TeamMDS. For details on the day, please email us to fundraising@mdspatientsupport.

MDS, Myelodysplastic Syndromes, are complex blood cancers. The impact of MDS on an individual’s quality of life can be dramatic and devastating. At the current time there is no cure for MDS other than a bone marrow transplant and even then as few as one in 10 patients will be fit enough to survive the rigours of treatment.

Prudential Ride London: Team Cashew and Ginger

Team Cashew and Ginger

Prudential Ride London: Alex Myers

Alex Myers


MDS Treatment: Prof. David Bowen talks about genetics, where we are now and where we’re heading

Sophie Wintrich, Chief Executive of the MDS UK Patient Support Group, interviewed Prof. David Bowen – Consultant Haematologist at St James University Hospital, Leeds. Watch the video and read the excerpts below.

"We've always practiced personalised medicine"

"Personalised medicine means that you sit with an individual in front of you and you consider them as an individual, and you talk about their disease, their type of MDS in the context of their problems, their symptoms, so it's always been personalised. It's always been personalised in that you use your intuition, your experience and your judgement in the management of that patient."

"To practice good, proper precision medicine, you need the biological data, you need an idea of their quality of life, you need an idea of the diseases affecting that patient and you need an idea of that person's preferences. There are many factors now playing into the concept of personalised or precision medicine. The general view is that precision medicine is all about genomics, but it isn't..."

Should we start to insist that all MDS patients must have a genetic mutation test to establish what treatments may work out best for them?

"Genomic medicine is very much the happening field of cancer biology at the moment, and MDS is no exception. In fact MDS has been leading the way"..."We can tell from a set of mutations that we analyse which MDS patient has which mutations; but there are many technical reasons why one mutation may be relevant, and the same gene mutated in another patient might not be causing the disease or might not be present in a high enough quantity to be sure that it's actually relevant."

"The more we know about this field, the more complex the analysis of the data becomes." "Whether every patient needs a genetic test for routine management is debatable, because there are relatively few drugs that we use that are actually able to target the mutations that we know are there. If we see mutation X, we use drug Y - we are not quite there yet."

What would be the research benefit of collecting tissue samples from all MDS patients? How can patients ensure this happens?

"Research is always important. Without research we don't make progress. There is more of an acceptance today that large data sets from routinely treated patients are just as valuable as clinical trials that we do in parallel."

"We have a big registry programme here in Yorkshire and Humber where we are doing mutation analysis on all MDS patients, following over time, from a population of about 3,000,000 people... In the European Registry we are doing something similar. It is great if a patient can participate in this. All these initiatives are going to inform the way we treat patients in the future."

Learn more about the Registry Trial

Check other current clinical trials


More Good News: The Cabbage Patch 10 Mile Race

We have 20 running places at the Cabbage Patch 10 Mile Race!

MDS UK is delighted to announce that we have secured 20 running places in this year’s Cabbage Patch 10 mile race thanks to our wonderful supporter and Patron, Caitlin Limmer.

We have a place for you

The race takes place on 14th October 2018 and previous winners have included none other than Mo Farah!

If you would like an opportunity to help MDS UK raise funds to support patients with myelodysplastic syndromes - rare forms of blood cancer - then email us in the first instance fundraising@mdspatientsupport.org.uk .

All we ask is that you commit to raising £100 for MDS UK and use the Virgin Money Giving website to do this.

Get to know more about this amazing event The Cabbage Patch 10 Mile Race Official Website


Volunteer With Us

Could you help us to help you?

We are looking for enthusiastic new volunteers to help with various aspects of our expanding patient services.

Anything from Admin to Zen meditation, anywhere from Land's End to John O'Groats.

MDS Volunteers Raising Hands

Volunteer with us

Interested? Please send us details of any skills you think you can bring, your contact details and a little about yourself.

Write to us

MDS UK Patient Support Group,
Haematology – Bessemer Wing, King’s College Hospital,
Denmark Hill, London SE5 9RS

MDS Volunteers Call

Make a real difference in your spare time

Our volunteers are the heart of MDS UK Patient Support Group. Without them, we would not be able to continue to provide information and support to MDS Patients and their families.

Our volunteers have a range of experiences: some have MDS and are patients themselves, some have supported a friend or family member, others have professional or personal skills that can support our activities. Many of our volunteer roles can be undertaken in your own home.

As a volunteer you could be involved in any of these activities or others:

Why Volunteering?
The top two reasons for volunteering are that volunteers 'find it rewarding to know they are helping others', and 'they enjoy volunteering as they themselves benefited from our services and so they enjoy giving something back'.


Vidaza / Azacitidine: Learn all about this drug

Are Vidaza and Azacitidine the same drug? Why does it have two names?

Vidaza and Azacitidine are the same drug

Azacitidine is the official generic and non-proprietary name given to the drug active ingredient while Vidaza is its trade name.

The drug is widely available in the UK for the treatment of MDS since its approval in February 2011 by NICE - the National Institute for Health and Clinical Excellence (NICE). MDS UK Patient Support Group was in consultation with NICE during the approval process and campaigned for the approval of drug.

Is Azacitidine (Vidaza) a chemotherapy?

Azacitidine is a chemotherapy drug, however, it is a "hypomethylating agent". Hypomethylating agents are considered a non-intensive treatment.

They are aimed at slowing the progression of the disease with as few side effects as possible, maintaining a good quality of life. They will not cure MDS but may ‘modify’ it.

How does Azacitidine work?

Azacitidine works at the DNA level, "switching on" genes that stop the cancer cells growing and dividing. This reduces the number of abnormal blood cells and helps to control cell growth.

It is recommended as a treatment option for adults who are not eligible for stem cell transplantation and have intermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS) (See more at Nice Website).

How is Azacitidine administered?

You have azacitidine as an injection just under your skin (subcutaneously) given by a doctor or nurse. This can be in your upper arm, leg, buttock or stomach. You usually have it as an outpatient but there have been successful experiences with home administration.

You will have azacitidine as a course of several cycles of treatment. You can a treatment each day for a week and then 3 weeks with no treatment. This makes up a treatment cycle. You normally have at least 6 cycles and the treatment continues for as long as it is working.

You can also have it every day, for 5 days. Then have 2 days off and have azacitidine again for 2 days at the start of the next week.

The Treatment Involves Several Courses

The Treatment with Vidaza/Azacitidine Involves Several Courses
Joseph Bella: MDS patient experience of Azacitidine and Bone Marrow Transplant

Joseph Vella: MDS patient experience of azacitidine and stem cell transplant

"I hope and trust that my little story could encourage other MDS sufferers to decide to go through with the treatment"

Azacitidine (Vidaza): Latest research

Azacitidine is an important drug for the treatment of MDS but not all patients will respond to the treatment. Some will progress to leukaemia, others won't have an adequate response in terms of their blood count.

At the 14TH INTERNATIONAL SYMPOSIUM ON MYELODYSPLASTIC SYNDROMES, that took place in Valencia in May 2017, one of the topics discussed was the latest research around this important drug. Read more about how researchers are trying to establish which patients will have a good outcome with Azacitidine and whether the use of Azacitidine together with other drugs can make the treatment more effective.

Learn more about the latest MDS research: Download the full MDS Symposium Patient Summary

Predicting Good Outcomes with Vidaza/Azacitidine Treatment

Researchers are exploring which factors might be useful for predicting a good outcome in patients with MDS.

Certain treatment decisions for patients with MDS are based on cytogenetics, i.e. the study of the chromosomes. Azacitidine is appropriate for patients with higher risk MDS who often have mutations in chromosome 7 or three or more abnormalities in their chromosomes.

Dr. Raphael Itzykson, Université Paris Diderot, France, presented a study showing that if the platelet count after one cycle of the drug doubles, this is a good sign for an overall success of the treatment. However this happens in only a small proportion of patients.

Several ongoing efforts, including the HARMONY study, have a good chance of identifying more factors that predict azacitidine outcomes in MDS and other blood cancers and of predicting the effects of treatment on the patient's quality of life, healthcare costs, and care strategies.

The Best Partner for Vidaza/Azacitidine in Higher-Risk MDS

Dr. Mikkael Sekeres (Cleveland Clinic, Ohio) focused his presentation on combinations of Azacitidine and other drugs for higher-risk MDS.

The combination of Azacitidine and vorinostat seemed promising. In a phase II clinical trial, about 70% of patients with untreated higher-risk MDS, CMML, or AML responded to the treatment, which was about double the expected rate for azacitidine alone. These responses lasted an average of 16 months.

Similarly, response rates and duration of response were promising in a phase I-II clinical trial of the combination of lenalidomide and azacitidine for higher-risk MDS.

Dr. Fenaux added that studies are also evaluating combinations of Azacitidine with other treatments, such as valproic acid, venetoclax, immune checkpoint inhibitors, and idarubicin for higher-risk MDS or CMML.

Establishing The Correct Dose

Other research is assessing more intensive hypomethylating treatments or lower doses for longer use. Studies are testing different drugs, including venetoclax, cenersen, and a 10-day decitabine cycle (another hypomethylating agent) for MDS with TP53 mutations.

Dr. Sekeres concluded that azacitidine alone is still the standard treatment for higher-risk MDS. But some evidence
hints at better and more long-lasting responses for combination treatments if patients stay on them long enough. The hypomethylating drug “partners” under investigation might become options for higher-risk MDS in some patients.

Clinical Trials open to recruitment in the UK


Jan Buchanan

It is with huge sadness that we announce the passing of Jan Buchanan.

Jan had very recently stepped down from the committee of MDS UK Patient Support Group.

Regrettably, shortly after, and just before Christmas, she suffered a brain haemorrhage from which she did not recover.

Jan Buchanan

An inspired fundraiser, always positive and engaging

Jan was an energetic and determined businesswoman. She had an eye for detail and had quite a reputation for researching her topics. Recently, she had been a source of inspiration as part of our fundraising team and had been a supporter for a good few years.

Jan represented MDS UK at events in Parliament and took an active interest in MDS Patients. She was acutely aware that MDS was, and remains, a hidden illness, largely out of the public eye and was keen to raise awareness as a priority.

A great many people who have met Jan were struck by her positive attitude and desire to improve the lives of those around her. She was one of those people that you always wanted on your team to forge forward, where problems were just solutions in waiting.

Jan was an entertaining, engaging and confident individual who a great many people will miss and was taken from us far too soon.

She leaves a husband, Peter, for whom such a tragic and unexpected passing will leave a huge gap and we wish him our most sincere condolences and help where we can.

We hope that Jan will figure in everyone’s memories and her positive nature will live on.


Living with MDS: Top Tips to Improve Your Quality of Life

LIVING WITH MDS

Having MDS will have impact on your daily life. Each person will cope in their own unique way.

Not everything in this gallery will apply to you, but there might be feelings that you are familiar with. It is hard to directly "change an emotion", while thoughts and behaviours are more easily changed.

We hope you try some of these tips, those that suit you best. They can help you to gain back control. The way we think affects the way we feel.

(Click on the images for more information)


MDS UK Patient Support Group Newsletter – December 2017

Our seventh edition of the MDS UK Newsletter is now out!

Read all about:
MDS UK new Patron Caitlin Limmer AKA “The Force of the Limmer” and “Force of the Limmer”, the Race Director of Twickenham’s famous Cabbage Patch 10 Race and The Turks Head 10k.
A campaign that was worth it: NHS England will fund 2nd stem cell transplants for patients whose blood cancer relapses.
New developments in MDS Treatment, Advice on Travel and Insurance and much more.
CLICK ON THE IMAGE TO DOWNLOAD


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