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UK MDS Forum Education Day 2021

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MDS Patient Support

Research FOR Patients
-For an informed and empowered opinion-
Have you made your clinical paper accessible yet?

UK MDS Forum Education Day 2021

This report is written by Chris Dugmore and Claudia Richards who attended the UK MDS Forum event virtually.

Having attended in person in previous years, and the event being cancelled last year, the offer of a Covid-secure attendance was very appealing! We were able to put questions to the presenters via a Q&A Chat facility. We both enjoyed the day and were impressed by the professional presentation of this hybrid event.

As ever, we left with our heads full of acronyms and bunches of letters and numbers representing the vast and ever-growing array of genetic mutations which are now known to have huge significance for people with MDS. We hope we have managed to capture the key themes from the day.

MDS Patient Support

The notes from the Education Day, which can be downloaded here have been checked for accuracy by the individual presenters.

We hope you will find them both interesting and accessible.

Have your say – MHRA’s public consultation on proposals for legislative changes for clinical trials

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Important MHRA survey about PPI and clinical trials

The MHRA is the organisation that regulates licensing of new drugs in the UK.
They took over from the EMA (European Medicines Agency) since Brexit.
They are now proposing to change a few aspects with regards to clinical trials.
If you have ever taken part in a clinical trial, or considered doing so – please consider answering their survey – it is really important.

MHRA Invitation:

We have just launched our 8-week public consultation on proposals for legislative changes for clinical trials.

We want to streamline clinical trial approvals, enable innovation, enhance clinical trials transparency, enable greater risk proportionality, and promote patient and public involvement in clinical trials.

We would like to hear from the public and patients, clinical trial participants, researchers, developers, manufacturers, sponsors, investigators and healthcare professionals to help shape improvements to the legislation for clinical trials.

You can read more about our proposals in our Press release and consultation document.

Our consultation will close at 11pm on Monday, 14 March 2022.

Patient, Public and Stakeholder Engagement team - Communications and Engagement

Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU
Telephone: 0203 080 6000
Email: engagement@mhra.gov.uk
Follow us on social media

MDS UK note:

Our support group has been involved in an increasing amount of PPI work in the last 5 years – shaping clinical trial protocols, advising on Quality of life tools, and reviewing Patient Information documentation.

This work is providing essential recommendations for most MDS clinical trials – in order improve treatment options for MDS patients.
We plan to expand even further on this type of research work.
For this work, we need more people (patients/carers/families) willing to be trained to review such documentation.
If you are interested, or know a patient or carer who could be interested – please email info@mdspatientsupport.org.uk with “PPI” in the header.

MDS UK opening times over the Christmas period

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Wishing you a very Merry Christmas and a Happy New Year

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Come to our Christmas Zoom cafe!

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Just a little reminder for you to let your hair down and come along to the Christmas Zoom café social today! (December 13th: 1.30 pm - 3.00 pm)

When: Tuesday 13th December
Time: 1.30pm-3pm
Where: Online via Zoom

 

Please register as soon as you can so we can plan the activities but, in advance, here are some handy hints for attending:

  • Please wear a Christmassy / winter jumper / dress / shirt and/or Christmassy hat
  • Have a pen and paper handy for a short fun quiz
  • Think about introducing yourself with a short, little-known,  fact about yourself!
  • Bring an actual Christmas cracker along for a Christmas cracker screenshot and also share a few Christmas Cracker jokes - the cornier the merrier!
  • Have you got an amusing Christmas story to tell - disasters or triumphs?
  • There will be some singing but all fully-muted - so NOBODY will hear you!

To register just click the red button below and complete the registration page.  (After registering, you'll receive a confirmation email with information about how to join the meeting).

MDS UK Christmas Tree 2022

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Blood Cancer: The Forgotten Fifth

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Blood Cancer and MDS, the forgotten cancers

Blood cancer patients are less likely to see their needs fully met than patients with the four most common cancers - breast, colorectal, lung and prostate.

The blood cancer community, via the umbrella group Blood Cancer Alliance, has launched an important new campaign, called the Forgotten Fifth, pointing out that blood cancer is just as dangerous as the 4 main cancers, but often not given the same attention, nor allocated the same resources.

The Forgotten Fifth campaign aims to achieve equal status for blood cancer patients to the other four most common cancer patients, enabling better treatment and faster diagnosis. 

MDS Patient Support

MDS, the most forgotten

In addition, MDS is ‘the forgotten cancer’, as it is often not labelled as a form of cancer, and therefore not captured in data collected by the health authorities. As a support group, we have seen hundreds of cases where diagnosis of MDS was delayed. Delays means impaired quality of life for most patients, frequent infections, or, for a few of them a death sentence.

This campaign reinforces the evidence shown in our national MDS survey.

We are calling for attention to blood cancers, and MDS specifically.

"Neil had a stem cell transplant scheduled for early March. Then UCLH checked his ferritin levels. If you’re having regular transfusions your iron levels should be monitored, Neil’s weren’t. After a year of iron-rich blood transfusions these were found to be stratospheric, so the transplant was put on the back burner in order for these levels to be brought under control. Sadly, this wasn’t a treatment routinely offered by our local NHS Trust due to funding issues."

Read Neil's story >

What are we asking?

  • The Alliance is now calling for the NHS to treat blood cancer patients as equal to those with the four most common cancers in NHS policy making and decision making.
  • As a basic measure, the Alliance is asking that NHS England add data on blood cancer patients to the Cancer Data Dashboard it uses as a key information source for cancer strategies.

Do please point your MP to this campaign, to ensure that blood cancer stops being forgotten. Help us get there, please.

  1. Share your story with your MP. You can find out their email here.
  2. Share the images below on social media and with friends and family.

[envira-gallery id="33044"]

Managing MDS in the wake of a global pandemic

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MDS Patient Support

This article was first published on the MDS Foundation Fall/Winter 2021 Newsletter. Many thanks to our colleagues from the MDS Foundation.

Important: The article below is destined to an American audience, and it lists some drugs and trials only available in the USA. Patients in the UK – please bare that in mind when reading.

By AMY ELIZABETH DEZERN, MD, MHS
Director, Bone Marrow Failure and MDS Program
Associate Professor of Oncology Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland

MDS Patient Support

Introduction

Few people would dispute that 2020 into 2021 has been an unprecedented time throughout the world. Much of this is attributable to Coronavirus disease 2019 (COVID-19). Briefly, COVID-19 is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, leading to an ongoing pandemic. The disruptions have ranged from modest to supreme and have affected all differently. However, patients suffering with myelodysplastic syndromes (MDS) have had unique and specific challenges.

Risk to MDS patients defined

Older and immunocompromised populations appear to be at a higher risk for severe, potentially life-threatening illness related to COVID-19 compared with the general population, with reported case fatality rates as high as 15% in patients aged 80 years or older in early series from China.1

The initial study of COVID-19 and Cancer Consortium (CCC19) data found that 30-day all-cause mortality was 13% among patients with active or prior cancer and confirmed SARS-CoV-2 infection.2 This presents a particular concern for patients with MDS. More specific to MDS, a systematic review and meta-analysis quantified the outcomes (deaths, hospitalizations, and complications) of patients with hematologic malignancy and COVID-19.3 This included MDS as an acquired bone marrow failure syndrome. This analysis of 14 studies and a total of 231 patients included showed a pooled risk of death of 53% (95% CI, 34-72; I2, 77%) for patients with MDS, the highest of all hematologic malignancy subtypes. These sobering data nearly a year into the pandemic required us to “double-down” on our efforts to protect our patients.

Issues specific to MDS patients

As we know, patients diagnosed with MDS may have various disease manifestations depending on their disease phenotype. Management can range from close observation of mild cytopenias to supportive treatments with transfusions all the way through active chemotherapy and even early allogeneic hematopoietic stem transplantation (BMT).

Nonetheless, as the world was shutting down, all of these were impacted, disrupting the therapeutic pathway for patients with MDS. This interference with standard clinical care was compounded by the added fear that immunosuppressed MDS patients were at increased risk of morbidity and mortality from COVID-19. This led to many discussions (often via telemedicine) between patients, families, and providers. In the early days of the pandemic, there were few hard data to guide treatment or protective recommendations, and guidance was limited to expert opinion.4,5

For patients whose disease required close observation and monitoring, care interruptions may have manifested as limited access to laboratory appointments for blood work assessment. Patients who required transfusional support, especially those who lived in areas with few transfusion facilities, were markedly impacted by the nationwide shortage of blood supply. And patients undergoing chemotherapy were faced with decreased clinic/infusion center operating hours and inaccessible providers.

Moreover, for patients in need of chemotherapy there was the ongoing concern that the ensuing immunosuppression after chemotherapy could further predispose them to COVID-19 infection and severe disease. In many cases, this may have altered the balance between risk and benefit of chemotherapy. Finally, there were simply the fear of unknown. How long could patients go without treatment? What risk does an active cancer, whether low- or high-grade, impart to an individual human being? And from a human perspective, how could patients weigh the risks of seeing family or friends, knowing both that social gatherings would increase the risk of infection and that their remaining time together may be shortened due to their diagnosis of MDS.

MDS Patient Support

As the world was shutting down, all treatments were impacted.
This interference with standard clinical care was compounded by the added fear that immunosuppressed MDS patients were at increased risk of morbidity and mortality from COVID-19.

General recommendations 5

Expert consensus panels rapidly assembled to pool knowledge and provide guidance to patients and clinicians.6

These panels emphasized that, as always, treatment decisions should be based on category in the revised international prognostic scoring system.

Close observation without definitive treatment remained a reasonable strategy in patients with only modest cytopenias.7

For higher risk disease, newly diagnosed patients requiring treatment with a hypomethylating agent should commence therapy (and patients already on a hypomethylating agent should continue therapy).

It was thought reasonable to maintain normal treatment intervals until evidence of response is seen, but in order to balance risk of exposure with risk of disease progression, once a response is evident, lengthening the duration between treatment cycles and reducing dosing within each cycle is reasonable.

Subcutaneous azacitidine is preferred over intravenous azacitidine to decrease the time spent at infusion centers and in contact with potential COVID-19 exposures.

For lower risk MDS, consensus agreement favored a longer watch-and-wait approach for most patients. Erythropoiesis- stimulating agents (for patients naive to these agents) and early luspatercept initiated may avoid or delay the need for red blood cell transfusions.

Most experts agreed with deferral of lenalidomide in newly diagnosed patients with del(5q) disease given the risk for myelosuppression.

Over the course of the pandemic, this guidance has migrated back to baseline practice patterns of more aggressive treatment. This is primarily due to increasing comfort and confidence in infection prevention practices.

Unfortunately, clinical trials, a long-time priority in MDS, were dramatically and negatively affected by the COVID-19 pandemic. Many studies were paused, and study participation was nearly non-existent.8 For studies that continued, rates of study deviations increased, and the shortage of laboratory supplies was a significant barrier to continued sample collection.

Blood is an (even more) limited resource

MDS patients have always been counseled that blood is not an unlimited resource, but relatively few have truly not had potential access to transfusional support. However, during the first summer of the pandemic, the US national and even world- wide blood supply reached an all-time low.9,10

This posed an even greater challenge for patients in whom supportive care with red cells or platelets represented a way of life. Certainly, anemia from MDS causes decreased quality of life, but there are relatively sparse data regarding the minimum hemoglobin values for which a MDS patient may safely forgo transfusions with no evidence of end-organ damage. The work of Dr. Abel and colleagues provided some guidance on this topic during COVID.

The authors applied a modified Delphi method with 13 expert MDS clinicians to discussions of minimum safe hemoglobin for this population. There was a 100% consensus that it be no greater than 7.5 g/dL.11

This was a comfort to patient and physicians alike as we were able to pull back on individual transfusions to lower levels as well as single unit (as opposed to two) transfusion episodes to ration the blood supply where feasible.

MDS Patient Support

Over the course of the pandemic, treatment has migrated back to baseline practice patterns. This is primarily due to increasing comfort and confidence in infection prevention practices.

Drugs approved during the pandemic

Ironically, given that it had been over 15 years since the last regulatory approval for a drug for patients with myelodysplastic syndromes, two drugs were approved during the pandemic timeframe. Both actually have particular relevance in the setting of goals to decrease healthcare interactions and space out clinic visits.

On April 3, 2020, the Food and Drug Administration approved luspatercept- aamt (REBLOZYL, Celgene Corporation) for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). It is a first- in-class erythroid maturation agent that binds to the select transforming growth factor-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. (Editor's Note: more information on Luspatercept for the UK will follow next week).

In the MEDALIST trial 12 randomized, multi-center, double-blind, placebo-controlled trial in 229 patients with IPSS-R very low, low, or intermediate-risk myelodysplastic syndromes who had ring sideroblasts and required RBC transfusions (2 or more RBC units over 8 weeks), patients were randomized 2:1 to luspatercept or placebo. All patients received best supportive care, which included RBC transfusions. The main efficacy endpoint in MDS-RS and MDS- RS-T was the proportion of patients who were RBC-transfusion independent (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period between Weeks 1 and 24. Of the 153 patients who received luspatercept, 58 (37.9%, 95% CI: 30.2, 46.1) were RBC-TI for at least 8 weeks, compared to 10 patients (13.2%, 95% CI: 6.5, 22.9) who received placebo (treatment difference 24.6% (95% CI: 14.5, 34.6; p<0.0001.) The most common (>10%) adverse reactions to luspatercept are fatigue, headache, musculoskeletal pain, arthralgia, dizziness/ vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, and hypersensitivity. The recommended starting dose of luspatercept is 1 mg/kg once every 3 weeks by subcutaneous injection. This was adopted efficiently in eligible patients in hopes of augmenting hemoglobin enough to avoid transfusion during the pandemic and beyond.

Also approved during the pandemic (July 7, 2020) was Inqovi (decitabine and cedazuridine) for treatment of adult patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). The approval was based on two open-label, randomized, crossover clinical trials that showed similar drug concentrations between IV decitabine and oral decitabine/cedazuridine. Additionally, about half of the patients who were formerly dependent on transfusions no longer required transfusions during an eight- week period. Both trials provided comparisons of exposure and safety in the first two cycles between oral decitabine-cedazuridine and IV decitabine and a description of disease response to the new medication. Comparison of disease response between decitabine- cedazuridine and IV decitabine was not possible because all patients received decitabine-cedazuridine starting in cycle 3. The overall safety profile of oral decitabine- cedazuridine was similar to IV decitabine.

Data on active covid infections in MDS patients

For ASH 2020, Feld and colleagues 13 prospectively reviewed the records of all patients seen in the MDS clinic in New York City in the spring of 2020 to report on the effects of COVID specifically on MDS patients. Overall, 27.1% of the patient population was diagnosed with COVID-19 and 39.1% of these patients died, or 10.6% of the overall cohort. The mortality rate reported here is higher than anticipated, but at the time of the abstract, the majority of patients recovered and have resumed MDS directed therapy.

This has been my personal experience as well. Further results hinted at another problem others were seeing as well: persistently positive PCR tests up to 6 weeks post infection and COVID-19 antibodies were found in 85.7% of COVID-19 PCR+ patients tested. This suggested that MDS patients may have delayed viral clearance, but can mount a humoral response. 14 We encouraged our patients to limit exposures but get tested where feasible. There have been persistently positive patients by PCR who required longer term isolation. We look forward to MDS specific data on convalescent plasma to inpatients, and monoclonal antibody therapy for outpatients as we have gained knowledge and use.

MDS Patient Support

Persistently positive PCR tests up to 6 weeks post infection and COVID-19 antibodies were found in 85.7% of COVID-19 PCR+ patients tested. This suggested that MDS patients may have delayed viral clearance, but can mount a humoral response.

Vaccination

Based on randomized phase III clinical trials, several COVID-19 vaccines became available throughout the world in late 2020, early 2021, with the BNT162b2 (Pfizer/ BioNTech), ChAdOx1 nCoV-19 (Oxford/ AstraZeneca), mRNA-1273 (Moderna) vaccines and the Johnson & Johnson single- dose COVID-19 vaccine approved. 14-16

Ten patients with MDS were evaluated in a larger cohort for data on immunogenicity of SARS-CoV-2 vaccine in patients with hematologic malignancies.17 Through robust evaluation of immune response after 2 BNT162b2 inocula including functional seroneutralization assay and assessment of T- cell response, the authors concluded a second BNT162b2 inoculum translates into a significant increase in humoral response, allowing almost half of the patients to achieve immune protection against COVID-19. Given the increase in seroconversion rate between the first and second vaccine injections, the authors noted that evaluation of the effectiveness of such a third inoculum will be imperative.

As such, in the late summer 2021, the U.S. Food and Drug Administration (FDA) has recently authorized a booster shot of either the Moderna or Pfizer COVID-19 vaccine for certain immunocompromised people. Studies show that some people with weakened immune systems — those who have received solid organ transplants and people with conditions considered to have an equivalent level of immunocompromise — are less likely to create an antibody response from two doses of the Pfizer or Moderna COVID-19 vaccine, and these people could benefit from a third dose.

Changes here to stay and future directions

MDS patients are special. No reader (provider or patient or family and beyond) of this editorial will disagree. We learned from our colleagues and listened to our patients as we tried to protect them and still carry on with appropriate treatment. One innovation quite helpful was the development of dedicated “biomode” treatment and infusion spaces (negative pressure) to allow for a person under investigation or diagnosed with COVID to receive treatments and transfusions in an ongoing fashion. Centers also pioneered the concept of drive-up phlebotomy and shot clinics to allow patients to avoid even exiting their car to obtain routine labs and quick injections.

Perhaps the largest paradigm shift, however, was the rapid expansion of telemedicine. Not only does this allow infirm or driverless patients to see their provider, but also allowed a larger number of patients to consult both with their local hematologist as well as MDS experts. For their part, providers enjoyed seeing patients in their homes and perhaps with several generations of family members. Concerns about access to care and drug availability were mitigated through increased prescription allowances: for example, Celgene REMs allowed a 56-day supply during the pandemic. Many of these initiatives were mandated by the COVID times but are likely a permanent part of MDS care in many areas.

The NHLBI MDS Natural History Study (NCT02775383) is an ongoing prospective cohort study conducted across 144 sites in the U.S. and Israel intended to establish a data and biospecimen repository to advance the understanding of MDS. In response to the COVID-19 pandemic, the study also collected data on COVID-19 infection and management. We will look forward to summary of COVID-19 outcomes from participants in this study and the impact of the pandemic in this population of MDS patients.

Clinical trial opening and accrual are also recovering as the pandemic enters a new stage. Uniquely, in 2021, there are more phase III studies in higher risk MDS than ever before. This has produced an interesting dynamic in which agents (and their developers) are competing both for accrual and to become the new standard of care. The trials all share a similar design in their phase III registration studies with the novel product in combination compared to single-agent azacitidine. Each trial has reasonable earlier phase data, usually in both AML and/or higher risk MDS, upon which they have based their current clinical investigations.

A trial of magrolimab (NCT04313881) will examine first-in-class macrophage immune checkpoint inhibitors that targets CD47, a key molecule mediating cancer cell evasion of phagocytosis by the innate immune system. Venetoclax (NCT04401748) will be studied in higher risk MDS at a truncated dosing schema (14 days) relative to its AML trials. Dual targeting of immune effectors and leukemic cells by sabatolimab (NCT04266301) is also a trial enrolling the same higher risk patients. SY-1425, a selective RARα agonist called Tamibaterone (NCT04797780), is a biomarker driven study for those MDS patients who overexpress RARα. Having this plethora of options brings back hope to MDS patients for the future after the pandemic.

MDS Patient Support

Studies show that some people with weakened immune systems are less likely to create an antibody response from two doses of the Pfizer or Moderna COVID-19 vaccine, and these people could benefit from a third dose.

Conclusion

In conclusion, this has been a most unusual and unprecedented time throughout the world in 2020–21. We’re learning to adapt to the “new normal” — just as all MDS patients bravely adapt to their own novel routines after their MDS diagnosis. The COVID-19 pandemic has affected patients with MDS in a myriad of ways, including diagnostic and treatment delays, scarcity of blood products, higher risks of morbidity and mortality from the viral infection itself, as well as necessity of vaccinations and additional boosters. Nonetheless, we forge ahead to find novel approaches to improve the quantity and quality of life for all MDS patients.

References

  1. 1. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323:1239–42.
  2. Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet. 2020;395:1907–18.
  3. Vijenthira A, Gong IY, Fox TA, et al. Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta- analysis of 3377 patients. Blood. 2020; 136:2881–92.
  4. Shah MA, Emlen MF, Shore T, et al. Hematology and oncology clinical care during the coronavirus disease 2019 pandemic. CA: a cancer journal for clinicians. 2020;70:349–54.
  5. Zeidan AM, Boddu PC, Patnaik MM, et al. Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts. Lancet Haematol. 2020; 7:e601-e12.
  6. Mossuto S, Attardi E, Alesiani F, et al. SARS- CoV-2 in Myelodysplastic Syndromes: A Snapshot From Early Italian Experience. Hemasphere. 2020;4:e483.
  7. Komrokji R, Al Ali N, Padron E, et al. What is the optimal time to initiate hypomethylating agents (HMAs) in higher risk myelodysplastic syn- dromes (MDS)? Leuk Lymphoma. 2021:1–6.
  8. Unger JM, Blanke CD, LeBlanc M, Hershman DL. Association of the Coronavirus Disease 2019 (COVID-19) Outbreak With Enrollment in Cancer Clinical Trials. JAMA Netw Open. 2020;3:e2010651.
  9. Almalki S, Asseri M, Khawaji Y, et al. Awareness about Coronavirus (COVID-19) and challenges for blood services among potential blood donors. Transfus Apher Sci. 2021:103211.
  10. Schiroli D, Merolle L, Molinari G, et al. The impact of COVID-19 outbreak on the Trans- fusion Medicine Unit of a Northern Italy Hospital and Cancer Centre. Vox sanguinis. 2021.
  11. Tanasijevic AM, Revette A, Klepin HD, et al. Consensus minimum hemoglobin level above which patients with myelodysplastic syn- dromes can safely forgo transfusions. Leuk Lymphoma. 2020:1-5.
  12. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. 2020;382:140–51.
  13. Jonathan Feld, MD, Erin P. Demakos, RN, Rosalie Odchimar-Reissig, RN, Douglas Tremblay, MD, Saudia Alli, NP, Darshanie Sewah, RN, Shyamala C. Navada, MD, Lewis R. Silverman, MD. Myelodysplastic Syndromes (MDS) & COVID-19: Clinical Experience from the US Epicenter of the Pandemic. Blood. 2020;136.
  14. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021;384:403–16.
  15. Ramasamy MN, Minassian AM, Ewer KJ, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime- boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet. 2021; 396:1979–93.
  16. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid- 19 Vaccine. N Engl J Med. 2020;383: 2603–15.
  17. Malard F, Gaugler B, Gozlan J, et al. Weak immunogenicity of SARS-CoV-2 vaccine in patients with hematologic malignancies. Blood cancer journal. 2021;11:142.

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

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Take part in this survey to have a say on clinical treatment and trials

To better understand and raise awareness of your needs, the MDS Alliance has designed the MDS Global Survey.

The survey includes a validated quality of life tool (QUALMS) and is available in 11 languages.

The findings will support patients, caregivers, and advocates around the world to better understand your quality of life and address your needs as an MDS patient.

Have a say! A call to patients, carers and advocates

This survey WILL make a difference in how future clinical trials in MDS will be conducted, and what information will be collected.

Remember – you are the patients, carers and advocates. Only you can provide the patient voice for your needs in MDS care and treatments!

Deferasirox (Exjade) access in MDS – Myelodysplastic Syndromes Overview of a UK wide postcode lottery – 2015 to 2021

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Deferasirox is only licensed second line for the treatment of chronic iron overload despite real-world experience showing that deferasirox is better tolerated and its compliance is far superior than first line treatment.

This has badly affected many MDS patients as some pockets of the UK still will not grant funding to this drug, effectively creating a postcode lottery.

We request an end to this postcode lottery. In the absence of a NICE submission/decision, access should be aligned to the positive Scottish Medicines Consortium (SMC) decision.

Below you'll find excerpts of the document and explanations for:

  1. Patients (and families) affected by MDS, Myelodysplastic Syndromes and on regular blood transfusions
  2. MPs representing these patients in parliament
  3. 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. 

Read more:

https://www.england.nhs.uk/integratedcare/what-is-integrated-care/

https://www.pharmacymagazine.co.uk/analysis/ccgs-to-be-subsumed-into-ics-before-end-of-2021

Part 1 - BSH Guidelines for MDS – June 2021 revision

MDS Patient Support
  • 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. 

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

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