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David P. Steensma, MD, looks for a novel therapy to treat TP53-Mutant MDS

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TP53 gene mutations or chromosome 17 loss which results in TP53 deletion is present in up to 20% of MDS patients. Therapies for these patients have been relatively unsuccessful in delaying the progression of the disease.

Emerging treatments for patients with MDS are frequently based on cytogenetics, i.e. the study of the chromosomes. For this reason it's becoming more important for haematologists to check for mutations, and for patients to know those results.

Ask your haematologist for the results of your molecular test, to find out if you have any mutations, and which ones they are. This information also helps when reading news about future MDS treatments.

In this excellent, very clear interview with USA MDS expert Prof David Steensma, he lists some positive news for MDS patients with the TP53 mutation. It involves a combination of drugs, eprenetapopt  (APR-246) and azacitidine. Combining treatments seems increasingly promising generally in MDS.

Click here to read the full article on Onclive
Prof David Steensma

David P. Steensma, MD, is the clinical director of the Center for Prevention of Progression at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School both in Boston, Massachusetts.


OncLive: Historically, how have TP53 mutations been targeted, and how effective have these therapeutic strategies been?

Steensma: TP53-mutant disease is one of the biggest unmet needs in MDS. When patients with TP53 mutations receive allogeneic hematopoietic cell transplantation, they tend to do more poorly than those without TP53 mutations, including frequent early relapses. We know that TP53 is enriched in therapy-related MDS, so people who have had treatment for some other type of non-myeloid cancer many years later may develop MDS as a result of the treatment, and when that happens, it is often TP53-mutant disease.

TP53 mutations are associated with short survival, especially when both copies of TP53 are lost. Clinically, the TP53-mutant population is a very high risk group that is often treated with one of the DNA hypomethylating agents, either azacitidine or decitabine, and those lead to a high rate of response. But the response duration is often pretty short, with a median of 8 to 9 months, so the overall survival for these patients tends to be less than 1 year.

How do recent data support the use of this agent in the treatment of TP53-mutant MDS?

One of the exciting things is that on phase 1 and 2 trial eprenetapopt (APR-246) was associated with quite a high overall and complete response rate, certainly higher than we would typically expect to see when looking at historical controls of azacitidine monotherapy. Anytime patients are enrolled in uncontrolled clinical trials, though, we wonder, “Are they just healthier than the general population? Were they destined to do well otherwise?” So the uncontrolled data are difficult to interpret but are encouraging. Still, in MDS, we’ve been burned many times by phase 2 trials in which interventions looked like they had a high response rate, were then taken into phase 3, and showed no improvement.

Some examples are the combination of azacitidine with histone deacetylase inhibitors, such as vorinostat [Zolinza] or entinostat. More than 4 randomized trials of azacitidine with deacetylase inhibitors showed no benefit compared to azacitidine monotherapy, just more adverse events with the combination. Azacitidine plus lenalidomide [Revlimid] also looked pretty good in a phase 2 study but didn’t pan out in the phase 3 investigation [NCT01522976]. The phase 3 trial that is testing APR-246 plus azacitidine versus azacitidine alone [NCT03745716] has now completed accrual and hopefully will report out by the end of the year. It is a really important study for trying to understand if this is a viable strategy.

UPDATE FROM MDS UK - 20-01-2021:

A second phase II study to evaluate if it is possible to improve outcomes for patients with TP53-mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia, who had poor outcomes with standard-of-care azacitidine therapy, produced again encouraging results.

This second study was conducted by David A. Sallman, MD; Amy E. DeZern, MD; Guillermo Garcia-Manero, MD; David P. Steensma, MD and others.

Read the full study in the Journal of Clinical Oncology

The combination of azacitidine and eprenetapopt (APR-246) was well-tolerated in patients with TP53-mutant MDS or acute myeloid leukemia.

Azacitidine and eprenetapopt resulted in a 71% overall response rate and 44% complete remission rate in MDS patients, comparing favourably with a therapy of azacitidine alone.

These results support the ongoing pivotal phase III, multicenter, randomised study of eprenetapopt in combination with azacitidine versus azacitidine alone in patients with TP53-mutant MDS.

Please explain the rationale for combining eprenetapopt and azacitidine.

Both azacitidine and decitabine are important standards of care for patients with MDS. Those are the backbones of therapy, and azacitidine is the only agent that’s been shown to improve overall survival for higher-risk patients in a randomized trial—so patients deserve to have exposure to this drug.

The reason for combining azacitidine with APR-246 is that reactivating TP53 alone only may partially sensitize the cell to dying if it is an abnormal cell. Normally if there’s DNA injury detected in a cell, that cell would be programmed to die, and that program would be mediated by p53. If you restore a p53 function in an abnormal cell but there’s not enough DNA damage to the cell, then the cell may still survive. If you combine APR-246 with an agent that causes DNA damage or cellular stress like azacitidine, then that intact p53 may finally be able to sound the alarm and kill the cell, so to speak.

In MDS, we’ve seen a number of trials where there was no logic behind combining agents with azacitidine. Previously, it’s been, “Oh, our drug has a little bit of effectiveness, or even no effectiveness, but maybe it will be better if we combine it with azacitidine,” and that’s kind of a desperate move. Here, as with venetoclax—which also sensitizes cells to death but doesn’t have a lot of independent activity on its own in myeloid disorders—there’s a real rationale for combination.

What do we know about the safety profile of eprenetapopt (APR-246)?

From what we’ve seen so far, APR-246 has a favorable safety profile. The recurrent toxicity that we’ve seen is a peculiar form of neuropathy where patients may feel altered sensation, such as their skin feeling especially sensitive. They may feel like ants are crawling on their skin or other peculiar sensations, and this usually gets better with prochlorperazine, which is a widely used antinausea medicine. So, for the most part, that adverse event has been manageable.

I was impressed in the phase 1/2 experience by just how well patients did with the drug. Overall, APR-246 didn’t seem to cause a lot of trouble, other than the neuropathy. We will see in the randomized comparison how the toxicity patterns compare to azacitidine alone, and that will provide more information. My suspicion is that we’ll see more neuropathy with the combination group, but probably not a lot of other differences in terms of adverse events.

What challenges remain in other subtypes of MDS?

There are a number of unmet needs for patients with MDS outside of TP53-mutant disease. In the higher-risk population, for the majority of patients, hypomethylating agents will either stop working within 1 to 2 years or they weren’t working in the first place. We don’t have a second-line therapy that’s useful and has been shown to improve survival or delay disease progression, so that’s a big unmet need. In fact, the long-awaited, randomized trial [INSPIRE; NCT02562443] of rigosertib just reported out in that post hypomethylating agent setting, and data showed that rigosertib failed to improve survival compared with physician’s choice of alternate therapy.

The second big unmet need is for the lower-risk patients, whose main problem is low blood counts that could cause them to be transfusion dependent on a regular basis, which is quite inconvenient for them. We had luspatercept [Reblozyl] approved for MDS with ring sideroblasts and SF3B1 mutations in April, which was the first new drug approved for an MDS indication in 14 years. However, luspatercept only helps a subset of patients, and the approval was only for those with ring sideroblasts, which is 15% to 20% of patients at most. There are a lot of other patients with low blood counts that either aren’t good candidates for luspatercept or have been failed by luspatercept, and the question becomes, “How can we improve counts for them?”

These are probably the 2 biggest needs, but there are others. For the transplant population, how to prevent relapse after transplant is also a key question.


  1. Aprea Therapeutics receives FDA breakthrough therapy designation for APR-246 in combination with azacitidine for the treatment of myelodysplastic syndromes (MDS) with a TP53 mutation. News release. Aprea Therapeutics January 30, 2020. Accessed August 25, 2020.
  2. Sallman DA, DeZern AE, Garcia-Manero G, et al. Phase 2 results of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). Blood. 2019;134(suppl 1):676. doi:10.1182/blood-2019-131055

Trial to test existing drugs against rare blood cancer

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Cooperation to support a new clinical trial for MDS

A new clinical trial for MDS has just been launched.

Designed by clinical experts, using existing (repurposed) drugs in a new way, with wide PPI (Patient and Public Involvement) input and feedback by MDS UK advocates and patients, funded via Bloodcancer UK.

This trial will test existing drugs against the rare blood cancer Myelodysplastic Syndrome to improve patients' outlook and health.

It is run by UoBbiosciences & Warwick Clinical Trials Unit.

Best practice and cooperation at all levels for research benefitting MDS patients.

By making a donation to MDS UK, you are also funding our time, for the work we conducted with patients, enabling the subsequent approval of this trial.

Full details:

A clinical trial designed to test existing drugs in the treatment of a rare blood cancer has been launched at the Universities of Birmingham and Warwick.

Funded by Blood Cancer UK, the trial seeks to repurpose existing drugs to improve the outlook, health and quality of life for people with Myelodysplastic Syndrome (MDS), a condition in which the patient does not have enough healthy blood cells.

Called REPAIR-MDS (Repurposed drugs to improve haematological responses in Myelodysplastic Syndrome), the trial will test a number of treatments designed to improve the formation of healthy blood cells, reducing or reversing life-limiting deficiencies in red blood cells. The trial is expected to begin recruiting patients in May 2021.

Professor Chris Bunce, in the School of Biosciences at BHP founder-member the University of Birmingham, who led the application to Blood Cancer UK and whose research contributed to the design of the trial treatments, says: “REPAIR-MDS represents a significant turning point in UK medical research. It is the first ever UK randomised trial delivered in this neglected patient group, establishing the precedent for future trials in the UK and elsewhere.”

Professor Janet Dunn, Head of Cancer Trials at Warwick Clinical Trials Unit at the University of Warwick, says: “It’s an important trial for these patients as currently treatment options are limited. We are excited to be working closely with Birmingham and the patient groups, in particular Sophie Wintrich who is CEO from the MDS UK patient support group.”

Although rare, MDS is estimated to be more prevalent in older people, over 70 years old. There is currently no cure for the disease and treatment is usually chemotherapy-based, although in some cases a stem cell transplant may be possible.

Dr Fatima Sulaiman, Head of Research for Blood Cancer UK added: “Blood Cancer UK are really excited to be supporting this trial. We believe that within the next generation, we’ll be able to beat all types of blood cancer, and this trial will take us one step closer to doing this.

“Sadly, only 31% of people diagnosed with myelodysplastic syndrome (MDS) survive 5-years, and we urgently need better treatments. Being able to repurpose existing drugs for people with MDS would mean we would be able to get new treatments to people, sooner, giving everyone the best possible chance of survival.

“Anyone worried about blood cancer can call our free and confidential helpline on +44 (0) 808 2080 888.”

The project is a national effort by the UK MDS research community and will recruit patients from across the UK. The trial was developed by the National Cancer Research Institute (NCRI) MDS clinical studies sub-group and has arisen from research carried out in the School of Biosciences and the School of Medical and Dental Sciences at the University of Birmingham led by Professor Bunce. It will be carried out in collaboration with Queen Elizabeth Hospital Birmingham.

The funding of REPAIR-MDS by Blood Cancer UK has been made possible by a donation made in open competition to the charity from the Jon Moulton Charity Trust.

How have you coped over the past few months of COVID-19? Please let us know

Patients and caregivers/supporters survey on care during the COVID-19 pandemic

MDS UK has teamed up with the NCRI MDS subgroup (National Cancer Research Institute), the UK MDS Forum (National MDS clinical experts group), and created a survey for MDS, CMML and AML patients and caregivers.

What does this survey cover?

This national survey is about

  • your perspective and experience of the COVID-19 pandemic generally
  • the clinical care and support you received
  • the information you had access to
  • treatment of COVID-19, if applicable

How will this data be used?

The data collected will inform clinical staff about any beneficial changes to practice they can take forward to improve the care of MDS and AML patients as well as understand what barriers and difficulties patients came across during this period.

We also hope to pass on some of this data to PHE (Public Health England), to also improve the way they provide information and services to patients and families.

We will publish results on our website as well, and use the information to improve our services to members too.

Confidentiality and GDPR

This survey is set up to be completed totally anonymously, in line with GDPR regulations for this type of work.

MDS UK members will be sent a link, but it will not be possible to trace back answers to individuals.

The link can only be used once per device.

Other surveys on COVID-19

You may have completed other surveys on the topic of Covid-19, for other organisations, but we kindly ask you to complete this one too, as it is the only survey fully dedicated to MDS, and prepared by the team of clinical experts in MDS and the NCRI sub-group on MDS.

Your MDS clinicians may also forward you a link to this particular survey.

It does not matter which link you end up using, as data will be collected together.

How long does it take to complete it?

It may take you up to 30minutes to answer all questions.

Some questions can be skipped.

We thank you for taking this time to provide these very important answers, to help us help you.

Technical Queries?

Please email

MDS UK team

Many thanks to the clinical staff and MDS UK team involved in this survey:

NHS staff: Dr P Krishnamurthy, Dr S Killick, Nurses J Hayden and M Kenyon, Dr J Chadwick, Analyst A Jackson

MDS UK staff and volunteers: C Dugmore, C Richards, IT expert E Fuste, S Wintrich, C McGovern

News for MDS patients from the European Registry

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What is the European Myelodysplastic Syndromes Registry (EUMDS) project?

The best way to study a typical group of MDS patients is to set up a registry. A registry involves obtaining consent from patients and collect information about their MDS and the treatments they receive at their usual clinic or Day Case Unit visits.

The European MDS Registry (EUMDS), was initiated in 2008 by a large group of European haematologists. It contains information on treatment and disease of more than 2500 MDS patients from 17 countries and it continues to include new patients.

Many of you will be familiar with the EUMDS project and some of you are registered and actively sharing your MDS data, helping researchers to improve their understanding of the disease. This helps to shape better clinical trials, and ultimately may lead to better treatments for MDS.

Which scientific studies have been performed so far by the Registry?

The information collected in the EUMDS registry forms the basis for scientific studies. In these studies MDS experts seek to answer scientific questions on MDS and the treatments available. By answering these questions scientists aim to improve the diagnosis and treatment of MDS.

The results from EUMDS scientific studies are published in scientific journals and presented on large haematological congresses.

In addition, the EUMDS publishes summaries of these scientific studies for patients and the general public, in a patient friendly format. These are published on the "Lay English Summaries":

See, for example, two topics which have been published under "Lay English Summaries":

The effect of transfusions on patients quality of life

Impact of red blood cell transfusion dose density on progression-free survival in lower-risk myelodysplastic syndromes patients.

Red blood cell transfusions (RBCT) are an important part of the general medical care for MDS patients. However, the overall life expectancy of patients treated with RBCT is often decreased compared to untransfused MDS patients. It is unclear whether this lower life expectancy is due to the nature of the disease (more severe illness and therefore greater need for transfusions) or whether it is due to unwanted side effects of the RBCT itself. We observed that even patients transfused with small quantities of blood transfusions have a negatively affected life expectancy. We are unsure what causes this negative association, and hypothesize that it could be related to the release of toxic iron radicals after transfusion. Future studies are needed to confirm these observations and in addition, it is necessary to perform dedicated intervention studies with the aim to overcome this negative effect.

Ways to improve diagnosis and prognosis for new patients

Validation of the revised international prognostic scoring system (IPSS-R) in patients with lower-risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry

The Registry has been opened for a while, and in this timeframe the scientific community has upgraded the criteria which were used to calculate the prognosis of patients with MDS. These new criteria (IPSS-R) were validated on the first 1000 EUMDS patients who were characterized using the ‘’old’’ (IPSS) criteria. This study shows that using the new criteria, our risk assessment improved for the various MDS patient groups. Currently, both the old and the new criteria need to be reported by the physician for each patient who joins the Registry.

Visit the Lay English Summaries of articles published by the EUMDS Registry about the topics below


  • Early platelet count kinetics has prognostic value in lower-risk myelodysplastic syndromes
  • Health-related quality of life in lower-risk MDS patients compared with age- and sex-matched reference populations: a European LeukemiaNet study.
  • Labile Plasma Iron Levels Predict Survival In Patients With Lower-Risk Myelodysplastic Syndromes
  • Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome
  • Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry


If you found the articles above of interest to you, please also read on about MDS Right.

MDS-RIGHT (Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time) is a research project that has been granted 6 million Euros from the Horizon2020 programme of the European Union. In this project – which started in May 2015 and will end in 2020 - fifteen European partners have joined forces. By comparing existing health care interventions and by defining and implementing more effective and safer interventions for elderly European citizens with anaemia and/or lower-risk MDS, the project aims to lead to better treatment compliance and more (cost-)effective use of healthcare resources. “

What is CMML? Latest Research on a Unique Syndrome

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CMML: Not a form of Myelodysplastic Syndromes

A recent article in the American Society of Hematology (ASH) Clinical News has identified how, for too many years and despite its unique clinical and biological characteristics, CMML (Chronic Myelomonocytic Leukaemia) has been treated as a form of myelodysplastic syndrome (MDS).

The contributors highlight the woeful lack of CMML-specific treatments and research. They call for improved international disease-specific response criteria to be agreed which can be used in future trials and research involving CMML patients.

Please read the full article below.

CMML: A Unique Overlap Syndrome Receiving Increased Attention

For many years, chronic myelomonocytic leukemia (CMML) has been treated as a form of myelodysplastic syndrome (MDS), despite its unique clinical and biological characteristics.

“Everyone recognized that, clearly, there were some patients who had highly proliferative features that weren’t at all typical of MDS, but CMML was still considered to be part of MDS for decades,” Mrinal Patnaik, MBBS, a hematologist at the Mayo Clinic in Rochester, Minnesota, told ASH Clinical News.

Inclusion of CMML under the umbrella of MDS for so long – beginning with the 1976 and 1982 French-American-British MDS classifications – has hindered a deeper understanding of the disease that might have resulted from studying it as a separate entity. There also are no CMML-specific approved drugs.

In recent years, clinicians and researchers have ramped up efforts to clarify the pathogenesis, natural disease progression, and presentation of CMML. ASH Clinical News spoke with Dr. Patnaik and other specialists about these efforts, as well as the challenges of defining uniform response criteria to guide clinical trials of CMML-specific treatments.

What Is CMML?

CMML is a clonal hematopoietic stem cell disorder that frequently progresses to acute myeloid leukemia (AML). It is classified as a rare disease and is estimated to occur in four of every million people in the U.S. each year. It occurs more commonly in men and rarely in young people – 90 percent of the people diagnosed with CMML are age 60 or older.(1)

Its incidence may be slightly higher than previously estimated, according to Eric Padron, MD, from the Moffitt Cancer Center in Tampa, Florida, because it often is recognized only when a patient with MDS seeks a second opinion. The disease is an “overlap” syndrome that displays characteristics of both MDS (such as peripheral blood cytopenias) and myeloproliferative neoplasms (MPNs; such as leukocytosis and splenomegaly).

The 2001 World Health Organization (WHO) classification of leukemias and other hematopoietic neoplasms first separated CMML from MDS and created a distinct category of MDS/MPN overlap syndromes. In 2008, the WHO separated CMML via blast proportion into CMML-0 (<5% blasts), CMML-1 (5-9% blasts), and CMML-2 (10-19% blasts). Finally, in 2016, the WHO again revised its classification, including recommending that CMML be classified into two subtypes: proliferative (MPN-CMML) and dysplastic (MDS-CMML) depending on the patient’s white blood cell count.(2)

Dr. Patnaik said that the WHO’s decision to confirm that CMML should not be put into either MDS or MPN but should stand alone was a positive step forward. In addition, investigators have identified certain genetic mutations such as SRSF2, ASXL1, CBL, SETBP1, and JAK2 that are not exclusive to CMML but are more commonly found in patients with CMML than MDS without proliferative features, which can aid diagnosis.

Expected survival for patients diagnosed with CMML ranges from just a few months to a few years, depending on a variety of risk factors that are not yet well defined.

Fifteen to thirty percent of patients will progress to AML, at which point survival rates drop to 4.7 months without a hematopoietic cell transplantation (HCT) and 14.3 months with an HCT.

“The whole story with CMML is that it is a spectrum in the process of evolution to AML,” said Dr. Patnaik. “So, about 30 percent of all patients with CMML will eventually transform to AML within three to five years. When that happens, survival is very poor.”

One known prognostic factor for survival is CMML subtype. The dysplastic and proliferative subtypes affect patients very differently: Patients with the dysplastic subtype have low blood counts and their natural history and clinical problems related to marrow failure are more similar to patients with MDS; those with the proliferative subtype have high blood counts and often have constitutional symptoms or symptoms related to organomegaly. Patients with proliferative forms of the disease also have shorter survival and a higher risk of transformation to AML.

How Is CMML Treated?

There is only one curative treatment for CMML: allogenic HCT. Unfortunately, only a minority of CMML patients will qualify for the procedure.(³)

Complicating matters further, there are no studies that define when a transplant is the most appropriate option for CMML. Dr. Padron recommends that all patients with high-risk disease who are young and fit enough to be considered transplant candidates should be referred for consideration of an HCT.

Two other treatments are approved for CMML, both hypomethylating agents approved for MDS for which the FDA indication included CMML: azacitidine and decitabine. However, the pivotal trials included few patients with CMML, and response rates are low, especially in proliferative forms of the disease.

“There’s an injustice that has been done to this disease, going back almost a decade,” Dr. Patnaik said, referring to the WHO’s 2008 classification, which introduced the MDS/MPN category of diseases that displayed proliferative and dysplastic characteristics.

“Essentially all the trials that included patients with CMML used disease response criteria designed for MDS,” he explained. “There is clear evidence that [treatment with hypomethylating agents] does not alter the disease biology. In fact, in Europe, if a patient has proliferative CMML, hematologists can’t even use these drugs.”

Instead, doctors tend to treat patients with drugs that target specific symptoms of CMML, such as cytopenias, splenomegaly, and infections with transfusions, blood cell growth factors, and antibiotics. While these can improve patients’ quality of life, Eric Solary, MD, and Raphael Itzykson, MD, wrote in Blood, ”they barely modify disease evolution. … Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.”(4)

How Do We Know if a Treatment Is Working?

The higher prevalence of MDS had a negative effect on CMML clinical trials. “For a long time, the community was so interested in MDS that CMML-specific trials were almost absent,” Dr. Patnaik added. For example, he said, drug studies can enrol 400 patients with MDS, and 10 with CMML.

A major impediment to conducting CMML-specific drug trials has been a lack of uniform response criteria. Without these, it is extremely difficult to prove to regulatory agencies that a drug is working, even if a doctor can tell a patient is doing better. This decreases the likelihood of trials being supported or even considered.

“One of the difficulties in trying to understand how patients with different types of CMML respond to different therapies is that we never had [disease-specific] response criteria at all,” said Michael Savona, MD, a hematologist at Vanderbilt University in Nashville, Tennessee. “When we go to different trial sponsors to try to access new drugs, the most common response we get is, ‘Well, how do you know if it’s working?’ And, to be honest, we don’t have a very good answer.”

Defining response criteria is a challenge because the natural history and prognosis of CMML are poorly understood. There are about 10 prognostic scoring systems that have been proposed for CMML, explained Dr. Padron, adding that “there are no good data telling us when the best timing is for transplant.”

To fill in the knowledge gaps, Dr. Padron and colleagues have launched a project to sequence nearly 1,000 patients with CMML both before and after treatment “to see whether we can confirm what the prognostic mutations are and try to answer that question of which prognostic scoring system we should be using.”

In 2015, Drs. Savona and Padron were part of an international working group that published a proposal of uniform response criteria for CMML, which they hope will be independently validated and refined over time.(5)

“The FDA is quite keen on quality-of-life–associated response elements, and my sense is that if we can improve some of these quality-of-life metrics, specifically how patients are feeling and their spleen size, then that will translate to improved survival,” said Dr. Savona, who was first author on the response criteria paper. The proposal included criteria for measuring improvements in blood counts and reduction in myeloblasts, similar to MDS, but also meaningful reductions in spleen size and clinical symptoms.(5)

At the end of 2018, the European Hematology Association and the European LeukemiaNet released new guidelines for CMML diagnosis and management that update and revise criteria put forth by the MDS International Working Group (IWG) in 2000 and 2006.(6)

“While response to treatment can be evaluated by IWG 2006 criteria in [dysplastic] CMML, recently proposed ad hoc MDS/MPN criteria should be preferably adopted,” the guideline panel wrote. “With respect to pivotal phase III clinical trials, we recommend robust primary endpoints such as overall survival, progression-free survival, or event-free survival, and incorporation of the MDS/MPN criteria as secondary endpoints.”

Where to Next?

While the recently proposed international response criteria have increased interest in studying and developing treatments for CMML, researchers still have a long way to go. The patient population is exceptionally heterogeneous and the disease relatively rare, making clinical validation a challenge.

Studying this rare disease might require new trial designs. Dr. Savona is the principal investigator of the ABNL-MARRO study, an initiative from the MDS/MPN IWG and Vanderbilt University Medical Center in which Drs. Patnaik, Padron, Solary, and Itzykson are also involved.(7) ABNL-MARRO, or “A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes,” will enrol patients with MDS/MPN overlap syndromes in the U.S. and several European countries.

The basket design allows new compounds and therapy combinations to be introduced easily among MDS/MPN IWG clinical sites where patients with MDS/MPN are treated. Researchers also will study the biology and pathophysiology of the diseases to identify potential markers of severity, prognosis, and response.

“We’re proud of this study because it is going to open across the U.S. and Europe with the same protocol,” said Dr. Savona. “It’s been the challenge of my career to try to operationalize something across different countries like this.” —By Emma Yasinski


    1. American Cancer Society. “What Are the Key Statistics About Chronic Myelomonocytic Leukemia?” Accessed April 10, 2019, from
    2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391-405.
    3. Deeg HJ, Sandmaier BM. Who is fit for allogeneic transplantation? Blood. 2010;116:4762-70.
    4. Solary E, Itzykson R. How I treat chronic myelomonocytic leukemia. Blood. 2017;130:126-36.
    5. Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015;125:1857-65.
    6. Itzykson R, Fenaux P, Bowen D, et al. Diagnosis and treatment of chronic myelomonocytic leukemias in adults. HemaSphere. 2018;2:e150.
    7. ABNL MARRO. Accessed April 10, 2019, from
Image By Simon Caulton - Own work, CC BY-SA 3.0,

In CMML, there are increased numbers of monocytes and immature blood cells (blasts) as well as abnormal looking cells (dysplasia)

Chemotherapy at home: less visits to the hospital and better quality of life

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Written by Janet Hayden - Lead Myeloid Clinical Nurse Specialist - King’s College Hospital

MDS specialist nurse Janet Hayden gave two talks at our recent London Patient meeting at King’s College Hospital.

The first one was a report about the MDS International Symposium in Copenhagen, which she attended thanks to a travel grant from MDS UK. The symposium included a 1 day nurse programme, attended by nurses from several countries.

Janet says:

It is important that those of us lucky enough to attend these events get the opportunity to share that learning and knowledge back at base camp and especially to the MDS patient community who may not readily have access to some of this knowledge via other forums . So I have attempted to summarise some of these main points which may be of interest to you.

Janet says:

The program this year was heavily scientific. The presentations showed the ever increasing complexity of both evolution of MDS and the diagnosis. it is clear that the science has moved on tremendously in the past decade. The list of somatic mutations acquired in MDS is ever growing and the understanding of which of these genes does not respond or does respond continues to evolve. Challenges remain due to the heterogeneity (patients having more than one acquired mutation) that presents major challenges for treatment strategies.

A large team from Denmark presented their news and developments for patient services. These services included a Chemotherapy at Home, or mobile chemotherapy option, enabling patients to lead as normal a life as possible, whilst receiving their treatment. It also covered a patient peer to peer support scheme, as well as an exercise regime to help boost energy for AML and MDS patients.

Chemotherapy at Home scheme at King’s College Hospital

Her second talk introduced the Chemotherapy at Home scheme that will soon be in place at King’s College Hospital.

Click here or on the image to read and download Janet Hayden's presentation.

The Benefits for Patients

From the patient point of view there are a number of patients who struggle with travelling and travel costs. They experience long waiting times, increasing time off work for the patient and their carer.

In addition, the fact that they do not need to stay at the hospital environment while receiving treatment reduces their risk of infection so patients may choose chemotherapy at home to avoid the regular trips to the hospital.

The Benefits for the NHS

Moving care out of a hospital setting, is an important goal for the Institute’s and the broader NHS. There is evidence that it improves patient experience and quality of life, while reducing NHS burden and costs. As it releases capacity from busy outpatient clinics the scheme will help to improve NHS ability to deliver effective care.

The scheme has proven to be the preferred option by patients in Birmingham and other areas. Both King's College Hospital NHS and Guy's and St Thomas' NHS Foundation Trust staff are very supportive of the initiative, citing the positive impact it could have on patients.

Chemo at Home could be financially sustainable, and cheaper for the Institute than traditional clinics.

Chemotherapy at home in Spain

Would like to speak to KCH MDS nurses Janet Hayden or Geke Ong?

As ever, if you would like to speak to KCH MDS nurses Janet Hayden or Geke Ong, they are available during our MDS meetings at King’s.

These meetings are free and open to all patients in the UK.

The next London meeting is planned for 18th November. Click here for details of our next London Meeting.

Click here for dates and venues for all our patient meetings in the UK.

Familial/inherited MDS: rare but important to keep in mind

Research FOR Patients
-For an informed and empowered opinion-
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Is MDS likely to be passed down from parent to child?

Written by Prof Jude Fitzgibbon, Prof Tom Vulliamy and Prof Inderjeet Dokal, Queen Mary University of London

When a patient is first diagnosed with myelodysplastic syndrome (MDS), one of the most frequent questions posed is whether the disease is likely to be passed down from parent to child, and if other family members could conceivably develop this malignancy too.

Conventionally, heritable (i.e. passed from parent to child) forms of MDS are thought to be rare and are typically, NOT considered to run in families.

Our research group at Queen Mary University of London (QMUL), with funding from the charity Bloodwise, have been collecting and storing blood and bone marrow samples from these rare patients and their families in order to better understand the nature of the faulty genes responsible for inherited MDS. This research is important for the individual families, as it provides valuable
information for treatment of the disease, assessing risk and genetic counselling, but it also offers a unique opportunity to identify the critical early genetic events that give rise or predispose patients to MDS.

Jude Fitzgibbon talks with Sophie Wintrich about familial MDS. Watch the video

Since 2016, inherited forms of myeloid malignancies, including MDS, have been included as a separate disease entity in the World Health Organisation (WHO) classification of haematological cancers.

This is leading to a greater awareness on behalf of haematologists regarding the existence of these forms of disease, enabling more tailored management of this group of at-risk individuals.

This is important, as patients with ‘familial MDS’ (i.e. with a predisposing mutation present in every cell) tend to develop symptoms at a much younger age compared to people with ‘sporadic disease’ (i.e. mutations are restricted to the MDS only).

We also appreciate that MDS can arise as part of a wider syndrome, with many patients/families initially exhibiting bone marrow failure syndromes such as Fanconi anemia, dyskeratosis congenita, and Shwachman–Diamond syndrome which often subsequently lead to MDS.

Why is it important to identify patients with familial MDS?

Our research is demonstrating that there isn’t a singly mutated gene responsible for familial MDS but many different genes,
some of which are also mutated in sporadic forms of the disease (RUNX1, GATA2). In comparison other mutations (in the germline) appear enriched or exclusive to inherited forms of MDS (DDX41, SAMD9) and this is offering researchers novel insights into the causes of MDS and the prospect of developing better treatments for all MDS patients.

It is, therefore, important that, when a new patient is diagnosed with MDS in the clinic, steps are taken to determine whether the disease has a significant genetic-inherited component. This is crucial, as in some subtypes of inherited/familial MDS subsequent therapy must be modified.

  • For example, if a patient has MDS associated with an underlying telomerase mutation then the chemotherapy conditioning regimen performed prior to a bone marrow transplant has to be reduced.
  • Equally, a haematologist would want to ensure that, in selecting bone marrow/stem cell donors, an asymptomatic family member with the same genetic defect is not used as the donor as the recipient could go on to develop MDS again at a later time point./li>

Germline vs Somatic (Sporadic) Mutation

Which services does the research group provide?

In order to facilitate identification and genetic categorization of inherited/familial MDS our research group (in collaboration with the Genetics Laboratory at Birmingham and support from Bloodwise) provides genetic testing in such cases. This means if a clinician suspects that their patient may have a significant genetic component they can send blood samples directly to our laboratory.

Indeed, in the future, our expectation is that every MDS patient will have a molecular profile performed as part of their overall management, to identify the specific mutations that are exclusive to their MDS and to assess if there is a significant inherited component, linked to their disease, where a mutation is present in all cells in the patient’s body.

We are also able to provide specific advice on the management of patients if a genetic defect is found in one of the many genes that are associated with inherited/familial MDS by contacting us directly (email

Furthermore, if a genetic defect is not found in one of the known familial MDS genes and there is a strong clinical suspicion for familial MDS (for example, if there is a history of multiple MDS cases in the family) then these samples are put forward for research studies aimed at new gene discovery.

In summary:

  • Familial/inherited MDS is a very heterogeneous and complicated disorder. It is thought to be rare but the precise figures on its incidence and prevalence are not known.
  • Over the last 20 years many genes have been identified that are responsible for familial/inherited predisposition to MDS and they have highlighted the importance of making specific modifications to therapy to achieve optimal outcomes.
  • Our ongoing research programme at QMUL provides genetic testing for all of these genes as well as a strong focus on identifying new disease genes where current genetic tests fail to identify a defect in at-risk families.

Precision medicine is coming to the clinic to treat MDS

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

by Niels Jensen

What is precision medicine?

In precision medicine the basic idea is to develop a treatment for the specific cancer of individual patients based on a genetic understanding of their disease. Precision medicine has also been called personalized medicine or targetted medicine.

The basic idea is not completely new. Already in November 2013 Esquire Magazine reported the development of a treatment specifically for Stephanie Lee's colon cancer . The treatment effect had been verified on a banana fly, but the board of oncology at Mount Sinai in New York hesitated to give the experimental treatment to the patient and opted for a more conventional treatment. Read the story in Esquire

In Denmark, a collaboration between clinicians at Rigshospitalet and researchers at the Copenhagen University Biotech Research and Innovation Center (BRIC) has systematized a procedure for the development of a precision treatment for each MDS or leukemia patient who is signed up for trial, which has very few exclusion criteria, and straight forward inclusion criteria: you must have either MDS or leukemia and being treated at one of seven hematological centers in Denmark.

Read the full article: New Research Centre to improve personalized treatment for Danish patients with blood cancers

How does precision medicine work?

When a patient signs up for the trial, they are given a standard protocol treatment depending on the disease and the stage of the disease.

While the patient gets the protocol treatment' clinicians and researchers get to work: blood and bone marrow samples are collected from the patient. The patient's tumor cells are then screened in the labs against treatment effect from one or two of more than 400 already commercially available drugs.

If a drug or mixture of drugs shows a positive effect on the patient's cancer cells, then the second step is initiated. This involved growing the patient's cancer cells in the lab. Once enough cells are available they are injected into a mouse together with some of the microenvironment from the patient's bone marrow.

Then the researcher treats the mouse with the drug or drug mixture showed as having a positive effect during the laboratory screening.

If the mouse is successfully treated, then the clinicians have a precision medicine which, in Denmark, can be legally offered to the patient in the clinic.

Doctors in Denmark are allowed to use drugs off-label if they have evidence that the treatment works. This has been done for many years with EPO-like substances to improve red blood cell counts in low risk MDS patients.

Simultaneously, a whole genome next generation sequencing of the samples from the patient is performed to identify the specific mutations in the patient's cancer cells. This helps researchers to understand why a particular drug or drug mixture have a positive effect, and add the laboratory screening.

Precision Medicine - A specific drug for each genetic mutation

Professor Kirsten Grønbæk: "While we try to treat a specific patient, we also learn something for the benefit of future patients"

A scientific article published by the University of Copenhagen, Danish Research Center for Precision Medicine of Blood Cancer, explains that the program aims at improving the immediate and long-term outcome for blood cancer patients by coordinating and strengthening ongoing blood cancer research into a program pursuing research questions and integrating results from bench-to-bedside and bedside-to-bench.

The goal is to optimize the use of already approved drugs, identify new targets for therapy, develop novel therapies, test potential novel drugs in pre-clinical models, and collaborate with pharmaceutical companies on developing new drugs and test these and other novel drugs in Phase I-II clinical trials.

Professor Kirsten Grønbæk, PTH Professor and Chief Physician at Rigshospitalet, says:

Via 'drug screening' the cancer stem cells from the individual patient could be exposed to 400 different drugs.

In this way, we hope to find the medicine that accurately affects the individual's cancer stem cells, which is the cause for the cancer to return.

At the same time, we will try to find the molecular changes that indicate that this is the perfect treatment. For some patients, we will immediately find one or more drugs that work, but not for all who are in the need for treatment.

The idea is that while we try to treat a specific patient, we also learn something for the benefit of future patients.

The equipment for this trial have been financed by a grant from the Novo Nordic Foundation. A grant from the Danish Cancer Society covers the expenses for the first three years, and also access to the trial across the country. The trial was conceived by a collaboration between clinician Kirsten Grønbæk, and BRIC researchers Kristian Helin (currently part time at Memorial Sloan Kettering) and Bo Porse.

Clinical Trials open to recruitment in the UK

Harmony: a European project with good news for MDS patients

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

The Harmony Alliance is a first-of-its-kind partnership of over 80 private and public organisations aiming at enabling better and faster treatments for patients with blood cancers such as MDS.

Patient Organisations have a very active role in Harmony, and we are permanently involved in the definition of outcomes for patients and the design of research projects.

At the heart of Harmony is the sharing of big amounts of data from patients with blood cancer from all over Europe.

Watch this video to understand how Big Data can help clinicians to treat blood cancer

The Harmony Alliance aims to develop treatments that are:

  • more effective
  • have fewer side-effects
  • secure a higher quality of life

However the best possible treatment may differ from one person to another. This is partly due to biological differences such as the genetic characteristics of the tumor cells.

By studying big amounts of data, researchers can learn how to predict the development of a particular disease and how certain subgroups of patients will respond to treatment.

This should result in tools that will enable clinicians and doctors to rapidly select the most promising treatment for a particular patient.

How does Harmony ensure data quality, safety and privacy?

The Harmony Alliance has developed very careful data-handling procedures to provide maximum protection of the patients’ privacy, while leaving the data rich enough for meaningful scientific analysis.

Watch this video to understand how Harmony ensures high quality and secure data that will help improve the treatment of blood cancers.

The new generation of MDS diagnostics: the Myeloid Gene Panel

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

Report from the MDS Education Forum that took place in November 2018. Interviews by Sophie Wintrich Chief Executive of MDS UK Patient Support Group.

What are Myeloid Gene Panels and how are they used in MDS?

Myeloid Gene Panels are a set of specific genes present in MDS patients, whose mutations are thought to be driving MDS. These genes can be identified with innovative genetic tests.

Prof Nick Cross, professor of Human Genetics at the University of Southampton says:

MDS is a very complex disorder, but, as with all these different types of disorders, they are fundamentally driven by abnormalities of genes that are acquired during the lifetime of an individual.

What we are looking for is the large number of genes that are involved in MDS to see whether there are specific mutations, changes in those genes, that may actually be driving MDS.

Finding these can increase the confidence that this is really a diagnosis of MDS. We also know that some particular genes are associated with a better or a worse prognosis, and that they may indicate specific types of treatment.

Take a look at what is being done in the Wessex region, through a number of services, including Myeloid Gene Panels, and why such tests and technologies are used to help scientists and physicians in their diagnosis of MDS.

Scientists Interviewed:

  • MS Sophie Laird, Clinical Scientist , Wessex Regional Genetic Laboratory
  • Dr Sally Killick , Consultant Haematologist, Bournemouth Hospital
  • Prof Nick Cross, professor of Human Genetics at the University of Southampton

The Myelod Gene Panel and how it helps MDS Patients

Dr Lynn Quek, Consultant Haematologist and Research Scientist at Oxford University Hospital, is interviewed by Sophie Wintrich.

She explains the impact that Myeloid Gene Panel data has on treatment decisions in MDS, and how the genetic information of individual patients helps to personalise and tailor their clinical care.

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