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Understanding MDS and the biological processes driving treatment response

Understanding MDS and the biological processes driving treatment response

Steven Lane in the lab

Understanding how myelodysplasia (MDS) forms from normal cells is the goal of a Leukaemia Foundation-funded* research project led by Dr Steven Lane at QIMR Berghofer Medical Research Institute (Brisbane).

“MDS is a very common disease; we see it a lot, and it can turn into acute leukaemia,” said Dr Lane, Principal Investigator of the study titled, Understanding the pathways that regulate transformation of normal stem cells to myelodysplasia and leukaemia.

Azacitidine is the only specific treatment for MDS in Australia and while a lot of people with MDS try azacitidine, more than 50% of them don’t benefit from the drug. Azacitidine is unpredictable as to which patients it will and won’t work on, and information about how it works in patients is limited.

The only other treatment option for MDS is transfusion support to keep people’s blood counts up.

“We can’t offer good treatment to a lot of patients and there’s nothing available to people with low-risk MDS, so this is an area of very high need in the community,” said Dr Lane.

“MDS is a group of diseases that is poorly understood, and the genetics of all the myelodysplasias might all be quite different.

“We know that for patients with high-risk genetic features such as changes in the chromosomes, or changes in a particular gene such as P53, the survival and outcomes from myelodysplasia is extremely poor, and very similar to acute myeloid leukaemia (AML).

“There also are patients with low-risk MDS who may live for many years without any treatment.

“It’s important to understand how the genetic factors found in a patient’s blood cancer, and other clinical factors such as their age and other illnesses, contribute to their overall prognosis,” said Dr Lane.

In normal blood formation, there is a tightly regulated process where the blood stem cells in the bone marrow mature into functioning cells such as neutrophils and red blood cells, and these are the cells that are reduced in patients with myelodysplasia.

Research at Dr Lane’s lab concentrates on understanding the disease-causing cells in MDS, AML and MPN, and how these disease stem cells drive the transformation to disease, as well as looking into resistance to treatment.

“We’ve generated a new, unique model** that we use in the lab to understand the transformation from normal blood formation to myelodysplasia,” said Dr Lane.

“With the Leukaemia Foundation grant, we will use this model to better understand how azacitidine works, to get a better idea of the processes regulating the response, and then use the model to test how new drugs might be used in MDS.

“The model develops low blood counts, particularly in the platelets, which then progresses to low counts in other cells as well, then transforms into acute leukaemia after 6-12 months.

“It is a step-wise progression from normal blood through to myelodysplasia, through to acute leukaemia, so we can look at all the different stages of the disease.

“Azacitidine is an epigenetic therapy and we know its mechanism of action changes the methylation of DNA. Put simply, that means it turns genes back ‘on’ that have been switched ‘off’ in the myelodysplasia cells. Turning those genes back on, allows the cells to progress back to normal blood formation.

“We’ve shown that the MDS stem cells are very responsive to azacitidine, by taking those cells before and after azacitidine treatment to look at how the genetics of the cells might change and what signals they are putting out,” said Dr Lane.

“By doing that, we can understand the biological processes that drive the response to azacitidine.

“Now we are going back to the original model to understand if particular pathways might be different in these cells compared to normal cells.

“One of those pathways is apoptosis, which is basically the way a cell dies, and we’ve seen a difference in apoptosis between the model and normal blood stem cells.

“Therefore, we’re using new drugs that might target apoptosis to see if they work in this myelodysplasia model.

“We think this is really important research at the international level,” said Dr Lane.

“If we can show that this apoptosis process is different or abnormal in the model with myelodysplasia, and we can show the best way of combining treatments, we hope these can then be used in a clinical trial, and in the clinic moving forward.

“We’re keeping our eyes open for other drugs that work, but the predominant focus of this project is to improve the response to azacitidine.

“Some people have a spectacular response to azacitidine and do really well. We want to improve on that treatment, so most people do really well, not just a small percentage.”

The protocol Dr Lane is testing is azacitidine combined with venetoclax***.

“We hope we can use these drugs together to improve responses in all MDS patients,” he said.

“There’s a published trial using azacitidine and venetoclax in AML and we would hope this drug combination can be used in myelodysplasia as well.

“One of the difficulties will be getting around the toxicity of these drugs.”

Azacitidine is given daily for one week by injection, followed by three weeks with no treatment.

“We have shown in our model that by giving azacitidine continuously (every day) at a much lower dose, there’s an improved response rate, and the response is a little more specific for the MDS cells. So, this protocol may be better,” said Dr Lane.

On this project, Dr Lane’s lab is working with collaborators in Germany, at the National Centre for Tumour Diseases (Heidelberg), the German Cancer Research Centre (Heidelberg), and Professor Andrew Perkins’ group at Monash University (Melbourne).

* $160,000 over two years, as one of the Leukaemia Foundation’s Strategic Ecosystem Research Partnerships (SERP) to support high impact research. This project has been part funded through the estates of Rina Chow and Professor Patrick Quilty AM and the generous support of individuals in the community.

** Therese Vu was the postdoctoral researcher who worked on this project.

*** The Leukaemia Foundation provided funding for early work on the precursor to ABT-199 (now known as venetoclax). This research, undertaken by Dr Kylie Mason, Professor Andrew Roberts and collaborators at the Walter & Eliza Hall Institute (Melbourne) through the Leukaemia Foundation’s National Research Program Grants-in-Aid 2012 and 2012, assisted in the development of venetoclax.

Further support is critical to ensure all Australians can reap the benefits of scientific advancements. If you would like to invest in blood cancer research, contact us 1800 620 420 today to find out how.

“Every two weeks I need two bags of blood”

“Every two weeks I need two bags of blood”

Amber Walker has relied on fortnightly blood transfusions since being told she had blood cancer for the second time.

After conquering blood cancer three years ago, Amber was devastated to learn that she had another blood disease in April 2020.

“I had been really sick since the previous November and was nauseous or vomiting nearly every day,” explained the 27-year-old.

Amber Walker in hospital
Amber rocking her bald head during treatment.

“They eventually confirmed I hadn’t exactly relapsed, but I had a very similar blood disease called myelodysplastic syndrome.”

Myelodysplastic syndromes (MDS or myelodysplasia) are a group of diseases which all affect the production of normal blood cells in the bone marrow.

Amber has since relied on fortnightly blood transfusions while her medical team determined whether she will need chemotherapy or a transplant.

“Every two weeks I need two bags of blood to keep my red blood cell levels up,” Amber said.

“I definitely notice the difference after having a transfusion. It’s like drinking an energy drink and you feel ready to go again for the week.”

Amber is incredibly grateful for blood donors who have given her a lifeline while she plays the waiting game.

“I’d honestly not be here if it weren’t for all those who donate, it really does save lives,” said Amber.

“I heard on the radio the other day that donated blood only lasts 42 days. That really stuck with me. We’re always going to need more blood because there is no infinite supply.

“You never think about it until you really need it. To anyone considering donating please don’t wait, just go and get it done.

“I’ve even convinced my sister and mum to do it. Their blood may not come to me, but it could save so many others who really need it.

“You just have to think it could be your sister, mum, partner one day – this disease doesn’t discriminate.

Amber Walker and partner Cal
Amber with her partner, Cal who has been her “rock”.

“I only wish I had donated more before I got sick.”

In early June 2020, Amber was told she would need a bone marrow transplant from an unrelated matched donor. Again, she will need to rely on the generosity of a stranger to give her a second chance.

“I think this second time around has been harder because I have time to think about it and mull it over,” said Amber.

“I’m so god-damned scared, but I’m equally keen to get it done and get on with my life.”

Until then she will continue to have her fortnightly transfusions, owing her life to the many wonderful Aussies who choose to donate blood.

If you’re 18-76 years old, healthy and weigh over 50kg, you may be able to give blood. Visit donateblood.com.au to see if you’re eligible or to make an appointment.

Leukaemia Foundation invests in innovative MDS research 

Leukaemia Foundation invests in innovative MDS research 

Better understanding and treating MDS is the focus of five new research projects that are part of the Leukaemia Foundation’s National Research Program over 2019-2022.

This $940,000 investment into MDS research at some of Australia’s leading research centres is aimed at understanding the genetic changes that drive disease progress, developing genetic testing, preventing infection, investigating better treatment options, and providing access to new treatments through clinical trials.

Strategic Ecosystem Research Partnerships (SERP)

Of the Leukaemia Foundation’s nine current Strategic Ecosystem Research Partnership projects, two are focused on MDS.

Dr Steven Lane at his desk
Dr Steven Lane

Understanding the pathways that regulate transformation of normal stem cells to MDS and leukaemia is the title of  Professor Steven Lane’s project at the Queensland Institute of Medical Research (Brisbane). Prof. Lane is seeking to understand the genetic changes that occur as normal cells progress to become MDS and then to become leukaemia. He also is examining the mechanism of action of azacitidine (Vidaza®), the only PBS-funded therapy for MDS. On this project, Prof. Lane’s lab is working with collaborators in Germany, at the National Center for Tumour Diseases (Heidelberg) and the German Cancer Research Center (Heidelberg), and Professor Andrew Perkins’ group at Monash University (Melbourne).

Precision medicine is an approach to patient care that allows doctors to select treatments based on a patient’s genetic profile and has the potential to transform the delivery of healthcare today and into the future.  Genetic and genomic testing, also known as genomics, is the pathway to precision medicine. However, the widespread use of genomics as the standard of care in clinical practise is not yet a reality for blood cancer patients.

Anna Brown in the lab
Dr Anna Brown

Dr Anna Brown at the SA Genomics Health Alliance, Haematological Malignancies Node, University of South Australia (Adelaide), is developing state-of-the art genomic testing which can be used to diagnose blood cancer and monitor disease progression as well as helping the clinical team in treatment selection. Twelve months into this project, Dr Brown and her team have developed, tested and put into clinical practise a single tube genomic test  which can identify mutations in more than 40 clinically relevant genes in MPN, MDS, Primary and Secondary AML, atypical CML, chronic neutrophilic leukaemia, mastocytosis, CMML and JMML. In the next few months this test will be expanded to identify more than 60 genes and in myeloma. Read more on Dr Brown’s research that is due to be completed in November 2020.

Translational Research Program (TRP)

The Translational Research Program  is an initiative that aims to take new and innovative research out of the research laboratory and helps move it into the clinic. The Leukaemia Foundation has partnered with the Leukemia & Lymphoma Society (U.S.) and Snowdome Foundation to co-fund these grants. One of the five current TRP projects is for MDS, which is one of the most common blood cancers among the elderly, and which has few treatment options.

Dr Ashwin Unnikrishnan
Dr Ashwin Unnikrishnan

While the drug, azacitidine is the best available treatment for people with MDS, more than half of those who receive the treatment don’t respond. As well, a significant number of MDS patients who do respond to azacitidine will eventually relapse, which highlights a need to develop more effective and durable therapies. At the University of NSW (Sydney) Dr Ashwin Unnikrishnan is investigating molecular mechanisms within MDS cells affected by azacitidine, as a means to developing new treatment options for MDS. His project title is Beyond azacitidine: investigating new therapeutic strategies for the treatment of MDS and he is collaborating with St Vincent’s Hospital (Melbourne) and Technical University of Denmark. Read more about Dr Unnikrishnan’s research.

PhD scholarships

The Leukaemia Foundation is helping the brightest medical and science graduates pursue a research career in blood cancer by collaborating with the Haematology Society of Australia and New Zealand (HSANZ) to co-fund PhD scholarships. Over the last two years we have been proud to award six scholarships through our PhD Scholarship Program and one of them focuses on allogeneic stem cell transplants, the most common type of transplant for people living with MDS.

Julian Lindsay
Julian Lindsay

Julian Lindsay is a bone marrow transplant pharmacist and his research project, Antifungal management optimisation in haematological malignancy and haematopoietic stem cell transplantation, is aimed at preventing infections in people with blood cancer and those undergoing bone marrow transplants. These patients have highly suppressed immune systems due to having chemotherapy and the transplantation techniques used to achieve better cure rates. Based at the Fred Hutchinson Cancer Research Center in Seattle (U.S.), Julian will address critical knowledge gaps related to specific patient risk factors for developing infections such as cytomegalovirus, Epstein-Barr virus and invasive fungal infections, and investigate the optimisation of antimicrobial therapies to prevent infections and improve the survival of these patients.

Trials Enabling Program (TEP)

In an Australian first, the Leukaemia Foundation has established a Trials Enabling Program in partnership with the Australasian Leukaemia & Lymphoma Group (ALLG). The aim of this initiative is to help people with blood cancer access the latest therapies by bringing international clinical trials to Australia.

Associate Professor Andrew Wei in the lab
Associate Professor Andrew Wei

Associate Professor Andrew Wei is principal investigator for the AMLM24 trial for newly diagnosed AML and those with MDS (FLT3 mutation). It is a multi-centred trial run out of Monash University (Melbourne), in collaboration with the ALLG.  Most clinical trials are for people who have relapsed or no longer respond to available treatments, but this trial is looking at a new treatment regimen as a frontline treatment at diagnosis. The AMLM24 trial is co-funded by HOVON (the Haemo Oncology Foundation for Adults in the Netherlands) and AMLSG (the Acute Myeloid Leukaemia Study Group, Germany).

Professor Ulrich Steidl describes research as “a team sport”

Professor Ulrich Steidl describes research as “a team sport”

Dr Ulrich Steidl
Ulrich Steidl is an experimental haematologist who specialises in MDS and AML research

The Professor of Cell Biology and of Medicine (Oncology) at Albert Einstein College of Medicine, and associate chair for translational research in oncology at Montefiore Health System (New York) spoke to MDS News at the International Society of Experimental Hematology (ISEH) conference in Brisbane in 2019. His presentation was on Understanding and Targeting the Stem Cell Origins of Myeloid Malignancies.

What does an experimental haematologist do exactly?

The treatments applied to patients in the clinic involve a decade-long process of research and development. An experimental haematologist does all the work that happens pre-clinically; the experimental work that ultimately leads to something that helps develop therapies. This is everything that goes on before and including clinical Phase I, II or III trials – the clinical testing. It also includes the study of normal blood and bone marrow and normal blood cell formation and generation, and how blood cells function, which is a very important part of that research. This basic biology is an extremely important starting point for the study and understanding of diseases.

“If you don’t know what’s normal, you can’t understand what is going wrong.”

Tell us about your background

I trained as a physician scientist. At medical school I quickly realised just medical school was not what I wanted to do. I wanted science training and education, so simultaneously pursued a PhD in a leukaemia lab. For my clinical training, I picked medical haemato-oncology, but found the clinical care of patients, especially with leukaemia, incredibly frustrating because the cure rates of many of the diseases I am now researching in the lab are very low, especially MDS and AML. You see the patients; you want to do the best. You do the therapy, you develop personal relationships with the patients, but ultimately you see 90% of your patients die. You realise you are just delaying the inevitable in most cases. After a few years, I decided I wanted to make a more fundamental difference and I knew where the real improvements were coming from. I had to focus on research and that is what I am doing now – laboratory research and translational research on devastating diseases like MDS and AML.

What is your overall objective?

Ultimately, to improve patient outcomes, that is still the goal. But there are many steps and I see a high value also in generating and contributing to the fundamental knowledge, biological knowledge, and understanding of diseases that enables others (colleagues and the field in general) to do better research, to think about things differently and to help other researchers to succeed. Research is a matrix-type endeavour. You do your own thing, but you are in this network and meetings like this (ISEH, Brisbane, August 2019) are a great example. You hear what everybody else is doing, you read [scientific] papers, the data, and this constantly changes how you think about a problem. It is a huge team effort. I contribute my little piece to this mosaic. Maybe other people make the big discoveries or have a great idea that ultimately leads to a breakthrough. Of course, we all want to be the one that makes the next big step, but we all are moving together as a field and everybody makes little additions here and there. Then hopefully, for one of us, this all will lead to a big leap at some point.

“This is a team sport. There is no doubt about it.”

What’s new in your research?

We have been very interested in the stem cell origin of diseases like MDS and AML for a long time. If you go back 15 years, the field had a rather simplistic view of cancer, and it was not fully recognised what the contribution of different subpopulations in a tumour are. Around 2005, people started to realise there are differences between the cells, and that in a complex process like cancer one of the biological requirements is that multiple events can accumulate and lead to tumour formation. It basically requires cell types to have a sufficient lifespan to actually accumulate multiple steps of transformation. In simplistic terms, if you take a skin cell that is shed off every day, essentially, if something bad happens to that cell, a day later that is irrelevant because that cell has fallen off and cannot acquire another event. But if bad things happen in stem cells, which have a very long lifespan and are around for decades in the human body, these cells have the biological ability to accumulate multiple aberrations. That is a concept that we, and others, started to pursue many years ago.

In the last few years, we have made significant advances in our understanding of the stem cells in MDS and AML. Technological advances allow us to isolate these stem cells better and to analyse them better through molecular biological methods. We’ve made a lot of progress pinpointing the problems at the stem cell level that cause the production of bulk tumour cells that are ultimately diagnosed in the clinic, and that cause all the symptoms. We are now much closer to a causative treatment approach, where we get to the root of the problem rather than dealing with the symptoms and with late-stage consequences of the disease-driving events.

Some of these discoveries have led to new therapeutic approaches that we hope will lead to a more lasting disease control. A good analogy is… if you have a weed and you can use a lawnmower to cut it back, that works for a few days, but it grows back. Unless you get to the root of the problem, you will never truly get rid of the weed. Using that metaphor, we are now much closer to the root of the problem, which I think is at the stem cell level. We are now better able to understand what is wrong and we’ve reached the point where we can begin to interfere with that in a targeted manner and to develop targeted therapies for some of the abnormal pathways that we and others have discovered in these abnormal stem cells. Some of those have reached early-phase clinical trial status, so we will see in the next five to 10 years how and whether some of these approaches will pan out.

How do targeted approaches work?

These targeted therapy approaches won’t necessarily fully replace chemotherapy and that is something that is very important to understand. Bulk tumour cells cause a lot of the clinical symptoms patients deal with and is why they initially show up in the clinic or doctor’s office and are diagnosed. You must get rid of those cells just to alleviate acute symptoms, then stem cell targeting hopefully will lead to lasting control of the disease. Chemotherapy is actually very good at eradicating or eliminating the bulk tumour, but the problem in MDS and AML is that it is a very transient success. Most patients will respond very well to chemotherapy, but only for a few weeks or months, then the disease grows back. Ultimately, a combination approach would mean initial chemotherapy supplemented with a targeted therapy, to keep the stem cell compartment in check. In an ideal world, we would love to just give targeted therapy and not do all the chemotherapy with all the bad side-effects. Chemotherapy is good in the short-term but has lots of dangerous and problematic long-term consequences because it is genotoxic. This means it induces additional mutations in other cells, including these long-lived stem cells, on top of the mutations that are already there because of the cancer. We would love to reduce chemotherapy as much as humanly possible, to the bare minimum required, even get rid of it entirely, but that really may be a long-term goal for AML and MDS in particular.

Ulrich Steidl at a computer with a colleague
Ulrich Steidl: “What you get out of experiments is almost always more complicated than you thought”.

What is your lab working on?

We are an academic lab with about 15 researchers – a 50/50 mix of post docs and graduate students and a few research technicians. We have been very active in target identification and we collaborate with other academic groups or companies that have drugs that are active against the targets we identify. One is a cell-surface target our lab discovered in MDS and AML stem cells, called IL1RAP, and which other groups have validated. We publish our results, so everybody has access, and there is significant interest. Several companies and academic groups are developing immunotherapy approaches now against IL1RAP. These range from antibodies, and T-cell engagers, to CAR-T cells, and we will see some in the clinic soon. We discovered another target in MDS and AML stem cells; an endogenous inhibitor of p53, which is one of the key tumour suppressor genes in human cancer. That molecule, called MDMX, is frequently overabundant in MDS and AML stem cells. After making this finding, we collaborated with a company that developed a new therapeutic, called a stapled peptide, which is now being tested in a clinical trial. This modified biologic is an MDMX inhibitor, so it acts against the target we discovered.

What happens in your lab day-to-day?

Molecularly, we are very interested in transcription, which is still an understudied area in disease-focused, translational cancer research. There are genes that encode the information that cells, and the body, need to produce proteins, and the genes are the same in every cell. Transcription factors are the molecules that regulate gene activity – decide which gene is switched on and off, and which genes are used to make RNA (and then ultimately translated into a protein). Transcription factors are very hard to target therapeutically but we know they are very important biologically as activators and suppressors of genes. And they are key biological components of the transformation process in cancer. Our lab focuses on abnormal transcription, to understand it better, and we have made considerable progress in the therapeutic targeting of transcription factors, which five to 10 years ago were considered ‘un-drug-able’. Now, more and more people believe many of them are actually ‘drug-able’. The targeting of aberrant transcription, as opposed to targeting more general epigenetic regulators or kinases, is something we have a huge focus on. We want to add something that not everybody else is already doing.

We spend a lot of time doing experiments to test an idea and a lot of thinking and planning is involved to come up with a waterproof plan to either prove or disprove a so-called hypothesis. We have an idea that this or that could be relevant for the function of leukaemia cells. Then we come up with an actual experiment to test that idea, based on what we must do to either prove our idea is right, or wrong. What model do we need? Do we need a cell line, and do we need cells from a patient, or do we need cells from a mouse model system, or a combination of all? Experiments are hands-on work that is very labour intensive and once you have done the experiment you get the data and interpret it. The reality is that what you get out of experiments is almost always more complicated than you thought. We sit down, scratch our heads and try to make sense of what came out of an experiment. Then the next experiment we do is to further clarify or refine it or make the next step.

There are other things beyond the research to do, as a lab head. You make sure the results are disseminated; publish papers, go through a peer review process and get funding. And when we have success stories, we go out there and say, “look, we have done things that are helpful for the patients and the scientific community”. Then we have a new idea and a new plan, so we also spend a lot of time writing and proposing these ideas and convincing other people they are worth being funded, so we can actually do them. That is particularly time-consuming, and I spent a lot of time on that rather than in the wet-lab.

What is the overall aim of your research and why focus on MDS and AML?

It is to improve our understanding of the development of MDS and AML and to ultimately use those insights to develop more effective targeted therapeutics. Blood cancer was attractive to me for a variety of reasons. From my clinical experience, MDS and AML are really devastating diseases with cure rates below 15% in the majority of patients. There is a real need and that has always motivated me from the get-go. The other reason is the accessibility of specimens and samples, so it is relatively easy to study because you need blood or you need bone marrow, but you don’t need complicated surgery to remove a tumour. And because of that, blood cancer and/or experimental haematology in general, has always been one step ahead of other tumour entities in science. Blood is a very well-defined organ in terms of where the stem cells are, where they come from and how do they differentiate [become different]. So, you have a very good baseline, which is not necessarily as good in other organs, to then compare to what is going wrong in leukaemia. I felt, therefore, the study of blood is a more exact, precise science, and has better possibilities to make fundamentally important advances then starting to study tumours of other organs. There are many examples of discoveries, initially made in blood and in leukaemias, that are then looked at in other organ systems and then they find similar things.

“Experimental haematology has always had a spear-heading kind of function in all cancer research.” 

Have you any advice for people undergoing or recovering from treatment?

It is very important not to believe every piece of information you have access to on the internet or from other sources. For a variety of reasons, some information is just plain wrong, and it is very difficult sometimes to see what’s a solid source and what’s not. And, some of information you find in the literature is outdated because it’s based on research done five or 10 years ago. It is important to connect with the experts; people who know what is going on right now and who can give the best advice of what possibilities there are to move forward, and what the newest clinical trials are, especially for MDS and leukaemia. You need to see specialists who really know what is going on. There is a lot of research progress so even something that wasn’t available last year may be in a new trial this year, and a new experimental drug may be worth trying. That is just very important, and you only know about this if you work with the actual specialists and the best doctors that are available. There are logistical challenges, because even if you have the trials, they are often available in the big centres, and in a country like Australia, and in parts of the U.S. as well, the distances are very big. It is sometimes challenging to get state-of-the-art care if you have a very complicated and rare disease like MDS and AML.

What is your holy grail – the one thing you would like to achieve in your career?

I would love to see some of the things I have described [above] come to fruition. I would be the happiest man in the world even if there was just one subset of patients or subset of leukaemia that we could cure, and where my lab contributed a piece of knowledge that helped make that possible. That would be extremely great to see. Of course, we want to cure cancer in general, but it is not realistic in the short term. That’s a big vision. The problem right now is, MDS and AML are fairly rare diseases. You can’t screen the entire population to look for abnormal stem cells, just to fish out four or five from 100,000 that may be at a particular risk. But we are getting to a point where, with markers like clonal haematopoiesis, if we understand a little bit more about what makes them progress, we could do targeted screenings in subpopulations that we think are at risk. We may get to that point, with our increased understanding, in the next five or 10 years. I also would really love to prevent MDS and AML altogether. It is possible in principle, to detect the stem cells from which the blood cancer is coming from early, and when that is happening, to intervene pre-emptively. There are other cancers where breakthroughs have come from prevention – e.g. cervical carcinoma and certain types of colon cancer, and a few others. We must get to a point of early detection and then ideally, prevention. There is good data to support that concept and approach in MDS and AML now, so I am really hopeful.

Haemo-globetrotter Bryan has blood tranfusions on his travels

Haemo-globetrotter Bryan has blood tranfusions on his travels

Bryan and Winona Mitchell visiting a winery in Croatia
Bryan and Winona Mitchell visiting a winery in Croatia

When veteran traveller Bryan Mitchell, 74, journeys from country to country, he gets treatment for his MDS along the way… that is until COVID-19 put a stop to his travels.  

His last overseas transfusions were in Marseille and Paris during a six-week trip to France last September which he described as “very good and very expensive”. 

“If you can afford a holiday overseas you can afford the medication” he said.

Since his diagnosis with MDS, he hasn’t let his fortnightly blood transfusions stop him from travelling the world with his wife of 38 years, Winona. It just requires some extra planning.

“I need to ensure that I have enough blood in my body to get me from A to B,” said the Shepparton (Victoria) resident.

Bryan sitting in a boat, with the Murray cod caught on a fishing trip at Lake Mulwala
Bryan with the Murray cod caught on a fishing trip at Lake Mulwala

The couple has three adult children and four grandchildren and has tackled Bryan’s illness for a third of the time they have been together.

“Until the age of 55, I was in excellent health. I was still playing cricket and participating in long-distance running and down-hill skiing.”

But his heart health was faltering. Bryan developed angina, had stents put in and then bypass surgery in 2005.

“My life changed from that time.”

In 2007, a routine blood test prompted the beginning of what Bryan felt was a “long-term downturn in health”.

He was initially diagnosed with MDS which he said, “was something I had never heard of”.

Bryan’s condition is now categorised as an MDS-type chronic myelomonocytic leukaemia (CMML); a rare blood cancer that has characteristics of both MDS and myeloproliferative neoplasms (MPN).

Until this diagnosis, he had been “active and enjoying life” and, impressively, Bryan didn’t retire from the Public Service until 2014, aged 68, when he was quick to take up contract work.

“I was flippant to begin with. I went to see a respected oncologist in Melbourne who fully explained the illness. At the time, it seemed to have no impact on my life.

“However, my coexistent ischaemic heart disease is impacted if my haemoglobin drops too low (80-85),” Bryan explained.

“Recently, I have been as low as 74 and once I was 55 which was pretty scary.”

Having been transfusion-dependent since 2011, he currently has two to three units of transfused blood every two weeks.

“There is no treatment available to me other than blood transfusions, and deferasirox [Jadenu®, an iron overload medication] to help regulate my iron levels,” said Bryan, and this ongoing regimen is a frustrating reality for him.

Winona and Bryan on the Champs Elysees during their trip to Paris in 2019
Winona and Bryan on the Champs Elysees during their trip to Paris in 2019

“MDS and ever-increasing iron levels have a significant impact, and anaemia is also a real problem,” he said.

“I have overcome heart disease and two strokes, one of which left me blind in my right eye.

“I am a true one-eyed Magpies’ supporter,” joked Bryan, but his struggles don’t stop there.

“As a result of a carcinoma, I have had plastic surgery to repair a crater in my scalp that wouldn’t heal.

“During the four operations I have had on my head, infection has caused many problems and MDS has had a big impact with my body’s ability to fight the infection,” he said.

“The last six months have been quite an adventure, but we’re getting there.”

But Bryan’s dreams along with encouragement from his family and friends have inspired him to continue his MDS journey.

“As well as my ambition to see the world and a desire to see my grandchildren grow up,” he added.

And these motivations have seen Bryan accomplish many feats.

“Three years ago, we decided to realise a dream and travel to India. We organised a two-week small group tour of three major areas, including the Taj Mahal,” said Bryan.

“I am so glad we did. Many travellers would not attempt a trip to India.

“We love to travel overseas but I need blood every two weeks. In 2018, we went on a three-week cruise through the Baltic counties. To achieve this, we needed to organise a blood transfusion somewhere,” Bryan explained.

“We found that at the major hospital in Stockholm [Sweden]. I was able to have two units of blood, enough to enable us to finish our holiday.

“There is a charge, but it’s worth it.”

Beside the Ganges in India which Bryan described as “one of life’s most amazing places” to visit
Beside the Ganges in India which Bryan described as “one of life’s most amazing places” to visit

Years ago, the pair had met an old veteran on a cruise from Turkey to Amsterdam. The man, in his 80s, had been escorted to a hospital when they stopped in Vienna, to receive a blood transfusion.

“We had thought that was pretty good, but then we forgot about it. Now, here we are, doing the same thing,” said Bryan.

The amount of travelling Bryan does is impressive, blood cancer or not.

In 2020, the couple had planned four trips, but Bryan’s doctor said ‘no’ to him going on a family holiday to Bali with Winona and their daughter in late-January.

“They went without me as I was susceptible to infection.”

Then their Mekong River cruise in March was cancelled as the COVID-19 pandemic intensified.

“We have one planned to Portugal and Spain in July. We won’t be going, that won’t happen. And later, in August, Canada and there’s a real prospect that won’t happen either.

“Winona is my rock,” said Bryan about the help his wife provides so he stays on top of his medical regimen.

Bryan explained how, through all her own struggles, Winona has stayed strong and continues to make chasing their dreams possible.

“With the assistance of Mr Google and my wife’s persistence, we were able to organise transfusions at major hospitals in Marseille and Paris last year. The hospitals were modern and clean and English was spoken. Payment was upfront, and there was a 24-hour aftercare service.

“Some of the procedures are different, but don’t be alarmed, the lunches are great,” joked Bryan.

He has few regrets, except one – not participating in a new clinical trial, but hefty expenses and extensive travel due to living in a regional area made the trial seem inaccessible.

“I would jump at the opportunity now,” he said.

A regular at the oncology unit in Shepparton, Bryan feels that being surrounded by a support system, including others living with MDS, has made all the difference.

“The staff there are fantastic. They make attending so much easier, and happy. I admire their sense of humour and professionalism,” said Bryan.

Despite desperate struggles with severe anaemia and angina, Bryan still considers himself lucky.

“At least I know that if I get into trouble, I can get blood from someone like you,” said Brian when he spoke to MDS News.

“I see people in much worse situations than me. It makes me feel very humbled.”

Bryan wants to see MDS better understood as an illness.

“I’ve got close friends, one of 25 years and one of 40 years, who don’t understand,” he said.

“At times, I look terrific to my friends and family, but feel terrible. That is the nature of the beast.”

“I’ve gone from being as fit as a Mallee bull to nowhere near that person.”

Travel gives Bryan “something to really look forward to” but he also understands that “eventually the travelling will have to stop”.

Although physical activity is limited by his condition, Bryan keeps himself busy with many hobbies and he continues to play lawn bowls.

One of Bryan’s award-winning photographs of a tree
One of Bryan’s award-winning photographs

“I am also into photography and gardening; the environment is very important to me,” said Bryan. He has taken lots of travel shots over the years, and last year he won seven photography awards at the Shepparton Agricultural Show.

To others living with blood cancer, Bryan says, “enjoy what you can and do not be put off. Look for alternatives to help you achieve your dreams”.

Through everything, he assures others, “you can do it”.

Some of his friends tell him he pushes the boundaries too much, but he knows better.

“It can be done… just be positive and sensible.”

Quest to better understand MDS and find out more effective therapies

Quest to better understand MDS and find out more effective therapies

Dr Ashwin Unnikrishnan

When someone with MDS is treated with azacitidine (Vidaza®), it takes six months to find out if they are responding to the drug. 

This “really is a wait and watch scenario”, according to Dr Ashwin Unnikrishnan, Group Leader and Senior Research Fellow of the Adult Cancer Program at Lowy Cancer Research Centre (Sydney).

But he hopes to change that with his latest translational research building on discoveries in his lab.

This research, co-funded* by the Leukaemia Foundation, Leukemia & Lymphoma Society (U.S.) and Snowdome Foundation over the next three years, involves collaborators in Australia and overseas working closely together to solve the problem of MDS.

“My work focuses on how we can improve the treatment of MDS. We need to develop more effective and durable therapies,” said Dr Unnikrishnan, who chose to investigate MDS when he was a basic science researcher, for both personal and professional reasons.

Dr Unnikrishnan’s personal interest in MDS

“My great uncle succumbed to this disease exactly 20 years ago, when I was in high school. He’d be rushed off to hospital in the middle of the night with a nosebleed. Then he’d get transfusions and all the conglomerate problems that went with that.

“I saw how MDS affected his health and its impact on the person he was. This was prior to azacitidine being available, when the mode of treatment was sub-optimal,” said Dr Unnikrishnan whose PhD was in epigenetics.

“I realised that epigenetics is one of the major things that goes wrong in a number of cancers including MDS.

“Epigenetic mutations are different to DNA mutations, and epigenetic alterations underlie a lot of what’s going wrong with MDS,” he said.

Understanding how azacitidine works

“Azacitidine is an epigenetic modifying drug and the best available treatment for people with MDS.

“There are individuals who benefit from azacitidine, even if it isn’t lifelong, and some people are almost cured; they’ve been on azacitidine for 10+ years and are still healthily tolerating the drug.

“But it only works in about 50% of the patients exposed to the drug, and we don’t understand why.”

This means around half of all azacitidine recipients will never respond to the treatment for MDS, and a significant fraction of those who do respond to azacitidine will relapse within two years.

“That’s the sad reality. And the prognosis for people who fail azacitidine treatment is quite poor,” said Dr Unnikrishnan.

“We’re trying to work out why azacitidine only works for a period of time before patients then relapse on the treatment.”

Dr Unnikrishnan has identified what is happening in patients who do respond to this treatment.

“Azacitidine isn’t eliminating the MDS cells that contain the mutation, so these mutated cells continue to exist in the bone marrow but the patient’s ability to produce blood improves, which is why they are identified as being responders to azacitidine treatment,” he explained.

“This reservoir of ‘bad cells’ in the bone marrow is the foundation for eventual relapse.”

Developing more effective therapies for MDS

Dr Unnikrishnan’s ongoing research has two goals – to better understand how azacitidine works and to use that information to develop more effective therapies, “because azacitidine isn’t a cure and most people eventually will relapse”.

“We need to do a better job of identifying how we can target the cells that cause MDS in the first place and aren’t being eliminated by azacitidine treatment,” he said.

“Then alternative therapies could be used to eliminate those abnormal cells and hopefully improved treatment options may lead to longer life spans as well.

“We have tantalising hints on what might be happening and what we can potentially do,” said Dr Unnikrishnan.

“But these findings are preliminary at this stage and need to be validated and confirmed. This will be done using samples collected in clinical trials and those banked in the past, and that’s where funding for this project is absolutely essential.

Validating initial discoveries  

“We have applied advanced technologies, such as next generation sequencing, to make these initial discoveries and this new funding helps us follow up on those initial discoveries, with experiments to validate our hypotheses and to generate high quality pre-clinical data which is essential to move our discoveries forward to early stage clinical trials.

“We have collected bone marrow [samples] from MDS patients before they receive treatment and at different stages when they’ve received treatment.

“From those samples, we extract the hematopoietic stem cells and early progenitor cells that sit in the bone marrow. We think MDS arises from those stem cells or progenitor cells, so our investigations are focused on those cell populations.

“A lot of our pre-clinical work involves using these patient samples to work out what’s different about them, compared to healthy individuals; what’s happening in those cell populations in an individual as they get treatment, and what’s changing or not changing in individuals based on whether they do or don’t respond to treatment?

“We generate hypotheses based on that, then utilise the samples in lab experiments to validate whether our hypotheses are correct or not correct.”

Identifying responders and non-responders

Dr Unnikrishnan also has started to uncover reasons why people don’t respond to azacitidine.

“They have a baseline molecular characteristic that is quite different to the responders,” he said.

“Molecular pathways seem to distinguish individuals, even before they begin treatment, identifying those who will become responders and those who won’t.

“One striking discovery is that bone marrow cells in people who don’t respond to this treatment are more cell cycle quiescent; their bone marrow cells don’t go through the cell cycle (dividing and replicating) as healthy cells should.

“We also identified molecular pathways that we think are linked to this increased cell cycle quiescence.

“Emerging from that work, through the technologies we are developing, we hope to identify pre-existing differences up front – before treatment is started – about whether individuals will respond or be resistant to azacitidine.

“Predicting that a person won’t respond to treatment is one of the things we’re trying to work on,” he said.

“A bone marrow transplant is the best therapy for people with MDS who have a matched donor and whose age and health suggests they can tolerate a transplant,” said Dr Unnikrishnan.

“And at some stage a clinical decision might be made for these individuals, rather than waiting six months on a futile treatment (if they turn out to be non-responders to azacitidine).”

However, Dr Unnikrishnan said it was important for patients to understand that was being worked on and was not yet in the clinic.

“It would be unethical to deny people treatment if we couldn’t make that prediction with a high level of confidence.

“We hope to find alternative ways to rectify these aberrant molecular pathways and we might be able to target the MDS more effectively than azacitidine currently does,” said Dr Unnikrishnan.

“We will investigate molecular mechanisms within MDS cells affected by azacitidine, as a means to develop new treatment options for MDS.”

Boosting azacitidine with an alternative therapy to make it more effective, or that works separately, may be an option.

And there may be drugs already on the Pharmaceutical Benefits Scheme or approved by the Federal Drug Administration (in the U.S.) that need to be tested on clinical trials as possible alternative therapies for MDS.

Collaborative partnerships interstate and internationally

Dr Unnikrishnan said new collaborations over the last two years, in Melbourne, interstate and overseas, had brought new insights into the problem he has been thinking about for many years.

“To look at MDS in a different light and mindset, to discover new things and solve this disease, you need to bring in a team of collaborators with different skill sets and expertise in different areas, including immunology, mathematics and biology, to complement one’s own.

“It’s exciting to work on multi-disciplinary research in this manner, and that integrates Australian research with the research community across the world.”

*  Beyond Azacitidine: Investigating new therapeutic strategies for the treatment of MDS? University of NSW, (Sydney). Collaborating institutes: UNSW (NSW), St Vincent’s (Vic), Technical University of Denmark. Funding: USD600,000, co-funded through LLS (USD300,000), Leukaemia Foundation (USD150,000), Snowdome Foundation (USD150,000).

Merrick from Berwick has “reported for duty” since 2012

Merrick from Berwick has “reported for duty” since 2012

Brian Merrick

“G’day girls… it’s Merrick from Berwick reporting for duty.” 

For almost eight years, this has been Brian Merrick’s greeting when entering the treatment room in Melbourne for his monthly round of azacitidine (Vidaza®) injections on a clinical trial.

He hasn’t let blood cancer limit his boundless positivity and love of life.

“My life is more precious now,” said Brian, 76, who has become a voice of support for others living with MDS and an advocate of participating in clinical trials.

Before his diagnosis with MDS, Brian “took everything for granted”.

“Now I cherish every moment.”

Brian’s symptoms pre-diagnosis

In 2011, Brian started to become breathless on the job, escorting prisoners to court at the Melbourne Custody Centre. He was also fatigued and realised something was wrong.

A blood test showed he had anaemia, then his red blood cells plummeted, and later that year Brian was diagnosed with the MDS subtype Refractory Cytopenia with Multilineage Dysplasia (MDS-RCMD).

“The word is about a kilometre long,” said Brian laughing.

Continuing to work soon became a risk and he retired when he was 69.

Initial treatment and the decision to go on a trial

He started treatment – blood transfusions – but after his third one, Brian learned that ongoing transfusions had its own concerns and decided this treatment was not right for him.

His haemotologist suggested he participate in a clinical trial for azacitidine and without a second thought, Brian agreed.

“If there’s a recommended clinical trial or treatment, definitely pursue it,” Brian suggests.

He started the trial in July 2012, which involved a daily azacitidine injection for seven days every four weeks. At first, Brian struggled with the side-effects – nausea and vomiting – after each day of treatment until a nurse consultant suggested an anti-nausea drug.

“I haven’t been nauseous or vomited for nearly seven years,” said Brian who now takes ondansetron to prevent nausea and vomiting and he often recommends this drug to others on azacitidine.

His current treatment regimen is five days of azacitidine injections each month and to make it easier, he stays with a friend near the hospital in Melbourne for a week. This saves him more than an hour’s travelling to and from Berwick each day.

Brian’s journey with azacitidine has been a long one and while his MDS hasn’t gone away, his disease also hasn’t regressed.

The value of support

He understands the value of emotional support and the power of positivity. He uses his experience to help other people with MDS and is always keen to offer encouraging words and advice.

“Keep going with the treatment, no matter what,” are words he often shares with them.

Actor and singer, Olivia Newton-John has had a positive impact on Brian’s journey and he will never forget Christmas 2016. That’s when he met and chatted to Olivia at her namesake Cancer Wellness & Research Centre in Melbourne. This was a privilege and Brian both admires her and draws inspiration from Olivia’s own cancer experience.

Brian Merrick and Olivia Newton-John
Brian met Olivia Newton-John at the Cancer Wellness & Research Centre Christmas party in 2016: “It’s one of my favourite photos.”

“Her tenacity of staying positive – she has instilled that in everyone – and the way she talks to everybody, she’s a real angel.”

“I know that she’s gravely ill at the moment, but she’s not giving up one little bit. She’s in there fighting.”

Dealing with other health issues

Earlier this year, Brian battled health problems unrelated to MDS when he began to feel breathless and exhausted again.

“I had a major blockage and two minor blockages in the heart and had open-heart surgery – a triple bypass. Talk about having everything thrown at me,” he said.

Fortunately, everything is now under control.

“I’ve just got all these zipper markers over me now,” he said.

Brian turned to the Leukaemia Foundation for support and was grateful to attend a seminar on what to expect during azacitidine treatment. He also joined the Foundation’s MDS support group in Melbourne on a visit to Melbourne Zoo.

“It was a good therapy session,” said Brian.

“You could go and support each other, that’s what we did.”

Brian Merrick Giovanna and nurse
Giovanna and Brian in the Olivia Newton-John Cancer Wellness & Research Centre garden in 2018, with Melissa, a staff member.

Brian is certain that taking part in the azacitidine clinical trial has changed his life.

“Like Olivia, you’ve got to keep positive, keep having the treatment, do what the doctors and the specialists recommend, and keep the fingers crossed.

“And keep enjoying life, including a glass of red wine,” said Brian who is intent on continuing his mission.

“What I’m most looking forward to right now, is that my story assists others in their journeys and to pursuing the best in health life can offer.”

Stepping up to the challenge of curing MDS

Stepping up to the challenge of curing MDS

Brett and Louise in Dubrovnik

Louise Coventry felt well but tired, which she’d put down to her busy job and long hours, before her shock diagnosis with a blood cancer called MDS in April 2016.

It came out of the blue one Saturday morning when she got an urgent call from the pathologist after a routine blood test the day before. Suddenly, she was on her way to the emergency department.

She was 55 years old and until then had never spent a night in hospital, let alone two. But Louise felt confident there had been a “lab error”.

Only two weeks earlier, she’d been kayaking, and she’d been in a charity bike ride within the last month as well.

When a bone marrow biopsy was scheduled, she was more terrified of the actual procedure than finding something was wrong.

“I’m so healthy, this can’t be right’, I kept telling myself,” said Louise, of Sydney.

“I hung on to that denial for quite a while.”

Even when Louise was diagnosed with MDS, she kept waiting to find out it was all a mistake.

“My husband [Brett] and I only told my sister. We waited until we had all the accurate information before sharing [my diagnosis] with the rest of our families.

“When I finally accepted that this was not a mistake, Brett and I went into shock. He had some anger, but I was just frightened,” said Louise.

Louise in hospital

Initial treatment and the stem cell transplant

“Unfortunately, I’ve got RAEB-2 MDS which can quickly escalate to acute myeloid leukaemia (AML). My only option for a cure was a stem cell transplant.”

Her two siblings were tested as possible stem cell donors, and it was her sister, Cath, a psychologist and former nurse, who became her donor – twice!

“Even though she wasn’t a perfect match, there was no one closer on the world register,” said Louise.

“I found not knowing what was ahead very frightening.

“I was very fortunate to have the support of a psychologist [her sister] to talk things through with.”

Louise also found the Leukaemia Foundation’s information booklets “very informative” and speaking to an MDS survivor to be “so important and hugely supportive”.

In the lead-up to her transplant, to prevent the MDS escalating to AML, Louise was treated for three months with azacitidine (Vidaza®). The drug was administered by injection into her stomach, which increased her anxiety.

“Being needle-phobic, I was terrified even by that,” she said.

As it was difficult for Brett to take much time off  work, her friends and family created a roster to take her to appointments, and “to hold my hand, literally”.

“I felt so unprepared [for the transplant]. I literally had no idea of what to expect. It was the first time the inner strength, of which I’ve always been quietly proud, deserted me.

But as the transplant date drew closer, Louise started taking ownership of what lay ahead.

“I knew it just had to be done, and I could do it,” said Louise, who had the transplant on 7 September 2016.

Love got Louise through

Louise and Cath during Stem Cell Transplant
“While I was receiving my sister, Cath’s life-saving stem cells. She was just out of recovery and came to hold my hand.”

“Love is what got me through. So much love. From everyone!” said Louise.

“Brett was calm and encouraging. He framed a quote that sat in my hospital room: ‘You might not be there yet, but you are closer than you were yesterday’.”

Cath created a quote box – personal reminders and messages – for Louise to take to hospital “to remind me this was just a setback and I would get through it”.

And her friends rallied. They phoned, brought books, sent inspirational messages, took her for walks in the park, movie afternoons, drives, afternoon teas and knitting sessions.

A private Facebook group kept everyone updated on Louise’s progress, even when she devastatingly learned her transplant had failed, and she needed to have another one.

Getting on with life post-transplant

When Louise got home after her first transplant, the first few months were good.

“We started to plan our life again, caught up with friends, talked about taking an overseas trip, returning to work, and rebuilding my fitness,” said Louise, who went back to the job she loved, as a Reading Recovery tutor with the Department of Education and Training, but part-time – five days a fortnight.

Louise and her daughter Flora
“With my beautiful mum” – Louise and Flora Hutchinson.

“Unfortunately, at the four-month mark, the doctors discovered my DNA was 100% mine.

“In a successful transplant the recipient (me) changes DNA and blood group to that of the donor (Cath). There was no evidence of Cath’s DNA in my bone marrow. The transplant had failed,” said Louise.

“We were devastated. I would need another transplant.

“The wheels were set in motion and although I was dreading it all over again, it was a tad easier as I knew what was ahead.”

Two stem cell transplants

Her second transplant was on 22 March 2017 – her 20th wedding anniversary – which she took as a good omen.

“It was much like the first – tough but doable – although I did have a stint in ICU with an infection,” said Louise.

She was very fragile afterwards and unable to walk more than 50 metres, so driving was out of the question. Even having the energy to make a sandwich for lunch was challenging at first.

“Mum and Dad came daily, ensuring I was eating to regain my weight and energy,” said Louise.

“The memory of my illness, transplant and recovery were forefront in my mind.

“As I regained my strength and my energy, I became much more resilient to the fear of relapse.

“Gradually my gratitude for this opportunity to recover from a serious life-threatening disease became my dominant emotion.

Transplant success

Six months after the transplant, Louise found out her DNA was 98% Cath’s and her blood group had changed to her sister’s as well – the transplant had been a success.

“I regained my sense of fun and enjoyment in the small things (sunny days, swims in the ocean, meals with family and friends, long walks) and planning for the big things (weekends away and a month-long trip to Croatia).

“Now MDS is embedded in my past. It’s time for cancer to live with me!

“I’m no longer living with cancer!

The two-year mark

Louise and family on 7 day of stem cell transplant
Celebration on 22 March 2017 – “the day of my second transplant was actually our 20th wedding anniversary”

In 2019, March 22 was a special day of 2s for Louise. It marked Brett and Louise’s 22nd wedding anniversary as well as being two years since her second transplant.

“My health has continued to prosper. All my results are in the normal range and I have no ongoing issues or side-effects,” said Louise, now 58.

“My health is back, I’m emotionally stable, I’m still very happily married and supported by amazing family and friends.

It’s time to get back to living and enjoying life, and we are so grateful for the chance to enjoy life again.”

Louise and Brett both retired early, to enjoy a more relaxed life and to travel as often as they can including an overseas trip each year. They’re off to Bali in August 2019, and they’ve bought a camper trailer and next they’re taking it to the Coonawarra and across to Kangaroo Island.

“My most favourite thing, when time permits, is to read quality literature,” said Louise, who has coordinated a book club “for the books, the discussion, and most of all the catchup with friends”.

Louise is content to live a “good life”.

“I try always to be kind, and I’m really working on not judging others.

“Buddha says ‘Health is the greatest gift, contentment the greatest wealth, faithfulness the best relationship’.”

Advice to others

“Be brave, be strong.

“Lean heavily on family and friends.

“Use a psychologist and anti-depressants if warranted.

“Don’t be afraid to feel fear but own it.

“You can do this, no one but you.”

Read more details about Louise’s diagnosis and treatment in this story she wrote.

This story features as part of Blood Cancer Awareness Month 2019, helping to raise awareness of every blood cancer.

Searching for biomarkers and better treatments for B-cell lymphomas

Searching for biomarkers and better treatments for B-cell lymphomas

 

Dr Pilar Dominguez with Professor Ricky Johnstone
“We need to find better treatments” – Dr Pilar Dominguez with Professor Ricky Johnstone.

Finding new treatments for B-cell lymphomas is the goal of a Leukaemia Foundation co-funded* and collaborative** research project led by Professor Ricky  Johnstone  at the Peter  MacCallum  Cancer Centre (Melbourne).   

An urgent clinical need underlies this research, as around 40% of people with B-cell lymphomas either don’t respond to the standard treatment (they’re refractory to the chemotherapy-immunotherapy regimen) or they respond, then the lymphoma comes back (they relapse).

“We need to find better treatments,” says Dr Pilar Dominguez, who moved to Australia last year to join Prof. Johnstone’s lab.

“I want to broaden my knowledge and have more impact by doing work that is more translational, so a step closer to the clinic,” said Pilar.

After completing her PhD in molecular biology, followed by a post-doctoral degree in immunology, in Spain, Pilar went to the U.S. to further her post-doctoral work in lymphoma with Professor Ari Melnick at Weill Cornell Medicine in New York (U.S.).

Now based in Melbourne, Dr Dominguez heads this three-year project titled, Targeting deregulated epigenetic mechanisms in B-cell lymphomas, which involves pre-clinical studies in diffuse large B-cell lymphoma (DLBCL). DLBCL is a lymphoma that develops from the B-cells in the lymphatic system, and makes up one third of all patients newly diagnosed with non-Hodgkin lymphoma.

Prof. Johnstone and Prof. Melnick are co-principal investigators on this research project that follows on from preliminary data published in late-2018 in Cancer Discovery – one of the world’s leading cancer journals.

Dr Dominguez was first author on the paper that described the genetic basis of this disease and showed the gene, TET2, was mutated in DLBCLs.

“That publication set the scene for this project,” said Prof. Johnstone, “and gave us the confidence that the gene we were looking at – TET2 – was indeed an important gene in DLBCLs.

“This allowed us to form hypotheses about how we might be able to treat these lymphomas with some new world-first compounds.

“We think this is world leading research that will have enormous impact internationally,” said Prof. Johnstone.

Dr Dominguez said that trying to understand how normal cells transition to become cancer cells “is a major focus of Prof. Johnstone’s lab”.

“Our goal is to find new biomarkers for B-cell lymphomas and develop new therapeutic approaches,” she said.

“This involves screening patients who don’t respond to standard treatment to find out what’s wrong with those cells, then selecting the right treatment for those patients.

“The advantage of these therapies is they will be personalised  to the patients who are going to benefit the most,” explained Dr Dominguez.

“There are two angles to this project – to test new treatments in pre-clinical models of DLBCL using human lymphoma cells, and to find out what defects are in these cells at the DNA level that lead to normal cells becoming lymphoma cells.

“And, there are two clinically relevant sides to this research – prevention and therapy,” said Dr Dominguez.

“For patients in whom current standard therapy doesn’t work and those newly diagnosed in the future, we can use precision medicine to change the way we diagnose lymphoma, then select those patients who are going to benefit from more specific, targeted treatments.

“This is a relatively new field that looks not only at the DNA level, where cells receive instructions, but at another level, the epigenetic level, where proteins control how genes are expressed at any time.

“It’s difficult to explain epigenetic power in simple terms – the mechanism is very technical,” said Dr Dominguez.

“Each cell contains the same genetic information, but each cell has a different function and that depends on epigenetic changes. These epigenetic proteins control and regulate which genes are turned ‘on’ and ‘off’ at any time.

“If the proteins that control epigenetics don’t work properly, genes may be are turned ‘on’ and ‘off’ when they shouldn’t be, and the cell becomes altered. In some cases, this leads to cancer.

“When the epigenetic proteins or systems are not working, tumour cells use that to their advantage, to keep growing.

“But the good thing about the epigenetic system is that those processes are in most instances reversible, so once you know how this process goes wrong, you can try to reverse it.

“The therapies we are developing are designed to convert cancer cells in which the epigenetic processes have become abnormal back to normal cells.

“TET2 is a protein that is highly mutated in 10-15% of patients with DLBCL. In these lymphoma patients, TET2 doesn’t work and the tumour uses this to its advantage,” said Dr Dominguez.

She has demonstrated that TET2 is a tumour suppressor in DLBCL by showing that when TET2 is mutated, the progression of lymphoma is accelerated.

“That’s why we’re focusing on TET2. We’re studying its function in cancers compared to normal cells. We want to know how it works in normal cells to prevent cancer formation, and understand the consequences when this molecule is not working.

“We think patients with the TET2 mutation will benefit most from a targeted, precision medicine approach, where we plan to combine two epigenetic therapies that block two different chemical modifications in the DNA.”

One of the drugs is azacitidine, which is already used in the clinic for other blood cancers – myeloproliferative neoplasmsmyelodysplastic syndrome and acute myeloid leukaemia – and is in clinical trials as a monotherapy for B-cell lymphomas. Azacitidine will reverse the epigenetic changes caused by TET2 mutation.

The other compound – an HDAC3 inhibitor – doesn’t yet have a commercial name because it is still in development by a small biotech company in the U.S.

“This research will test this drug combination in human cells and we will perform pre-clinical studies so we have some proof that it works and that this new therapeutic approach can be effective and safe,” said Dr Dominguez.

“This will potentially change how lymphoma is treated. It will be very different to chemotherapy, which is non-selective in that it kills tumour cells and normal [healthy] cells.

“At the end of this project, we hope to have enough data [results] for the next step; establishing a clinical trial. That would be the final goal for this project,” she said.

After the completion of this study, to prove this epigenetic drug combination is a new option for patients with this form of DLBCL with these genetic lesions, Prof. Johnstone hopes to run a clinical trial at two sites – at Peter MacCallum Cancer Centre and at Monash Medical Centre with associate investigator on the project, Dr Gareth Gregory.

“This project is significant on two levels – the science and the strong collaborative opportunities – and we’re thankful to the funding agencies for giving us the opportunity to test our hypotheses,” said Prof. Johnstone.

“It’s a unique and innovative way to fund research; bringing together Leukaemia Foundation, Snowdome Foundation and the Leukemia & Lymphoma Society in the U.S.

“I love the collaborative nature of it. It’s not just one group working in isolation, it’s a global effort,” he said.

 

*This project is funded under the Leukaemia & Lymphoma Society – Snowdome Foundation – Leukaemia Foundation Translational Research Program. (US$600,000 over three years)

* Collaborating institutions: Monash University, Melbourne; Weill Cornell Medicine, New York, U.S.; University of Miami, Florida, U.S.; The Jackson Laboratory Cancer Centre, Conneticut, U.S. Further support is critical to ensure all Australian can reap the benefits of scientific advancements. If you would like to invest in blood cancer research, contact us on 1800 620 420 today to find out how. 

Further support is critical to ensure all Australians can reap the benefits of scientific advancements. If you would like to invest in blood cancer research, contact us 1800 620 420 today to find out how.

Talking myelodysplastic syndrome with Dr Melita Kenealy

Talking myelodysplastic syndrome with Dr Melita Kenealy

Dr Melita Kenealy covered the basics of myelodysplastic syndrome (MDS), current treatments and living with the disease when she spoke at the Leukaemia Foundation’s Blood Cancer Conference (Melbourne, October 2018).

A consultant haematologist at Cabrini Hospital (Melbourne), Dr Kenealy has an active research interest in MDS and runs Australia-wide clinical trials looking to pioneer new and improved treatments.

At the conference, she spoke about azacitidine (Vidaza®), the first treatment available through the Pharmaceutical Benefits Scheme in Australia for high-risk MDS, and the potential of targeted therapies in the future.

“We’re learning a lot about the bone marrow in MDS and different faults that can happen in some of the genes and chromosomes that cause the disease,” said Dr Kenealy.

“That means we can start to develop targeted treatments for those specific abnormalities.

“At the moment we’re learning about these gene faults and a few drugs are coming out on clinical trials and gradually becoming available that will be relevant for some sub-types of MDS.”

She said MDS was a difficult disease to understand and highlighted the importance of people learning about their disease.

“The Leukaemia Foundation has a great website,” said Dr Kenealy.

She talked about blood transfusions for people with anaemia or low red blood cell counts and the most common question patients ask her is: “at what blood level or haemoglobin level should I have a transfusion?”.

“There’s really no one answer,” Dr Kenealy said, “because it’s an individualised decision that depends on how people feel and what other medical conditions they may have.”

That depends on how people feel and what other medical conditions they may have.”

To listen to the audio of Dr Melita Kenealy’s entire presentation, click here.