Magrolimab – potential new treatment for newly diagnosed MDS
A ‘first-in-class’ therapy that recently received FDA Breakthrough Therapy designation in the U.S. for the treatment of newly diagnosed MDS will be available “very soon” to Australians in a clinical trial.
Magrolimab is an investigational anti-CD47 monoclonal antibody that is being studied in the randomised Phase III ENHANCE study which is evaluating the safety and efficacy of magrolimab in combination with azacitidine (Vidaza®) in higher risk MDS.
Professor Andrew Wei, haematologist at the Alfred Hospital (Melbourne), said magrolimab “was a potential important advance for patients with MDS” and “a treatment option with a highly novel mechanism of action”.
“Magrolimab activates specialised immune cells to recognise, engulf, and digest malignant cells,” with response rates in single arm early-phase trials “that are very promising”.
“Randomised clinical trial validation is now the next step,” said Dr Wei.
Dr Wei is on the global steering committee for the randomised studies in MDS and AML (in which magrolimab also has shown activity in poor risk patients) and is the principal investigator for the ENHANCE registration trial which is in the process of opening in hospitals across Australia.
The Alfred has just commenced recruitment for the trial, with other sites coming online over the next few months.
This means most eligible newly diagnosed patients with higher risk MDS should be able to access the trial “as long as they pass eligibility assessments”.
“There are other studies in this area as well, such as venetoclax plus azacitidine, which is also open to recruitment to patients with newly diagnosed MDS. The field has never been so active,” said Dr Wei.
Clinical haematologist, Professor Steven Lane, who heads a research laboratory at QIMR Berghofer Medical Research Institute (Brisbane) and whose focus is on myeloid disorders including MDS, has described magrolimab as “a super exciting drug”.
Dr Heshaam Mir, Medical Director Australia & New Zealand, Gilead Sciences, which has developed the drug, said, “magrolimab represents an alternative treatment for those patients with limited options”.
“But it is important to remember it is still an investigational medicine whose safety, efficacy, and clinical benefit have yet to be established.
“Magrolimab is not yet licensed or approved for any use by any regulatory authority.”
The FDA granted Breakthrough Therapy designation for magrolimab based on the positive results of an ongoing Phase Ib study, evaluating magrolimab in combination with azacitidine in previously untreated intermediate, high, and very high-risk MDS and AML.
In data presented at the 2020 European Hematology Society Congress, 91 per cent of evaluable MDS patients treated with magrolimab plus azacitidine achieved an objective response, with 42 per cent achieving a complete remission. The combination of magrolimab plus azacitidine was generally well-tolerated. No maximum tolerated dose was reached and no MDS patients discontinued treatment due to a treatment-related adverse event.
Breakthrough Therapy designation is designed to expedite the development and regulatory review of investigational treatments for serious or life-threatening conditions that, based on preliminary clinical evidence, have the potential to substantially improve clinical outcomes compared with available therapy.
“The Breakthrough Therapy designation recognises the potential for magrolimab to help address a significant unmet medical need for people with MDS,” said Dr Merdad Parsey, Chief Medical Officer, Gilead Sciences.
Magrolimab is a monoclonal antibody against CD47, a protein that works as a ‘don’t eat me’ signal used by cancer cells to avoid being ingested by macrophages — a kind of immune cell that engulfs invaders.
The investigative therapy works in a similar way to checkpoint inhibitors, but instead of activating T-cells, it improves the ability of macrophages to identify and eliminate cancer cells.
Because this evading mechanism is used by several cancer types, magrolimab represents a promising approach for a wide range of solid and blood cancers. Magrolimab has already received fast track status for diffuse large B-cell lymphoma and follicular lymphoma.
Speak to your haematologist regarding your eligibility and referral to the trial. For further information, contact the Alfred Hospital trial manager, Nola Kennedy, on ph: 03 9076 2217 or email: firstname.lastname@example.org
Familial research key to blood cancer prevention strategy
The Australian Familial Haematological Cancer Study (AFHCS) leads the world in the field and has a research cohort of more than 200 families with a history of blood cancer.
The AFHCS was initiated in 2004 by Adelaide geneticist, Professor Hamish Scott. Prior to this, it was recognised that blood cancers did run in some families, but very few of the gene mutations that cause this to occur were known.
Prof. Scott and Dr Anna Brown, who was working collaboratively with him in another lab, started studying a few families.
“Of course, as soon as people realise you’re studying genetics, they come to you with their stories,” said Dr Brown, Head, Molecular Oncology in the Department of Genetics and Molecular Pathology at SA Pathology (Adelaide).
Enrolling patients in the study
A framework was developed for haematologists with patients where MDS, AML or other blood cancers ran in their family, to enrol them in the research study, which started looking into the gene changes underlying these family’s histories.
“We have one of the longest running familial blood cancer studies in the world. It’s a systematic study to find answers for these families,” said Dr Brown.
“Over 200 families are enrolled and because there are multiple family members with all kinds of different blood cancers, or carrying a mutation, we’ve got thousands of individuals across the families we are studying.
“We have very good relationships with haematologists all over Australia.”
Most referrals to the AFHCS come from haematologists treating a family member with a blood disorder/blood cancer whose medical history showed a strong family history of the condition. Information about the study was then given to the patient, via their haematologist, to see if the patient was interested in participating in the research.
“If they are, a research nurse then contacts a family member for more information and to give more information about the study. If they want to go ahead, the research study consenting process is started.
“The study coordinator normally starts with one family member and gets a family history, then sequentially contacts other family members who are interested in participating as well,” said Dr Brown.
“We build up a very detailed family history, go through their medical background, and if there is blood cancer in their family, collect samples from them for genetic testing.
“All this is done in a research setting and the information is de-identified, so we don’t see names of individuals we are studying.
“Some people are really happy to participate in the research, want to know everything and are really engaged. Others want to help for the betterment of everyone, but don’t necessarily want to know that personal information about themselves,” said Dr Brown.
“We do gene sequencing on family members who have provided material, researching their genomes, to see if we can find a genetic change that’s present in the family members who have reported either a blood disorder or a blood cancer.”
Dr Brown said the AFHCS often gave presentations to organisations, including the Leukaemia Foundation, at their patient education days, “and sometimes individuals contact us directly.”
Familial linkages occur in “pretty much all the different types of blood cancers and disorders to some degree or another”, she said.
“We have MDS and AML, but we also have a lot of lymphoma families, myeloma families, and chronic lymphocytic leukemia. Basically, in every type of blood cancer we can find a family where it seems to be occurring more often than you would expect.
“That suggests that there’s something genetic underlying that.”
In 2016, the World Health Organisation published clinical testing guidelines for familial predisposition to myeloid malignancies.
“As well as our research study, for families with a history of myeloid blood cancers such as MDS and AML, we are part of an international clinical network of experts and our laboratory offers accredited genetic testing that can be ordered through clinical genetics centres and clinical haematologists,” explained Dr Brown.
Why does it seem blood cancer may be occurring more often?
“Diagnosing blood cancers has become a lot better with modern medicine,” said Dr Brown.
“In the past, people might have been affected by leukaemia and passed away without it being diagnosed or identified as the reason they passed away.”
And blood cancer is more visible now.
“If someone younger gets this kind of disease, it stands out more, and makes it easier for us to identify when there is a family history.
“There is some concern that the age of diagnosis of some of the blood cancers is getting younger in more recent generations, and that is something we’re actively researching.
“The field hasn’t done the right studies yet to show whether that’s actually true, but in some cases it seems like it might be.
“That’s something we definitely want to look into – whether other factors are also interacting with the genetic changes in these families, maybe environmental factors, but we don’t know of any at the moment.”
Why familial research is important
“There are benefits in participating in this research,” said Dr Brown.
Information from this research is most important when a family member is looking at having a stem cell transplant or bone marrow transplant as a curative therapy, “because most frequently you’ll look for a family member to be the donor”.
“It is really important to offer genetic testing to these people, to make sure they’re not carrying any mutations that we can identify that might be causing that family history, and to make sure any potential bone marrow donors aren’t carriers of those mutations without realising.
“You don’t want to transplant bone marrow that’s got an inherited mutation. We know that gives you a risk of complications with how well the bone marrow transplant works.
“We’re focusing on identifying carriers of known gene mutations early, and enrolling them in the study, so we can work with their haematologist, to monitor them more closely.
“What we would like to do in our research is figure out ways to stop leukaemia from developing in people who’ve inherited a mutation.”
“A new aspect of the study is looking at why they go from a state of having an inherited mutation, to developing blood cancer. Something else has to happen in between, to trigger that. What is it?
“Can we find out how that happens and find a way to treat at that point? So patients don’t go on to get leukaemia. We’ve got a lot of research projects in that area.
“And having this knowledge, the haematologist knows to keep a really close eye on someone who’s at a greater risk, which allows them to manage their health better,” she said.
Testing a blood cancer prevention strategy
Dr Brown said clinical frameworks were being put in place “to find clever ways to test a leukaemia prevention strategy” because it is being given to a patient who has a gene mutation but is otherwise well, and it may take a longer time to know the answer, and “that’s ethically difficult”.
“We’re still working through the ways in which we could get to the point where we could have a human clinical trial. I don’t think it will be too far away.”
Stopping blood cancer from developing “is absolutely the aim of a lot of the research we are doing right now”, she said.
“The field recently moved from just trying to identify what some of the mutations are, to figuring out a pathway to generate models in the lab and find therapies that might intervene at a much earlier point than waiting for a person to get full-blown leukaemia.
“The main thing for treating someone, to prevent leukaemia, is finding a compound with a good safety tolerability profile, unlike intensive chemotherapy which is used to treat acute myeloid leukaemia.
“You wouldn’t give that to somebody who’s otherwise healthy, because there’re just too many side-effects,” said Dr Brown.
“We’re looking at other agents that might change the blood compartment in ways that relieve some of the stress that the inherited mutation puts on it.
“If we can relieve that stress on blood cells and stem cells, it might reduce the chance that they become leukaemia,” she said.
Christine has a rare genetic predisposition to MDS
Christine (left) and husband Greg (right) at their daughter Ashleigh’s end of year school service in November 2018.
After losing her dad to MDS, and her brother’s diagnosis just a month before hers, Christine Heath’s family underwent genetic testing to understand whether their MDS couldbe hereditary.
Christine, a high school maths teacher, fell suddenly, back in 2015, when walking up the stairs to class, then fainted while lining her students up.
“It was just for a split second and I only dropped my books,” said the now 53-year-old from Port Lincoln, South Australia.
But she thought to herself, “that’s not right”, and went to the doctor to be checked out. Her blood tests returned some “funny results” and her doctor was particularly concerned about her haemoglobin level.
She was given the option of redoing the test in three months or going straight to a specialist.
“Given my dad, Geoff, had died from MDS in 2011, I opted to go to the specialist,” said Christine.
She saw the same haematologist who had treated her father, and he assured her any blood issues could not possibly be hereditary, that it was unlikely to be MDS, but he would monitor her over the coming years.
A ‘double-whammy’ diagnosis
After being closely monitored for several months, Christine was formally diagnosed in April 2016 with myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)*.
“This was just a month after my older brother, Stephen, who was also going to our dad’s haematologist, received the same diagnosis – a double whammy,” said Christine.
“My daughter, Ashleigh, was in year 10 at the time and I really wanted to be actively involved in her life, see her graduate, and live with my husband, Greg a lot longer.
“To begin with, I was put on ‘watch and wait’ with tissue and blood samples taken to find a stem cell donor.”
Even after her diagnosis, her haematologist was still reluctant to class her MDS as hereditary.
It wasn’t until Christine, Stephen, and their partners attended a Leukaemia Foundation MDS workshop in September 2016 that they started to find some answers.
“The workshop was in Adelaide and there was a geneticist there, Professor Hamish Scott, who we approached after his session, and told him about our situation,” said Christine.
“He said straight away, ‘oh I definitely want your genes… let us do some testing’.”
Another haematologist arranged for samples from Christine and Stephen to be shared with Prof. Scott and extra information about their dad and grandmother was provided.
The researchers asked her mum, Gill, for permission to use Christine’s dad’s blood samples. These had been stored as they looked different, but Geoff’s medical team was unable to understand why at the time.
“My mum also remembered that other family members had experienced blood issues and so they did a family tree and tracked it back a couple of generations,” explained Christine.
“It was then confirmed that we do indeed have a genetic predisposition to MDS!”
Ashleigh also has provided hair and blood samples, but she chose not to ask for information about any findings.
“She said she might when she has a family one day, but right now she’s focused on living for every day and doesn’t want that hanging over her head,” said Christine.
“She has just begun studying science at the University of Adelaide, majoring in immunology and genetics.
“We are really proud of her and the interest she has in the science behind all this. She could be the one who makes a difference for us in the future.”
In October 2016, Christine flew to the Peter MacCallum Cancer Centre in Melbourne to get a second opinion.
“I learnt there that there were no clinical trials suitable for me and to just continue to maintain a balanced diet and consider part-time work.”
Early the following year, Christine needed to begin having blood transfusions and erythropoietin (EPO) injections every two months.
In 2018, as her condition worsened, she stopped work altogether.
“I’ve been on income protection ever since,” she said.
“I strongly encourage people to check whether their super gives them the option.”
Time for transplant
After living with Ashleigh in Adelaide for 12 years while she completed her schooling, Christine moved back to Port Lincoln to be with her husband in early-2019. Greg had stayed at Port Lincoln to support his parents as his father was battling leukaemia at the time.
When Christine’s transfusions got closer and closer together, her haematologist said, ‘time’s up, we’re going to transplant’.
“A sudden drop in two of the blood lines had appeared, which was the marker he was waiting for,” she said.
“I was a bit scared, but I knew that’s what I wanted to do.
“I felt far too young to die and I didn’t want to have to deteriorate like my dad had done before he passed.”
Ashleigh had produced a booklet for her senior school research project on the associated benefits and risks of transplants.
“Her project question was, ‘do the positive outcomes of getting a stem cell transplant to treat blood cancer outweigh the risk factors?’” said Christine.
“She interviewed a number of haematologists, ran a patient survey, and did a heap of research.
“She did an amazing job, and I think it really helped her to understand the process and cope with what I was going through.”
Christine and her family were given the time to take a holiday together before her transplant.
“We went up to Queensland and did ‘the worlds’,” said Christine.
“We were able to visit Ashleigh’s cousins there, and I didn’t want to take the risk of going overseas in case something went wrong.
“It was such a great trip. I’m not a big ride person but I was chief bag holder and took all the photos while they went on the rides.”
On 16 August 2019, Christine had her transplant with stem cells donated from the umbilical cord blood of two baby girls, after a previous donor match was no longer viable due to age.
“When I got to the hospital everything happened very quickly. I was started on chemotherapy and then I had full body radiation.
“On transplant day, I had Greg and my mum there, as well as Stephen and his wife, as he was about to have his own transplant and wanted to see the whole process.
“My niece, Stephen’s daughter, was also there. She had just finished her honours degree in science, supervised by haematologist, Dr David Yeung.
“Shortly after, she was employed to work with the transplant team doing all the data collection for transplant patients and looking for trends in treatment.
“It was feeling a little bit like a party, but it was kind of a letdown as the transplant itself is like having a transfusion.”
Christine needed to stay in hospital for seven weeks after the transplant.
“I consider myself extremely lucky as I didn’t have any long-term issues with graft versus host disease (GVHD) and didn’t go into intensive care once,” she said.
“I did go off my food for a bit and had to have a feeding tube, which I hated. I had a bad reaction to cyclosporine**, and they put me on steroids for suspected GVHD which caused me to develop steroid-induced diabetes.
“That was only temporary for about three months and by the time they had taught me to do the injections myself, it was time to stop.”
Leukaemia Foundation support
Christine and Greg stayed at the Leukaemia Foundation patient and family accommodation village in Adelaide for six months during her transplant and recovery.
“It was really important to stay close to the hospital as Port Lincoln is a seven-hour drive from Adelaide,” said Christine.
“We loved it there and we made quite a few friends around the village. We all kept an eye out for each other.
“There’s morning teas and the staff put on a Christmas lunch for everyone. There’s also a nice little games room where my husband and I would play a bit of ping pong or table tennis when I was feeling better.
“I cannot thank everyone from the Leukaemia Foundation enough – they were brilliant.”
Christine was kept busy during her recovery, with regular appointments and blood tests.
“These were weekly to begin with, then steadily decreased to fortnightly and monthly appointments,” said Christine.
“I also had lots of physio to build my muscle as I had lost about 15 kilos while in hospital.”
Although the Heaths had hoped to return home in February 2020, the COVID-19 outbreak meant they had to remain in Adelaide until the situation stabilised.
“I actually think I would’ve struggled being away from a major hospital during that time. You want that peace-of-mind that help is just down the road should you need it,” she said.
Focused on the future
Eventually returning to Port Lincoln in April 2020, Christine has been focusing on slowly settling back into everyday life.
“Life is looking really good and I’m now even talking about when I can return to work,” she said.
“I try to exercise every day and do what housework I can. I keep busy with people dropping in, and I’m really looking forward to summer so I can get back to the beach.
“But I’m always conscious of not overdoing it as I can still get really tired some days.”
Christine has regular tele-health appointments with her haematologist and travels back to Adelaide every two months for a face-to-face check-up.
“I can have my blood tests in Port Lincoln and I need to have a venesection fortnightly because my iron levels are too high from all the transfusions,” explained Christine.
“I also have an immunoglobulin infusion once a week which is a subcutaneous injection, two little needles into my stomach which I’ve been taught to self-administer.”
Now she is firmly focused on living for every day and is confident that with medical advancements, outcomes for people with genetic diseases will improve.
“I’m still in contact with Prof. Scott and serve as a consumer advocate whenever the opportunity arises,” said Christine, who together with two other women, started an MDS/MPN-RS-T Facebook support group.
“I also want to stress that our family is an extremely rare case and MDS is not typically a hereditary disease,” said Christine.
*MDS/MPN-RS-T is a rare subtype of MDS/MPN characterised by anaemia, bone marrow dysplasia with ring sideroblasts and persistent thrombocytosis ≥450 × 109/L with proliferation of large and morphologically atypical megakaryocytes.
**Cyclosporine is an immunosuppressant used to prevent rejection, following allogeneic bone marrow transplantation.
MDS-survivor, Danny now dedicated to raising awareness
This MDS World Awareness Day, Danny Palmer will celebrate achieving remission after undergoing a life-saving transplant earlier this year. He’s now committed to raising awareness of the many different blood cancers, encouraging others to donate blood and plasma, as well as fundraise in support of the community.
“I just assumed I was working too hard – I maintain parks and recreation areas for the local council and was walking a lot of kilometers every day,” said the 50-year-old who lives on the Gold Coast in Queensland.
“I have type-1 diabetes and bipolar disorder as well, so I was in regular contact with my doctor.
“I had an appointment in August 2019 and told him what was going on, he said, ‘you’re due for a blood test for your diabetes anyway but I think there’s a bit more to this’.”
“Low and behold, when the results came back it looked like I had leukaemia.”
Danny was taken to the local Gold Coast Hospital where he received a blood transfusion and underwent further tests.
“It was then confirmed that I actually had high-risk MDS. I was told it was a blood cancer, but I had no idea that there were any other types than leukaemia,” said Danny.
“It was a steep learning curve, and I was pretty scared.”
Danny was put on a drug called azacitidine, a daily injection for a week every four weeks, and was given only eight months to live.
“My case was then submitted to the Royal Brisbane and Women’s Hospital (RBWH) board as an ideal candidate for a transplant,” said Danny.
“My haematologist at Gold Coast Hospital has a great relationship with my now haematologist in Brisbane, Dr Siok Tey.
“I was really lucky that I didn’t have to go the roundabout way to get to transplant but I was put forward to the right people from the outset.
“They assess a lot of things like your survival chances, any comorbidities, your age and the progression of your disease.
“In the new year I was told I had been accepted but that I would need a 10/10 perfect-match donor.”
Both Danny’s sister and brother were not a match, so the search was widened to find an unrelated donor.
“They first found a perfect-match donor from Germany; however, the COVID-19 pandemic had just hit, and we were told no more stem cells were making it into the country,” explained Danny.
“We were back to the drawing board for a while there. Thankfully, another 10/10 match was soon found down in Victoria and I was all set to go in April.”
On 2 April 2020, Danny underwent the transplant in Brisbane spending a total of 24 days in hospital.
Understanding MDS and the biological processes driving treatment response
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).
** 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.
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.
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.
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.
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.
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 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 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”
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.
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
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.
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.
“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.”
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.
“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.
Quest to better understand MDS and find out more effective therapies
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).