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The importance of molecular response in CML

The importance of molecular response in CML

By Professor Susan Branford PhD, a medical scientist with the Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology and the University of South Australia and University of Adelaide.

My PhD research in biomedical science involved assessing people with CML to determine if monitoring the level of disease during therapy using a molecular marker could predict treatment outcome.

I also investigated the reasons for drug resistance that occurs in a small number of patients.

Key levels of molecular response on the International Scale 
Key levels of molecular response on the International Scale

The tests I developed are now incorporated into routine patient monitoring along with the other blood tests a person with CML has on a regular basis after diagnosis.

CML is a genetic disease. A change in the structure of DNA within cells leads to the formation of a new gene that does not behave normally and causes CML. The new gene is formed from the fusion of two different genes and is called BCR-ABL1.

BCR-ABL1 is a molecular marker that can be measured during therapy. Importantly, a blood sample is required to measure BCR-ABL1 levels rather than bone marrow, the collection of which is associated with greater discomfort for patients.

In the past, there was a greater need for people with CML to have bone marrow biopsies to diagnose their disease and to monitor their response to therapy. Bone marrow collection is still necessary at diagnosis and is a very important part of patient management.

In Australia, however, molecular monitoring of BCR-ABL1 during therapy, using a blood sample, has largely taken over from bone marrow testing. The advantages of molecular testing include a shorter time for the result to be ready, and the test is 300-1000 times more sensitive for detecting low levels of leukaemia, compared with cytogenetic testing.

Professor Susan Branford
Professor Susan Branford

Our laboratory has been monitoring BCR-ABL1 levels in patients with CML for a long time and was one of the first laboratories in the world to develop this technique.

We monitored patients in early clinical trials for imatinib – the first drug that was truly effective for most CML patients and since then there have been many clinical trials of different and more powerful drugs.

All the trials have consistently shown that the molecular test can provide very useful clinical information for the prediction of response to drug therapy, and many labs around the world are now performing the test.

The molecular technique is not easy for new labs to develop and BCR-ABL1 values can vary from lab to lab. To overcome these differences, about 10 years ago it was decided that all labs adopt a common way to report the results, so a BCR-ABL1 value is similar no matter in which lab it is tested.

Working with many labs around the world, we developed a set of recommendations for the testing procedure and BCR-ABL1 values are now reported on an international reporting scale. This has improved the quality of the results.

A panel of experts recommended that BCR-ABL1 values reported on the international reporting scale be used to determine if a patient is responding well to therapy or if a change of therapy is necessary to improve response.

BCR-ABL1 levels indicate molecular response
BCR-ABL1 levels indicate molecular response

The critical timepoints to assess response is at three, six and 12 months of drug treatment. A value of 10% at three months, 1% at six months, and 0.1% at 12 months is an optimal response, and no change of therapy is necessary. Most patients reach these levels.

A small number of patients develop drug resistance and the main reason is a change in the DNA sequence of the BCR-ABL1 gene that can stop the drug working properly.

A rise in BCR-ABL1 level can indicate that drug resistance is occurring. When a rise occurs and the doctor suspects relapse, a blood sample can be used to check for a change in the DNA sequence of BCR-ABL1. The haematologist can then decide whether a change of therapy is necessary.

There is still a lot we don’t know about CML. At the time of diagnosis, we can’t identify those patients who will fail their therapy. But technology is rapidly advancing, and over the next 10 years, we hope to more thoroughly examine and understand the molecular changes that occur, which will lead to improved treatment and better outcomes for all patients.

Latest ALLG clinical trials recruiting for AML

Latest ALLG clinical trials recruiting for AML

Four clinical trials run by the Australasian Leukaemia & Lymphoma Group* (ALLG) are currently open to a range of people with acute myeloid leukaemia (AML) across Australia.

Professor Andrew Wei
Professor Andrew Wei

AMLM21 – leading doctor, Professor Andrew Wei

The AMLM21 study is evaluating ponatinib (Iclusig®) in combination with 5-azacytidine (Vidaza®) in FLT3-ITD or CBL positive patients with AML who have failed prior therapy or are unfit for intense chemotherapy.

The trial is open to recruitment at the following sites:
Victoria – Alfred Hospital, Barwon Health
New South Wales – Liverpool Hospital, Calvary Mater Newcastle, Westmead Hospital
Queensland – Royal Brisbane Hospital.

AMLM22 – leading doctor, Professor Andrew Wei

The most appropriate treatments for AML patients in their maintenance treatment phase are being evaluated in the AMLM22 platform trial.

This randomised, multi-arm study platform is comparing the efficacy of experimental therapies versus standard of care in patients with AML who are in first complete remission. The AMLM22 trial is an adaptive trial platform designed to compare the efficacy of novel therapies or combinations flexibly and efficiently to the current standard of care. Several treatment domains are proposed on the platform with patients randomised to the domain they are eligible to participate in, and then randomised to either an investigational or standard of care treatment arm.

This trial is open to recruitment at the following sites:
Victoria – Alfred Hospital, Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Austin Health, Barwon Health, Monash Health
New South Wales – Calvary Mater Newcastle, Border Medical Oncology, Prince of Wales Hospital, Concord Hospital, Gosford Hospital, Royal North Shore Hospital, Orange Health Service, Wollongong Hospital
Queensland – Princess Alexandra Hospital, Townsville Hospital, ICON integrated Cancer Centre
South Australia – Royal Adelaide Hospital
Tasmania – Royal Hobart Hospital, Launceston Hospital
Western Australia – Fiona Stanley Hospital, Sir Charles Gairdner Hospital, Royal Perth Hospital
Northern Territory – Royal Darwin Hospital.

Professor Paula Marlton
Professor Paula Marlton

AMLM23 – leading doctor, Professor Paula Marlton

The HO150/AMLM23 trial is an international trial led by the Heamato Oncology Foundation for Adults in the Netherlands (HOVON).

This placebo-controlled study compares ivosidenib (Tibsovo®) or enasidenib (Idhifa®) in patients newly diagnosed with AML or myelodysplastic syndrome (MDS). The purpose of the study is to investigate the efficacy and safety of ivosidenib and enasidenib in patients with AML or MDS.

This trial is open to recruitment at the following sites:
Victoria – Royal Melbourne Hospital, St Vincent’s Hospital, Alfred Hospital
New South Wales – Royal Prince Alfred Hospital, Concord Hospital
Queensland – Princess Alexandra Hospital, Townsville Hospital
Tasmania – Royal Hobart Hospital
Western Australia – Fiona Stanley Hospital.

AMLM25 – leading doctor, Professor Andrew Wei

The AMLM25 trial is a Phase II trial evaluating the most appropriate treatments for older AML patients.

AMLM25, also known as the INTERVENE study, is aimed at improving treatment for people aged 60 or older with adverse risk and non-adverse risk AML who have not already received previous chemotherapy (treatment-naïve), or those who are not able to receive intensive initial chemotherapy. It is hoped that the treatment will improve the initial response, prolong the duration of response, and increase overall survival.

The aim of the first part of the study is to determine the safest dose of the study drugs midostaurin (Rydapt®) or pracinostat when given in combination with venetoclax (Venclexta®) and cytarabine (LDAC).

The second part of the study will compare the effectiveness and safety of midostaurin and pracinostat when used in combination with venetoclax and cytarabine.

This trial is open to recruitment at the following sites:
Victoria – Alfred Hospital, Peter MacCallum Cancer Centre, Royal Melbourne Hospital, St Vincent’s Hospital, University Hospital Geelong
New South Wales – Calvary Mater Newcastle
Tasmania – Royal Hobart Hospital
Queensland – Townsville Hospital, Princess Alexandra Hospital
South Australia – Royal Adelaide Hospital, Flinders Medical Centre
Western Australia – Fiona Stanley Hospital.

For more information on current clinical trials in AML, visit the ALLG website, or speak to your treating haematologist.

* The ALLG is the only not-for-profit collaborative clinical trial group in Australia and New Zealand delivering research projects focused on blood cancers. The ALLG’s purpose is to achieve better treatments and better lives for people with AML and other blood cancers. ALLG clinical trials are taking place at 93 accredited hospital sites and cancer centres across the the country and more than 800 physicians and haematologists, nurses, scientists, and professional support staff are ALLG members.

New 3D models could revolutionise drug testing

New 3D models could revolutionise drug testing

Dr Laura Bray has made it her life’s work to develop 3D models which she hopes will provide answers to the many unknowns faced by people with AML and other life-threatening diseases.

Dr Laura Bray in the lab
Dr Laura Bray – recipient of a $200,000 Priority-driven Collaborative Cancer Research Scheme grant from the Leukaemia Foundation in collaboration with Cancer Australia

There is so much uncertainty when they are diagnosed, she said. They want to know how aggressive their cancer is, whether it will come back after treatment, and if so where.

“I want to develop predictive technologies that give people more clarity about their illness, personalised treatment, and a better understanding of the long-term risks into the future.”

Dr Bray is a bio-scientist who has worked on three-dimensional (3D) tissue microenvironment models of acute myeloid leukaemia (AML) for seven years.

She is the lead investigator of a new study aimed at improving our understanding of the biology of AML and treatment resistance by developing new models for drug testing.

The 3D testing models she is developing more accurately mimic the natural environment of the human bone marrow compared with the traditional two-dimensional (2D) laboratory methods.

Dr Bray is a Group Leader and Deputy Director of the ARC Training Centre for Cell and Tissue Engineering Technologies at the Queensland University of Technology (QUT).

Dr Laura Bray and her research team
Dr Laura Bray, right, and members of her research team

She was awarded a $200,000 Priority-driven Collaborative Cancer Research Scheme grant from the Leukaemia Foundation in collaboration with Cancer Australia (July 2019-July 2022).

The title of Dr Bray’s research project is Development of a translational bioengineered microenvironment model to advance pre-clinical acute myeloid leukaemia research and is supported through the Estate of Florence Brown.

Dr Bray said 3D tissue microenvironments can replicate many natural mechanical, chemical, and cellular processes that cannot be depicted in the 2D cell cultures currently used for most drug research.

“My fascination with 3D models began in 2009, during my PhD project at the Queensland Eye Institute. I was using tissue engineering to grow three-dimensional corneas for potential future applications in patients who needed a replacement,” said Dr Bray.

“I could see the remarkable potential then of these models as an alternative to animal or human testing.”

Dr Laura Bray in the lab 2
Bio-scientist, Dr Laura Bray, is working at finding answers to the many unknowns faced by people with AML

After being awarded her PhD, Dr Bray moved to Germany for on a three-year research fellowship and her focus shifted to AML.

“I had a real personal drive to bring my knowledge of tissue microenvironments back into the oncology field, as my family, friends and colleagues have been affected by cancer in many different forms,” she said.

“In the lab, when you’re using a standard culture of leukaemia cells, they are just floating around in a solution and we know it’s not replicating the way that leukaemia cells grow in the actual bone marrow environment. There are other cell types in the bone marrow, including blood vessels which act as a conduit to nutrients and flush out waste in the body.

“But these blood vessels can also act to protect leukaemia cells, giving them the ability to hide and become resistant to treatment.

“By developing these 3D bone marrow microenvironments, we hope to understand how these leukaemia cells interact with the surrounding natural cells, and hopefully develop new targets to stop them growing in that space.”

These models have the potential to be utilised as research platforms for fundamental biological studies and pre-clinical trials, as well as to study new targeted therapies for cancer patients.

Dr Laura Bray with computer
Dr Bray is a Group Leader and Deputy Director of the ARC Training Centre for Cell and Tissue Engineering Technologies at the Queensland University of Technology, Brisbane

Dr Bray is eager to see the study build on previous findings which her research group has already published.

“We were able to recreate part of a 3D bone marrow microenvironment and watch the leukaemia cells interact with it in real time,” she said.

“We then applied a certain drug that inhibits the ability of the cancer cells to adhere to the blood vessel and watched the cells successfully detach from the vessels in the model, showing that our models can reproduce quite complex biological processes.”

Having Leukaemia Foundation funding will enable Dr Bray to determine which cells will survive after certain treatments and then start to grow again.

“Over time we need to be able to identify these specific cells and then remove them out of the model to study what makes them resistant,” said Dr Bray.

“By being able to profile these cells, we can hopefully find some new targeted treatments.”

A major driver for developing these models is to reduce the number of animals used for drug testing, and in 2015, Dr Bray was awarded a Lush Prize for her work; the largest global prize fund in the non-animal testing sector.

“The regulatory structure in Australia stipulates that animal testing must be done prior to human trials,” she said.

“But we know that 95% of drugs that have positive results in a lab setting will fail in human clinical trials.

The 3D tissue microenvironment models under the microscope
The 3D tissue microenvironment models under the microscope

“We want to change that pipeline with these 3D models acting as a middle ground where those non-effective drugs can be weeded out.

“This will save time, money, and many animals from having to be sacrificed just to find out that the drug will not work on a human.”

Due to the COVID-19 pandemic, Dr Bray’s lab was closed for four months last year and was unable to source specialised blood vessel cells from the U.S. supplier during that time.

“That was really difficult as it takes a lot of time to build up these cell cultures,” explained Dr Bray.

“It takes a few months of work, either side, to wind it down and then start it up again, but hopefully we are through the worst of it now and the Leukaemia Foundation has been really understanding and permitted an extension to my grant funding period.”

Over the past few years, Dr Bray and her team have worked to promote the benefits of 3D models and encourage biologists at the bench to adopt the technology.

“Traditional 2D cultures are easy and they’re cheap, but we and others are trying to bring these 3D models into the mainstream research space.

“This project will certainly help our case with the dream to see these three-dimensional technologies applied across all diseases, not just blood cancer.”

Why Dr Morrison pays attention to his vitamin C intake

Why Dr Morrison pays attention to his vitamin C intake

Internationally recognised leader in stem cell research, Dr Sean Morrison, makes sure he gets his daily requirement of vitamin C – not a lot more and definitely no less!

Dr Sean Morrison
Dr Sean Morrison

Why? Because his research has discovered a connection between vitamin C levels and leukaemia, and the importance of meeting daily requirements as opposed to taking megadoses.

Dr Morrison is director of the Children’s Medical Center Research Institute at UT Southwestern*, Dallas (U.S.). He was in Brisbane in 2019 to present at the International Society of Experimental Haematology (ISEH) meeting where he spoke to AML News.

His lab focuses on the blood forming system and studies stem cells in cancer.

“We study the mechanisms stem cells use to replicate themselves, which is how they persist throughout life in our tissues, and the ways in which cancer cells hijack those mechanisms,” said Dr Morrison.

“Cancer is a disease of dysregulated self-renewal, where cancer cells hijack the mechanisms that stem cells use to self-renew and over-activate those mechanisms to form tumours rather than normal tissues.

“We are trying to improve the treatment of disease, including cancer, by better understanding the underlying biology.

“Anything that promotes those mechanisms is a potential regenerative medicine therapy, and anything that inhibits those mechanisms is a potential anti-cancer therapy,” explained Dr Morrison.

“We have done a lot of work to characterise the micro-environment that maintains stem cells in the bone marrow.

“There are specialised cells in the bone marrow that help to maintain blood forming stem cells.

“One thing leukaemia cells do, is eliminate the normal cells partly by destroying those niche cells that help to maintain the normal cells.

“We discovered these leptin receptor positive cells that are the main source of factors that promote the maintenance of stem cells.

“Cancer cells kill off those normal leptin receptor positive cells and the normal stem cells, and by eliminating the competition from the normal cells it helps the leukaemia cells to progress more quickly,” he said.

Understanding the metabolic regulation of stem cells is another area of Dr Morrison’s research.

“We are looking very widely at whether there are metabolic pathways that are active in stem cells, more so than in other cells, and whether those pathways could be involved in supressing the development of leukaemia. And we found that they are,” he said.

“It turns out that haematopoietic stem cells take up more vitamin C than other haematopoietic cells.

“They have to take up vitamin C to regulate normal gene expression in the stem cells.

“Part of what vitamin C does is that it suppresses the development of leukaemia from blood forming stem cells.”

“You’ve heard your whole life… eat fruit to suppress the development of cancer,” said Dr Morrison.

“There were old epidemiological studies done, where it was seen that people with below average vitamin C levels get more cancer, but the underlying mechanisms were not at all clear.

“We’ve discovered some of the underlying mechanisms, where there is a particular tumour suppressor, called TET2, in the haematopoietic system that gets mutated in a lot of leukaemias.

“TET2 function requires vitamin C, and vitamin C is limiting for TET2 function,” he said.

“So, people who don’t get enough vitamin C in their diet don’t have adequate TET2 activity and they’re walking around with messed up stem cells in a way that predisposes them to leukaemia.

“That research has been published in the journal, Nature, and we’ve continued to refine and develop these methods for studying stem cell metabolism.”

Dr Sean Morrison
“Part of what vitamin C does is that it suppresses the development of leukaemia from blood forming stem cells,” says Dr Morrison

Dr Morrison said another exciting discovery in recent years is that clonal haematopoiesis is more common than originally thought. This is where a haematopoietic stem cell (HSC) acquires mutations that allows it to outcompete normal HSCs and it starts to take over blood cell production.

“Normally, thousands of blood forming stem cells contribute to blood cell production, but as you get older, or if you have been treated for cancer, a surprisingly high fraction of people have clonal haematopoiesis.”

Dr Morrison said that by age 70, at least 10% of all people have clonal haematopoiesis, and about 30% of people who have been treated for cancer – who have received radiation therapy or chemotherapy – have clonal haematopoiesis.

“We are talking about a lot of people in the Western world, most of whom have no idea they have clonal haematopoiesis.

“This is a pre-leukaemic condition and in addition to increasing their risk of leukaemia, it predisposes to other diseases of aging, like cardiovascular disease,” said Dr Morrison.

“The people who discovered clonal haematopoiesis think the existence of this condition, along with the loss of TET2 function, causes the blood forming system to become more inflammatory.

“Inflammation makes us old and causes the changes that occur during aging.

“One of the most common mutations – the second most common mutation in clonal haematopoiesis – is loss of one allele** of TET2.

“While most people with clonal haematopoiesis never develop leukaemia, it is just a subset.

“We think the people who are most likely to develop leukaemia are those who have not only lost one allele of their copies of TET2, but who are also not getting enough vitamin C in their diet. If you are down to one good copy of TET2, you better get 100% of your daily vitamin C requirement in order to maximise the leukaemia-suppressive activity of the copy of TET2 that you have left,” he explained.

“And we know there is a dosage relationship, that the more you reduce TET2 activity, the more likely you are to get leukaemia.

“We are testing that in patients now, by offering to test vitamin C levels in everybody with clonal haematopoiesis. We are collecting that data over time to test our prediction that people with lower levels of vitamin c are more likely to progress to leukaemia.

“If it turns out that we are correct, and we can predict who is going to get leukaemia and who is not, based on their vitamin C levels, then it could have a major public health impact to insist that everybody with clonal haematopoiesis drinks a glass of orange juice every day or takes a multivitamin to ensure that they get 100% of their vitamin C.”

Dr Morrison said testing for clonal haematopoiesis involved sequencing and was not routinely done by doctors now.

“But I think, someday, it will start to be done routinely,” he said.

“In the future, when we hit 60 years old, or have been treated for cancer, we will be tested for clonal haematopoiesis. And then people will start paying attention to their vitamin C levels.

“After we saw from our experiments that blood cancer was particularly sensitive to vitamin C, we went back to the Centres for Disease Control and Prevention data and found that for most cancers, risk doesn’t change with vitamin C nutrition.

“There are only a few cancers that go up with low vitamin C and myeloid leukaemia is number one on the list.”

“If we could ensure that everybody with clonal haematopoiesis got optimal ascorbic nutrition, I bet we could cut down on the number (thousands) of people who would otherwise have got cancer,” he said.

So, does Dr Morrison pay attention to his vitamin C intake?

“Historically, I never did. I feel like I eat a pretty good diet. But after we published this paper, I was thinking that there are some days where I really don’t get 100% of my vitamin C, so I started taking a multivitamin.

“I don’t want people to misinterpret what I’m saying. I’m not suggesting people go out to the drug store and buy those megadoses of vitamin C,” emphasised Dr Morrison.

“I just think getting 100% of your daily requirement is good, and that doesn’t mean that 1000% is better. But getting 100% is good. That is why I take a multivitamin that has a little bit of vitamin C in it.”

Pre-COVID-19, Dr Morrison flew 200,000 miles (320,000 km) a year travelling the world to meetings like the ISEH meeting in Brisbane.

“I probably do travel too much,” he said.

“I prefer to be at home. It’s a healthier lifestyle to be at home, sleeping in your own bed, eating healthy food that you control, and getting exercise.

“But on the other hand, I almost never come to a meeting and feel like it’s a waste of my time.

“I learn something every time I come to meetings. I sit there, emailing questions back to people in the lab – ideas about doing new techniques or new ways of testing the things that we are working on. It does accelerate the science, and that undermines my willpower to say, ‘no’ more.”

Melanoma, in particular melanoma metastasis, is another area of study in Dr Morrison’s lab, which resulted in the discovery that melanoma cells are unusually sensitive to oxidative stress during metastasis.

“Let me give one piece of advice that your readers may not have heard elsewhere,” said Dr Morrison.

“The idea is so strong in people’s minds that antioxidants are good for you. For many years, there was this idea that if you ate antioxidants you would age more slowly and get less cancer.

“In fact, many clinical trials show that people who take antioxidants get more cancers, have worse outcomes with cancer, and are more likely to die of different causes,” said Dr Morrison.

“In our experiments with melanoma, we see that the cancer cells benefit more from the antioxidants than the normal cells do. If we take a mouse with melanoma and give it antioxidants, the melanoma progresses and kills the mouse faster.

“I worry that people who are diagnosed with a serious cancer and become very health conscious, then go to the drugstore and start buying all these supplements and antioxidants and things, are increasing their risk of dying because the cancer cells benefit more from the antioxidants.

“I’m not telling anyone to eat an unhealthy diet,” said Dr Morrison, who specifically mentioned people buying a pill that has 500% of the daily requirement of an antioxidant (vitamins A and E).

“In clinical trials, when people supplement their diet with large levels of vitamin A or vitamin E precursors, they have worse outcomes in terms of cancer.

“Now that people like us are finding the underlying molecular mechanisms, when combined with the earlier clinical trials that show worse outcomes, I think the scientific community is really flipping over to recognise that while it’s good to get 100% of your daily requirement of these things to be healthy, it’s not good to get 500%, especially if it is from a pill.

“If you eat a salad, those vitamins get released into your system over a period of time as you digest it. But if you eat a pill, your system gets blasted with these chemicals very quickly and the idea that if a little of something is good, more must be better, doesn’t turn out to be true,” said Dr Morrison, whose overall career goal is for a new therapy to emerge from his lab’s work that cures people who wouldn’t otherwise be cured.

* UT Southwestern is a premier academic medical centre in the U.S. that integrates pioneering biomedical research with exceptional clinical care and education.

** A variant form of a gene.

Dr Traver’s fascination with how leukaemia happens

Dr Traver’s fascination with how leukaemia happens

Dr David Traver is an experimental haematologist who specialises in haematopoiesis*. The Professor of Cellular and Molecular Medicine, and of Cell and Developmental Biology, at the University of California (San Diego, U.S.) spoke to AML News at the International Society of Experimental Hematology (ISEH) conference in Brisbane (Aug 2019), where he was awarded the Leukaemia Foundation-sponsored McCulloch and Till Award and gave the closing lecture on Decoding the molecular cues that regulate HSC specification.

Dr David Traver
Dr David Traver

How do you feel about receiving this award?

It was quite a surprise and an honour. This has always been my favourite meeting. I gave my first talk in science at this meeting when I was a graduate student, in Vancouver in 1997 or 1998. I was terrified. There were all of these big names in the audience who I had only read about as a third-year student. But everyone was so open and welcoming, and they were all very approachable. It has been my favourite meeting ever since.

And now you’re one of those famous people!

I guess [laughter] but I’ve never cared about being famous. I’d like to be rich, but I think I chose the wrong career for that. I generally don’t like to be the centre of attention, so I sometimes wonder why I chose this career. The idea of being the lab’s spokesperson was initially challenging for me, but I’ve learned over the years to enjoy it. I love the science and love to always be learning.

How did you become an experimental haematologist?

I joined the immunology program at Stanford University, where I had a choice of about 30 labs working on things related to immunology. I was attracted to Irv Weissman’s group because he was focused on haematopoiesis, meaning the study of how blood cells arise, how stem cells work, and how leukaemia happens. And those were the questions I found really fascinating, rather than classic immunology. I liked the process of blood formation, then became intrigued with development, genetics, and imaging, and fell in love with the zebrafish, which was an emerging system at the time.

Dr David Traver and team in the lab
Dr David Traver, rear right, and team in the lab

What is your lab working on?

We are trying to understand how the stem cells that make the entire haematopoietic system are born. In other words, how they are first formed during development of the embryo. One of the big goals of regenerative medicine is to harness the technology of induced pluripotent stem cells [that have the potential to make all the cell types in our bodies], as discovered by Shinya Yamanaka, to make patient-specific blood cells. What we can’t do yet is make blood stem cells from this primitive precursor. A transplant for a person with leukaemia or a blood-based disease needs haematopoietic stem cells (HSCs), to provide lifelong regeneration of the lineages they need. Ultimately, the goal for many of us in the field is to try and take these human pluripotent stem cells and instruct them to generate HSCs. Despite attempts for 30 years, we’ve never been able to do it because we don’t yet know enough about how the embryo does it.

What are your big picture goals?

One is to understand how the embryo makes HSCs. That’s why we use zebrafish. They are born externally from their mother and are completely translucent for the first week of life. They develop into a free-swimming animal with a beating heart and stem cells within 24 hours of fertilisation. We can use fluorescent transgenes to light up the HSCs to watch how they behave inside a living animal in real time.

“We saw the HSCs being born out of one of the major blood vessels, just by watching to see what happened.”

There were several theories about where HSCs were born in the embryo. We imaged animals with fluorescent blood vessels and fluorescent HSCs via a 24 hour time-lapse and the evidence was irrefutable. That is what we’ve been working to better understand ever since.

What does this finding mean?

Once we knew, finally, where stem cells were coming from, we could then work to figure out how, genetically, those cells were born… how they are made, how the environment instructs them what to become. What we are working on now is to target single HSCs at the site of emergence [where they are born] and activate a single oncogene** in a single stem cell.

“This is how everyone thinks cancer starts.”

You take one hit, probably to a stem cell because it has to live long enough to accumulate more mutations. We can ask, is that sufficient? It is not thought that one mutation is ever sufficient to cause cancer, but it might be sufficient to start the process.

What questions are you asking now?

If a clone we are working on does give risk to leukaemia later on, how does it do it?

We can pull out those clones and ask every week… how does that clone change in a molecular way? We can activate an oncogene in a single stem cell in a hundred different embryos and pull out 10 embryos every week or month and ask… how are they changing? This is the five-year plan; what we are working to do now. You can only do these amazing experiments in zebrafish because everything happens ex utero. This approach cannot be taken in mouse models because you can’t effectively target those stem cells that early.

“And the powerful thing is that we’ve all come from a common ancestor.”

So, the things that we discover in zebrafish are almost always applicable to studies in mice, frogs, or humans, since our immune systems have all derived from a shared ancestral source. The zebrafish we work on are really beautiful. They’re remarkable little creatures. You can see every cell in their bodies and how they behave in real time. My talk [at ISEH] includes a few time-lapse movies people in the lab generated. We do a lot of our early work, genetics, imaging and stem cell biology in the zebrafish, and revalidate our findings usually in the mouse embryo, where my early training was. Then often we take what we’ve learned and test it in human pluripotent cell systems. I think, ideally, if we can show the same thing is true in systems as different as fish, a rodent, and us, then it is fundamental and a great foundation to move forward.

Dr David Traver
Dr David Traver has been researching where stem cells are born in the embryo, in order to find out how they are made.

How is your work contributing to blood cancer treatment?

We are studying the genetic mechanisms of how stem cells are born and how are they are maintained, and a big part of that is self-renewal. The hallmark of the stem cell is how it can make copies of itself forever, without becoming cancerous. Stem cells and cancer cells are the flipside of the same coin because cancer cells should never self-renew but somehow can. There could be a lot in common with the normal self-renewal mechanisms of stem cells and how cancer cells become transformed. Once we can generate these models of leukaemia starting with a single cell, we can do chemical screens and rapidly discover compounds that specifically kill that cancer.

For children with translocations in the mixed-lineage leukaemia (MLL) gene there is no effective treatment and it [MLL] is invariably fatal. It is thought that these translocations happen very early in development, because if you find identical twins where one has the mutation, the other almost always does too – meaning it happened very early in development, when each shared a circulatory system. So, this particular translocation is intimately involved in HSC emergence. It happens very early, which is one reason we think if we can activate expression of the human oncogene in a single stem cell it may accurately model what happens in these children.

What happens in your lab day-to-day?

It depends on the day. We have lab meetings once a week, where my students and fellows present their work and receive feedback from myself and others in the lab. I like to have a lab of 10-12 people, that is my ideal size. We have a journal club where we talk about papers that are relevant to what we do. I meet individually with everyone for at least half an hour a week to talk about their projects, their results, and to troubleshoot. One of my main jobs is to facilitate – to know the bigger picture, and how the individual components connect. I teach a fair amount – classes in stem cell biology, and there are grant cycles that are never-ending. It usually takes a couple of submissions to land a grant these days. And there are lots of faculty meetings and different seminars to participate in each week. I don’t do much experimenting anymore, I’m too busy with writing, grants, travelling, teaching and everything else that comes with this often crazy job.

David Traver
David’s work has special meaning after losing his own mother to AML 10 years ago.

What advice can you offer people with a blood cancer like AML?

One thing to try and do is to stay on top of what’s developing. If you have a disease that is typically hard to treat, see what is out there in terms of trials, talk to your doctor, and talk to researchers. A lot of patient-specific immune therapy, like the CAR T-cells, have had amazing success. But it has only worked so far for a handful of cancers and leukaemias. The cancer immunotherapy field is moving fast.

“I lost my own mother to AML 10 years ago.”

It was very demoralising and disappointing to see her taken by something I felt I knew a lot about and should be able to understand. My mum had a perfect match for the bone marrow transplant, she just couldn’t handle the preparative regimen. Her body rejected the platelets that were transfused following the chemotherapy. I think we just still don’t know enough. The regimens used are very generic, and damages all systems in the body. We need to get better at finding regimens that are more specific for each disease type.

What is your holy grail?

I would love to contribute to the recipe on how to effectively build a blood stem cell from scratch. Then we can translate our findings, from our embryonic settings, to in vitro settings in human pluripotent stem cells. I think, in a couple of years, we and others in the field will figure it out… but I have thought that for a while [laughter]. In the second phase of my career I would love to contribute more directly to human health and to helping people, because what we do in basic science often takes a long time to find its way to helping patients.

*Haematopoietic stem cells (HSCs) are the stem cells that give rise to all blood and immune cells. This process is called haematopoiesis and occurs in the bone marrow, in the core of most bones. 

**An oncogene is a gene that has the potential to cause cancer.

Developing mutation-specific targeted therapies for AML – “a new era of medicine has begun”

Developing mutation-specific targeted therapies for AML – “a new era of medicine has begun”

A/Prof Dan Thomas
Associate Professor Dan Thomas

After working with world class stem cell biologists at Stanford University in California (U.S.) Associate Professor Daniel Thomas returned to Australia last year. He set up the Myeloid Metabolism Laboratory in the Precision Medicine Theme at the South Australia Health and Medical Research Institute in hometown Adelaide. It’s a basic and translational research lab where Dr Thomas and his team are designing new therapies and finding new targets for acute myeloid leukaemia (AML) and myelofibrosis (MF). He’s 2020/2021 Translational Research Program Grant recipient through the Leukaemia Foundation and was awarded the 2020 CSL Centenary Fellowship. But that’s not all… Dr Thomas also is a clinical haematologist who has just begun a precision medicine trial for myeloid leukaemia (CMML) based on his research and has dedicated his medical skills in helping refugee populations escaping war-torn countries.

Associate Professor Daniel Thomas believes a whole new age in cancer precision medicine is underway and AML is the testbed due to its low number of mutations, live pre-clinical models for testing, and stable chromosome numbers.

“I’m so grateful to have established my research group at this time back in Australia,” said Dr Thomas.

Many Australian philanthropic donors pooled together to bring him back and he is extremely thankful for their generosity, including the Leukaemia Foundation.

Dr Dan Thomas, at rear, with his team of researchers from the Myeloid Metabolism Laboratory
Dr Dan Thomas, at rear, with his team of researchers from the Myeloid Metabolism Laboratory

“Australia is a safe and peaceful place with outstanding technology to do world class research. We need to mentor and prepare the next generation of physician-scientists in this country,” he said.

Dr Thomas chose to work on AML because this aggressive leukaemia had been “neglected”.

For 30 years, there had been no breakthrough therapies, with only small increments in supportive care and modest improvements in stem cell transplantation for high-risk patients. But recently that has all changed.

“In the last two years four new mutation-specific drugs have been approved for AML overseas, which has been a watershed time for AML,” said Dr Thomas.

These new drugs include midostaurin, which is available through the Australian Pharmaceutical Benefits Scheme (PBS) and gilteritinib, enasidenib and ivosidenib, available through clinical trials in Australia run by the Australasian Leukaemia & Lymphoma Group.

“We’re anticipating this will continue for other common mutations in AML, and that’s why I do my research; we’re finding new vulnerabilities in the cancer that can rapidly lead to new medicines.”

Dr Daniel Thomas with son at the farm
Dr Thomas and his son, Joseph, “at the farm”

“We’re hoping that, as we have observed in myeloma, the more therapies available that give responses without serious side-effects, the longer people survive, simply by moving from one non-toxic treatment to another. Some then are able to undergo transplantation.

“Then, when we have at least seven or eight mutation-specific therapies available to us that are effective, we can begin to talk about cure.”

Medicine is Dr Thomas’ calling

“Ever since I was a young boy, I was very interested in how the body works, and used to enjoy house visits to people who were sick and helping my grandma when she volunteered in aged care and Meals on Wheels. I just knew I was called to do medicine,” Dr Thomas explained.

“I learned a lot about white blood cells in year six and seven, went straight into medicine at Adelaide Uni, and was inspired by the research I did learning about how growth factors (cytokines) signal and how white blood cells talk to each other.

“At the time, cytokine receptors and growth factors had just been discovered, many of them by outstanding Australian researchers at the Walter and Eliza Hall Institute. I was mentored by some of the best cytokine experts in the world and I was able to apply that knowledge to leukaemia during my haematology training at the Royal Adelaide Hospital and as part of my PhD.

“My mother’s close friend’s son died of leukaemia under my watch when I was the junior registrar. He was an outstanding cricketer and all-round athlete. His leukaemia developed quite quickly after surviving a tsunami in Phuket and we were not able to get him to transplant with his brother’s stem cells in time.

“At his funeral, his father said to me, “Dan you have been given unbelievable gifts. You need to do something about this disease.”

“I knew in my heart it was my calling when he said that. Like a moment of sudden realisation of purpose.

“I finished my PhD, then was invited to go to Stanford University Department of Medicine to continue cutting-edge research into acute myeloid leukemia. To be honest, I didn’t want to go overseas at the time, but my mother and my boss encouraged me.”

Mutations in AML

Dr Thomas said there are 22 common mutations that are found in 90% of AML patients. In other words, for any new patients with AML, there is 90% chance that their leukaemia will have at least one of these common mutations.

“At the moment we have four mutation-specific therapies for three mutations [FLT3, IDH1 and IDH2] but there is so much more to do.

Dr Daniel Thomas 2019
Dr Thomas in 2019 when he was at the Stanford University Department of Medicine in the U.S.

“I’m hoping very soon we’ll have at least eight effective therapies for about 10 of these mutations,” said Dr Thomas. “The epigenetic mutations and gain-of-function mutations are most amenable to targeted therapy or synthetic lethal approaches.”

This is in addition to venetoclax (Venclexta®), which he describes as a “game changer” for older patients with AML when used in combination with hypomethylating agents, but which is not strictly a mutation-specific precision therapy.

“Venetoclax is a small molecule, in part developed by outstanding research in Australia. It works in many older patients with AML and we’re just beginning to work out which mutations respond best to it and which mutations are resistant.

“Australia is a fantastic place to work and innovate, and we’re beginning to develop drugs here, run world class Phase I trials and the world is beginning to notice.

“The mutations we find in AML also occur in many other cancers, which means the vulnerabilities we find in AML can be rapidly applied to other cancers, as has been demonstrated for tyrosine kinase inhibitor drugs.

“A lot of what we’re doing in AML we know will be very quickly applied to many other solid cancer genotypes, and that offers precious hope.

“Acute myeloid leukemia is unique among cancers because it has a relatively low number of mutations compared to breast, colon and prostate cancer, and its gene make-up–its DNA–is completely stable,” said Dr Thomas who has been involved in the discovery of a new epigenetic subtype of AML (with WT1 mutation).

“In AML, there is a high chance that anything we discover is almost certainly targeting the somatic mutation that is driving the cancer, the one that we see on the sequencing report. With other cancers, you cannot be guaranteed that what you’re reading on the sequencing report is actually driving the cancer’s growth.”

To find out a person’s mutational profile means having their DNA sequenced, when diagnosed, and this can be done with a blood test if they have leukaemia cells in their blood.

“There are pathways by the Federal government, collaborative research groups, and clinical trials to get many cancers sequenced and the costs reimbursed, but not every physician is aware of these opportunities or has been trained to read the sequencing report.

“Most hospitals do the most common five mutations, including FLT3, NPM1, IDH1, IDH2, CEBPA. But they wouldn’t do TET2 or some of the other epigenetic mutations,” he said.

“But now, for less than $700, you can get all recurrent mutations sequenced at a good molecular pathology laboratory in Australia, such as SA Pathology in Adelaide, and for childhood leukaemia, we do this for free at SAHMRI.

“We need to build therapies around this information.”

Mass spectrometry opens a new branch of research

“The most exciting method that we are using now that is gaining rapid results in my research is mass spectrometry, using leukaemia cells that have been purified from a patient’s bone marrow and blood.

“It allows my team to find metabolic vulnerabilities that only occur when a certain mutation is present, and to measure every single small metabolite (or food derivative) that is inside a cell at any one time.”

And what is metabolic vulnerability?

“It allows us to see certain nutrients, or carbon fuels, that the cancer cells are either struggling to make or are completely dependent on. We never would have seen these if we had just used standard approaches of gene expression or flow cytometry.

“We are realising that some mutations make cancer cells extremely fussy in what they’re able to process as food to make them grow, and this has been a real breakthrough.

“Normally, we think of cancer cells eating sugar, and that’s why most cancers show up on a PET scan, but we have discovered many cancers are not eating sugar at all. They’re actually using alternative fuels, such as glutamine, lactate, and alanine, and they’re very fussy if you suddenly change that food.

Dr Daniel Thomas at the South Australia Health and Medical Research Institute in hometown Adelaide
Grateful to have established his research group back in Australia, Dr Thomas at the South Australia Health and Medical Research Institute in hometown Adelaide

“This is why we were awarded the [Translational Research Program] grant. The possibility that you can stop a leukaemia growing without harming normal cells is one reason why I get up every day.

“We’ve set up a fluxomics platform that can measure what happens to any carbon food or carbon fuel inside the patient’s leukaemia cell, and how it helps that cell grow. Then we target the enzyme that cell is using, and we can block it from proliferating [reproducing rapidly].”

“We’ve already done mass spectrometry in many patients and by the end of this year [2021] we should have done more than 100, but we’re already seeing mutation-specific differences and growth pathways that we never believed possible.

“Cancer cells are using metabolic enzymes which we do not often use as healthy adults. That is good news for the field.

“We’re finding certain mutations have unique metabolism profiles, and we can see which enzyme they’re using. That’s how we find the target, and we’re building drugs to block these enzymes.

“We’ve found many of these enzymes, when you inhibit them, do not produce any toxicity. And that breakthrough realisation gives you a therapeutic index, and that’s what we didn’t know three years ago.”

But more to the point, says Dr Thomas, you can target these enzymes without producing side effects. They’re not damaging DNA, and patients won’t be given chemotherapy or radiotherapy.

Dr Thomas said development of these drugs, which are often given as oral therapies, “is getting faster due to computational docking methods and improved medicinal chemistry resources”.

“In the old days, getting a lead to market would be seven years and most drugs would fail. Now it looks like we can bring it down to four years, especially if the indication is compelling for a rare cancer,” he said.

“We have one lead target that I developed with my supervisor, Dr Ravi Majeti, at Stanford. It’s very exciting,” said Dr Thomas.

He is hoping to do Phase I trials here in Australia using the new therapeutics his team is developing.

“Adelaide is renowned for doing Phase I. We’re very lucky to have some of the best Phase I trialists in the world here because of close collaborations between industry and hospital, and Melbourne is becoming a world-class Biotech Hub for drug development.”

Dr Thomas has several projects underway and says each one is “a minimum seven-year saga from concept to translational development”.

They include a clinical trial for another form of myeloid leukaemia, chronic myelomonocytic leukemia (CMML); “a nasty MPN that transforms into AML eventually in many patients”.

“It’s a big trial where we’re giving patients access to new drugs depending on their mutation profile.

“One of the most common mutations in CMML is a mutation in a gene called TET2 which occurs in at least 60% of all cases and can be reversed by vitamin C, by enhancing the residual enzymatic activity of the enzyme core.

“So, CMML patients with TET2 mutations will receive intravenous high-dose ascorbic acid, (vitamin C). In other cancers a number of studies have shown an improvement in cancer markers and patient well-being after high dose vitamin C infusion but no one has yet demonstrated dramatic response of the cancer cells themselves.

“This will be the first trial in the world to see if vitamin C can improve the quality of life and survival of patients with CMML when combined with azacitidine. It will tell us which type of mutations can be reversed or rescued with a simple non-toxic therapy.”

AML’s greatest unmet need

Dr Thomas considers effective drugs that work in older patients (those aged over 60) at the time of relapse to be the greatest unmet need in AML. He’s on that case.

“Five years ago, we thought most relapse cases had gained new mutations, such as TP53.

“But we’re realising relapsed cases of AML are very different from diagnosis, and they actually don’t have many new mutations. Something’s changed in the biology and epigenetics and we need to figure that out and develop good metabolic drugs or immunotherapies for them.

Dr Daniel Thomas with Syrian refugees in Lebanon
“Refugees taught me not to stress and over-medicalise our lives,” said Dr Thomas about his work serving Syrian refugees in Lebanon

“That’s good news because we can easily block epigenetics and we can block metabolism, whereas you can’t fix a gene mutation in every single cancer cell… that’s hard.

“We’re doing fluxomic metabolic profiling on those very cases right now using world-class equipment.

“And the good news is, they all seem to be doing the same thing… moving towards the one central metabolic state. If they were all different, I wouldn’t know where to start in designing a therapy or a drug.

“It’s almost like they start different, then they all start to merge as they relapse,” said Dr Thomas.

“My biggest contribution is a computational tool we built working with Stanford Computer Science (Professor David Dill and Dr Subarna Sinha) that predicts vulnerabilities in cancer when you have a certain mutation. We have realised most cancer cells cannot easily evolve around a bottleneck when two pathways are broken at once. These are called synthetic lethal pairs and was first demonstrated for breast cancer.

“Our algorithm will give you approximately 10-20 druggable targets that might make that cancer stop growing, and that you would never otherwise think of, based on these synthetic lethal pairs.

“In theory it could work for many cancers, including AML, but many of the synthetic lethal pairs have simply not had therapies developed against them… yet.”

From a current treatment perspective, Dr Thomas said venetoclax was very effective in combination in many older patients and the FLT3 inhibitors, such as midostaurin, is providing a bridge to transplant in young people without having to give further chemotherapy.

“But if these older patients relapse after venetoclax, or after they’ve had induction chemo, that’s what we’re working on.”

The long-term goal to cure leukaemia

Dr Thomas said the overall aim of his research was to find weak spots; “the Achilles heels of myeloid cancers that we can exploit to design new therapies”.

“My long-term goal is to see a molecular subgroup of leukaemia cured without significant toxicity in an older person.”

“We’re moving towards the point where we might be able to keep people alive, and even cured long-term, by a series of mutation-specific targeted therapies, without using chemo. And that’s exhilarating.

“It may even mean changing to precision diets in certain cases, if some of our metabolic research turns out to be transformative.”

Dr Thomas has discovered that one of the common mutations responds to loss of fat.

“It can’t cope with very low fat in its surrounding environment. It needs fat to grow but if you remove lipids the cells go strange and super-thin. They have run out of a metabolite (NADPH) required to make fat.

“We have to be very careful with potential precision diet information until it’s shown to be true in a strong Phase III trial, because many diets are based on fads, not proper science,” he emphasised.

“One of the common forms of AML–APML (which makes up 20-25% of AML)–we routinely cure without chemo, simply by giving these patients high-dose vitamin A. Vitamin A is found in kale, broccoli and cod liver oil and is needed for our retinal vision.

The Thomas Family
The Thomas family – Dan, his wife, Anafia, and baby, Joseph

“So we know, if you can get the right molecular group, it’s possible. Some cancers can respond to changes (large increases or large decreases) in nutrients and vitamins.

“I truly believe we will have precision dietary modifications, depending on the molecular subgroup, for some cancers in the next 10 years.”

“I can’t exactly say which one will do what, but a classic example is APML responding to high dose vitamin A. Some of these other ones will have low lipids with high oxidants. Others might have low glutamine or aspartate.

“We’re heading in this direction because so many of the mutations are metabolic enzymes or affect metabolic enzymes that change the way these cancers process food sources.”

According to Dr Thomas, “if we can’t do precision medicine for AML, we’re not going to be able to do it for breast cancer, colon cancer, brain cancer, or prostate cancer because they are more complex than AML”.

Advice for those newly diagnosed

Asked what advice Dr Thomas would give somebody newly diagnosed with AML, he said, “I would say get molecular testing and get it reviewed by a comprehensive molecular tumour board”.

“Get in a clinical trial with a non-chemotherapy, if possible. Stay fit and healthy. Don’t let them over medicalise your life, stay out of hospital* as much as possible.

“If you’re under 60 and your leukaemia has a poor prognosis on molecular testing, then you want to stay fit and active, and prepare for an allogenic transplant from a suitable donor.

“If you’re older, you would want to get molecular testing and see how far you can get on targeted therapies without being exposed to chemo. Any response will help thousands of others around the world with AML.

What would Dr Thomas do if he got AML?

“I would have leukapheresis, and get cells stored down for testing later on, if needed.

“I would get molecular testing, get my mutation profile discussed by the molecular treatment board and do whatever was recommended.

“I’d get supportive care, so I get rid of any fungal infection. I would stay away from building sites, attics and damp cellars, and hot tubs. I would focus on my person as a whole being–spirit, soul and body. Not just see myself as a physical blob of atoms.

“I’d get tissue testing to see if there were any donors available for when and if I needed it [for an allogeneic transplant].

“I’d stay out of hospital as much as possible, using a home transplant program with outstanding nurses, and continue to do things that I enjoy before I got a hospital-acquired infection.

“I would continue to walk in parks and gardens, beside gently flowing waters and stay embedded in a strong community who will love and support me no matter what happens.

“I would focus on the relationships that have meaning in my life and anything lovely, pure, honourable, and peaceful.

“Many of my convictions regarding wellbeing have been formed from working with Syrian refugees in the Middle East where fear of sudden violence is high, and parks and places of beauty are rare. Refugees taught me not to stress and over-medicalise our lives.

“There is always something to be thankful for, but we often don’t see it every day. Australia is fast becoming one of the safest and healthiest places on earth to go through a treatment program for AML.”

*There are infections that can be resistant to antibiotics that you don’t see if you stay at home.

Deborah’s one of the first Aussies to have CAR T-cell therapy for CLL

Deborah’s one of the first Aussies to have CAR T-cell therapy for CLL

Deborah Sims and children
In February 2019, when Deborah Sims and her children participated in the announcement that venetoclax would be listed on the PBS

Deborah Sims, one of the first Australians to have CAR T-cell therapy for CLL, was back at work within a month of having the new form of immunotherapy in hometown Melbourne.

And now, the mother of three is officially ‘a genetically modified human being’ after having an infusion of her own re-engineered T-cells in September to treat her aggressive CLL.

Diagnosed at 38, Deborah, now aged 47, had failed chemo (FCR), failed a novel therapy (venetoclax [Venclexta®], and was on her second novel therapy (ibrutinib [Imbruvica®) when she went on an international CAR T-cell therapy trial.

CLL News 2016“I’m at Day… at 37,” said Deborah when she spoke to CLL News in late-October.

“I’ve lost track of how many days because I’m not even counting anymore, because my life’s back to normal.”

This is the story of how Deborah got on that trial, due largely to her own self-advocacy efforts.

But first, read about Deborah’s diagnosis and early treatment, including a monthly commute to the UK on a venetoclax/obinutuzumab (Gazyva®) trial.

The previous time CLL News spoke to Deborah was in 2016, a year she describes as “all a bit of a blur from permanent jet lag”.

When her appointments stretched out to being three-monthly, in 2017, this “took a bit of pressure off” for her.

“I would fly to London, mainly to get the drug, three months’ supply. I’d get a blood test, see my consultant, then fly home,” said Deborah.

“Then, in 2018, I was told the trial was ending; they’d got the data they needed.”

At her last appointment in London in April 2018, she was given two months’ supply.

The drug’s manufacturer, AbbVie, then granted Deborah compassionate access to venetoclax in Australia… right at the time when the drug stopped working for her.

When she went to the Peter McCallum Cancer Centre in Melbourne to pick up her venetoclax, she had a blood test.

“That test showed I was no longer MRD negative; they found some CLL,” said Deborah.

She was devastated by this finding.

Deborah Sims with her children at Light the Night
Deborah with her three children at Light the Night at Melbourne’s Federation Square in 2018

“I was really sad because I was the beacon of hope for this disease.

“Venetoclax is an amazing drug and I’d had so little side effects from it. I was truly grateful it had given me a four-year remission and had beaten my disease down in a way chemo had never achieved.

“I’d had a completely normal life for four years on that drug, with the exception of having to fly to the UK so much to get it.”

On March 1 last year, ventoclax became available through the Pharmaceutical Benefits Scheme (PBS) for Australians with relapsed/refractory CLL.

“I was delighted to help with the campaign to get it listed on the PBS. My children and I were with Health Minister Greg Hunt the day it was listed,” said Deborah.

“It’s so important that patients can get this treatment. I still think it is the most powerful drug we have in our arsenal (apart from CAR T-cell therapy),” said Deborah.

“I’d like to see venetoclax/obinutuzumab front line.”

“And I’d really like to see the end of FCR*, which is chemotherapy, except for people with the right [genetic] markers to respond well to it, which is a very small proportion of CLL patients.

“I was one of the earliest people on venetoclax,” said Deborah, but some people had been on it since the first trial in 2011.

“Unfortunately, because of all the patient journalism I’ve ended up doing, when I went to an international conference for CLL in November 2017 in New York and saw Dr Mary Ann Anderson presenting her research, I discovered that resistance [to venetoclax] was developing in some of the early patients.”

Read an interview with Dr Mary Ann Anderson about the development of venetoclax in Australia

Deborah stayed on venetoclax for four years because she didn’t have any side effects and it wasn’t known what would happen if she stopped it.

“But the standard of care now is that you’re on venetoclax for two years,” explained Deborah.

Deborah Sims and her children at Brighton Beach
The family together at Brighton Beach in 2019

“There’s a theory that because I stayed on drug for four years, maybe that’s why the resistance developed. Other people haven’t relapsed after the two years, and those who have relapsed have actually responded again to the drug when they’ve had it [again, after a break].

“I don’t want people to hear my story and go, ‘Oh, but I’m going to relapse’, because that’s not the case.

“I have very aggressive disease. I was already relapsed and refractory when I started it.

“I got one of the deepest remissions they’d seen on this treatment, and I got no detectable disease in the bone marrow for two years on it.

“Dr Piers Blombery and Dr Mary Ann Anderson have identified a gene that has developed in patients while they’ve been on venetoclax that has made their disease resistant to it.

“Basically, ventoclax turns off a pathway, and CLL is so smart it finds a way around that pathway to start growing again in some patients with aggressive disease.”

Deborah’s relapse and what happened next

When venetoclax stopped working for Deborah, she had a “very slow relapse”.

“We’re talking a tiny amount of disease. They were finding it at the molecular level, but knowing my disease doesn’t stay molecular very long–it really takes off–they were trying to find out how quickly it was progressing before deciding to switch treatments, because I had done so well on venetoclax,” said Deborah.

In February 2019, the decision was made for Deborah to try four cycles of rituximab (MabThera®), as an experiment, to see if that would help the venetoclax hold the line a bit longer.

“It wasn’t going to be a cure for me, but I was really running out of options as to what we’d do next.

“It gave me two months where the disease was knocked back a bit, but it was pretty unpleasant.

“It was the third time, I’d had a monoclonal antibody and I think I was starting to develop resistance to that. I struggled with a lot of pain. I’d had a nice easy ride on venetoclax and it was quite a shock having a treatment that was hurting me and causing all these side effects,” said Deborah.

“By August the CLL was really coming back and I was planning to go to the American Society of Hematology (ASH) conference in Orlando in the U.S. that December,” said Deborah who has been going to the European Hematology Association meetings, the International Workshop on CLL, and to ASH each year.

“I interview doctors from a patient perspective about scientific research and clinical trials, and tailor that information for Australians,” Deborah explained.

“The way I see it is… patients don’t have to read scientific papers, but they need to be aware of what science is doing because at some stage, especially with CLL, they are going to need the latest treatment.”

Joining the Blood Cancer Taskforce

Motivated by the lack of a standard of care practice for CLL and her annoyance at people not being referred on to clinical trials, Deborah accepted an invitation to join the Federal government’s Blood Cancer Taskforce in September 2019.

During a flight to Canberra to attend a Taskforce meeting, she sat next to Dr Michael Dickinson, a haematologist who specialised in aggressive lymphoma, who asked how she was going.

“I said I’d relapsed on venetoclax and all I really had left was a BTK inhibitor, that I could get ibrutinib on the PBS, but I’d much prefer acalabrutinib, and zanubrutinib was in trials, and we’re discussing which one to put me on,” she said.

He asked if she knew of the CAR T-cell trial** that was opening soon at the Peter MacCallum Cancer Centre and explained that, to qualify, trial participants had to have been on ibrutinib for six months. Deborah knew about this one-off treatment. She had met people who’d had the new form of immunotherapy in America and whose disease had not relapsed.

Then, in early-December last year, Deborah set off once again to the ASH conference in the U.S.

“I did all these interviews with CAR T experts including with Professor Tanya Siddiqi of the City of Hope National Medical Centre (California) and decided if I couldn’t get to the Peter Mac [trial] I would go to the City of Hope and have my CAR T-cell product there, although that was going to cost a million dollars, so I wasn’t sure how I was going to do that.”

Deborah doesn’t know why, but the decision was made to take her off venetoclax the week before she went to ASH.

“So I get to America and my disease is going off.

“My neck is suddenly swollen. I’ve got lymph nodes under my armpits. I’m actually panicking because I was not expecting to get bulky disease immediately,” she said.

“It’s not something you see when you come off venetoclax, so my disease obviously decided it’d had enough.

“But luckily I’m with every great haematologist in the world and I’m interviewing them.”

“I said to [Professor] Miles Prince, ‘before we do the interview, can you just feel my neck, tell me what you think?’, and he’s like, ‘you’ve definitely got some lymphadenopathy but I don’t know what your neck was like before, I’m not the person to ask’.

“Basically, I got 40 opinions at this conference,” said Deborah.

When she returned to Australia, she spoke to her lead haematologist, Professor Con Tam, and although he wasn’t sure if she’d get on the CAR T-cell trial in Australia, he put her on ibrutinib in January this year.

“I didn’t tolerate it as well as I had venetoclax. I had quite a lot of side effects–joint pain, bruising–but it worked, and my disease started going back into remission.

“We got to June and, in the meantime, COVID happened and the CAR T-cell therapy trial had been put on hold.

“I asked about the CAR-T trial and Con checked with Michael.

“It had reopened, and Con said, ‘let’s get you on it’, so screening [a bone marrow biopsy, CT scan, ECG, and bloods] was booked for the day after I’d been on ibrutinib for six months!

“And the way the trial works is that they do the leukapheresis [the T-cell harvest] before you even know if you’re on the trial.”

It’s a three-hour process that involved “a massive needle” and an anti-blood clotting drug that made Deborah vomit.

“I thought… I’ve got stable disease, I could have had years of ibrutinib, what am I doing?

“Anyway, it just happened really quickly.”

Deborah’s T-cells were sent to America to be re-engineered, but there was a hold-up due to COVID, and she waited seven weeks for them to be returned.

This meant she needed another round of screening to provide a new baseline for the trial.

“It showed very little detectable disease and the CT scan was clear. I was very well,” said Deborah who at the time was having “major second thoughts”.

“I could not get my head around what I was doing.”

Deborah Sims and Michael Dickinson in hospital
Deborah with Dr Michael Dickinson when he visited her in hospital after her CAR T-cell therapy procedure

The anguish of having CAR T-cell therapy while well and healthy

“A private counsellor helped me reason that this was about long-term survival, rather than waiting for another drug to fail, then running out of treatment options, or having a bone marrow transplant as salvage therapy, which was the last thing I wanted to have.

“My mental anguish was about the decision to do something which could have killed me.

“Even though the doctors said, ‘you’ll be fine, you’ve got little disease, we’re not expecting you to have side effects, I’ve lost two friends within hours of having their CAR-T transfusion.

“They were very much like me, patient advocates campaigning for the best treatment, and they got those treatments first.”

On top of this, Deborah was getting a CAR T-cell product that was new.

“Anything new is scary, and you don’t really want to be the first patient having something. But equally, this was such an amazing opportunity for me. My disease was in its best state ever to have this. My doctors were confident it would work, and if it didn’t work, that it wouldn’t harm me.

“With CAR-T, it really does either work, or it doesn’t. And if it doesn’t, there’s a risk of mortality,” said Deborah.

Deborah Sims being monitored in hospital
Being closely monitored when Deborah was in hospital after having her CAR T-cell infusion

“I’m on an international CAR-T patients Facebook group. There’s 2000 of us on it and every day you’re hearing great news from someone, then devastating news from someone else. It’s that black and white.

“What scared me was that first month after infusion; what I was going to go through? I was very scared about how sick I might get.

“It was the first time in 10 years of having this disease that I’ve done an advanced care directive and sorted my will out. I prepared everything in case I died.

“So mentally, to go into something where you really thought you might die, when you’re well, was incredibly difficult.

“I’ve always been a pioneer. I genuinely think it’s the bravest thing I’ve ever done, but I was worried that it was also the most reckless. I was very scared that I wasn’t being brave as much as reckless with my good health.

“But I’ve spent years making sure I’ve had the best doctors and I’ve trusted them. That’s always been my mantra to patients; find doctors you trust.”

Once Deborah’s cells had been re-engineered, she decided to go ahead with the procedure.

“This is a $600,000 treatment and I was getting it free, and a lot of people had gone to a lot of effort to make sure I got it.”

Three days after her T-cells arrived back in Australia, Deborah had three days of lympho-depleting chemotherapy, just enough to wipe out her immune system. After having the weekend to recover, Deborah went to the apheresis ward on a Tuesday.

“A nurse infused a vial of my engineered T-cells and that was it. It was so weird.”

“This was a really expensive, amazing product and thousands of people had been involved in getting it into me and this senior nurse just infused it, then did a flush, and that’s it.

“Then I spent three days just watching Netflix, and writing, and reading, and nothing at all happened to me,” said Deborah, and she went home on the Friday.

She was told that Day 11 was when they could expect to see some activity.

“But because I have CLL and very little disease they weren’t expecting much of a reaction and they certainly weren’t expecting something called cytokine release syndrome, which causes fever and can become serious.

“They know how to manage it better now, than when my friends died.”

On Day 10 Deborah started getting a “massive amount of pain” in her bones, “like someone was giving me a bone marrow biopsy all over my body”. The pain worsened, she started getting a fever and started shaking. When the fever spiked, she spent the night of Day 11 in the high dependency ward at Royal Melbourne Hospital and on Day 12 she was pleased to see the haematologist was Dr Mary Ann Anderson who until then she had admired but never met, and she was transferred back to the Peter Mac.

“She was pretty sure I had cytokine release syndrome,” said Deborah.

“They said I might have had more disease than they thought.”

Mild pain continued for another week.

“I swear I could feel the CAR T-cells going around my body mopping up the CLL cells.”

Con Tam, Carly Burgess and Deborah Sims
Deborah Sims, centre, with Professor Con Tam and her trials nurse, Carley Burgess

“I’d get a pain suddenly in my armpit, which was where my lymph nodes would always grow the most, and hang around there for the day, then it went up to my jaw, on to the lymph nodes in my face, and the back of neck, which was sore for a few hours.

“It was like going around, just cleaning out everything. It was incredibly exciting.”

Deborah doesn’t think CAR T-cell therapy should be a salvage or last-ditch treatment.

“I think if you’re as well as you can be going into it, the outcomes are better. That’s what I’ve found talking to CAR T-cell therapy doctors. Tanya Siddiqi, in particular, wants to see it become second line treatment.

“Patients like me put themselves on the line, not for unselfish reasons, but we’re the ones that are going to make it a lot easier for the patients in a few years’ time, like with me now saying, ‘I went around the world to get venetoclax and obinutuzumab’.

“There are so many really good trials out there that are better than standard of care and patients really need to ask their doctors about them.

“It’s really up to everyone to say, ‘are there any new treatments I should be aware of? Is there a clinical trial, even if it’s not in my state?’.”

You can read Deborah Sims blog, abtandme.

* Fludarabine, cyclophosphamide, rituximab

** An international trial, with four sites in the U.S. and one in Australia (at the Peter MacCallum Cancer Centre). The trial has three arms, for CLL, DLBCL, and ALL.

Deborah Sims and children
Before Deborah has her CAR T-cell treatment, at home with Cameron, Natasha and Marlowe



Expert Series interview with Professor Constantine Tam on CLL–now and into the future

Expert Series interview with Professor Constantine Tam on CLL–now and into the future

Professor Constantine (Con) Tam is a Melbourne-based expert in CLL and low-grade lymphoma whose sights are focused on curing these blood cancers. He is Clinical Lead for CLL and Low-Grade Lymphoma at Peter MacCallum Cancer Centre/Royal Melbourne Hospital and Professor of Haematology at the University of Melbourne where he teaches and supervises PhD students. Prof. Tam is the global lead for the novel BTK inhibitor, zanubrutinib, and he completed the world’s first study combining ibrutinib and venetoclax. Born in Hong Kong, he came to Australia as an 11-year-old and after completing his undergraduate degree, trained in medicine and haematology and worked at St Vincent’s, Peter Mac and Alfred hospitals before heading overseas for a two-year CLL fellowship at the MD Anderson Cancer Center in Texas (U.S.).

The latest news on CLL research are the small molecules–the BTK and BCL-2 inhibitors–and there’s a resurgence of interest in CAR T-cell therapy in CLL, says Prof. Con Tam.

Professor Constantine Tam
Professor Constantine Tam: while yet to be proven, CAR T-cell therapy “probably gave the best chance of giving someone a cure in the long term”

“There are now many studies to show that we can combine BTK and BCL-2 [inhibitors], and those combinations are tolerable and get very deep responses,” he said.

“The most recent clinical trials have shown that these drugs, as either monotherapy or in combination with an antibody, are better than standard chemotherapy.

“But I think the next generation of trials will look at whether the combinations of both a BCL-2 and a BTK inhibitor will be even better than single agents.”

He is referring to ibrutinib (Imbruvica®) and the newer generation BTK inhibitors, zanubrutinib (BGB-3111) and acalabarutinib (Calquence®), which have all been studied in combination with the BCL-2 inhibitor, venetoclax (Venclexta®).

“Adding venetoclax to the regimen gives the advantage of patients potentially being able to come off these drugs.

“At the moment, you go on the BTK inhibitor and you’re pretty much stuck on it forever, because you never clear minimal residual disease (MRD),” explained Dr Tam.

“Whereas in combination with venetoclax, it seems most people can be cleared of MRD and can potentially stop taking both drugs; take a drug holiday.

“That’s quite an exciting prospect… being able to take tablets for a fixed duration–12 to 24 months of therapy–that will clear MRD. Then, just like after having chemotherapy, having a break.

“And CLL being CLL, we anticipate that the majority will eventually relapse and will be retreated. Hopefully, it will be years before that will happen.”

CAR T-cell therapy for CLL

Dr Tam said, “the other exciting thing” is the resurgence now of interest in CAR T-cells in CLL”.

CLL was one of the first diseases to respond to CAR T-cells in early trials.

“The first major report from the University of Pennsylvania was in fact in CLL, where three patients were successfully treated with CAR T-cells, and to my knowledge they remain cured.

“The attention has shifted since then to diffuse large B-cell lymphoma [DLBCL] and ALL [acute lymphoblastic leukaemia] because they’re more urgent diseases.”

Another reason is that in CLL patients, the quality of the CAR T-cells is not as good as in DLBCL and ALL patients, due to both the CLL itself and the cumulative effects of previous therapy.

“Often the CAR T-cells don’t work as well in CLL because the T-cells are less fit,” explained Dr Tam.

Ibrutinib has been used to improve the quality of the T-cells before they are collected for CAR T-cell therapy, and Dr Tam said it was time CAR T-cell therapy was used “in a more intelligent manner” to treat CLL; not as a “Hail Mary manoeuvre” when all other treatment options had stopped working and when a patient had a lot of CLL onboard.

“Under those circumstances, CAR T-cells are probably not expected to work well,” he said.

But if, for example, for patients in stable remission on ibrutinib, the T-cells are a lot more fit and there is a lot less CLL onboard to be treated, and CAR-T cells may be applied as a ‘curative’ procedure to achieve MRD clearance and terminate the need for indefinite ibrutinib therapy.

“You might be able to provide someone with a permanent cure to consolidate a good response to some other therapy,” said Dr Tam.

In other words, use CAR T-cell therapy more effectively by using it as an earlier line of treatment.

“If trials, like the one Deb’s [Deborah Sims] on are able to show that people can get off indefinite ibrutinib therapy with CAR T-cells, then this might be quite worthwhile because CAR T-cells are expensive–$500,000 for the procedure–but that’s only about three years’ of having ibrutinib, in terms of costs,” said Dr Tam.

“And if you can have CAR T-cells, and no longer need ibrutinib, you are saving money in the long-term for the government.

“Also, ibrutinib doesn’t last forever, so you are circumventing the problem of future ibrutinib resistance and the side effects that may be associated with ibrutinib.

“These drugs are so expensive. CAR T-cell therapy is an expensive procedure and so are the drugs CLL patients are on [like ibrutinib and venetoclax].

“It may work out that this [CAR T-cell therapy] is a worthwhile thing, for both quality of life reasons and economic reasons,” he said.

The availability of CAR T-cell therapy

Dr Tam pointed out, however, that CAR T-cells for CLL are currently only available on a clinical trial.

“No government anywhere in the world has approved the use of CAR T-cells in CLL.”

Access to this immunotherapy for CLL patients depends on the nature of the trials that are open and what sort of CLL patients those trials are looking to enrol.

“In the past, they have enrolled patients with active CLL who had failed other therapy, and those trials have not resulted in such good outcomes, because these patients, like I said, had poor T-cells anyway, and quite a lot of disease to be treated,” said Dr Tam.

“The newest generation of trials is looking to consolidate an incomplete ibrutinib response, to try and convert someone who has got residual disease on ibrutinib to someone who is MRD negative.

“These trials are moving in the right direction; they’re using CAR T-cells as consolidation and as an earlier line of therapy, not necessarily frontline, but as an earlier line of therapy. I think this is an intelligent way to use this technology.”

Dr Tam said the reason CLL was not an approved indication for CAR T-cell therapy was because it was not yet proven.

“We know using CAR T-cells in just any old-fashioned CLL doesn’t produce such great response rates. They are far lower than in DLBCL and ALL, and cures are probably achieved in less than one in five people with CLL.

“That’s probably because we’re using the CAR T-cells in the wrong way. So, until we’ve proven that the CAR T-cells can be used in a more effective way, in different settings, through clinical trials, the government is not going to approve CAR T-cells for CLL.”

Dr Constatine Tam
Constantine Tam, in 2007, with a poster when he was a Fellow at MD Anderson

CLL diagnosis and treatment

Dr Tam said CLL was the most common leukaemia in the western world, with about 1000 new cases of CLL diagnosed in Australia each year.

On average half these patients would go on watch and wait and never require treatment in their lifetime. For them the disease doesn’t worsen or cause problems.

“The best thing to do is to just watch very carefully, to get a feel for the pace of the disease for the individual patients, and to wait for a better treatment to come along,” he said.

For those whose disease progresses and needs to be treated, he said access to prognostic panels that helped to define very precisely the subtype of a person’s CLL was important.

“All our patients undergo a FISH¹ study, an IgVH² mutation study, and next-generation sequencing³ to identify gene mutations, so we know which patients are not suitable for chemotherapy.

“These are patients who have p53 deletions and mutations, and we stream those patients towards clinical trials on novel therapies.

“We also know which patients are really suitable for chemotherapy. For example, there is a small subset of patients with a 13q deletion, and more importantly, a mutated IgHV status, that get FCR chemotherapy and will be cured of CLL in the long-term.

“Then we have a big group of patients where the disease is not curable with chemotherapy but who potentially may respond to chemotherapy; they’re not chemo-resistant but they’re not curable [with this treatment].

“We tend to favour putting these treatment-naïve patients on clinical trials that compare chemotherapy with a combination of novel agents, such as a BTK inhibitor and a BCL-2 inhibitor.

“For patients who have relapsed after chemotherapy, often we’ll put them on either an ibrutinib- based regimen or a venetoclax-based regimen, depending on patient preferences and the logistics of a situation.

“Ibrutinib is very easy to start, but you’re stuck on it pretty much forever, and you have to put up with the low-grade side effects forever, versus venetoclax, which is trickier to start because of tumour lysis⁵ risk, but tends to have a limited duration; in the frontline it’s 12 months, and in the relapsed setting it’s 24 months.

“It’s a question of whether you put in the work right from the start and you’ve got a difficult tumour lysis monitoring period, for a chance at a fixed duration of therapy, or whether you take the easy option, which has got less work to do in the start but treatment needs to be continued indefinitely.”

Dr Tam said CAR T-cell therapy, which is not proven and is just a principle “probably gave the best chance of giving someone a cure in the long term.”

What’s next on the treatment horizon?

Next generation “reversible” BTK inhibitors are coming online and “they are all looking quite active”, said Dr Tam.

“At the moment, all the BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) bond to the same site on the BTK enzyme, so once you get a resistant mutation at the site where the drugs bind, you’re resistant to all the current BTK inhibitors.

“But the next generation drugs, like ARQ-531 and LOXO-305, don’t bind to that site and they bond differently.

“They look quite active in patients who have failed ibrutinib. They’re also looking quite active in themselves, and they might start to come to the frontline or may end up being used ahead of ibrutinib, if the clinical trials show that they are more effective and/or better tolerated than ibrutinib.”

“And there are new versions of venetoclax coming. It’s very hard to improve on this really good class, but we’re now starting to get new drugs within that class that overcome some of the problems with the previous class, and include drugs that are 10 times more potent than venetoclax.

The importance of clinical trial participation

Dr Tam said clinical trials were “very worthwhile” to go on for several reasons.

“From a patient point of view, when you go on a clinical trial, you’re usually seeing an expert who’s got a particular area of interest and these doctors are highly skilled in that particular disease.

“Some are early-phase trials which have a single arm, and others are randomised trials.

“Now in randomised trials, the control arm–the arm we’re comparing against–is chosen carefully as the most active treatment in that disease. So you can be assured when you go on a trial you’re getting the best available treatment anywhere in the world for your disease. Or, you might get a treatment that is even better than standard of care, on the experimental arm.

“So I think, from a selfish point of view, patients get very good medical care when they join clinical trials.

“The other thing about being on a clinical trial is that you are monitored very closely, so you get better than the usual monitoring, as well as access to new drugs that are potentially five to 10 years ahead of the time.”

But there are drawbacks and you have to be prepared to accept uncertainty, Dr Tam said.

“There’s no guarantee that the new drug on the experimental arm is better. The experts think it is, but we do the clinical trial to help us to determine whether that’s true or not.

“And sometimes you have to travel, because all the scans and blood tests need to be done at the hospital where the trial is based. That may be an issue for patients who live in the countryside and where standard therapy may be easier for them.

“The last thing about clinical trials that I often describe to my patients is an altruistic view. It is the “warm and fuzzy” feeling that by helping us do the research, you’re helping advance the cause of medicine in general.

“By participating in a trial, you’re helping us understand the disease better, you’re helping us develop the next generation of treatments, and you may be the reason why the next generation of patients gets even better therapy.

“People on a clinical trial not only get treatment that might benefit them, they were contributing to the body of knowledge that may benefit many generations in the future.”

“All the new exciting treatment we’ve got at the moment, which is doing a better job in controlling leukaemia than we’ve ever done before, with less side effects, have all occurred because previous patients volunteered their time and their trust by going on a clinical trial 10 years ago.

“There are many clinical trials and the most exciting ones are comparing chemotherapy, which is still the frontline standard of care, against combinations of new agents. Hopefully, in five years these will show that new drugs and new drug combinations would do a better job of treating CLL frontline than chemotherapy.

“And that might effectively end chemotherapy as we know it.”

That’s Dr Tam’s holy grail; to develop a permanent natural, meaning nonchemotherapy, solution with treating CLL. To work out a way that the immune system not just controls but is a cure for CLL for all patients.

“That is an achievement I would be extremely proud of. It’s probably 10 years away. I might be out of a job!”

¹ Fluorescence in situ hybridization (FISH) analysis is the single most common cytogenetic abnormality in patients with CLL.

² The immunoglobulin variable region heavy chain (IgVH) gene encodes antibodies that function in the immune response.

³ Next generation sequencing (NGS), massively parallel or deep sequencing, are related terms that describe a DNA sequencing technology which has revolutionised genomic research.

⁴ FCR regimen is a combination of fludarabine, cyclophosphamide, and rituximab .

⁵ Tumour lysis syndrome can occur as a complication during the treatment of cancer, where large amounts of tumour cells are killed off (lysed) at the same time by the treatment, releasing their contents into the bloodstream.

Familial research key to blood cancer prevention strategy

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.

AFHCS research team
The AFHCS research team, (front row) Chris Hahn and Anna Brown, (middle row) Kerry Phillips, Hamish Scott and Nicola Poplawski, (back row) Parvathy Venugopal, Milena Babic and Peer Arts.

“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.

Anyone interested in the AFHCS can contact Dr Anna Brown on or Professor Hamish Scott on

PhD scholarships focused on improving outcomes for people with AML and MPN

PhD scholarships focused on improving outcomes for people with AML and MPN

The Leukaemia Foundation and the Haematology Society of Australia and New Zealand (HSANZ) are proud to announce the successful recipients of the 2021 round of PhD Scholarships Basit Salik and Dr Julian Grabek. The work of these recipients will help improve the understanding and treatment for acute myeloid leukaemia (AML) and myeloproliferative neoplasms (MPN).

The Leukaemia Foundation has been supporting Australian blood cancer research and the careers of promising scientists and clinicians for over 20 years. These PhD Scholarships, valued at $130,000 each, are part of the Leukaemia Foundation’s National Research Program which has invested more than $54.5 million into research since 2000. To date that funding has supported over 370 researchers across 290 research projects, through PhD scholarships and research grants, at over 50 hospitals, research institutes and universities.

Accelerating research and providing access to best practice treatments are two key research priorities of the Leukaemia Foundation and were identified as key priority areas in the State of the Nation: Blood Cancer in Australia report and recently released National Strategic Action Plan for Blood Cancer. These reports show us while significant gains have been made, it is projected that more than 186,000 Australians may die from blood cancers by 2035. These reports highlight that research has the potential to reduce blood cancers mortality rates and the associated economic costs but to do so will required increased and sustained investment in research. That is why the Leukaemia Foundation is committed to funding research the drives rapid advancements in treatments, diagnostics and novel therapies and gives Australians access to the latest treatments through clinical trials.

The Leukaemia Foundation thanks Brydens Lawyers and the Bourne Foundation for their generous contribution and support to the PhD Scholarship program.


Details of the research projects include:

Dr. Julian GrabekDr. Julian Grabek – Clinician researcher, Queensland Institute of Medical Research (QIMR) Berghofer, Brisbane

Myeloproliferative neoplasms (MPN) are clonal haematological disorders of stem cells.  These stem cells undergo a mutation that drives an overproduction of blood cells. Throughout the course of the disease the stem cells are driven by specific mutations (JAK2, CALR and MPL) but over time additional genetic mutations are acquired leading to progression of the disease to either secondary myelofibrosis and bone marrow failure or acute myeloid leukaemia. These outcomes have limited treatment options and have a poor prognosis.

High risk stem cells with the potential to develop into leukaemia can be identified early in the disease but are often a “needle in a haystack” when compared to the rest of the MPN stem cells.  By using cutting edge single cell technology, the aim of Dr Grabek’s project is to separate each individual cell of the MPN stem cells. Through a combination of mutational analysis by novel nanopore technology and assessment of downstream gene signalling they will be able to determine the early stages of leukaemia development in these disorders. In future, it is hoped to establish which treatments have the potential to arrest these early changes and prevent transformation to leukaemia.


Basit Salik - Research scientistBasit Salik – Research scientist

Over the last 4 decades, chemotherapy-directed management of acute myeloid leukaemia (AML) patients has remained largely unchanged. While most patients achieve complete remission after chemotherapy, most patients with AML relapse and ultimately die of the disease.

A high relapse rate in AML suggests that current standard therapies do not target these highly self-renewing leukaemia cells and that immune subversion by the primary tumour leads to an ineffective anti-tumour response. Cancer cells including leukaemias can adapt to oncogenic and/or environmental stressors such as chemotherapy, hypoxia, and metabolic stress. Indeed, several stress-induced molecules augment pro-survival signalling and aggressiveness in cancer cells. By contrast, either by direct recognition of stress-induced molecules on cancer cells or by exposure to environmental stress factors, immune cells also undergo functional impairment.

Basit and his team will investigate biological pathways that regulate cancer cell-intrinsic adaptation/aggressiveness as well as immune dysfunction by utilising patient samples and mouse models of AML. The team is hopeful that this research will lead to improved therapeutics that can effectively inhibit leukaemia growth with the potential of harnessing anti-leukaemia immune responses for durable disease control.

This PhD scholarship is kindly supported by Brydens Lawyers.

The Leukaemia Foundation receives no ongoing government funding, and the National Research Program relies on the continued support of generous donations. Donations allow us to continue to invest in Australian blood cancer research and to support the next generation of researchers, driving this type of innovative research for better treatments, better care and ultimately a cure for blood cancer. To find out how to support the Leukaemia Foundation’s National Research Program call 1800 620 420.