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.
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.
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.
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.
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.
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.
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!
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 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.
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.
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.
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.
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.
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”
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 upthe 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 labwhere Dr Thomas and his team are designing new therapies and finding new targets for acute myeloid leukaemia (AML) and myelofibrosis (MF).He’s a 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.
“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.”
“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.
“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.
“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  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”.
“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.
“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.
“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.
Myeloma patients can look forward to a targeted new treatment option on PBS in 2021
Monday December 28, 2020
The Leukaemia Foundation is celebrating the news that for the first time in more than a decade, a new type of medicine targeting multiple myeloma will be added to the Pharmaceutical Benefits Scheme (PBS), with the listing effective from day one of the new year.
The Federal Minister for Health, The Hon. Greg Hunt MP, has announced multiple myeloma patients whose blood cancer has progressed after initial treatment will be able to access daratumumab through the PBS starting 1 January 2021. The medicine will be used in combination with bortezomib and dexamethasone as a second line treatment.
Multiple myeloma is a complex blood cancer affecting the body’s plasma cells, which produce antibodies. Myeloma develops when plasma cells undergo a cancerous change and multiply at an increasing rate, taking over the bone marrow. It most commonly occurs in people aged 40 and older, and it is slightly more prevalent in men. Patients experience weaker bones which are more prone to breaking, as well as bone pain, kidney damage, frequent infections, anaemia and increased bleeding and bruising.
Currently, 2,339 people are diagnosed with myeloma each year, however it is expected 4,952 people will be diagnosed with this type of blood cancer in 2035. Sadly, 1,054 Australians already lose their life to myeloma each year, and this figure is projected to increase to 3,037 people by 2035.
Daratumumab is a targeted therapy that works by attaching to a specific protein on the surface of a myeloma cell, and by doing so triggers the patient’s own immune system to attack and destroy myeloma cancer cells.
The Minister’s announcement is the first time in 13 years that an innovative new agent encompassing a different mode of action against myeloma has received a PBS listing, with an estimated 1,000 Australians reportedly eligible to benefit from the listing each year.
Leukaemia Foundation General Manager of Blood Cancer Partnerships Tim Murphy said the Minister’s announcement marks an important and progressive step to address a high unmet need for new myeloma treatment options.
“While treatment options and survival rates for some blood cancers are improving, the sad reality is that myeloma is an incurable disease which becomes progressively harder to treat after each relapse as patients become refractory to different treatments, so the impact of a diagnosis of myeloma on peoples’ lives and the ongoing affect to their health remains severe,” he said.
“This is a fantastic and important win to kickstart a new year for around 18,000 Australians who are currently living with myeloma.
“This innovative treatment option is ground-breaking and has the ability to truly turn the tables for some myeloma patients in what can be a long fight against this debilitating blood cancer.
Mr Murphy said the Leukaemia Foundation has been advocating for access to innovative treatment options, including for increased access to daratumumab, and welcomed this result for Australians living with myeloma.
“We are proud to stand beside Australians living with blood cancer to be their voice and fight to get them access to the best therapies, wherever they live, as we work with the broader blood cancer community towards the shared vision to see zero lives lost to blood cancer by 2035,” he said.
In 2019, the Leukaemia Foundation released the State of the Nation: Blood Cancer in Australia report, which led to Minister Hunt supporting the Leukaemia Foundation to establish a Blood Cancer Taskforce.
The Blood Cancer Taskforce is a unique collaboration of Australia’s leading haematologists, researchers, patients and members of the blood cancer community who have spent the past year working with the Leukaemia Foundation to develop Australia’s first National Strategic Action Plan for Blood Cancer.
In September this year, the Minister announced the release of the National Action Plan, which provides a blueprint to tackle key issues facing people affected by blood cancer today and into the future, and maps the path to achieve zero lives lost to blood cancer by 2035.
Mr Murphy said the release of the National Action Plan marked a major milestone for the blood cancer community which will set the national agenda around blood cancer for many years to come and ultimately improve outcomes for patients, including those diagnosed with myeloma.
“Enabling access to novel and specialised therapies, including removing roadblocks to patient access to these therapies, is a key priority of the National Action Plan,” he said.
“This announcement by the Minister is a step in the right direction to break down these barriers for some Australians living with blood cancer, and we look forward to seeing further progress in this area into the future as the National Action Plan is implemented.”
Combination treatment option for CLL patients now available through PBS
Monday 30 November, 2020
The Leukaemia Foundation has welcomed news that a new specialised combination treatment will be made available to some Australians living with Chronic Lymphocytic Leukaemia (CLL) through the Pharmaceutical Benefits Scheme (PBS) from tomorrow.
The Federal Minister for Health, The Hon. Greg Hunt MP, has announced that CLL patients unsuitable for standard chemotherapy-based treatments will now have access through the PBS to venetoclax in combination with obinutuzumab as a first line combination treatment option.
CLL is a slow-growing leukaemia affecting developing B-lymphocytes which is commonly diagnosed in people over the age of 60. These specialised white blood cells usually produce antibodies to protect against infection and disease, but instead undergo a malignant change to become leukaemic cells.
CLL can remain stable for months and years causing minimal impact on lifestyle and general health for many people diagnosed with this blood cancer, however in other cases, the leukaemic cells multiply uncontrollably, crowding the bone marrow and interfering with normal blood cell production, and these cases can require treatment soon after diagnosis.
While CLL is a relatively rare type of cancer, it is the most common type of leukaemia diagnosed in Australia. Currently, 1,875 Australians are diagnosed with CLL each year, however this figure is projected to reach 3,800 by 2035. The number of Australians losing their life to this blood cancer each year is also expected to more than triple during this time, from 306 Australians annually in 2020 to 1109 in 2035.
Leukaemia Foundation General Manager of Blood Cancer Partnerships Tim Murphy said while conventional chemotherapy is often the starting point for CLL treatment, there has been a strong unmet need for access to additional first-line treatment options for this blood cancer, which the organisation has been advocating to change.
“The Leukaemia Foundation is committed to empowering Australians with blood cancer to better manage its impacts and live well after diagnosis, which is especially important for people with blood cancers like CLL that develop and progress slowly,” he said.
“Unfortunately some CLL patients are unfit for chemotherapy or struggle tolerating its side effects, and it is crucial that these Australians have an accessible and affordable alternate option available to them as they undertake what can be a lengthy blood cancer journey.
“As a daily orally-administered treatment which can for the most part be taken at home, venetoclax in combination with obinutuzumab is an effective and relatively unobtrusive option for these patients which avoids the debilitating side effects they would otherwise face with chemotherapy-based therapies, thereby improving their quality of life and simplifying access to the treatment they need.
“The Leukaemia Foundation has been advocating for access to innovative treatment options and we celebrate this result for Australians living with CLL.
“The Leukaemia Foundation is proud to stand beside all Australians living with blood cancer to be their voice and fight to get them access to the best therapies to treat their specific disease, wherever they live, as we work towards our shared vision to see zero lives lost to blood cancer by 2035.”
The Blood Cancer Taskforce is a unique collaboration of Australia’s leading haematologists, researchers, patients and members of the blood cancer community who have spent the past year working with the Leukaemia Foundation to develop Australia’s first National Strategic Action Plan for Blood Cancer.
The Minister recently announced the release of the National Action Plan, which provides a blueprint to tackle key issues facing people affected by blood cancer today and into the future, and maps the path to achieve zero lives lost to blood cancer by 2035.
Mr Murphy said the release of the National Action Plan marked a major milestone for the blood cancer community which will set the national agenda around blood cancer for many years to come and ultimately improve outcomes and quality of life for patients.
“Breaking down barriers to patient access to therapies which are most effective and appropriate for them is a priority of the National Action Plan,” he said.
“We commend the Minister for listing this therapy on the PBS as another step in the right direction providing access to treatment for some Australians living with blood cancer, and we look forward to seeing further progress in this area into the future as the National Action Plan is implemented.”
The Leukaemia Foundation provides free practical, emotional and educational support to Australians diagnosed with a blood cancer including CLL and other leukaemias. The Leukaemia Foundation produces a series of disease specific newsletters including CLL News, and invites all Australians living with the disease to subscribe to ongoing information here.
Latest grants announced in Australia-US blood cancer research co-funding partnership
Sunday November 29, 2020
Two new research projects co-funded through a partnership between America’s The Leukemia & Lymphoma Society (LLS), Snowdome Foundation and Leukaemia Foundation will focus on acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS), seeking to improve understanding and treatment of these blood cancers.
2019 marked the first time the Snowdome and Leukaemia Foundations partnered with LLS to enable four Australian researchers access to funding through a special Australian round of the LLS Translational Research Program. The goal of the translational research was to reduce the time between laboratory findings and actual treatment. The announcement today of the 2019/20 grant recipients Majeti, Thomas and Pimanda brings together a total of six projects across Australia and the US, which have benefitted from this partnership to date.
Leukaemia Foundation General Manager of Blood Cancer Partnerships Tim Murphy said the organisation welcomed the opportunity to again unite with LLS and Snowdome Foundation to support leading Australian blood cancer researchers to undertake innovative work with a potential global impact.
“Accelerating research to achieve rapid advancements in blood cancer treatment is a key priority of the Leukaemia Foundation and by partnering with other organisations with the same goals, we can increase the depth of research we are able to fund,” he said.
“The more we know about specific blood cancers and best treatment options, the better our chances of curing and conquering this complex set of diseases, and the closer we are to realising our vision to see zero lives lost to blood cancer by 2035.”
Chief Scientific Officer of The Leukemia & Lymphoma Society Lee Greenberger, Ph.D. said: “It is a privilege for The Leukemia & Lymphoma Society to work with the Snowdome Foundation and the Leukaemia Foundation, as we join forces to bring better therapies to patients with blood cancer. This international collaboration between the most talented blood cancer scientists and clinicians in both Australia and the U.S., has already improved outcomes and will pave the way for a brighter future for these patients. We are at a pivotal time in blood cancer discovery and there has never been a more important time to work together towards our common goals.”
Snowdome CEO Kirstee Macbeth added: “We are extremely pleased to continue the collaboration between The Leukemia & Lymphoma Society, Snowdome Foundation and the Leukaemia Foundation to support Australian researchers in 2019/20. Australia is fortunate to have such talented blood cancer researchers however, crucial funding is needed to support their work. This partnership enables those investigators to facilitate further advances into blood cancer research, to increase the reach and ultimately, provide positive treatment outcomes for patients. Snowdome is passionate about making hope real for all blood cancer patients and we look forward to seeing the inspiring research proposals.”
Myelodysplastic syndromes (MDS) are a group of blood cancers that result in progressive failure of normal blood cell production and can transform into acute myeloid leukemia (AML).
AML is the name given to a group of leukaemias that develop in the myeloid cell line in the bone marrow. AML is characterised by overproduction of immature white blood cells, preventing normal blood cell formation by crowding the marrow and potentially spilling into the bloodstream and circulating around the body. AML is an aggressive blood cancer with a low average 5-year and long-term survival rates. Whilst most patients appear to achieve a remission with treatment, the majority eventually relapse.
The Leukemia & Lymphoma Society-Snowdome Foundation-Leukaemia Foundation Translational Research Program 2019/20 recipients and their respective research proposals to improve understanding of, and treatment for, MDS and AML are:
Prof. Majeti and Assoc. Prof. Thomas recently discovered a strong link between the metabolism of leukemia cells and common leukemia-causing mutations through modulation of a central metabolic factor called alpha ketoglutarate. They have since developed innovative methods that can assess the fate of alpha ketoglutarate-dependent reactions on DNA, histones, lipid production, and energy metabolism. This research proposes to apply these methods to characterize AML patient samples to inform a precision medicine therapy approach to treating the blood cancer. It also aims to investigate pharmacologic agents targeting the alpha ketoglutarate-dependent reactions. The objective of the research is to develop personalised medicine through metabolic targeting to deliver mutation-directed therapies to AML patients. Prof. Majeti is Professor of Medicine, Chief of the Division of Haematology, and Member of the Institute for Stem Cell Biology and Regenerative Medicine at the Stanford University School of Medicine. Assoc. Prof. Thomas is a clinical haematologist and blood cancer scientist. He has recently returned from working with Prof Majeti at Stanford University to lead his own Myeloid Metabolism Laboratory at SAHMRI. He has developed algorithms to predict and design mutation-specific therapeutics and novel stem cell assays to study leukemia stem cells.
This project is also kindly supported by a gift to the Leukaemia Foundation made in honour of John and Maureen Wilson.
The most effective medicine to treat MDS, azacitidine, works in only half of MDS and associated AML patients who commence treatment. Over the past decade, Prof. Pimanda and his team have identified treatment alternatives for patients who have been proven, or have potential to be, non-responsive to azacitidine. The research proposes to discover new medicine that improves azacitidine efficacy by using a novel chemical-genome screen using a MDS cell line to identify specific genes that can make MDS cells more sensitive to the medicine. This information will then be used to identify molecular pathways amenable to pharmacological manipulation to achieve the same effect. Efficacy of medicine combinations in enhancing azacitidine activity can then be assessed, using azacytidine non-responder MDS cells to undertake pre-clinical testing in preparation for a future clinical trial. Prof. Pimanda heads a research group at the Prince of Wales Clinical School at UNSW Sydney. He is the founder of the NSW Myeloid Malignancy Network and one of Australia’s leading researchers in the field of MDS.
About The Leukaemia Foundation:
The Leukaemia Foundation stands with Australia to help cure and conquer blood cancer – with care. Together we are attacking every blood cancer, from every direction, in every way we can. We stand beside every Australian to be their voice and their someone-to-turn-to, fighting to get them access to the best care. We also accelerate research that’s delivering rapid advancements in blood cancer diagnosis and treatments. Plus, we provide services and support that empower people living with any blood cancer to live well after diagnosis. You can learn more about the Leukaemia Foundation and blood cancer at leukaemia.org.au
About The Leukemia & Lymphoma Society
The Leukemia & Lymphoma Society® (LLS) is a global leader in the fight against cancer. The LLS mission: cure leukemia, lymphoma, multiple myeloma, and improve the quality of life of patients and their families. LLS funds lifesaving blood cancer research around the world, provides free information and support services, and is the voice for all blood cancer patients seeking access to quality, affordable, coordinated care. Founded in 1949 and headquartered in Rye Brook, NY, LLS has regional offices throughout the United States and Canada. To learn more, visit www.LLS.org. Patients should contact the LLS Information Resource Center at (800) 955-4572, Monday through Friday, 9 a.m. to 9 p.m., ET.
About the Snowdome Foundation
Snowdome was formed in 2010 with a mission to accelerate next-generation treatments for Australian blood cancer (myeloma, lymphoma and leukaemia) patients to help them live longer, better lives. It aims to accelerate access to innovative blood cancer treatments by channelling government and private philanthropic investments into ground breaking research, clinical trials, and personalised therapies. To date, Snowdome has raised more than $37 million and Snowdome support has assisted over 410 Australian blood cancer patients to gain access to early-phase clinical trials. Find out more at www.snowdome.org.au
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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.
“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.”
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 FCR⁴ 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.
Professor Judith Trotman, MBChB, FRACP, FRCPA, Grad. Cert. Clinical Trials, is Head of Haematology at Concord Repatriation General Hospital, Sydney.
A clinician researcher, she was the Founding Director of the Clinical Research Unit at Concord Hospital (Sydney) 2005 -2019. She provides global leadership in charting the role of PET scanning in lymphoma and, based on her data, was successful in obtaining an MBS listing of PET for indolent lymphomas. She has developed digital research initiatives in collaborations with patients, including ClinTrial Refer and the WhiMSICAL study, and is currently developing the My Hodgkins, My Health app. Recently, she started the new international collaborative group, Women in Lymphoma. She is a Board Member of the Australian Clinical Trials Alliance and the Foundation for A Bloody Great Cause.
Q. Why did you study medicine and specialise in haematology?
“I’d wanted to do medicine since I was a teenager. I had a serious motor vehicle accident at the age of 13 and, although I don’t remember much of the intensive care stuff, I found it fascinating being in the hospital setting. I had great training in New Zealand and was interested in HIV medicine. After doing a paediatric HIV elective in New York in 1992, I decided to come to Sydney to do HIV medicine at St Vincent’s Hospital. I found HIV absolutely tragic, but an incredibly fascinating multi-system medicine. Then I really enjoyed my haematology term and inspired by fantastic mentors I thought, ‘I’ll do haematology and HIV medicine together’. Fortunately, there became very little HIV, and I ended up doing just haematology. Lymphoma has always interested me, but I’ve always wanted to remain a generalist haematologist because I love the variety.
What really motivated me to do clinical research, as a registrar at St Vincent’s Hospital, was a woman my age, in her 20s, who had Philadelphia positive acute lymphoblastic leukemia and we battled for a couple of years to keep her alive. Back then, we had just started to get a sense of the importance of the tyrosine kinase inhibitor, imatinib, and 25+ years ago we had just started using email, through which we contacted our U.S. colleagues and desperately tried to get our hands on imatinib for this young woman, but she died before we could get it.
I remember thinking, if I was to practise as a haematologist, it would be within a big clinical research setting that was at the cutting edge, so I could access emerging new drugs for my patients. Back then, rituximab (MabThera®) was just coming out, and I remember, as a registrar, supervising a patient having their first rituximab infusion because we were so nervous about infusion reactions to rituximab. It was my first exposure to what has since been an explosion in targeted immunotherapies and biologics for blood cancers.
I’ve been very privileged to be a haematologist over the last 25 years, when there’s been so much change. Incrementally building our clinical research unit was jolly tough, but also incredibly rewarding and gave us the opportunity to contribute to global change and to be at the cutting edge for our patients, accessing Bruton tyrosine kinase (BTK) inhibitors for so many CLL and Waldenström’s patients and the PD-1 inhibitors for Hodgkin’s, immune therapies for myeloma, close molecular monitoring for CML patients, and of course PET scanning and then PET-adapted therapies for lymphoma patients. It’s just been amazing, and I couldn’t imagine practising haematology outside of a really active clinical research unit. With Dr Jane Estell’s fresh leadership at Concord Haematology’s Clinical Research Unit, we are expanding our Phase I portfolio and accessing the promising new bi-specific antibodies for myeloma and lymphoma.
A real change for me was having a year “off” in France, in 2009, when I immersed myself in the clinical trials unit at Hospital Lyon-Sud and the operations of the now French Lymphoma Study Association (LYSA). Lyon-Sud was one of the biggest lymphoma research units in Europe, but I realised that just a decade earlier it had been establishing itself like us at Concord. Being in that sort of environment makes you realise anyone can be a clinician researcher if you’ve got the will and the commitment, the people with the shared commitment beside you, and by making international connections with many colleagues.”
Q. What is Women in Lymphoma and how is this group instigating change?
“Things are changing. It’s increasingly recognised that whether viewed with a social justice or a business lens, gender equality is imperative. There’ll be a huge amount of change with this amazing group of women from all over the world who will increasingly collaborate. Women in Lymphoma (WiL) may have been catalysed by Australians, I’m the Chair and Eliza Hawkes from Monash also is on the steering committee, but it is a global initiative. Our mission is to support and advocate for greater leadership of women in lymphoma by inspiring and empowering women in lymphoma care, research, and teaching. We plan to map the metrics of their engagement and, with wit and grit, be a collective voice to encourage productive diversity in lymphoma leadership internationally, not just on behalf of women in lymphoma, but all lymphoma clinicians, researchers, and patients. Some British colleagues emailed WiL about the European School of Haematology’s How to Diagnose and Treat Lymphoma series; only one of the 42 speakers was a woman. That’s 2.5%! The WiL initiative, which had by then formed a steering committee, established governance, a website (womeninlymphoma.org) and 130 members, wrote to the ESH. Nothing changed, so we set up our own free WiL Education Series. Our first five-week series, in early-September, was on diffuse large B-cell lymphoma (DLBCL), and our first lecturer was Professor Sonali Smith (Chicago), and 86 people attended via Zoom. The entire series was a huge networking and educational success, to be followed by a Hodgkin Series in 2021.”
Q. What do you consider your career highlights?
“There are so many individual patient highlights with milestones achieved, but career-wise it would be my global leadership in PET lymphoma, in particular PET in follicular lymphoma (FL), and establishing PET as the gold-standard imaging modality for staging and response assessment of FL. It provides a platform for PET-adapted trials, designed to improve outcomes and develop an individualised approach for patients. Being able to translate the global data into access to PET locally for patients with low grade (indolent) lymphoma in Australia was just as important to me. Kiwis to follow, hopefully.
Being a part of enhancing and increasing the Australasian Leukaemia & Lymphoma Group’s international collaborations. I’ve really enjoyed our collaboration with the RATHL (Response Adapted Therapy in Hodgkin Lymphoma) study, with the UK National Cancer Research Institute, and the REMARC study with the French lymphoma group, LYSA. It’s been an absolute privilege to participate in the iNNOVATE Phase III trial with ibrutinib, the first BTK inhibitor for Waldenström’s, and then in the trials with zanubrutinib, the second-generation BTK inhibitor. It was amazing to see these patients, exhausted and unwell with relapsed/refractory disease, who were running out of options, take these incredibly well-tolerated oral agents and literally get up off their beds and live healthy lives.
The first BTK inhibitor had minor side-effects. But compared to a life living with or dying from refractory Waldenström’s, any of us would be happy to put up with a bit of bruising, arthritis and diarrhoea. And the second-generation BTK inhibitors, like zanubrutinib (Brukinsa®, formerly BGB-3111), have an even better toxicity profile. It changed the whole mentality around progression-free survival (PFS) being the most important (surrogate parameter) for overall survival (OS) because these drugs are a switch; they switch off the activity of the Waldenström’s or CLL. Studies like MURANO, and accessing venetoclax (Venclexta®) for our patients with CLL, have also been a privilege, to access all these incredibly well-tolerated and potentially time limited oral therapies that are keeping people out of hospital, keeping people alive, and living well; not just flogging people with repeated rounds of salvage chemotherapy. I’m so pleased I haven’t had to use toxic drugs like fludarabine for years.
Getting access to either brentuximab vedotin (Adcetris®), an anti-CD30 antibody-drug conjugate, or the PD-1 inhibitor, pembrolizumab (Keytruda®), an immunomodulatory antibody which harnesses the patient’s own immune response, in the KEYNOTE studies for Hodgkin lymphoma (HL). (Our lead investigator at Concord was Dr Robin Gasiorowski). It was quite amazing to witness young patients with refractory (resistant) HL respond so well and tolerate these smarter treatments so much better than blunderbuss chemotherapy. I don’t want to sound like a Pollyanna–we still have to use pretty intensive chemotherapy for many lymphomas–but there’s a real recognition of the fact that we’re getting a better understanding of the biology, and how we can interfere with the pathways that are driving the lymphoma proliferation. With greater sub-classification of lymphomas though collaboration between clinicians and patients, niche clinical trials for specific lymphomas will be even more important. And the immune revolution for patients is not restricted to lymphoma; our patients have accessed so many new antibodies for myeloma (daratumumab, elotuzumab) through the myeloma trial portfolio lead by Dr Jane Estell.”
Q. What do you consider is the greatest unmet need in lymphoma?
“Every different lymphoma histology has its own unmet need. Every different patient has their own unmet need and different priorities. In DLBCL, being able to identify and get better therapies for the poor prognosis patient is certainly an issue. We have various prognostic indices, but they’re not perfect. That’s clearly an unmet need. In FL, we’ve got this real focus on ‘progression-free survival’ as we develop new therapies. But I think that while PFS is absolutely a really important metric, it’s not always a surrogate for OS as the key metric, and with patients living so much longer, we can’t even easily and rapidly map PFS differences out with short-term clinical trials. We need a better surrogate for OS. I think it’s also about patients’ quality of life, and I think, finally, there is a growing recognition that patient reported outcomes measures are really, really important.
While we focus on PFS, because obviously that’s a key priority for industry and it’s a key priority for us too, we’ve got to have more of the patient voice engaged in setting the priorities. That’s why we (Ibrahim Tohidi-Esfahani and I, with the WMozzies and IWMF patient investigators) created WhiMSICAL. That’s why Gajan Kailainathan, Janlyn Falconer and I are building the My Hodgkin My Health App for long-term follow-up of patients. The challenge is that the patient voice is not just one voice; there are so many different unmet needs and different priorities. While a cure is priority #1 for many, for other patients, controlling their disease is the main priority; particularly for some older patients if they can control their lymphoma while living well without, or with minimal, side-effects of therapy. Yet, other older patients may say that’s very paternalistic/maternalistic of me to say that; they want cures too! Balancing the efficacy and toxicity of novel therapies was a key aspect of Dr Emma Verner’s ALLG IRiC study of Ibrutinib and Rituximab-Mini-CHOP in elderly patients with DLBCL. It’s really hard to say what’s the greatest unmet need.”
Q. What’s the most important news in lymphoma research at the moment?
“You know what? I don’t know. Perhaps the data showing that patients on the PD-1 inhibitor pembrolizumab are doing even better than brentuximab (another great antibody-driven therapy) in the relapsed Hodgkin’s setting, so I eagerly await the final KEYNOTE publication which shows that patients with relapsed and resistant HL are surviving for years on pembrolizumab. Our own Phase I-III zanubrutinib data, developed with our colleagues across Australia and globally, is now published in the journal Blood, revealing the very high (96%) response rates and long-term excellent tolerance of zanubrutinib for the treatment of patients with WM, is of course a favourite of mine. It’s really hard to know, particularly because everyone’s so focused on COVID at the moment. People haven’t been attending meetings as much.
COVID has completely transformed the whole way we manage our patients. And everyone’s tired, not just the Melbourne clinicians. And the patients are so fearful; so many of them have just gone into lockdown. They’re shielding themselves. COVID changed the way we operate, with telehealth. You can do a few telehealth appointments, but after a while you do need to see the patient face-to-face. You need to feel their lymph nodes and see their reactions and get a sense of what their anxieties and their worries are. Most patients are needing treatment for lymphoma, that’s the overriding priority, not COVID. But I expect, particularly for a lot of patients in certain hospitals in Melbourne, and in Europe and around the U.S., there are huge anxieties in coming in and having treatment. We had our own patients fearful of coming in when we had a very small, (and I’m proud to say), well contained outbreak at Concord. I recently reviewed a large overseas cohort of lymphoma patients infected with COVID and there are specific factors that may be associated with higher mortality risks, but I can’t share the data yet because it’s in press.” We are learning on the run with COVID.
Q. The NHL30* (PETReA) study is part of the Leukaemia Foundation’s Trials Enabling Program. How is it progressing?
“This is a 1200-patient study using a PET response to adapt ongoing treatment for patients after their induction therapy for what’s called high tumour burden FL. It’s a UK-linked study and the principal investigators in Australia are Dr Anna Johnston, in Tasmania, at the Royal Hobart, and me.
It’s effectively two clinical trials in parallel. After a patient has received antibody and chemotherapy treatment for their FL, they have a PET scan. On the basis of data in other clinical trials, for 80% of those patients the PET scan will become negative, and there will be no signs of any metabolic activity of the lymphoma in their body. Now in those patients, we are randomising them to antibody maintenance (rituximab/obinutuzumab [Gazyva®]), compared to no antibody maintenance. We predict that antibody maintenance given every two months for the following two years, even in the PET-negative will prolong PFS, but not their OS. It will keep the patient in remission for longer. But it comes at the price of increased toxicity, particularly increased troublesome infections like sinusitis, bronchitis, and respiratory tract infections. FL is generally seen as an incurable lymphoma, and when the patient relapses after antibody maintenance they don’t have as long a remission the second time round because they’ve already been exposed to a lot more antibody. So there are swings and roundabouts, there are trade-offs from this antibody maintenance. Firstly, what we’re wanting to do is to quantitate that trade-off in the patients who have the best prognosis, those who have become PET-negative after their initial antibody chemotherapy treatment. Secondly, less than one in five (<20% of the patients) will still have signs of glucose uptake attributed to the lymphoma on the PET scan, and we know these patients who remain PET-positive have a much worse prognosis. We know they are more likely to relapse much earlier and are >5 times more likely to die earlier because of their lymphoma. This is one of the real appeals of the PETReA NHL30 study, because in this PET-positive population, half of them are receiving the (rituximab or obinutuzumab) antibody maintenance, and half of them are going to have lenalidomide (an immune modulatory agent which harnesses the activity of their own immune system to fight the lymphoma) added to the antibody maintenance.
So, to summarise PETReA, we’re measuring the benefits and toxicities of maintenance in patients who become PET-negative, and the likely benefit and toxicity of additional lenalidomide in patients who are PET-positive. We’re trying to work out a PET-adapted approach; a specific personalised medicine approach for individual patients, rather than one-size-fits-all, where you give everybody intensive antibody-chemotherapy and ongoing treatment with antibody maintenance, which we know has significant toxicity.
So, significant benefits, but significant toxicity, and indeed in the very old, people over the age of 70, they’ve got a much higher risk of dying on antibody maintenance after drugs like bendamustine (Treanda®). There’s no point getting a complete response of your lymphoma and then dying of an infectious toxicity because of the treatment.
We’ve been in the study for about a year now and we’ve recruited 30 patients in Australia out of about 150 patients worldwide. We put it on hold initially with COVID, then we realised, with COVID, this study is even more important, because there’s potentially an even higher risk of toxicity of the maintenance antibody in the COVID setting. We genuinely don’t know, and that’s the setting where clinical trials are vital to advancing lymphoma care.”
Q. How important is the funding from the Leukaemia Foundation for the NHL30 study?
“The Leukaemia Foundation funding was a great enabler. While we got some funding for the study from the MRFF [Medical Research Future Fund], to get access to the trial for a decent number of patients across 15 sites, we needed more funding. And this helps not just current but future patients access clinical trials. By being able to contribute well patients to the UK RATHL study, we have had access to PETReA and soon we hope the RADAR study for patients with early stage HL, in 2021. We also then get access to new studies and new treatments for our patients. Maintaining these international collaborations is how you get access to new treatments. They really are.”
A previous study Professor Trotman was involved in received a $340,000 grant from the Leukaemia Foundation titled: RATHL – Randomised Phase III trial to a assess response adapted therapy using PET in newly diagnosed advanced HL, the results of which were published in the world-leading New England Journal of Medicine in 2016 – the day of the Brexit vote!