Drug discovery has remarkable potential for high-risk childhood leukaemia
Exciting research is laying the groundwork to develop a promising new targeted therapy for aggressive subtypes of childhood leukaemia including infant acute lymphoblastic leukaemia (ALL).
Lead investigator, Dr Michelle Henderson is a senior scientist, project leader and joint Research Manager of Molecular Diagnostics at Sydney’s Children’s Cancer Institute.
Before moving to the Children’s Cancer Institute, Dr Henderson spent 10 years working on the genetics and molecular biology of breast cancers at the Garvan Institute of Medical Research.
“Fourteen years ago, the opportunity to move to the Children’s Cancer Institute came up,” explained Dr Henderson.
“After spending years studying individual genes involved in cancer, I wanted to take a step closer to the clinic where I could potentially discover new treatments and have a more direct impact on people with cancer.”
While major research advancements have significantly improved survival rates in childhood leukaemia, Dr Henderson and her team are working to target certain subtypes of childhood leukaemia that still have very poor prognoses.
These include children who fail induction treatment, relapse during treatment or whose leukaemia harbours chromosomal rearrangement of the Mixed Lineage Leukaemia (MLL) gene*, an abnormality that occurs in 90% of infant ALL, with a survival rate of less than 50%.
“It can be an extra challenge with children as their bodies are still developing and these chemotherapeutic agents that work so well for leukaemia can still be very harmful to the patient,” said Dr Henderson.
“If it’s a more aggressive cancer then that child will receive more aggressive treatment and that can affect them later in life, leading to physical problems such as heart disease, osteoporosis, infertility, obesity, or even the risk of a second cancer.
“This presents an urgent need for the development of novel treatment strategies incorporating more selective, targeted therapies, allowing for a reduction in chemotherapy dosage and toxicity.”
For the past 10 years, Dr Henderson’s lab has collaborated with a lab in Buffalo, New York, conducting ‘screens’ with the aim of finding new drugs which specifically kill cancer cells without affecting normal cells.
Together they have discovered a new drug, OT-82, which has ‘remarkable’ potential to improve treatment in aggressive childhood leukaemia.
This grant was co-funded by the Leukaemia Foundation, The Kid’s Cancer Project and Cancer Australia.
“This drug, OT-82, blocks the production of a cellular biochemical called nicotinamide adenine dinucleotide (NAD) which rapidly dividing cancer cells can be dependent on for energy,” said Dr Henderson.
“NAD is also a co-factor for a number of enzymes that help the cell repair itself and so leukaemia cells can require a lot of it because they’re continually growing and need to repair themselves all the time.
“Based on the knowledge that cancer cells depend on NAD more than normal cells, researchers have tried for many years to design a compound that actively targets and inhibits production of NAD. But a suitable compound was yet to be found.”
Although not looking to target this pathway in particular, Dr Henderson and her collaborators in the U.S. came upon such a compound through a screening strategy aimed directly at blood cancer cells.
“We were surprised when the compound that came out of the search appeared to be an inhibitor of an enzyme called NAMPT (nicotinamide phosphoribosyltransferase), which is necessary for producing NAD in the cell but whose association with blood cancers was unknown,” she explained.
“This particular compound universally kills blood cancer cells, but the normal blood cells just go into a pause.
“The normal blood cells don’t die, they are just in pause and then when you stop treating them, they rejuvenate again, whereas the cancer cells don’t.
“It’s interesting that we’ve come across it through a completely blind approach of just screening thousands and thousands of compounds and found one that targets blood cancer cells.
“This compound seems to be very well tolerated so far in adult trials and is earmarked for going further into paediatric trials.”
With this grant, Dr Henderson and her team are laying the groundwork for these paediatric trials, by determining which children could be most responsive.
“Part of our research is to determine exactly which subtypes of leukemia will respond, both on a broad, phenotype level, and at a molecular level, to find which genes are expressed in that particular cancer,” said Dr Henderson.
“We want to have a set of biomarkers, or subtype markers, that say if a patient has this cancer and it expresses this gene or mutation, they are more likely to respond to OT-82.
“So far, we have found a set of very responsive patient samples that each have mutations in DNA repair genes.
“We think that when they have a weakness in their DNA repair, with the cancer cell having to grow so rapidly and requiring NAD for repair, that’s when they are particularly responsive to OT-82.
“We are also looking at how OT-82 can be used in combination therapy to promote the response to other drugs currently being used for leukaemia treatment.”
The impact of this project is further enhanced by a collaborative grant recently awarded to the Children’s Cancer Institute to deliver personalised medicine to every child in Australia.
“It’s going to become a reality that across the country every child’s cancer will be sequenced,” said Dr Henderson.
“Such a completely individualised approach to treatment means that OT-82 could have an incredible impact on patient survival outcomes.”
Inhibiting NAD also appears to be relevant to some other cancers that depend on the same pathway.
“They might be solid tumours like sarcoma or brain tumours with certain genetic mutations you can screen for that cause dependence on this particular pathway,” said Dr Henderson.
The next big challenge for the research team will be gearing up for a paediatric leukaemia clinical trial.
“That’s why this funding from the Leukemia Foundation, The Kid’s Cancer Project and Cancer Australia is so important,” said Dr Henderson.
“Even though a relatively small number of children may have these high-risk leukaemia subtypes, it will have a significant impact on survival outcomes for this group and may be applied across other cancer types.
“The whole team is so thankful to have the opportunity to gather this supporting evidence and make a real case for OT-82 to be taken to clinical trial stage for these deadly childhood leukaemias.”
*Also referred to as Mixed Lineage Leukaemia Gene Rearrangement (MLL-r). This occurs when a piece of DNA is swapped with another chromosome which results in two different genes being abnormally joined together. The resulting protein can no longer control the development of the blood system and blood cells grow out of control, resulting in leukaemia.
The Leukaemia Foundation’s National Research program has supported the careers of the brightest researchers and clinicians, like Matthew Witkowski, for almost 20 years.
His research is a prime example of how critical research funding is to understand the biology and genetics of blood cancers and to developing new treatments.
Matt’s career trajectory was kick-started when he won the under 11s footy grand final for Diamond Creek in Victoria! He has since moved from sport to science and, after completing his Honours at the Walter and Eliza Hall Institute (WEHI) in Melbourne, was awarded a PhD scholarship from the Leukaemia Foundation.
Now he’s working as a postdoc scientist at the New York University School of Medicine in the U.S. and his sights are focused on improving the effectiveness of CAR T-cell therapy.
When ALL News spoke to Matt, he had just presented on The relapsed B-cell acute lymphoblastic leukaemia immune microenvironment and won the first prize post-doctoral Eugene Cronkite 2019 New Investigator Award at the International Society for Experimental Haematology conference in Australia.
He explained that back in 2011, when he applied for a PhD scholarship, “the Leukaemia Foundation was very competitive, but I was lucky enough to receive it”.
Matt’s PhD, from January 2012 to December 2014, was valued at $120,000.
“It was my first scholarship. It was a big deal for me, and relieved a lot of the stress,” said Matt.
“You knew someone cared about what you were doing as a student and that it was worth investing in. That’s critical at the point when you are learning the lay of the land in science.”
“The Leukaemia Foundation was a big supporter of our lab and was a constant support and funding stream. Our lab thrived on that bit of stability,” said Matt.
“You do a lot of work all the time, in science. You’re constantly working, so you don’t want to worry about funding, especially when the Australian government can swing around in terms of how much they are investing in science.
“We were a small lab with one post doc, two students, and Ross as well. It was one of the few acute lymphoblastic leukaemia labs at WEHI at that time,” explained Matt.
“We were working on ALL because it is the most common cancer in kids and the most common cause of cancer-related death in children. I work on B-cell leukaemia, which is the most prevalent form of ALL.
“Students are the powerhouse of a lot of labs, especially ours.
“The other student in the lab, Grace Liu [also a Leukaemia Foundation three-year PhD scholarship recipient (2010-2012)] and I were producing a lot of the data.
“We both got meaningful papers out of it, which put us in good stead for building a career in the field” said Matt, and this was important for his career going forward.
Matt was investigating genes defective in leukaemia patients who showed resistance to chemotherapy, which would suggest that these particular genes dictated a patient’s ability to respond to chemotherapy.
“My work has focused on the Ikaros gene and defining how Ikaros interacts with other genes in a leukaemia cell to drive chemotherapy resistance and cancer development,” he said.
“By understanding these interactions, explanations for why patients who lack the Ikaros gene do not respond to therapy may become clear.
“Ultimately, this may lead to alternative therapy for ALL patients who would otherwise not respond to common chemotherapeutics.”
Matt had papers published in both Leukemia and The Journal of Experimental Medicine, and prior to completing his PhD, he went to a conference in Colorado in the U.S. where he met his current boss, Iannis Aifantis, an internationally recognised immunologist and cancer biologist, who heads a laboratory at New York University (NYU).
“He had read our papers and said, ‘do you want to come to New York for an interview in the lab?’.
“To be honest, New York wasn’t on my list. It seemed a little daunting. However, Luisa Cimmino, a previous postdoc with Ross Dickins, who was in the Aifantis lab, said ‘come to New York, it is really nice here’.
And so Matt went to further his career and research in New York. He went from a lab of four people to being a postdoc in a lab of 29! He’s still there now, continuing his work in ALL, “and it has been great ever since, just working away”, he says.
“I was able to extend on what I did in Ross’ lab. I worked in the same disease, ALL, but new technologies were coming out from the States and I could use them straight away.
“Leukaemia is a very complicated disease. You have a cell that is abnormal and it grows and grows in your bone marrow and spreads.
“What we did in Ross’ lab during my PhD, was provide really valuable information about what the genetic changes were in cells that made them transform into leukaemia. We used very novel tools to do that.
“Ross had brought that back from America and we took advantage of that to understand what underpinned leukaemia emerging and causing disease, and treatment resistance.
“When I went to America, I thought; how does the bone marrow itself influence the leukaemia? It obviously doesn’t grow on its own. It grows by interacting with everything around it.
‘When a patient presents with the disease that is throughout their bone marrow, then they get treatment, a small amount of leukaemic cells will just hang around and eventually the patient may relapse with the disease.
“My question was, ‘is there something that actually drives that small population of cells that are resistant to therapy to hang around, and what is the influence of the environment on these cells that would mean they would eventually not respond to therapy and inevitably cause relapse in these patients’.
“I was able to do a lot of that in the U.S. where we had new technologies where we could look not only at the leukaemic cell, but also everything surrounding it.
“We could deconstruct and pull apart the whole landscape of the bone marrow and understand all of the components and how they were talking to the leukaemia to keep it alive.
“What we have been able to do at NYU is use novel technologies to understand the whole system and how it evolves over time. We think we might be able to intervene with how the environment keeps the leukaemia alive, as a means of improving therapy,” said Matt, first author on a paper about this work that was published in Cancer Cell in June 2020.
“If you just stop these populations of cells from supporting leukaemic cells, you might be able to improve therapies that are already quite good in leukaemia.
“By just taking into consideration that you don’t just treat the leukaemia, sometimes you have to treat the things around it that would potentially support it surviving. This is a new paradigm in a lot of therapies.”
Matt has continued to keep in touch with an Australian ALL patient, India Papas, who he met through the Leukaemia Foundation when she was young.
“Every so often I ask Jodie [her mum] how India is going, and she seems to be doing really well…she has grown up.”
Matt said, looking to the future, his holy grail was to understand why some patients fail CAR T-cell therapy.
“This therapy harnesses a patient’s own immune cells to kill their tumour. It was originally utilised at the Children’s Hospital of Philadelphia and St. Jude Children’s Research Hospital (Memphis) as a way to treat B-cell leukaemia.
“Initially, it looked great. It looked like taking T-cells out of a patient and repurposing their own cells to kill tumour cells was going to be a really nice curative treatment.
“But it turns out that now we are a few years out from those initial trials, they [CAR T-cells] are not as effective as we thought. There are patients relapsing.
“It is an expensive therapy as well. In the U.S., it costs USD500,000 for a single treatment with this drug.
“There have to be ways to mitigate the relapsing that emerges from this. Not all of them are because of the drugs or because the B-cells they are targeting are naturally resistant. Sometimes there are other mechanisms.
“My goal is to start a group that tries to understand why patients fail this therapy.
“My initial work, in understanding how the bone marrow is composed, provides a good platform to understand how the environment informs how these new immune therapies are working.
“That is the goal in my immediate future, to start my own group where I can do this… to be around these therapies and take advantage of the fact that patients get biopsies which lets us see how they perform over time and why they don’t respond or why they do.
“There is also something called Bi-specific T-cell engagers. They hook leukaemic cells up to cells in the body that, if activated, kill leukaemia cells.
“There is a drug, called blinatumomab, that has done pretty well in this kind of field, where you are depending on the environment to kill the cells by using CAR T-cells and blinatumomab.
“Once we understand what the environment is and how it influences the leukaemia cells, it might inform us which patients may not respond to these drugs. We have made the assumption that the environment is going to allow these drugs to work, but we don’t know that,” said Matt.
Matt said he was open to potentially moving back to Australia to start his own lab or to do that somewhere in America.
“I may come back to Australia but I’m not definitive about anything at the moment,” he said.
* Dr Ross Dickins subsequently moved to the Australian Centre for Blood Diseases at Monash University.
** Mark McKenzie was supported by a three-year Leukaemia Foundation Postdoctoral Fellowship (2010-2012).
Research aims to improve QOL by decreasing treatment toxicity
Research aims to improve QOL by decreasing treatment toxicity
Exciting research is examining whether a new inhibitor can be used to prepare myeloma patients for bortezomib and other myeloma therapies, to increase the efficacy and potentially decrease toxicity of these therapies.
Dr Vandyke was awarded a Priority-driven Collaborative Cancer Research Scheme grant in 2019 to build on her finding that the novel N-cadherin inhibitor, LCRF-0006, can dramatically increase the antitumour efficacy of low dose bortezomib (Velcade®) treatment. This grant was co-funded by the Leukaemia Foundation, Cure Cancer Australia, and Cancer Australia.
“The project has been a long time in the making,” said Dr Vandyke.
“We’ve been working on a N-cadherin inhibitor (LCRF-0006) as a potential target for myeloma for almost 10 years.
In this project, Dr Vandyke is looking at one particular drug (bortezomib) that’s used in the majority of myeloma patients and which causes peripheral neuropathy in about a third of these patients.
“This is a really horrible side-effect affecting the nerves in the extremities. It causes pain in the hands and feet, pins and needles, numbness, and burning sensations – it’s really nasty,” she said.
“Bortezomib, as well as targeting the myeloma tumour cells, also targets some of the long nerve fibres that go into the hands and feet. It targets the long axons of these nerve fibres and causes damage.”
Dr Vandyke’s project will look to increase the way the drug is delivered intravenously from the bloodstream to the cancer cells.
“The way bortezomib moves out of the blood and into the cancer cell is limited by the blood vessels as they’ve got a strong boundary around them that stops the blood from seeping out,” said Dr Vandyke.
“We think that this N-cadherin inhibitor is just opening up that barrier a little bit to allow the drug to get through more efficiently. It’s working more on blood vessels in cancer rather than normal blood vessels.
“You’re getting more of the drug into the cancer and can decrease the amount that’s going elsewhere in the body which should decrease those side-effects.”
The research team has just published a paper in the medical journal, FASEBBioAdvances, using a pre-clinical model showing that using LCRF-0006 effectively increases the effect of the bortezomib.
“This means we can actually use a lower dose of bortezomib and therefore we hope side-effects will stop because you’ll get a better anti-cancer effect with a lower-dose drug,” said Dr Vandyke.
The next steps will be to see if the side-effects are actually decreased and to optimise the drug to be ready for human clinical trials.
“Because this drug hasn’t been used in patients before, it would have to go through Phase I trials and safety studies before going on to larger clinical trials,” said Dr Vandyke.
“Also, because we don’t have a pharmaceutical company that’s making the drug, the next big hurdle would be funding – always a challenge.”
Dr Vandyke is motivated by the people who are living with myeloma and whose quality of life could be improved significantly by her work.
“As a scientist, you can get bogged down in the finer details of what you’re doing and you forget the big picture,” she said.
“We have a lot of engagement with patient groups that come for tours and education sessions at the lab.
“While advancements in myeloma therapies have improved survival rates significantly, toxic side-effects and treatment-related quality of life (QOL) have become increasingly important factors for patients.
“Many patients won’t want to take the drug if it’s going to have such a detrimental effect on their quality of life, regardless of the long-term survival outcome.”
Dr Vandyke is also passionate about fostering the next generation of researchers.
“I really enjoy the teaching and supervision side of things. I’ve got quite a few PhD students that I co-supervise with Prof. Zannettino and I’m mentoring a couple of junior researchers as well,” she said.
“One of them, Dr Krzysztof Mrozik, has been a real driver for this project – we couldn’t have done it without him.
“It’s also great for them to be able to talk to the patients and their carers and families and see this is why we’re doing what we’re doing.”
Dr Vandyke said she was, “incredibly grateful to Leukaemia Foundation supporters for enabling me, and my team, to do the work we do”.
“They have made this project possible.”
Dr Vandyke has used this funding support to expand her research group; to hire a technical support staff member, and support the research of a junior researcher.
“These grants are given to some of the very best emerging talent from around Australia, and I am proud to be included in this group.”
Clinical trials critical to finding curative therapies for MPN
Associate Professor David Ross is a clinical and laboratory haematologist who has always had an interest in MPN. His clinical PhD scholarship in CML, monitoring residual disease, was funded by the Leukaemia Foundation. He is Head of the Clinical Trials Unit at the Royal Adelaide Hospital and Director of the South Australian Cancer Research Bio Bank. In this comprehensive interview he discusses everything from research, current therapies, clinical trials, diagnosis, prognosis, incidence, and more, and says, “it’s a very exciting time in MPN”.
After “almost nothing” by way of new treatments for 20 or 30 years, “there’s just been this massive explosion of clinical trial activity in MPN, said Associate Professor David Ross.
“We’ve gone from a situation where there were basically no new treatments, to one where a dozen drugs have been in clinical trials over the past few years.”
But one of the big issues in MPN remains.
“In CML, we have drugs like imatinib that essentially turn the disease off and, for most patients, ensure that it will never transform to a more aggressive phase, and the patient will never die from leukaemia,” explained Dr Ross.
“Therapies have improved some of the clinical manifestations in MPN, but the drug treatments available don’t change the long-term outcome of the disease.”
Does he see this changing?
“Look, I think it will. There’s been a huge amount of research on MPN in the last 10 or 20 years.”
Dr Ross said his holy grail is “to have a treatment for MPN that is curative, to be able to give someone a course of treatment that completely gets rid of the disease, gets rid of future risk, gets rid of any current symptoms or problems”.
“That key discovery, first published in 2005, has given scientific insights into these diseases that has spurred a lot of research and development,” said Dr Ross.
“Then there’s the calreticulin (CALR) mutation, found in about a third of patients with ET and MF. This second most common mutation was only discovered in 2013.
“That extra scientific information is a clue for academic researchers and drug companies to start understanding the disease and looking for drugs that can target those particular pathways.
“That’s where the JAK inhibitors came from, like ruxolitinib (Jakavi®), but as people better understand what CALR does, and what JAK2 does, and what MPL [another MPN mutation] does, they may find other targets that might be more effective.”
Next generation sequencing
Another important development was ‘next generation’ sequencing (NGS). Traditional sequencing looks at one small section of a single gene. NGS looks at many different sequences, often in many different genes, all at the same time.
“NGS panels are available for various blood diseases with lots of different mutations. These may test five or six genes, sometimes 30 or 40 genes, so a single test will give you a large amount of information,” said Dr Ross.
“There’s an increased use of sequencing panels to look for not only JAK2, MPL, and CALR, but also other mutations that may be associated with higher risk disease and that currently are most relevant for MF. They are IDH1, IDH2, ASXL1, EZH2, U2AF1, and SRSF2.
“The presence of a mutation in one of those genes increases the risk of MF, and for a small group of patients that’s really essential information, used in guiding transplant decisions.
Sequencing panels may also be useful to clarify the diagnosis.
Dr Ross went on to explain that if someone is intermediate risk, but doesn’t have any bad mutations, that might downgrade that person to being low-risk. Whereas, if someone is intermediate risk and has one or two of those mutations, that might push that person up into a high-risk group where the life expectancy might be only two or three years, and convert them from a watch and wait approach to going straight to a bone marrow transplant.
Dr Ross said this panel test was not currently funded by the Federal government.
“As is usually the case, the Medicare rebate for the test lags years behind research and clinical practice, so individual hospitals are paying for it, or sometimes individual patients pay to have it done privately.”
He said the cost varied from $400 for a small panel looking at the most common mutations in a particular gene, up to $1500 for a more extensive panel that sequenced 30-40 genes.
“But when you think that a bone marrow transplant might cost quarter of a million or half a million dollars, this is a trivial amount of money.”
Each state has different rules about getting tests done.
“In South Australia, everyone with MF who’s been discussed for transplantation would get this done; that’s a small number of patients out of the total MPN population, because MF is the rarest of the MPNs and only 25% or less of MF patients will be transplant-eligible.”
Clinical trials in MPN
Most recent studies have been for myelofibrosis, reflecting it being the MPN with the highest need.
Ruxolitinib was the original JAK inhibitor. Several studies have explored other JAK inhibitors (fedratinib, pacritinib, and momelotinib) on their own, or comparing them to ruxolitinib.
“Different companies are looking to see if one of the newer JAK inhibitors works after ruxolitinib has failed, or offers advantages over ruxolitinib in certain patients,” said Dr Ross.
“For instance, there is some hope that pacritinib might be better in people with a low platelet count, and momelotinib might be better in people with a low haemoglobin.
“Neither has been proven, but these are the questions that are being looked at in clinical trials.
“We currently have a momelotinib study [called Momentum] that is recruiting patients with myelofibrosis who are anaemic.
“The ‘mel’ in the name is because it was originally developed in Melbourne,” he explained.
“It’s already been used in hundreds of patients, so we know that it works.
“Most people on ruxolitinib have a modest drop in haemoglobin; they become more anaemic. It’s been observed that with momelotinib, the drop in haemoglobin is less, and some patients have an improvement in anaemia.
“So, whether momelotinib will offer an advantage specifically in the subgroup of people with myelofibrosis who are anaemic is being explored,” said Dr Ross.
Momelotinib and ruxolitinib both inhibit JAK1 and JAK2. Another study testing fedratinib will try to answer the question of whether there is some advantage to a pure JAK2 inhibitor [it doesn’t inhibit JAK1]. This study will recruit MF patients who have a had a suboptimal response on ruxolitinib, but is currently on hold due to COVID-19.
The Kartos study opened recently. KRT-232 is an MDM2 inhibitor being tested in MF patients who have failed on ruxolitinib therapy. Dr Ross said MDM2 was involved in the P53 pathway, which is important in lots of different cancers. It’s a quality control pathway within the cell that senses DNA damage and causes the cell to undergo apoptosis [cell death] if there has been DNA damage.
“These are all international studies that include Australian sites,” said Dr Ross.
And there are other drugs in completely different classes that have different mechanisms of action that have been tried in early phase studies.
Australians were among the first patients enrolled on an ongoing study of bomedemstat that inhibits an epigenetic enzyme involved in controlling blood cell production.
“It’s a tablet and it’s shown some improvements in symptoms and spleen size and is generally quite well tolerated,” said Dr Ross.
An initial study of ruxolitinib combined with another class of drugs, called BET inhibitors, showed some encouraging responses. Now a larger study is in the planning stage and may open in Australia in the next six months.
Experimental data suggests navitoclax, which is related to venetoclax, and inhibits another member of the BCL-2 family, may be useful in MF, and luspatercept is being explored to see if it improves anaemia in MF.
The ADORE study is open at several sites for Australian MF patients who are on ruxolitinib and are anaemic. It is a Phase I platform study looking at a series of experimental drugs being added to ruxolitinib. A small number of patients will try each combination and then the results will be reviewed to decide which combination is the most promising, to take it to a bigger study.
“So, it’s a ‘pick a winner’ study,” said Dr Ross.
Studies in PV and ET
Dr Ross said that the first clinical trial in Adelaide for PV closed recently. It was using another MDM2 inhibitor called idasanutlin, “and it definitely works in some people who failed standard treatment”. The study closed due to toxicity concerns.
“The main issue was nausea. You can imagine that if you’ve got PV and you’re going to live with the disease for 10 or 20 years, having a drug that causes nausea for a week every month is not very good for quality of life.”
He also is “quite excited” about an upcoming ET study, also using bomedemstat. The opening of this study has also been delayed by COVID-19 but is expected in late-2020.
“It will be our first ever ET study in Adelaide.”
“Because we’ve already had experience with that drug, we know that its safety profile is pretty good, so I’m optimistic about that.
“It will be for people who have been resistant to, or intolerant of hydroxyurea, which is the standard treatment for most people with ET.”
Ask about studies for you
“There are many studies for myelofibrosis at the moment – we’ve currently got four in South Australia – and a lot of the time they’re competing for the same rare patient population,” said Dr Ross.
“For companies to test their drugs, they need more patients.
“If we can’t enrol patients in clinical trials, it slows down the development of a drug and means that our patients won’t get normal access to the drugs because it takes longer to do the study properly.
“This is the problem of a rare disease.”
Dr Ross urged patients with MF to be proactive in asking their clinicians about clinical trial options in their city.
“A lot of these studies are open in only one hospital or maybe two hospitals in a bigger city. We need people to be referred to sites where a study is open, so we can put people on them,” he said.
“And they can look on the ClinTrial Refer app or website to see whether there’s anything that meets their particular circumstances.
“A lot of these studies are looking for only a few patients in each hospital, who meet very specific criteria, but if there are five or six studies, there is room for a lot of patients,” said Dr Ross.
The prime target population in MF are those patients on ruxolitinib or who have been on ruxolitinib and have not had an optimal response, and the main focus of these studies is to improve on the benefits already seen with ruxolitinib.
MPN is different from other blood cancers
MPN is a blood cancer, said Dr Ross, “but the way it behaves is completely different from lymphoma or leukaemia, so many people with MPN can go undiagnosed”.
“What sets ET and PV apart from other diseases, is that many people have either no symptoms or vague symptoms, like tiredness, together with blood count abnormalities, which means they may go undiagnosed for some time,” he explained.
“They’re often overlooked for a long period of time. That’s one of the standout features of ET and PV, and the main risk is bleeding and clotting (venous or arterial thrombosis) that can come out of the blue in people who didn’t know that they had an MPN.
“That makes it quite different from most other cancers. You’re not treating a tumour or trying to clear out the leukaemic cells, you’re mostly trying to protect the patient from having a clotting or bleeding episode.
“And the longer you leave it, the more chance there is of having a clot.
“What we know is that some people turn up and they have a clot that could potentially have been prevented if the diagnosis had been made earlier. So, a significant fraction of people with MPN will first be diagnosed when they present with a blood clot or a stroke or a heart attack.
“Sometimes, in those cases, we see someone who comes in having had a high platelet count for three years, and nobody’s done anything about it. So possibly, if that person had received appropriate treatment, he or she might never have had that clot,” said Dr Ross.
He cited the findings of a colleague with a long-standing interest in MPN, Dr Cecily Forsyth. She went back through the records at her centre, at Gosford (NSW), looking at people with a diagnosis of MPN and tracked their haemoglobin, white blood cell, and platelet counts.
“One of the patients had a high platelet count for 20 years before a diagnosis was made,” said Dr Ross.
“The estimated risk of having a clot is about 2% per year for ET, and maybe about five or 10% for PV. Many people, just by chance, will go years without having any problems, but someone’s got to be the one who’s unlucky.
“If someone has blood tests for other reasons and a mildly elevated platelet count is noted, it would often be disregarded if the person is otherwise well.
“In most laboratories, a normal platelet count is 150-450. In fact, your platelet count might be 300 or 200, but the top of the normal range is commonly close to 450.”
What complicates things is that if you are unwell, for instance if you have a chest infection, or if you are iron deficient, your platelet count might go up.
“In young women, in particular, it’s quite common to be iron deficient due to periods or pregnancy, so a slightly high blood count may be disregarded.
“And in an older person who’s got arthritis or other chronic health problems, a slightly high platelet count might be put down to inflammation.
“It’s when there’s a sustained elevation, with no obvious cause, that someone needs to think, ‘well, actually, this has been present two or three times. It needs to be looked into’.”
Myelofibrosis and stem cell transplantation
Dr Ross said myelofibrosis (MF) is completely different from ET and PV.
“Most people with MF feel unwell. They often have severe tiredness, itching, sometimes night sweats, and discomfort from enlargement of the spleen,” he said.
“The main aim of treatment is to lessen the severity of those symptoms, improve quality of life, and make people feel better.
“And, because MF is a more serious disease with a shorter life expectancy, we do bone marrow transplantation for higher risk MF patients who are young and fit, in whom the risks of transplantation are warranted.
“The age limit for transplantation has been continually creeping up over the past decades. Now, for most sites around the country, it’s up to age 70.
“Unfortunately, the risks associated with the transplant rise steeply once you’re above 50 [years old], and the chances of dying from the transplant if you’re nearly 70 are pretty high. The average age at diagnosis of MF is also around 70, so we don’t do very many transplants for myelofibrosis, but it is a potentially curative treatment,” said A/Prof. Ross.
Transplantation is not used for ET or PV because the risk is rarely justified. The treatments for those diseases are about controlling the blood counts and reducing the risk of clotting, but they’re not eradicating the disease or reducing the risk of future progression.
Diagnosis of MPN and its importance
MPN diagnoses are currently based on blood counts, bone marrow appearance, and clinical features, such as itching, sweating and spleen enlargement, said Dr Ross.
“It’s an old-fashioned classification system.”
He said Professor Tony Green’s group in the UK published a “highly influential” paper in the New England Journal on the results a large group of 2000 patients whose MPN was classified based on the results of genomic sequencing.
“They looked at patterns of mutation and showed that the behaviour of the disease and long-term survival could be predicted with some accuracy just by looking at the genes without the traditional pathological classification,” said Dr Ross.
“This hasn’t yet changed the way that we diagnose MPN, but it has emphasised the fact that you can get a lot of useful clinical and biological information from extended sequencing that may add to our old-fashioned classification system.
“And, in some cases where the bone marrow appearance is difficult to interpret, and one pathologist might think it’s ET, and another thinks it’s early myelofibrosis, looking at the sequencing for these difficult-to-classify cases might tell you, well, actually this is more likely to be MF, or actually, this is more likely to be PV.
“The biggest distinction is to identify early myelofibrosis and that’s important because the life expectancy is much shorter, and transplantation might be an option.
“And drug access is determined by having a biopsy that says you have myelofibrosis. You can only get ruxolitinib on the Pharmaceutical Benefits Scheme (PBS) if you have myelofibrosis; you can’t get if you’ve got PV or ET.
“It has been proven that ruxolitinib is effective in hydroxyurea-resistant and -intolerant PV, but it hasn’t been funded [by the PBS] because of the cost.”
“At the moment ET and PV are treated similarly. They both usually get hydroxyurea or interferon plus aspirin.
“The difference is that in PV, we aim to keep the hematocrit, which is a measure of haemoglobin, below 45%, as well as the platelet count and white cell count in the normal range. Whereas in ET, we only look at the platelet and white cell counts.
“Lots of drugs are being investigated at the moment and if any of those make it to clinical practice, the implication of making an accurate diagnosis will become more important,” said Dr Ross.
Incidence and prevalence of MPN
A paper published last year in the American Journal of Hematology based on epidemiology work by Professor Peter Baade reported on the latest available statistics on incidence, prevalence, and survival of MPN in Australia.
“This showed there are 23 cases of MPN per million population per year, so it’s a pretty uncommon disease, but because many people with MPN will live for many years, the prevalence is relatively higher, considering the low frequency of diagnosis,” explained Dr Ross.
“For instance, somebody with ET might live for 20-30 years, whereas for many cancers the survival will be much shorter.
“According to that study, new diagnoses of PV and ET were roughly equal; at about nine per million per year, and primary myelofibrosis is the rarest at about five per million per year.”
Regarding age at diagnosis, Dr Ross said the average age of diagnosis for all MPNs was 68. The oldest cohort, with an average age of 72 years, were those with primary myelofibrosis, and the youngest was ET at 66 years, closely followed by PV at 67.
However, he said, “there’s a tail of younger patients”.
“We see people in their 20s with ET, whereas myelofibrosis is rare below the age of 40.”
“The cause of MPN in most cases is unknown. If you have a family member with MPN, your risk of getting an MPN is increased about five-fold compared to the general population.
“Although it’s not an inherited disease, there’s an inherited risk component. We do occasionally see brothers and sisters or parents and children that both have MPN.”
Dr Ross said there weren’t any known strong risk factors, although there is an increased risk with exposure to radiation and, rarely, to industrial chemicals.
“No-one has ever done a proper, large epidemiological study of MPN risk factors.”
Disease progression and risk
Dr Ross said ET and PV can both turn into MF.
“It’s generally estimated to be something like 20-30% lifetime risk, but that might depend on the age at diagnosis.
“If you’re diagnosed [with ET or PV] at 75, you may never get myelofibrosis. But if you are diagnosed at 30, your risk of getting myelofibrosis might be substantially higher because you’re potentially going to live for another 50 years.
“All three diseases can turn into acute myeloid leukaemia (AML).”
However, Dr Ross said the risk of AML for ET patients is very low, around 2%, and 5% for PV, so it is rare.
“Every now and again it happens, and it is a shock for those people.”
For MF, the risk of AML is 20-30%.
* Dr David Ross received a Leukaemia Foundation clinical PhD scholarship (January 2006-January 2009, $120,000) for his research project, Characterisation of persistent CML cells in patients treated with ABL kinase inhibitors.
For information about any of the studies mentioned, download the Clinical Refer app on your smartphone and search using the name of a drug or study.
Dr Liesl Butler is investigating the gene mutations and biological pathways that lead to the development of MPN and hopes to make significant advances in blood cancer research.
The junior haematologist, based at the Australian Centre for Blood Diseases at Monash University (Melbourne), has a strong interest in molecular pathology and is looking to improve outcomes for Australians living with an MPN.
This provides funding of $120,000 from 2020 to 2023 and her project title is Development of improved biomarkers and targeted therapies for MPN.
Dr Butler is working under the supervision of Professor Andrew Perkins, a leading haematologist and group leader at the Australian Centre for Blood Diseases at Monash University.
Working as a clinician, Dr Butler appreciates that research is pivotal to successfully treating the blood cancers and she is excited at the prospect of her research being translated into meaningful outcomes for patients.
“Molecular pathology has had a considerable impact on diagnostic and therapeutic approaches in blood cancer,” she said.
“The area is rapidly expanding and its integration into standard practice is drastically improving clinical outcomes.
“I will study the gene mutations and biological pathways that lead to the development of the MPNs by undertaking tests in patient samples and mouse models,” said Dr Butler.
“Molecular techniques are now critical in the detection, classification and monitoring of many blood cancers, and are essential in the development of new treatment strategies and predicting disease response.
“The MPNs are a challenging disease group which causes significant morbidity and can limit life expectancy; the overall biology of these cancers remains elusive and new therapies are desperately needed.
“Additional research in the field will further our understanding of these cancers and lead to developments in treatment, hopefully improving the lives of patients,” said Dr Butler who is in the early stages of her PhD project.
“I have studied the current literature in the field extensively and begun preliminary experiments. Thus far, the results are very encouraging.”
She was “thrilled” to discover that she had been offered the PhD scholarship, overcoming what she considers the biggest hurdle for researchers; funding.
“I feel privileged to have the support of the Leukaemia Foundation and Haematology Society of Australia and New Zealand for my project,” said Dr Butler.
“And I am incredibly grateful to the Leukaemia Foundation supporters aiding my project.
“I look forward to what I can achieve over the next three years with the assistance of the scholarship and hope to make significant advances in blood cancer research.”
Head of the Leukaemia Foundation’s National Research Program, Dr Peter Diamond discusses his role, priorities for the program, and exciting breakthroughs coming up in blood cancer research.
What does your role as Head of Research involve?
I work closely with leading researchers, research institutions and organisations to identify emerging treatment trends and Australia’s newest and most exciting blood cancer research and clinical trials. These opportunities are presented to the Leukaemia Foundation’s Board of Directors to decide which projects we will fund through our National Research Program. Our overall aim is to strengthen the blood cancer research ecosystem in Australia. A strong blood cancer community in Australia leads to better treatment outcomes and improved access for all people living with a blood cancer.
What does a typical day at work look like for you?
I spend a lot of my time on the phone speaking to researchers and others about blood cancer research and new opportunities for the Leukaemia Foundation to be involved in.To be able to make informed funding recommendations, I’m always reading scientific literature and attending scientific/clinical meetings. Therefore, a lot of my day is devoted to keeping up-to-date with new trends in research and discovering where new breakthroughs in treatment will come from. Another increasingly important part of my role is to raise awareness about what research the Leukaemia Foundation is funding, what exciting breakthroughs and clinical practice changes this research is generating, and ensuring this information is communicated in a way that everyone can understand.
What excites you most about your role?
I know that every significant improvement in treatment is a direct result of investment in research. By creating partnerships and funding the best research and clinical trials in Australia, we will make a difference for everyone living with blood cancer. Clinical research is moving at a rapid pace and I’m excited to be part of supporting this process; to develop better treatments and ultimately cures for blood cancer. I am also grateful to be a member of the Leukaemia Foundation’s Blood Cancer Partnership team which leads advocacy within the community and government. Our bipartisan approach was very successful in getting blood cancer on the political agenda during the recent Federal election.
What motivates you every day in your role?
The thing that motivates me the most is seeing how what we do every day is helping someone. Sadly, I know all too well what it is like to have family members diagnosed with cancer, to see them go through treatment, to revel in the joy of every remission and to be devastated by every relapse. And, I’ve also seen some eventually lose their battle. I would like to live in a world where no one else watches their nieces and nephews grow up without a mum or dad, or a parent saying goodbye to their child because of blood cancer.
What’s the biggest challenge you face in your role?
There are so many great research projects, but we only have a limited amount of money to invest in research. If only we could fund all of them! We actively partner with other organisations, to pool our resources and fund a greater number of projects. Our current research partnerships are with Cancer Australia, the Haematology Society of Australia and New Zealand, Tour de Cure, Leukemia & Lymphoma Society (U.S.) and Snowdome Foundation. We’re always looking for new partners to collaborate with who share our vision.
What do you believe is the ‘next big thing’ in blood cancer research?
There’s no doubt, it’s genomics and precision medicine. Genomics looks at your genetic makeup to understand what genetic mutations may be driving your cancer. And precision medicine, also known as personalised medicine, is where a therapy is tailored to an individual. This means people are treated with targeted therapies which are based on their genetic makeup and mutations and the treatment is not just based on their disease. An example is imatinib (Glivec®) which was one of the first targeted drugs on the market. It specifically targets a genetic mutation found in many individuals with chronic myeloid leukaemia (CML). This drug revolutionised CML treatment and has crossed over into treatments for some acute lymphoblastic leukaemias (ALL). Imatinib started a wave of new targeted therapies over the past 20 years which are now at the forefront of research today.
Our commitment is to fund research innovations that drive rapid advancements in treatment, that discover new diagnostics and new therapies, and to enable Australian patients have access to the newest therapies available through clinical trials. The Leukaemia Foundation has a long and proud history of supporting research. Over the last 20 years, we have invested more than $47 million in research and clinical trials and have supported most major haematologists and senior blood cancer researchers in Australia at some stage of their careers. We will continue to support the development of tomorrow’s leading researchers and haematologists through our PhD scholarships and early career investigator initiatives while also investing in ongoing research and clinical trials. Over the next 3-5 years, we will support an exciting initiative – a precisionmedicine clinical trial program that has been piloted by the Garvan Institute of Medical Research (Sydney) for solid tumours. We will be extending the pilot to include blood cancers, in collaboration with Tour de Cure and expect to kick this off in early-2020.
Can you touch on the role/importance of clinical trials in blood cancer research?
Clinical trials have always had an important role in blood cancer and are a critical part of the research and development of new treatments, as well as improving current treatments. By taking part in a clinical trial, individuals can access the latest treatments on offer, potentially many years before they are available on the Pharmaceutical Benefits Scheme (PBS). Unfortunately, less than 20% of Australians living with blood cancer have participated in a trial. The reason? People either don’t know a trial is available to them (because no one has ever talked to them about this opportunity) or they think clinical trials are only for people who are not responding to current treatment. I urge everyone to discuss clinical trials with their treatment teams. There may be something out there for you.
What would you say to Leukaemia Foundation stakeholders (supporters/beneficiaries) who support the research program?
Once again, I would highlight that every significant improvement in treatment for people living with blood cancer has come from an investment in research. Without our supporters, we wouldn’t be able to invest directly in the important research work being undertaken by the best and brightest scientists and haematologists in Australia. This may be a small country, population-wise, but our scientific output and contribution is significant and of a very high quality. The harsh reality is that with our ageing population, the number of people being diagnosed with blood cancer will continue to increase. By 2025, it is predicted that every day, 50 people will be diagnosed with a blood cancer. We need better, more targeted treatments and the only way we can achieve that is by investing in research and clinical trials.
What sparked your interest in the blood cancer and research fields?
When I was a child, I was fascinated by biology and the inner workings of the human body. My family, like many others, has been touched by cancer many times and I wanted to do something that made a difference. This led me into science, a PhD in cancer immunology and a research career spanning almost 20 years, focused on understanding the genetic causes of cancer and the development of precisionmedicines as treatment options. After a three-year assignment working overseas, helping to implement HIV programs across South-East Asia, I started working for the Leukaemia Foundation and have been here for the last five years.
Who has inspired you in work and/or life and why?
In my time at the Leukaemia Foundation, I have been inspired by some of the greatest scientific and medical minds in the country, but also draw inspiration from the unsung heroes. Those who work quietly in the background; the technicians, research assistances, nurses, therapists, social workers and, most importantly, our amazing volunteers who will probably never get their name in the media or be acknowledged with an Order of Australia Medal or Nobel Prize for medicine. Without their hard work and determination, we couldn’t provide the level of care and support we provide and receive in Australia, nor would we have the big breakthroughs in medicine to celebrate.
What interests do you have that help create work-life balance?
My parents instilled in me a love of gardening and growing my own produce. As a child you could always find me with a shovel, digging something up, and covered in dirt. Not much has changed, I still like to spend time pottering about and cooking with what I have grown in my garden. I live near the beach and love to get down there as much as possible too, especially in summer.
Searching for “more effective and gentler” therapies for AML
Dr David Scadden is a haematologist/oncologist at Massachusetts General Hospital (U.S.) and a physician/scientist whose lab pioneered the research field known as niche biology. The Professor of Harvard University’s Department of Stem Cell and Regenerative Biology spoke to AML News at the 2019 International Society of Experimental Hematology (ISEH) conference in Brisbane, where he was awarded the Leukaemia Foundation-sponsored Donald Metcalf Award* and gave the opening lecture: Primitive sensing and communication mechanisms regulating bone marrow hematopoiesis.
Why did you choose a career in haematology?
Partly because of my personal experience. When I was an intern, my mother was diagnosed with a malignancy and died by inches. Then my father was diagnosed and died of a cancer as well. I hadn’t gone into medicine thinking I’d go into cancer therapies, but I realised… few things were as important as combatting cancer. I wanted to do something about that problem, hoping families would have a different story to tell than mine. As a haematologist, I thought the care of people with what we knew currently was hopelessly inadequate and deeply frustrating, and we had to do better. I was not trained as a scientist, but I wanted to be a part of solving the problem, not just for the individual patient but for a larger group of people. That’s what drove me.
What is the difference between a haematologist and an experimental haematologist?
A haematologist deals with problems in the blood using existing therapies. An experimental haematologist does things in the laboratory to understand the basis of blood problems by studying them with experiments and hoping to ultimately develop new therapies. You become an experimental haematologist by having a compelling interest and wanting to make a difference for people with blood diseases and cancer. Some people are also drawn to it (experimental haematology) just because blood is fascinating.
Why is blood so fascinating?
Blood has taught us a huge amount about every tissue in the body because it is so accessible. When a new technology comes around, blood is one of the first things looked at and tested. When microscopes came out centuries ago, one of the first things to be looked at was blood. Blood is very eloquent. When you go to the doctor, they sample blood because within it is information about all our organs and it can give us great insight into human health and disease.
Why did you want to do blood work?
One of the things that made me want to work with blood was because I could be with a patient and hear the symptoms they had, then look under the microscope and see the cells that were the basis for them. Going from a person to a cell and ultimately to a molecule is very unusual in medicine but is commonplace in haematology. The cause of the problem, progress of the therapy, or unfortunately, progress of the disease, are all measurable with simple sampling of the blood. And you can get hold of the cells that are driving blood cancer if you are interested in understanding the underlying biology. The first genetic analyses of what was driving cancers were found in the blood. And the first ability to use therapies, like stem cell transplantation, to cure people with otherwise absolutely incurable disease, was in the blood. The blood has largely driven what we think of as molecular medicine and the emerging field of cell therapies.
I was fortunate to have teachers and mentors who were experts in blood, and lucky also to be at places where they supported people trying to do both patient care and laboratory studies with their careers. And they tolerated a hack like me – an old literature major! [ Dr Scadden studied literature as an undergraduate.]
I also started my career when there was a new horrifying and fatal disease, AIDS. As part of my training, I worked in a lab studying viruses that cause leukemia in mice. It turns out that those viruses are related to the type of virus that was then found to cause AIDS. Few haematologists were willing to see patients with AIDS and yet those patients had blood disorders and cancers. Since I knew something about the virus, I felt I should be involved. I started working with people with blood cancers and AIDS. It was tragic because the people I was seeing had two death sentences and we had virtually nothing to offer them. That further compelled me to push for both a laboratory and clinical research aspect to my work and perhaps the work of others. A number of us organised and convinced the U.S. National Cancer Institute to establish an international AIDS malignancy consortium that remains active to this day.
How did you get into stem cell research?
I wanted to rebuild the immune system in AIDS from the stem cell up. I thought it might be possible to use gene therapy (delivered by the viruses I had worked on) to make the cells impervious to HIV. I was involved in the early clinical trials testing gene therapy for AIDS and that experience made me realise we needed to know a lot more about stem cells to make them better therapies. I got very involved in basic stem cell research. Realising that stem cells could have a far broader effect than on just blood disorders, I co-founded the Harvard Stem Cell Institute to accelerate stem cell research across fields. Within it, my lab remained focused on blood stem cells and the way they are governed. I wanted to make better, safer, more effective stem cell therapies and to figure out how we use the normal stem cell to teach us how things go wrong to cause leukaemia. People going through stem cell transplant have very intensive chemotherapy or radiation, or both, and the collateral damage is extensive. They get terribly ill. These therapies have not changed fundamentally for decades.
What are you doing differently?
We thought there were ways we could take advantage of more targeted therapies, specifically, antibodies. We’ve done some successful work in animal models that allows for the animals to get a transplant and have full engraftment without many of the side-effects or damaging consequences. My hope is to make transplantation a lot safer and move it to earlier in the care of people with disorders for which transplant is already used. It may also allow us to use transplantation to treat people with sickle cell anaemia, thalassaemia, or those who have autoimmunity. Transplants can be curative… it’s just not used very often because the process is so toxic. We’ve tried to reduce that barrier, with the hope that this curative therapy can be done without all the adverse consequences.
To understand the process of how the bone marrow can go awry and lead to AML, we’ve looked at how cells get ‘stuck’ on their path from an immature to a mature cell type. They retain stem cell characteristics that allow them to expand and fail to conduct the work of mature cells. This is fundamentally what happens in AML (and most cancers). We work on ways to encourage the leukaemia cells to differentiate (undergo change) to allow these cells to get out of the highly aggressive, malignant state. That’s been done for a small subset of leukaemias, those with acute promyelocytic leukaemia (APML), with therapies that don’t involve standard cell toxic chemotherapy at all. We can cure 98% of those people with all-trans retinoic acid (ATRA) and arsenic. That combination is incredibly effective. So, the question is, can this approach be applied to all the myeloid leukaemias, not just this tiny subset? We have worked on a system to try to do that. A discovery a couple of years ago has moved into clinical testing and five different companies are developing five different drugs to target it. We hope that that will end up being something useful for AML.
What is your overall research objective?
To reduce misery. That’s why I do science. Science is the only way to get good therapies. I love the quote, and I don’t know where it came from, that “every medical miracle began with a good basic science experiment”. I think that’s true. If we’re going to be better as care providers, we need to embrace and use and leverage science. Doing good science to develop new therapies in the service of people suffering from disease is what I would like my contribution to be.
What are you doing in the niche environment?
I work on the way haemopoietic stem cells make blood. It happens in a particular place – the bone marrow – and when it goes awry, it kills people. I want to understand the normal process in detail, to better understand how it goes wrong, and how to develop therapies that are not just big sledgehammers, like standard chemotherapy. We need something that is more effective and gentler.
A niche is like a neighbourhood. Cells, like us, don’t live in isolation. They are affected by their neighbourhood and there are very specific cells that are important neighbours. We’ve defined some of those and are using that information to help us be better at transplant or to understand how we might be better at treating leukaemias or MDS. Some experiments showed that if we put a normal stem cell in the context of an abnormal neighbourhood, like an adolescent who grows up in a bad neighbourhood, their chances of having a bad outcome are much higher. The niche (the environment/neighbourhood) can corrupt a normal cell, so we ought to be thinking about treatments, not just as therapies that target the leukaemia cells, but also their neighbourhood, and is that a way to give us a new set of treatments to augment the currently useful, but inadequate, treatments we have today?
The blood system is amazing in its ability to ramp up and respond to demand. That all happens in the context of this niche. Who drives it? Who says when the cells should stop growing? And who helps by being the gatekeeper or the bouncer, to make sure the good ones are preserved over the troublemakers?
We’ve identified some cells that we think are important for particular functions, and the ways in which, if they are abnormal, they can create problems in the blood. What we don’t know is how well these models reflect what happens in humans, and we don’t know whether intervening will change the frequency of cure or prevention of disease. We know that with leukaemia, we can get most people in remission, but we can’t keep them there.
Our hope is that by changing the environment, you disadvantage the abnormal cells so the normal cells can come back and proposer, and that they might sustain suppression of the malignant cells; hypothetical at this point. I think chemo will be a part of the way we treat leukaemia for a long time, but the hope is that we get to the point where we won’t. We’re looking at ways to modify the relative competition between the abnormal cells and normal cells without having to go as far as a transplant or intensive chemotherapy, and this might have the ability to either forestall or prevent AML or MDS.
Right now, we would like to make the activity of the chemo drugs have greater staying power and eradicate those residual cells that are the roots of the dandelion that allow the leukaemia to keep coming back.
There is something about the niche that enables leukaemic cells to tolerate the chemotherapy and this is part of the mechanism by which these cells are surviving the chemo.
What happens day-to-day in your lab?
There are 14 of us in the lab. We get patient samples but are dependent on being able to model human diseases in animals and analysing the molecular underpinnings of those diseases. We do things related to understanding the genes, their expression, and how that affects particular proteins, how that changes how the cells grow, and where they reside. We also work with physicists who design instruments to allow us to look inside the bone marrow in a living animal and to see a transplant happening in real time. We can see the leukaemia developing, we can see the leukaemia responding to chemotherapy, and then we can see the leukaemia relapsing.
We can extract those cells, and we work with people who do high resolution molecular analyses, like mass spectrometry, to understand the molecules and how they are changing in that environment. We work with a range of different scientists – people with sleeves rolled up, who are working hard through the day-to-day grind of doing experiments. We are also huddled around computers, analysing the information that we have. We are meeting as groups with other scientists, to determine how to best understand what we’ve got and best leverage it to get back to patients.
We are writing a lot… about what we’ve found, to give information to others in the field, and we spend a lot of time trying to get funding to continue the work. Some of us work with companies to see if these discoveries can also become therapies. That is something I care a lot about. Things that are published as papers are nice, but things that are published as papers and become medicines – that’s what I care about. That’s the only way we will ever get ahead in the therapy world, and that requires a commercial entity. You can’t do that in an environment of an academic institution alone; we must have partners who know how to make medicines.
Do you think we will have zero lives lost to blood cancer in the foreseeable future?
For certain blood cancers we are seeing marked reductions in deaths. When I started my training, APML was absolutely the worst blood cancer to get, and among the worst cancers to get. Now it is among the best. The survival curve has completely flipped because of science. This happened as better understanding enabled more rational treatments. So, can we do that with every blood cancer? I would say we are making progress on almost every one of them. I think we are also getting a better understanding of who is at risk. I think, 10 years from now, haematologists will have very different conversations with their patients. They will be discussing how to prevent disease and I hope, about enjoying the disease-free years ahead.
What is your holy grail – the one thing you would like to achieve in your career?
If something that came out of my lab makes a difference for patients with a blood cancer, I will die a happy man.
* The Donald Metcalf Award was established 21 years ago in honour of Professor Donald Metcalf, the Australian medical researcher regarded as ‘the father of modern haematology’ for his pioneering work on the control of blood cell formation. This award recognises distinguished scientists who have made seminal contributions in the field of haematology.
Adding the microenvironment to the AML therapy mix improves efficacy
For many years, Associate Professor Ingrid Winkler has worked on a new area of research to improve treatment efficacy, and her discoveries have “opened up a whole new field”.
This is based on the body organs’ microenvironments (niches) and how they can regulate our cells by protecting and nurturing them.
A/Prof. Winkler is investigating how leukaemia cells hijack the bone marrow microenvironment (where blood stem cells are made) then manipulate this niche to be good for the cancer but also bad for the immune system and normal stem cells. Her research goal is to reduce treatment-related mortality and improve treatment efficacy.
The senior research fellow at the Mater Research Institute – University of Queensland is driven by a passion for understanding how the body works, and in discussing her work, she frequently refers to a ‘seed and soil’ analogy.
“If you’re studying a seed, it’s really important to look at the soil it’s living in, and all of a sudden, it’s ‘oh wow’, and out comes an important clinical trial!” she said.
A/Prof Winkler’s laboratory findings supported an international multi-centre, multi-arm Phase I/II trial by the U.S. biotech company, GlycoMimetics, testing a new drug, uproleselan (also known as GMI-1271), for relapsed and refractory AML.
One of the trial sites was in Australia, at the Princess Alexandra Hospital, near A/Prof Winkler’s laboratory in Brisbane. Later, the trial was extended and eligibility was expanded to include patients with newly diagnosed, previously untreated AML, as well as those with relapsed/refractory disease.
Results of the Phase I/II clinical trial led to uproleselan being granted breakthrough therapy status by the FDA in the U.S. in 2017, and in 2018, the Phase III* trial opened with six sites** in Australia, including at Princess Alexandra Hospital, Brisbane.
This Phase I/II clinical trial tested the addition of uproleselan to a standard chemotherapy regimen (cytarabine/daunorubicin) in older patients with relapsed or refractory AML.
Although primarily conducted to determine safety, the relapsed/refractory AML patients on the trial experienced higher rates of remission than would historically be expected and reduced treatment-related side-effects.
When this small Phase I/II trial was extended to newly diagnosed older AML patients, the addition of uproleselan to the standard chemotherapy regimen appeared to further increase rates of remission compared to historical expectation and potentially also reduced events, something A/Prof. Winkler also observed in her preclinical laboratory studies and which is the subject of ongoing research in Queensland.
Background to this new field of research
A/Prof. Winkler’s interest is “the body’s stem cells and how they are regulated by the places where they are living”. The particular stem cell she works on are haematopoietic stem cells (HSCs) which live in the bone marrow and make the blood and immune system.
“HSCs have two roles. One is to be active, that is make new the blood in the immune cells if needed, and the other is that a proportion of them stay asleep,” said A/Prof Winkler.
“These sleeping HSCs are what we call dormant and are your long-term back-ups. These are the ones that will get you into old age, and they are the stem cells that we want to transplant.
“And that’s where a molecule called E-selectin comes in. E-selectin is made by blood vessels after injury or stress. It plays an important part in bone marrow regulation, waking up HSCs when needed to respond to that stress.”
A/Prof. Winkler started looking at malignant cells in pre-clinical laboratory models (to replicate what happens in people) and found the leukaemias themselves were making E-selectin levels go up, and began to ask why.
“I studied AML, partly because the prognosis is so poor. For me, I consider AML happens when the stem cells I study turn bad.
“Surprisingly, this molecule appears to have a completely different role in malignant cells like AML, it actually promoted the survival of the malignant cells; it has two roles. When we blocked it using the drug uproleselan (GMI-1271) in laboratory models, the leukaemia cells became more sensitive to the therapy.
“It sounds too good to be true and I have done a lot of work trying to understand this process – why the same molecule has the opposite effect on those two cell types (normal vs malignant).
“I think I understand it now, finally, and the fact is, it does,” said A/Prof. Winkler.
Her findings, recently published in Nature Communications, shows that blocking the interaction between leukaemia cells and their environment in the bone marrow (niche), at the same time as chemotherapy is administered, enables the chemotherapy to work more effectively in laboratory models.
A/Prof. Winkler’s findings describe how the same molecule affects normal HSCs differently from AML cells.
“This has a lot to do with the ‘abnormal degree of biological sugars’ on the surface of the AML cells, which helps them interact and receive signals from their environment in a different way,” she explained.
“These abnormal sugars mean the AML cells receive a survival signal from (E-selectin in) their environment that normal cells do not.
“Our laboratory models show that blocking this sugar interaction stops this ‘survival signal’ and sensitises the AML cells to cancer therapy.
“And if you administer uproleselan, which blocks E-selectin during therapy, you may be protecting the HSCs but sensitising the leukaemia cells to therapy.
“Given alone, this drug has no effect, but given with chemotherapy, it improves the outcome of leukaemia treatment better in our laboratory studies and there is less mortality.
“It’s really about how the leukaemia cells hijack these nice little environments that are actually designed for stem cells,” said A/Prof. Winkler.
“Leukaemia stem cells have intrinsic ways of resisting therapies; they are able to pump out the therapies and this is one of the ways they resist treatment.
“Everyone [researchers] has been focusing on these properties, to get rid of them.
“They are all missing the whole other side of the story; that there are all these places, where the leukaemia cells live in the bone marrow, that also protect them,” said A/Prof. Winkler.
Back to the “seed and soil thing”, she said, “nobody had really looked at the soil around those cells”.
“This work is really the first example of where a molecule from the soil is blocked.
“And it’s safe to block because this molecule shouldn’t really be there much if you are healthy.”
A/Prof. Winkler said her pre-clinical laboratory models suggests up to 80% of resistance to chemotherapy may be mediated by the environment. Back to the seed in the soil again.
“You really want to target both the leukaemia cell itself, and its supportive environment,” said A/Prof. Winkler.
“I think, long-term, that is where the big story is.”
A/Prof. Winkler said treatments were needed that target both the leukaemia and its microenvironment, because “stopping how the leukaemia manipulates its environment to gain support is at least half of the story”.
“Ideally, we would do away with chemotherapy, but it is great at triggering changes in the whole system, and low doses of chemotherapy could be used to stop those protective environments from popping up again,” she said.
“I think that achieving what we already can now, but with lower doses, fewer side-effects and a much better quality of life, is where we would like to be, at least in the short-term.
“Your body can’t really cope with more than a few rounds of high dose chemotherapy. Children with haematopoietic malignancies can more tolerate the doses of chemotherapy needed to achieve cure, whereas adults can’t.
“I would like patients with relapsed/refractory AML, who were going into therapy, to be aware that this trial is underway in Australia,” said A/Prof. Winkler.
“Over the next five years, I hope to see the balance changing as we find ways to mix and match available therapies, targeting both the malignant cells and at same time removing their environmental support, to give patients the best overall outcomes,” said A/Prof. Winkler.
** Calvary Mater Newcastle, Sir Charles Gairdner Hospital (Perth), Townsville Hospital, Princess Alexandra Hospital (Brisbane), Flinders Medical Centre (Adelaide), Cancer Clinical Trials Centre (Melbourne).
This investment of $2.99 million across the seven projects into AML research at some of Australia’s leading research centres is aimed at preventing infections in people during and after a transplant, testing new combination therapies, developing targeted therapies for childhood AML, international clinical trials that give Australians access to new therapies as well as a genomics trial, and new models for drug testing.
A bone marrow transplant (BMT) or peripheral blood stem cell transplant (SCT) is a possible treatment for AML. After having an allogeneic BMT or SCT, in which someone receives bone marrow tissue or stem cells from a donor, graft versus host disease (GVHD) may occur. Sometimes the donated cells view the recipient’s body as foreign and attack it. GVHD affects most BMT or SCT recipients, and 20% of those people develop severe acute GVHD that does not respond to conventional treatment. Along with opportunistic infections, GVHD accounts for most transplant-related deaths. Better outcomes for GVHD will be achieved by changing clinical practices for transplant recipients who have GVHD; discovering biomarkers with diagnostic, prognostic and predictive power, to prevent GVHD; and using agents such as CAR T-cell therapy, immunomodulatory and immunotherapy agents and genetically modified T-cells to reduce blood cancer relapse and improve patient survival. The Centre for Blood Transplant and Cell Therapy (CBTCT) is a recent Centre of Research Excellence endorsed by the National Health and Medical Research Council to develop a world class, multi-centre approach to design and deliver improved therapies for people with blood cancers. The Leukaemia Foundation is a major partner and the only non-government organisation supporting this project. The overall aims of the CBTCT are to meet the urgent need for new treatment approaches to better prevent and treat GVHD and to maintain and/or augment immunity to leukaemia. The chief Australian investigators – Professor David Gottlieb, Professor David Ritchie, Associate Professor David Curtis and Dr Siok Tey – are world leaders in transplant research, and the international chief Investigators on the team are Professor Bruce Blazar and Professor James Ferrara, both from the U.S.
Priority-driven Collaborative Cancer Research Scheme (PdCCRS) in collaboration with Cancer Australia
The Leukaemia Foundation, though its National Research Program, supports the best emerging early career blood cancer researchers and clinicians through the Federal Government’s Cancer Australia’s Priority-driven Collaborative Cancer Research Scheme. The scheme brings together cancer charities with similar research interests to combine funds and co-fund research with Cancer Australia. Nurturing early career medical researchers and clinicians is critical to keeping the most promising and exciting talent in Australia. Over the last two years, we have funded seven early career researchers through this scheme and three of those are in the field of AML.
Studies have shown that the standard culture of leukaemia cells for research purposes does not accurately mimic the natural environment of the bone marrow in the human body and this hinders the translation of lab results to the clinic. Dr Laura Bray’s study at the Queensland University of Technology’s Institute of Health and Biomedical Innovation (Brisbane) is Development of a translational bioengineered microenvironment model to advance pre-clinical acute myeloid leukaemia research. This project aims to develop new models for drug testing that provide information about the biology of AML development and mechanisms of drug resistance.
AML is the second most common type of leukaemia in children. Despite all the improvements in treatments for children with blood cancer, many children with AML will relapse after chemotherapy and less than 30% of patients with this aggressive form of blood cancer can be cured with current therapies The following two research projects are focused on understanding relapse and developing new therapies aimed at childhood AML.
Leukaemia stem cells (LSCs) are the major cause of relapse, and Dr Jenny Wang and her team at the Children’s Cancer Institute (Sydney) are studying how to eradicate LDCs without harming healthy cells. This project aims to develop a novel LSC-targeted therapy with minimal side-effects and toxicity that will improve the dismal outcome of childhood AML.
At the Walter and Eliza Hall Institute (Melbourne) Dr Gabriela Brumatti will test a novel combination therapy – the Smac-mimetic drug birinapant plus multidrug resistance inhibitors (MDR1i). Her project, Targeting multidrug resistance protein 1 (MDR1) enhances the efficacy of Smac-mimetic based therapy in Acute Myeloid Leukaemiawill determine how this therapy can be effectively used to increase the chances of cure, with reduced side-effects.
PhD scholarships in collaboration with the Haematology Society of Australia and New Zealand (HSANZ)
The Leukaemia Foundation is helping the brightest medical and science graduates pursue a research career in blood cancer by collaborating with the Haematology Society of Australia and New Zealand to co-fund PhD scholarships. Over the last two years we have been proud to award six scholarships through our PhD Scholarship Program including one that focuses on preventing infections in patients undergoing bone marrow transplantation.
Julian Lindsay is a bone marrow transplant pharmacist and his research project, Antifungal management optimisation in haematological malignancy and haematopoietic stem cell transplantation, is aimed at preventing infections in people with blood cancer and those undergoing bone marrow transplants. These patients have highly suppressed immune systems due to having chemotherapy and the transplantation techniques used to achieve better cure rates. Based at the Fred Hutchinson Cancer Research Center in Seattle (U.S.), Julian will address critical knowledge gaps related to specific patient risk factors for developing infections such as cytomegalovirus, Epstein-Barr virus and invasive fungal infections, and investigate the optimisation of antimicrobial therapies to prevent infections and improve the survival of these patients.
Trials Enabling Program (TEP)in collaboration with the Australasian Leukaemia & Lymphoma Group
Participating in a clinical trial gives a patient access to the latest ground-breaking research and innovative treatments. In an Australian first, the Leukaemia Foundation established a funding program to help blood cancer patients access promising new drugs that are currently being tested overseas. We have partnered with the nation’s leading blood cancer clinical trial group – the Australasian Leukaemia & Lymphoma Group (ALLG) – to establish the Trials Enabling Program so Australian patients can take part in internationally-led trials without leaving the country. TEP provides patients with access to new therapeutic drugs years ahead of the expected availability on the Australian market.
The prognosis for AML patients who relapse is poor, especially for elderly AML patients, due to the aggressive nature of the disease and the intensive treatment required.The aggressiveness of AML and its rapid onset is why most AML clinical trials have been offered to people who have relapsed or not responded to current standard therapies and have refractory disease. The Leukaemia Foundation, in collaboration with the ALLG, the Haemo Oncology Foundation for Adults in the Netherlands (HOVON), and the Acute Myeloid Leukaemia Study Group, Germany (AMLSG) is sponsoring two new clinical trials aimed at people with newly diagnosed AML.
Associate Professor Andrew Wei is the principal investigator for a multi-centre international clinical trial that will be run out of Monash University (Melbourne). The AMLM24 clinical trial for newly diagnosed AML and MDS (with FLT3 mutation) is looking at a new treatment regimen as a frontline treatment.
Professor Paula Marlton is the principal investigator for a second multi-centre international clinical trial, run out of the Queensland Institute of Medical Research. The AMLM23 clinical trial is looking at a new treatment regimen as a frontline treatment for newly diagnosed AML and MDS (with IDH1 or IDH2 mutations).
Understanding MDS and the biological processes driving treatment response
Understanding how myelodysplasia (MDS) forms from normal cells is the goal of a Leukaemia Foundation-funded* research project led by Dr Steven Lane at QIMR Berghofer Medical Research Institute (Brisbane).
“MDS is a very common disease; we see it a lot, and it can turn into acute leukaemia,” said Dr Lane, Principal Investigator of the study titled, Understanding the pathways that regulate transformation of normal stem cells to myelodysplasia and leukaemia.
Azacitidine is the only specific treatment for MDS in Australia and while a lot of people with MDS try azacitidine, more than 50% of them don’t benefit from the drug. Azacitidine is unpredictable as to which patients it will and won’t work on, and information about how it works in patients is limited.
The only other treatment option for MDS is transfusion support to keep people’s blood counts up.
“We can’t offer good treatment to a lot of patients and there’s nothing available to people with low-risk MDS, so this is an area of very high need in the community,” said Dr Lane.
“MDS is a group of diseases that is poorly understood, and the genetics of all the myelodysplasias might all be quite different.
“We know that for patients with high-risk genetic features such as changes in the chromosomes, or changes in a particular gene such as P53, the survival and outcomes from myelodysplasia is extremely poor, and very similar to acute myeloid leukaemia (AML).
“There also are patients with low-risk MDS who may live for many years without any treatment.
“It’s important to understand how the genetic factors found in a patient’s blood cancer, and other clinical factors such as their age and other illnesses, contribute to their overall prognosis,” said Dr Lane.
In normal blood formation, there is a tightly regulated process where the blood stem cells in the bone marrow mature into functioning cells such as neutrophils and red blood cells, and these are the cells that are reduced in patients with myelodysplasia.
Research at Dr Lane’s lab concentrates on understanding the disease-causing cells in MDS, AML and MPN, and how these disease stem cells drive the transformation to disease, as well as looking into resistance to treatment.
“We’ve generated a new, unique model** that we use in the lab to understand the transformation from normal blood formation to myelodysplasia,” said Dr Lane.
“With the Leukaemia Foundation grant, we will use this model to better understand how azacitidine works, to get a better idea of the processes regulating the response, and then use the model to test how new drugs might be used in MDS.
“The model develops low blood counts, particularly in the platelets, which then progresses to low counts in other cells as well, then transforms into acute leukaemia after 6-12 months.
“It is a step-wise progression from normal blood through to myelodysplasia, through to acute leukaemia, so we can look at all the different stages of the disease.
“Azacitidine is an epigenetic therapy and we know its mechanism of action changes the methylation of DNA. Put simply, that means it turns genes back ‘on’ that have been switched ‘off’ in the myelodysplasia cells. Turning those genes back on, allows the cells to progress back to normal blood formation.
“We’ve shown that the MDS stem cells are very responsive to azacitidine, by taking those cells before and after azacitidine treatment to look at how the genetics of the cells might change and what signals they are putting out,” said Dr Lane.
“By doing that, we can understand the biological processes that drive the response to azacitidine.
“Now we are going back to the original model to understand if particular pathways might be different in these cells compared to normal cells.
“One of those pathways is apoptosis, which is basically the way a cell dies, and we’ve seen a difference in apoptosis between the model and normal blood stem cells.
“Therefore, we’re using new drugs that might target apoptosis to see if they work in this myelodysplasia model.
“We think this is really important research at the international level,” said Dr Lane.
“If we can show that this apoptosis process is different or abnormal in the model with myelodysplasia, and we can show the best way of combining treatments, we hope these can then be used in a clinical trial, and in the clinic moving forward.
“We’re keeping our eyes open for other drugs that work, but the predominant focus of this project is to improve the response to azacitidine.
“Some people have a spectacular response to azacitidine and do really well. We want to improve on that treatment, so most people do really well, not just a small percentage.”
The protocol Dr Lane is testing is azacitidine combined with venetoclax***.
“We hope we can use these drugs together to improve responses in all MDS patients,” he said.
“There’s a published trial using azacitidine and venetoclax in AML and we would hope this drug combination can be used in myelodysplasia as well.
“One of the difficulties will be getting around the toxicity of these drugs.”
Azacitidine is given daily for one week by injection, followed by three weeks with no treatment.
“We have shown in our model that by giving azacitidine continuously (every day) at a much lower dose, there’s an improved response rate, and the response is a little more specific for the MDS cells. So, this protocol may be better,” said Dr Lane.
On this project, Dr Lane’s lab is working with collaborators in Germany, at the National Centre for Tumour Diseases (Heidelberg), the German Cancer Research Centre (Heidelberg), and Professor Andrew Perkins’ group at Monash University (Melbourne).
** Therese Vu was the postdoctoral researcher who worked on this project.
*** The Leukaemia Foundation provided funding for early work on the precursor to ABT-199 (now known as venetoclax). This research, undertaken by Dr Kylie Mason, Professor Andrew Roberts and collaborators at the Walter & Eliza Hall Institute (Melbourne) through the Leukaemia Foundation’s National Research Program Grants-in-Aid 2012 and 2012, assisted in the development of venetoclax.
Further support is critical to ensure all Australians can reap the benefits of scientific advancements. If you would like to invest in blood cancer research, contact us 1800 620 420 today to find out how.