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.

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.

*  https://clinicaltrials.gov/ct2/show/NCT03616470?term=GMI-1271+AML&draw=2&rank=1

**  Calvary Mater Newcastle, Sir Charles Gairdner Hospital (Perth), Townsville Hospital, Princess Alexandra Hospital (Brisbane), Flinders Medical Centre (Adelaide), Cancer Clinical Trials Centre (Melbourne).

Seven research projects that are part of the Leukaemia Foundation’s National Research Program over 2019-2022 focus on better understanding and treating acute myeloid leukaemia (AML).  

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.    

These research projects sit under several funding mechanisms – Strategic Ecosystem Research Partnerships, our PhD Scholarship Program in collaboration with the Haematology Society of Australia and New Zealand, the Priority-driven Collaborative Research Scheme, through Cancer Australia, and the Trials Enabling Program in collaboration with the Australasian Leukaemia & Lymphoma Group. 

Strategic Ecosystem Research Partnerships (SERP)  

 One of the Leukaemia Foundation’s nine current Strategic Ecosystem Research Partnership projects focuses on AML.   

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 Leukaemia will 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).