The ability to use haploidentical donors, or half matched donors, is the most important recent development in stem cell transplantation, says world leader in transplant research, Professor David Curtis.
“Traditionally you’ve needed a good, or full, HLA match for an allogeneic stem cell transplant,” he said.
“For small minority ethnic groups, unless you’ve got a matched brother or sister, you’re unlikely to find an unrelated match.”
With a haploidentical donor, Prof. Curtis says, “a patient goes from maybe a 40% chance of having a match, to 90%, which allows many more people to have transplants”.
The reason this type of transplant – a haploidentical stem cell transplant – is now possible, is the use of high doses of “a very cheap” chemotherapy (cyclophosphamide) which has been revolutionary in preventing graft versus host disease* (GVHD), the major complication following a transplant.
“The immune system of the new donor causes this nasty disease,” said Prof. Curtis, senior bone marrow transplant physician at the Alfred Hospital. The Monash University-based researcher is also head of the Division of Blood Cancer Research at the Australian Centre for Blood Diseases.
He said cyclophosphamide was first reported for matched transplants at the Johns Hopkins Hospital in Baltimore about 15 years ago and is used routinely in the U.S., “but without evidence that it is actually better than traditional methods”.
“Over the last five years, we’ve started to do a lot of these types of transplants in Australia and it’s used routinely in haplo transplants where there is a half match,” said Prof. Curtis.
“But cyclophosphamide isn’t used routinely here in transplants where there is a full match, so the question is – is it better than what we currently do or not? We think it’s better, but we don’t know.”
Prof. Curtis is an Australian chief investigator at the National Health and Medical Research Council (NHMRC) Centre for Blood Transplant and Cell Therapy (CBTCT), and to answer that question, he and colleagues are running a post-transplant cyclophosphamide clinical trial for transplants using matched sibling donors.
Among the aims of the CBTCT, which is supported by the Leukaemia Foundation through its National Research Program, is meeting the urgent need for new treatment approaches to better prevent and treat graft versus host disease.
The Australia-wide trial is testing the use of cyclophosphamide in “normal” stem cell transplants, “where we’ve got a fully matched donor”, and where graft versus host disease still causes about 20% of people to die of GVHD or its complications.
It is the only randomised trial of its kind in the world for people with acute lymphoblastic leukaemia (ALL), myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML). The trial, which opened in 2019 has recruited 90 patients of an anticipated target of 134 patients.
According to the trial protocol, participants are given chemotherapy or radiation before the donor stem cells are infused, then on days three and four after the transplant patients are “hit with high doses of this chemo [cyclophosphamide]”.
“The high doses of chemo given after the stem cell infusion kills off the T-cells which are the ones that cause graft versus host disease, so it selectively eliminates those cells.”
“You’d think that was counterintuitive, that you’d kill off the stem cells, but they’re actually highly resistant to chemotherapy,” explained Prof. Curtis.
“Part of the reason is that they [stem cells] are dormant. They’re just sitting there, and they don’t actually grow much.
“That’s why leukaemia is so hard to track because it comes from a stem cell that is already resistant and is the source of minimal residual disease.
“Strategies to awaken those leukaemia stem cells prior to giving chemotherapy, to make them more sensitive to chemotherapy, would basically eliminate them and reduce relapse, which I think would increase the cure rate,” said Prof. Curtis.
However, these strategies “haven’t really been explored at all”, and he is seeking funding to do experiments that awaken stem cells, to make them more sensitive to chemotherapy.
Participants on the cyclophosphamide clinical trial get either standard of care, which is cyclosporin and methotrexate on the control arm, or those on the experimental arm get cyclophosphamide plus cyclosporin.
Bone marrow and blood samples from patients on the trial are being collected at different time points throughout the trial, and for the following two years after the last patient has been put on the trial.
These samples are kept at four centres – the Alfred, Royal Brisbane and Women’s, Royal Melbourne, and Westmead hospitals.
Once the trial has finished, the samples will be analysed to answer specific questions about why the cyclophosphamide does or doesn’t work, including whether a trial participant gets graft versus host disease and whether they’ve relapsed. These include measuring the levels of the cytokines in the blood after transplant, and the detection of minimal residual disease.
“That’s looking for very small amounts of leukaemia before or after the transplant, and that will tell us, for instance, whether the cyclophosphamide, compared to standard treatment, is better at getting rid of the leukaemia,” explained Prof. Curtis.
Results from this trial are expected in 2024.
This trial is a major project of the NHMRC Centre for Blood Transplant and Cell Therapy. Funding also has been allocated to running a webinar series over the last three years that is playing a key role in training junior medical staff in cell therapies.
Background on Professor David Curtis
Science is what David started studying at university. When he found it “a bit dry”, he moved to medicine, “because of the personal interaction”, but he still loved the ‘discovery’ aspect of science.
During his training at the Alfred Hospital in Melbourne in the 1990s, David realised haematology was the most advanced discipline that mixed science and clinical patient care, and “the most developed from an experimental scientific point of view”.
“Blood goes around all the organs and it’s accessible,” said Prof. Curtis.
“The person who inspired me most to do haematology was a guy called Glenn Begley – a great mentor and supporter of junior people.
“He’s a haematologist and he was at Walter and Eliza Hall Institute, which is where I did my PhD. He gave a lecture when I was going through my training. Back then, the most cutting-edge thing was identifying genes involved in leukaemia, and he was the first person to identify a gene which he called SCL, which stands for stem cell leukaemia, and that is one of the causes of early T-cell precursor acute lymphoblastic leukaemia (ETP-ALL).”
ETP-ALL is a rare form of acute lymphoblastic leukaemia that Prof. Curtis has focused his research attention on due to the urgent need for new treatments.
Read more about ETP-ALL in a separate article, Planned clinical trial offers access to new therapy for rare acute leukaemia
“It’s a bit sad, but I’ve been working on this for almost 30 years just from a lecture from Glenn Begley!” said Prof. Curtis.
“And my interest in transplantation was based on that stem cell, ideas about stem cells causing cancer but also that you can use stem cells for transplant.”
After completing his training as a clinical haematologist and bone marrow transplant physician through the University of Melbourne in 1994, Prof. Curtis was awarded a National Health and Medical Research Council postgraduate scholarship at the Walter and Eliza Hall Institute for Medical Research.
Then, in 1998 he received a NHMRC CJ Martin fellowship and spent three years of post-doctoral studies in the laboratory of Dr David Bodine at the National Institutes of Health in the U.S.
When he returned to Melbourne, Prof. Curtis established a research program at the Royal Melbourne Hospital which focused on the fate of normal and malignant hematopoietic stem cells.
He specialised in ETP-ALL “because that’s been the most successful scientific part of my research”, with “some very good publications” including “the first to identify the stem cells that generate this leukaemia”, in the journal, Science, in 2010.
Since 2011, when Prof. Curtis moved to the Department of Haematology, Monash University and Alfred Health as the head of the new Division of Blood Cancer Research of the Australian Centre for Blood Diseases, his Curtis Group – Stem Cell Biology has collaborated closely with another group, in Belgium, and is recognised as a leading research group with a focus on ETP-ALL.
Advantages of being a dual clinician scientist
Prof. Curtis spends 30% of his time working as a clinical haematologist at Alfred Health.
“I started at the Alfred and now I’m back at the Alfred. I’m on ward service right now,” he said.
“The thing I love about medicine is the interaction with people, patients, families, and getting that satisfaction of helping them, even if it’s helping them to die, which I think a lot of doctors struggle with.
“Even if they have a terminal illness, if you can still provide help with that death experience, it’s really just as valuable in a way,” he said.
“The great advantage of being a dual clinician scientist is that the clinical side gives you that drive or passion to discover new treatments because you realise there are so many things we still don’t know.
“And being a scientist helps you be a clinician because it teaches you a different way of problem solving.”
From a job satisfaction perspective, he said “clinicians get instantaneous gratification because they are praised by their patients all the time, so that’s really nice”.
“Go to the science of it and you’d be lucky to get any praise or appreciation once every three years. So being a clinician provides a good balance because being a pure scientist is such a tough gig, unless you’re in that very small proportion of people that are incredibly successful and getting lots of funding.”
Optimal Care Pathways for best cancer care
Prof. Curtis was on the working group that developed an Optimal Care Pathway (OCP) for myelodysplastic syndrome (MDS), one of eight new guides to best cancer care launched earlier this month.
Download a copy of Myelodysplastic syndrome – your guide to best cancer care, available in nine languages
“My contribution was the role of transplantation for MDS, which remains a problem with getting timely referrals for patients to be evaluated or assessed to see whether a transplant would be useful, for two reasons,” said Prof. Curtis.
“One is that MDS is often treated as an outpatient, often in private, clinical environments, where transplants aren’t done.
“Transplants are a pretty boutique, specialised treatment and treating haematologists are not all aware of it as a treatment option [for MDS].
“The other reason is because the age of the person that gets MDS tends to be older, and we’re now doing transplants in people up to the age of 75.
“So the guidelines are becoming more relevant, to provide patients and the caring GPs or haematologists with some guidelines about being referred to see a transplant specialist for assessment to see whether a transplant would be their best treatment.
In the end, at the moment, a transplant is still the only curative treatment for MDS.
“Unlike AML, where chemotherapy can cure a significant proportion of people, particularly younger ones, MDS is not curable with anything other than transplant.
“We’ve got some new treatments, such as azacitidine, that has been around for many years, but it’s not curative.”
Prof. Curtis said it was important patients had access to the MDS OCP, so they can say to their haematologist, “hey, why am I not being evaluated for a transplant, because I see that it’s actually the only curative treatment, and I’d like to be cured?”.
“For the last three or four years we have been doing more transplants for people with MDS in their late 60s and early 70s. and I’ve got a number of patients who have been transplanted and they’ve done incredibly well.”
Commenting on OCPs, Prof. Curtis said, “treatment of blood cancer is becoming increasingly complex and providing some guidance for people that is in a simple form, language, and covers all aspects of the disease is great. Google can be very indiscriminate and candid.”
The difference a Leukaemia Foundation grant made
In 2011, Prof. Curtis received a Grant-in-Aid from the Leukemia Foundation for his research at that time in chronic lymphocytic leukaemia (CLL) at Monash University.
“That was a completely different project, and it did make a big difference because it was working on developing a new treatment for acute myeloid leukaemia.
“It was for CLL, and as research happens, it changes because you’re doing something and then you realise, oh, it works much better for acute myeloid leukaemia.
“It was the development of a new drug which inhibits an enzyme called PRMT5 through a collaboration with Cancer Therapeutics CRC. They were the chemists and we were the biologists, and together, they developed the drugs and we were testing them.
“We tested them in CLL and they didn’t seem to do a lot, but we also tested them in acute myeloid leukaemia and they worked very well. That led to what at the time was the largest pre-clinical licensing deal in Australia, but it’s got a sad ending.
“Merck took it over in 2016 and we worked with them for another two years and then they dropped the program unfortunately.
“It’s been relicensed back and a small biotech company here, called Synthesis has bought the rights and I’m working with them at the moment,” he said.
The future – fostering the next generation of researchers and clinicians
Prof. Curtis said his holy grail as a BMT physician and researcher is to foster the next generation of young researchers and clinicians.
One of the problems he has identified in Australia is “that there are too few clinicians that are going on and doing PhDs in basic science”.
“I think the way to help that is to develop better, stronger training programs, which are dual training programs, by offering career development awards,” he said.
“When a clinician has finished their training, they’ve got a choice. Usually, they’re 31 or 32 and often have a mortgage and a family to look after.
“You can go and work as a clinician and you can still do clinical research by running clinical trials, and we’ll pay you $200,000, or you can go and do a PhD in the basic science and earn $70,000, so it’s really hard to encourage clinicians to go there.
“They do it much better in the U.S. and part of that is because they do their PhD during their clinical training, which is a much more effective strategy. Here, we’ve got this funny situation where you do all your clinical training and then you go back and do your research science stuff,” said Prof. Curtis.
*Graft versus host disease (GVHD) occurs in the majority of allogeneic stem cell transplant patients, with up to 40 per cent of cases leading to death. GVHD, is triggered when the transplanted donor immune cells begin attacking the recipient’s organ tissues. GVHD can occur early (acute) or late (chronic) post-transplant. During chronic GVHD, ongoing damage from these attacks causes fibrosis (similar to scar tissue) of the skin and internal organs that resembles some autoimmune diseases. Fibrosis leads to a build-up of connective tissue that eventually destroys the normal tissue and causes internal organ failure.
