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“Trev is still looking after me” says Pauline

Trevor and Pauline with their dog
Pauline and Trevor with their beloved dog, Harry: “We loved him so much. He was so special to us.”

Had Pauline Vedelago been told, 3½ years ago, that she would no longer have her husband, dog, house, job, or live in Bundaberg, she would have said, “are you crazy?”.

“My life was so different 3½ years ago,” said Pauline, 58, who is retired, volunteers two days a week, and writes to her late husband every night, telling him about her day.

While there are many blood cancer success stories, unfortunately there also are stories where treatment is unsuccessful, the disease mutates, and in the end, devastatingly, there are no further options.

Sadly, this happened to Pauline’s husband of 31 years, Trevor Boyd, a teacher-librarian whose prognosis was “pretty good” when diagnosed with non-Hodgkin lymphoma (NHL) in May 2017, aged 55.

Over the next 2½ years, the couple, went back and forth from their home in Bundaberg to Brisbane, for tests and treatment.

Pauline and Trevor in hospital
Pauline with Trevor in January 2018 after his admission to hospital for his stem cell transplant

Trevor’s determination to beat blood cancer

When Trevor didn’t respond to his first or second lines of chemotherapy, he had an autologous stem cell transplant in January 2018, which his haematologist said gave him the best chance of a long-term good outcome.

After six weeks in Brisbane for the transplant, and being told that Trevor looked to be “in the clear”, they went home, but not for long, because an infection in Trevor’s Hickman line turned out to be serious.

“It was called mycobacterium fortuitum, which always made me laugh because I thought it doesn’t feel very fortunate,” said Pauline, so back they went to Brisbane for another month for round-the-clock intravenous antibiotics.

Finally, the couple returned home and glimpsed normal life again – camping together, catching up with friends, exercising regularly, and Pauline started her social work again, part-time.

“Life was starting to look good,” she said.

Trevor was in remission and he went back to work for the last six weeks of the 2018 school year.

“Trev led a very quiet life, very similar to what people do now, really, socially isolating. Any friends who were coming over, we’d make sure they were all well and kept their social distance,” said Pauline.

This year, when coronavirus started, Pauline said it felt really familiar: “This is what we used to do all the time. It felt like history repeating itself”.

Towards the end of 2018, Trevor started to feel unwell. He had fevers and fatigue and assumed it was a virus he’d picked up from the school kids, but after a month, when he didn’t get better, his GP suggested another round of scans.

Pauline and Trevor after Trevs knee surgery
The Boyds, in January 2017, after Trevor had knee surgery and just months before his diagnosis

Another relapse and two different diagnoses

On his 57th birthday, on December 29, he got the news. He had a mass on his lung and within days the Boyds were back in Brisbane. Trevor was diagnosed with a different blood cancer – chronic lymphocytic leukaemia – and started a new regimen of chemo. Soon, however, scans showed that it wasn’t working.

Miraculously, a new drug (venetoclax) had been listed on the Pharmaceutical Benefits Scheme that week, which Trevor started immediately, combined with another immunotherapy, not yet approved in Australia, and which cost the couple “several thousand dollars”.

Then, genetic studies revealed that Trevor had “a really bad mutation, c-myc, which doesn’t have a good prognosis”. An allogeneic stem cell transplant was his only option. Disappointingly, none of his three sisters was a match, and he was running out of time to find a matched unrelated donor.

Next, he was told he actually had Richter’s transformation; a disease that looks like NHL but is “something much worse” because it constantly mutates, and CAR T-cell therapy in the U.S. would give him the best chance of survival, providing he was accepted on to a clinical trial in Seattle.

“If we got the okay, we had to go right away, and have a spare half a million dollars!” explained Pauline. But first they needed passports, urgently, at $500 each.

“Mine had expired and Trev hadn’t had one for 20 years.”

They also were in the middle of selling their home in Bundaberg.

Trevor and Pauline in Adelaide
Trevor and Pauline holidaying in Adelaide

“We just thought, ‘oh well, we can do that’. We’d borrow money from everyone and anyone, get our super, and pay people back.

“That’s the kind of pressure you’re under. I thought I was going to go mad. I could barely cope,” explained Pauline.

“When we had the relapse in January 2019, I couldn’t cope… I had a real little meltdown.

“Trev was really tough, and he was stoic all the way through, but I started to fall apart.

“I got myself together, went to counselling, went to my GP, started antidepressants… because I’m a social worker; I know what you’re supposed to do to look after yourself.

“I thought, all right, I have to be like Trev, to be strong. We just have to keep going.”

Leukaemia Foundation support

Pauline had been in contact with the Leukaemia Foundation and one of our blood cancer support coordinators, Sheila Deuchars.

“Sheila was great. She put us in touch with some Australians who were over there [in the U.S.] at the time doing the same thing and we had been in contact with them.”

But, at the last minute, Trevor was told he wasn’t eligible for the American trial because his disease was mutating.

“That was so disappointing, but we were still hopeful,” said Pauline.

“Trev was writing to professors all over America to see what trials were coming up that targeted the CD20 mutation.”

Then, another miracle, a clinical trial was starting… in Brisbane! Trevor just had to have all the tests and tick all the boxes, which he did. He was eligible, and the trial paid for their travel and accommodation expenses.

“Fantastic, we could fly to Brisbane instead of driving or taking the train,” said Pauline.

Trevor started the trial in August [2019] but, after six weeks, he’d had “absolutely no response”.

“That’s when we had the big conversation with the specialist,” said Pauline.

“He said, ‘we’ve thrown everything at it… you might as well go home and make your end-of-life preparations’ blahdy blah, but there was still one option, ‘we could try high dose chemo as a last resort. Go home and think about it’.

“I knew Trev was never going to give up. He was going to keep fighting. That’s the way he had to go.

“He still was feeling pretty well, still working around the house and gardening.”

Pauline said her worst fear was that Trevor would go to 4W, the hospital ward for people on high-dose chemo, and be transferred to 4A, the palliative care ward.

“For three years, on and off, I’d look at that ward. My sister who died of cancer in 2013 had been in that ward,” she said.

When Pauline suggested they go on the Ghan, “something we’ve always wanted to do”, his response was ‘no, I can’t go on a holiday. I won’t enjoy it if I’m not fighting for my life’.

“I said to him, ‘of course, I’ll support you, whatever you decide’.”

Trevor started high dose chemo in September [2019] and had radiation as well.

“It was pretty awful, just one nightmare after the other, in October, November, until early-December when it didn’t work,” said Pauline.

“Trev was in hospital all that time. I just wanted to be with him, I didn’t want to be anywhere else.

“We were so grateful for the Leukaemia Foundation. I took up Sheila’s offer of a unit at Herston. It was so lovely. I’d get the bus in [to the hospital] in the morning, I could stay as long as I liked, and get an Uber at night to come home. It was so easy.”

It was Pauline’s 58th birthday on December 10, “we got some lovely photos”, and Trevor died eight days before his 58th birthday.

“While all that was happening, we sold the house, and the contract was a story in itself!

“Harry, our dog, died too last year, in April. We had to put him down. We loved him so much. He was so special to us because we don’t have children.”

When Pauline spoke to Living Well With Grief, six months after Trevor’s death, she said it “was wonderful” living in a granny flat that adjoined Trevor’s sister’s house in Brisbane, for the time being.

“I’ve been on my own, but not really alone. I’ve got contact with family, but without feeling like I’m in the way,” said Pauline.

“I appreciate the support and having someone who cares whether you get up in the morning, because so often I just didn’t see the point.

“But every day I’ve got out of bed, because Trev’s sister and her husband have been so lovely to me, I don’t want to worry them about anything.”

Pauline and Trevor on Paulines birthday
Pauline Vedelago celebrating her birthday with Trevor in their Leukaemia Foundation Unit at Herston, eight days before he died

Grief support there when needed

Since Trevor’s death, Pauline has been supported by Shirley Cunningham from the Leukaemia Foundation’s grief and bereavement team.

“I said to Shirley, ‘I’m the perfect client. I’ll do everything right to try and get through this. I’m not going to let it beat me’.

“But I still feel really sh*t, so that’s why I’ve come to counselling. I had my first appointment about two months after Trev died and I knew I wasn’t doing too well, and it was really lovely talking to Shirley.

“I was a social worker for 30 years. I’d never done grief counselling but thought I understood grief a bit. When my sister died, I thought, ‘okay, this is how it works, this is pretty sh*t, but okay, and when Trev was diagnosed, and then when I knew he wasn’t going to make it, I thought I was prepared.

“But you know, losing the person that you love most in the world, nothing really prepares you for that.

“One positive thing about cancer is that Trev and I had plenty of time together to say all the things you want to say, and I’m very appreciative of that, but it certainly doesn’t prepare you for the depth of grief you feel afterwards.

“Trev was really organised, making sure our super was good, so financially, I’m quite comfortable.

“We had grey nomad plans. We’d done a few three-month camping trips around Australia and we were just going to do more of the same… four-wheel driving.

“I do find that hard, letting go of the life that you thought you were going to have.

“It’s just accepting that things have to change. It’s trying to be mindful, trying to live in the present rather than focus so much on longing for the past.”

Pauline said she has experienced a loss of identity: “I was a social worker, but I’m not. I was married, but I’m not. I used to live in Bundaberg, but I’m not. I used to have a house, but I don’t.

“I used to be married, but now I’m a widow. I’m thinking, well, who am I? Who am I without Trev?

“I had a good chat to Shirley about regression, which I’d read about.

“You are stripped back to your most vulnerable self. I felt like I was in my teens again for quite some time. I felt so vulnerable. I didn’t want to talk to anyone, I didn’t want to go out.

“Then I did this complete about-turn. I became the Academy Award recoverer, where you say to everyone, ‘I’m fine. I’m going okay. Oh, not too bad’.

“I did that for a couple of months, because you want them to think you’re okay. You want them to think well of you, that you are recovering.

“I said to Shirley, ‘you’re the only person I’m crying with these days and I don’t think that’s good. I’m just covering up all the time’, so we had a good chat about that and what I should do.

“Grief is a very weird thing. I realise now why you do certain things and I’m very normal. The book I’m reading now is The Year of Magical Thinking which is about the difficulty you have with emotional acceptance.

“I was there when Trev died, but you still have so much trouble accepting it and you still think maybe somehow they’re still alive. I’d wake up in the morning thinking Trev was still alive.”

Making a new life

Pauline has decided to stay in Brisbane, plans to buy her own home there, and is putting things in place.

She has started going to church again and says, “I do have a faith, I do believe in an afterlife, and that has helped”, has become more active in her yoga practice, and has started bike riding with her brother-in-law.

She regularly sees her two brothers who live in Brisbane and has reconnected with a few friends, including an old uni friend she hadn’t seen for 30 years. And Simone, who she met when her husband Pete was sitting beside Trevor during chemo, has become a good friend.

Pauline had always wanted to “do something with people who care for wildlife” in her retirement and due to some divine intervention, she is volunteering two days a week at a koala sanctuary, which is helping her to “just be in the moment”.

And she’s started a journal.

“I’ve found journaling very helpful. At first, when I was just so miserable, I kept writing about how terrible I felt, and I didn’t know if that was helping. Then I received a random text from someone that said, ‘remember the joyful times you had with Trev’, and I thought, that’s what I need to do.

“So, every night I made sure that at the end of my journal writing, I’d write down a happy memory and thank Trev for that. Sometimes that was really hard, but I did that for months.

“And now I don’t do the happy memories anymore, I just do gratitude now. I’m still writing to Trev, but I finish with things that I’m grateful for that happened during the day,” said Pauline.

“I do believe Trev is still present in some form, in some way, and is still looking after me somehow. And I just figured, well, this is my way of communicating with him.

“I don’t think I’ll keep writing to him for the rest of my life, but I’m determined to keep going with it for this year.”

Pauline and friends kayaking Coonarr Creek, Bundaberg for Trev’s tribute paddle
Pauline and friends kayaked up Coonarr Creek, Bundaberg for Trev’s tribute paddle in March 2020

A tribute to Trev

Back in Bundaberg, Pauline used to kayak with a group of women, and one time Trevor joined them.

“One of my friends suggested it would be nice to have a paddle tribute to Trev, which I thought was a great idea.”

The tides were checked, a date was set, and Pauline went up to Bundaberg for the weekend.

“We ended up with 13 people and two dogs, and I decided to take half of Trev’s ashes for a little ceremony.

“Bundaberg ginger beer was Trev’s favourite drink before he went off all sugar, and I put half of his ashes in six Bundy ginger beer bottles, one for each of his best mates, and me, which we carried upstream to a lovely, quiet place.

“I thanked everyone, then they picked up their bottles and I put his ashes in the creek.

“I was so happy I did that and again, divine intervention, it was at the beginning of March, only a couple of weeks before coronavirus kicked in, and I thought, ‘oh, Trev, you’re looking after me’.”

Pauline wanted special mention made of how grateful she and Trevor were to the Leukaemia Foundation, “for everything they helped us with”. In particular, the practical support of “those two months when I lived in the Leukaemia Foundation unit”.

“I’m a regular donor now and I’ll be making a bequest in my will when I redo it again. And I’ve registered for Light the Night.”

Jennie’s had baby George since her MPN diagnosis

Jennie’s had baby George since her MPN diagnosis

Jennie Wigginton and her family on holiday at Wilson’s Promontory in September 2017
Jennie Wigginton and her family on holiday at Wilson’s Promontory in September 2017

Jennie and Russell Wigginton had to put their plans to have a second child on hold when Jennie was diagnosed “out of the blue” with essential thrombocythaemia (ET) in May 2015. 

Their son, Austin, was two at the time, and the Wiggintons had been trying for a second child for six months.

“We got pregnant quite quickly with our first,” said Jennie, now 39, a social worker who also runs her own business as a fitness instructor and personal trainer.

Jennie Wigginton in the park
Jennie Wigginton: “I do what I can to stay healthy, and ultimately my family is my inspiration”

In the build-up to her diagnosis, Jennie had been getting severe headaches.

“Really painful headaches, where you could take Panadol and Nurofen and it wouldn’t even touch the sides,” she explained.

Russell, concerned she may be diabetic, suggested she go to the doctor, and three days after having blood tests, Jennie got a call saying she needed to see the doctor again, straight away.

“My results showed my blood platelet count was up near the two million mark, and when I asked what the usual range was, it was 450, so it was massively out of the normal range.

“They said, ‘look, it’s in line with essential thrombocythaemia’ and sent me to the emergency department, to see whether I needed to see someone urgently about it.”

Jennie was told there was nothing they could do at that time, and to go home, take some aspirin and the haematology department would be in touch.

“Within a week, they did some very thorough work and checked all my levels. I had an ultrasound of my spleen, a CT scan of my brain, and a bone marrow biopsy, before I started any medication.

“Then I went on hydroxyurea, initially, to help control my platelet count.

“The bone marrow biopsy actually revealed the early stages of myelofibrosis (MF). I’ve got some scarring on my bone marrow,” said Jennie.

Her diagnosis was a combination of MF and ET and she began seeing her haematologist every fortnight and had regular blood tests.

“The platelets started responding straight away and they’ve gradually come down, but not ever to within the normal range.

“When I first found out I had this condition, I was told MPN normally affected people in their 60s or older,” said Jennie who was 35 at the time.

“I wondered what it meant for me as a younger person and somebody who wanted to continue with having more children. I didn’t know what the impact was going to be, so obviously it was a little bit scary.

“I remember that day coming back from the doctors and just being in shock and thinking, gosh, what does this all mean? You think about your own immortality… am I going to be around to watch my children grow up, or my child at that point, and am I going to be able to have more children? You just don’t know.

Jennie Wiggington and her sons
Jennie and her sons, George and Austin, wearing her Metafit Footscray business hoodies

“And I’d never heard of it [MPN] before and didn’t know anything about the condition.

“So, you’re just really shocked by it because it took me out of the blue. Suddenly I’m being told I’ve got a blood cancer, and not knowing what the future held,” said Jennie.

“I’m someone who likes to keep fit but I had to balance that as I was concerned because I was at risk of blood clots because of my high platelets.

“Once my blood platelets came down more into range, I felt more comfortable. I was taking aspirin to thin the blood, and the doctor said it was good to keep exercising and moving.”

When first diagnosed, Jennie mentioned to her haematologist that she had been unsuccessful in falling pregnant again. She was told it might be due to her blood condition and to stop trying for the moment.

“I went to a fertility specialist who talked about having cancer as a young person and the implications of different treatments and how they can impact on your fertility,” said Jennie.

“We talked through options about the possibility of freezing eggs, or IVF, stuff like that, but as we were not at that point, we would go down the natural route if we could and see how things go.”

Hydroxyurea successfully reduced Jennie’s platelet count over six months, from May to October 2015. Then, in November, she transitioned to interferon over three months before stopping hydroxyurea because of the implications that can have on a developing baby.

She initially injected herself with the interferon three times a week before the dosage was increased to five times a week.

“When you start that medication, often you get flu-like symptoms and start to feel quite groggy, but luckily it only lasted for the first few days. Your body adjusts and gets used to it. I was advised to take Panadol to help with any kind of aches.

“It was Roferon-A, not the pegylated one, I didn’t move on to that until later,” said Jennie.

“Before we could start trying to fall pregnant again, I had to be clear of the hydroxyurea for three months, so it had all got out of my system.

Jennie Wiggington with her medal for Melbourne Marathon
Jennie competed in the Melbourne Marathon (Half) in October 2019

“I remember the doctors saying not much is known about pregnancy and MPN because not that many people of childbearing age have the condition.

“So it was kind of, ‘we know that you can’t have children on hydroxyurea and we believe interferon is the safest option for you, and the research shows that there’s not an impact on the baby’.

“I guess they don’t know 100 per cent, but it’s the safest form of treatment whilst you’re pregnant.

“But there were still risks of clotting and haemorrhaging and the placenta coming away from the womb. I was told that those were the inherent risks around having another baby.

“It was hard because we’d had our son. Did we just say, ‘that’s it, we’re done, and we’re not going to risk it?’ because the risks weren’t just for the baby, but potentially for me as well because of the blood clotting.

“We just took each step at a time and listened to the advice from the specialist doctors,” said Jennie.

“We got pregnant again in August 2016. Because of my blood condition, it was deemed as a high-risk pregnancy and I was under the care of specialist doctors.

“I was getting the best advice and care with lots of support, regular appointments, and monitoring.

“They picked up very early on, when I was about six weeks pregnant, that my thyroid levels were through the floor and in the danger zone for the baby developmentally.

“I had to go on thyroxine. They don’t know if the interferon had impacted my thyroid and damaged it, which it can apparently do, or whether I got Hashimoto’s disease, which is hereditary – my sister and my aunty both have it. Or it could have been brought on by pregnancy,” said Jennie, who continues to take thyroxine.

Mid-way through her pregnancy, with the blessing of her doctors, the Wiggintons went back to England for a month and a family Christmas. Jennie and Russell had migrated to Australia in 2010.

“I just had to make sure I had all the medications with me,” said Jennie.

She took an anticoagulant (blood thinner) before, during and after each flight, to minimise the risk of blood clots, and she drank lots of water.

Wiggington Family in New Zealand
Holidaying in New Zealand in July 2018 – Russell and Jennie with George and Austin

All in all, Jennie’s pregnancy went well, and her obstetrician said she had done ‘amazingly well’. To minimise the risks during labour, the decision was made to induce her in the 39th week.

“Then nothing happened for 24 hours and, as I wasn’t dilated enough and the baby’s heart rate dropped, they did an emergency caesarean.

“He had some low blood sugar, because he was quite little when he was born, and had to go into special care for a few days until his blood sugar stabilised.”

George was born in May 2017, “a fine, healthy baby boy”, and Jennie and Russell, who had always hoped to have two children, and feeling lucky nothing major had happened, decided “enough’s enough, we’ll finish on a good note”.

Jennie continued her interferon medication until she heard that pegylated interferon [Pegasys®] become available on the Pharmaceutical Benefits Scheme.

“I went straight to my haematologist saying, ‘I’d like to try this’. I started on a low dose and that’s what I’ve been on since.

“It’s been great because it means now I only have to inject once a week rather than five days a week and have no ill effects from it. It’s just been a revelation, really, in terms of treatment for the illness.

“I never had any horrible side-effects on Roferon-A,” said Jennie, but she used to have “really bad itching” which was worse in winter when her skin was dry.

“I’d scratch so bad I’d bleed on my legs and on my tummy, but that’s gone for me now. I don’t know if it’s the pegylated interferon, or if it’s changing hormones or the environment.”

Jennie self-injects the pegylated interferon into the fatty subcutaneous area around her stomach.

“Sometimes, I inject into my leg, just to give my tummy a bit of a rest.”

Over the course of Jennie’s experience with MPN she has gone from seeing her haematologist every two weeks, to once a month, then six-weekly, and now it’s every three months.

When she spoke to MPN News Jennie had just received her latest results.

“My platelets were the lowest since I was diagnosed and only very slightly above the normal range which is really good.”

In June, Jennie asked to have her bone marrow tested again even though this is not usually done unless there is a change in presentation or bloods.

“Overall, it looks like the scarring has got worse since five years ago, but he [her haematologist] said it’s hard to decipher if it’s the progression of the disease or the impact of the interferon.

“As everything else looks good and there are no blast cells present, the decision was to carry on as normal.

“The only other options would be to go on ruxolitinib [Jakavi®] or a stem cell transplant but we decided, neither at this point.”

Jennie said she had been affected by “really bad headaches again”.

“Automatically, I go back to the worse-case scenario in my head, what’s wrong, something’s happening. Am I going to have a stroke because I have a blood clot or is the condition getting worse?”

“I’ve got a really good GP. She’s really thorough. She sent me for MRIs and referred me to the neurologist.

“I think it’s just about trying to keep a level head and also listening to your body.

“We’ve recently moved and had a lot of changes and I think it’s also about being kind to yourself and taking a bit of time out.”

In early-July, the family moved from Melbourne to rural Woodend where they have a “massive garden and a view of Mt Macedon”, and there’s been a new addition to the family, Monty, a kelpie puppy.

Since COVID-19, Jennie has worked her three days of social work a week from home rather than driving the hour into Melbourne, and she has moved her fitness business online and is training her clients from a distance. She keeps fit by running most days “for fitness and to clear your head”.

“I don’t let it [MPN] control me or dictate who I am or what I am, but sometimes I need to remember that I have this condition, and I do need to listen to my body and just slow down and rest, if my body’s telling me to,” she said.

But, as a mum with two young kids, running a family, and working, Jennie said, “it’s a necessity to keep going”.

“I do what I can to stay healthy, and ultimately my family is my inspiration.

“I want to be here for as long as I can to be with them and look after them and watch them grow up.

“It’s good to know that support is there if I need it.”

Jennie has joined the Leukaemia Foundation’s coffee mornings and been to the blood cancer conference in Melbourne a couple of times, although with a young family that’s not always easy.

“It takes quite a lot of effort for me to get to those meetings. I need to take time off work and find childcare,” she said.

“I’m on a few of the Facebook support groups. There are people in a similar situation to me, young, and wanting to talk about having babies with the condition. I’ve been able to share my knowledge and experience.

“It’s nice to know that you’re not out there on your own, especially when initially diagnosed, and that there are other people experiencing similar difficulties and that there are great support networks available to help and reassure each other.”

Clinical trials critical to finding curative therapies for MPN

Clinical trials critical to finding curative therapies for MPN

Dr David Ross and others in Tokyo
Associate Professor David Ross, centre, at a conference in Tokyo

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”.

Dr David Ross
Dr David Ross

JAK2 mutation – the key discovery

The JAK2 mutation is found in almost everyone with polycythaemia (rubra) vera (PV) and more than half of people with essential thrombocythaemia (ET) and myelofibrosis (MF).

“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. 

Improving outcomes for Australians with an MPN 

Improving outcomes for Australians with an MPN 

Photo of Dr Leisl Butler in her lab

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.

She is undertaking translational research and was awarded a 2020 Leukaemia Foundation of Australia PhD Scholarship, through the Haematology Society of Australia and New Zealand (HSANZ).

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.”

Q&A: Dr Peter Diamond – our head of research

Q&A: Dr Peter Diamond – our head of research

Dr Peter DiamondHead 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.    

Dr Peter Diamond with Prof Zannettino at SAHRMI
Dr Peter Diamond with Prof Zannettino at SAHRMI

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.

In coming years, what will be the major focus on the National Research Program? 

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 precision medicine 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 precision medicines 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.  

 

 

 

Blood Cancer Taskforce develops national plan

Blood Cancer Taskforce develops national plan

Australia icon

The Blood Cancer Taskforce has brought the Australian blood cancer community together to develop the first National Strategic Action Plan for Blood Cancer.

Development of the National Action Plan has involved consultation with clinicians, people with blood cancer, their carers and families, researchers, and a host of blood cancer experts.

Due for public launch in September, the National Action Plan is a once-in-a-generation opportunity to reduce the impact of blood cancer and re-imagine the way treatment and care of blood cancer patients is planned and administered across Australia.

As the Leukaemia Foundation’s State of the Nation: Blood Cancer in Australia report, released in 2019, so clearly demonstrated; the economic and personal costs of not acting with urgency on blood cancer are too great to bear.

The Leukaemia Foundation looks forward to working together with the blood cancer community to implement the National Action Plan and achieve zero lives lost to blood cancer by 2035.

New Leukaemia Foundation Website Launches today

New Leukaemia Foundation Website Launches today

The Leukaemia Foundation is proud to unveil new website providing over 900 pages of the latest trusted information about blood cancer, custom-built specifically with Australian blood cancer patients and their family’s needs in mind. 

Designed to inform and empower patients and their families right throughout their experience with blood cancer, the new website includes extensive information on the different types of blood cancers, the latest news on research, trials, tests and treatments as well as personal stories from those who have a lived experience with blood cancer.  

Leukaemia Foundation Acting CEO Alex Struthers said the Leukaemia Foundation is driven by the need to improve the lives of people affected by blood cancer by ensuring they have access to trusted, credible information and resources.  

“Drawing on more than four decades of experience and knowledge, we have built a patientcentric resource that will transform how Australians living with blood cancer access disease, treatment and wellness information, Ms Struthers said. 

Google trends confirm that in Australia the peak times people search online for information about blood cancer is between 1am – 4am every single day (1).  

“Now more than ever, Australians affected by blood cancer need accurate information that is relevant, relatable and easily accessible, at any time of the day. People living with blood cancer will be able to learn and digest information about their disease and treatment journey at their own pace and at a time that is convenient for them,” Ms Struthers said.  

Over the past year, the Leukaemia Foundation website has had more than 1.5 million-page views, with one million of those visitors accessing disease information.   

Blood cancer comes with so many questions and unknowns. Our supporters have made accessing information possible by ensuring families around the country find the credible, relevant facts they’re searching for,” she said. 

The 18-month long website project has come together through the efforts of a Leukaemia Foundation Steering Committee, Working Group and generous funding from Perpetual Trustees and pharmaceutical companies Janssen, Bristol-Myers Squibb / Celgene, Novartis, Astra Zeneca, Roche and MSD. 

“Health care professionals and stakeholders in the blood cancer community will know that when they refer a patient to the Leukaemia Foundation website, they will be accessing credible information which meets the health literacy levels for all patients,” Ms Struthers said. 

The Leukaemia Foundation’s new website will be live from Friday 17 July 2020. For further information please visit leukaemia.org.au 

Subscribe to receive the Leukaemia Foundation’s news and updates here.

ENDS 

 

(1) https://trends.google.com.au/trends/explore?date=now%201-d&geo=AU&q=Blood%20Cancer

Searching for “more effective and gentler” therapies for AML

Searching for “more effective and gentler” therapies for AML

Dr David Scadden at a lab meeting at Harvard University

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.

David Scadden
Dr David Scadden was awarded the Leukaemia Foundation-sponsored Donald Metcalf Award at the 2019 International Society of Experimental Hematology (ISEH) conference in Brisbane

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.

Dr David Scadden and Dr David Traver
Dr David Scadden at the ISEH 2019 conference in Brisbane, with fellow experimental haematologist, Dr David Traver, who received the Leukaemia Foundation-sponsored McCulloch and Till Award

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.

Expert interview series: Dr David Yeung discusses CML

Expert interview series: Dr David Yeung discusses CML

David Yeung

Dr David Yeung is a haematologist at the Royal Adelaide Hospital and a researcher at the South Australian Health and Medical Research Institute where his main research focus is CML. He works in Professor Tim Hughes’ internationally renowned CML group and currently leads three CML studies and is about to open a new clinical trial for newly diagnosed CML.  

Dr David Yeung’s interest in science and the reason he chose a career in medicine goes all the way back to his childhood in Hong Kong. 

“It sounds a bit corny but it’s a desire to help people from a very young age, and even when I was very young, I enjoyed reading the health columns in newspapers and magazines,” said Dr Yeung. 

“I like science. I like how advances in medicine are driven by science, and I really like the translational aspect of research. Having the two jobs, across the research institute and the hospital, enables me to combine these interests in my profession, translating the benchtop science to the patient in the clinic.” 

Dr Yeung specialised in haematology because, “it is an area of medicine that is continually advancing where ground-breaking laboratory findings can rapidly evolve into treatment strategies that benefit patients”. 

“You read about discoveries at a basic science level and the next thing you know you are applying it,” said Dr Yeung about the evolution and translation of discovery into the clinic.  

“That’s really exciting,” he said, also emphasising, “but none of these advances occur in a flash. New therapies only come into the clinic with a lot of hard work and persistence from a lot of people. 

At the other end of the spectrum, there’s the human aspect of medicine. 

“You’re looking after patients over the life of the illness,” said Dr Yeung. 

“In haematology, many of the illnesses we look after, such as acute leukaemia, have a high mortality rate, but it’s a privilege to be able to try and help patients through the most difficult times in their lives. 

“With the availability of better treatments, an increasing number of patients do well. When they get to live a long and normal life, and can be with their families, it’s very gratifying and that is the ideal situation.” 

Stats and facts about CML  

Roughly 300 new diagnoses of CML are made across Australia each year, but with life expectancy for CML patients now approaching that of the general population, Dr Yeung expects the number of CML patients to grow year by year, so the prevalence of CML will increase as this group of patients age.    

The median age of diagnosis is 50-55, so these are middle aged patients, with slight male preponderance, but not by much,” he said. 

Whether CML is a hereditary disease is a question Dr Yeung addresses with his CML patients if they are concerned about passing it on to their children. 

“I don’t think there’s any convincing evidence that CML, in and of itself, can be passed from one generation to another,” he says. 

“CML is caused by a very specific fusion gene called BCR-ABL; the BCR gene with the ABL gene, and that’s not inheritable. However, there are families with inheritable genetic defects that may increase the risk of blood cancer in general.” 

David Yeung in the lab
David Yeung and Randall Grose working the CyTOF (mass cytometry) together.

A brief 20-year history of CML 

The first tyrosine kinase inhibitor (TKI), imatinib (Glivec®) was the first targeted treatment for any cancer. This drug became available 20 years ago. CML treatment options prior to the introduction, of imatinib included interferon, and chemotherapy drugs like cytarabine and hydroxyurea.  

“In that era, you either used those somewhat crude therapies or you performed an allogeneic stem cell transplant (SCT) for CML patients,” said Dr Yeung. 

“If you didn’t have a transplant, the CML progresses to a more aggressive leukaemia which you would need to treat like AML (acute myeloid leukaemia). And if you did a SCT, you could cure the patient, but there was such a high risk of death associated with the transplant process, not to mention the multitude of potential complications,” he explained. 

“Then imatinib came in and very quickly haematologists noted significant and dramatic clinical responses in CML patients. But there were also reports of treatment resistance related to BCR-ABL mutations. 

“In the early days, no one was sure how much of a problem resistance was going to be. It turned out that if you used imatinib reasonably early in the course of the disease – such as in newly diagnosed patients – it worked very well and prolonged survival by decades. 

However, some patients did have side-effects to imatinib. Intolerance and the mutations/resistance issues spurred the development of better BCR-ABL inhibitors  dasatinib (Sprycel®) and nilotinib (Tasigna®) 

“These second generation TKIs are more potent than imatinib and can treat imatinib-resistant disease. They also offer patients with side-effects an alternative agent which they may be able to tolerate. The second generation TKIs became available to Australian patients through the Pharmaceutical Benefits Scheme (PBS) about 10 years ago; that was the next breakthrough in targeted treatment for CML patients,” said Dr Yeung. 

“Around the same time, there was work to show that in patients who were successfully treated and had undetectable disease for a very long time, about 50 per cent could safely stop therapy and not need tablets again.  

“This work, stopping studies specifically, was pioneered herein Adelaide, by Tim Hughes and David Ross, together with Francoise Mahon and Delphine Rea from the French CML group. Patients who have achieved close to, or undetectable BCR-ABL, and successfully stopped their drug have achieved what we now call treatment-free remissions (TFR). This was a seminal discovery. 

“Before that, everybody was too scared to take patients off drugs. We thought that stopping therapy would lead to a high rate of relapse, and that relapses may be fatal. The flip side of that is, you had an increasing cohort of patients who needed to be on therapy for life and some had low-grade chronic toxicities that affected their quality of life. There was also the cost issue for the [health] system. 

“TFR is now a central theme of CML research – how can we predict when patients are ready to come off their tablets and how to maximise the probability of these patients not needing therapy again,” said Dr Yeung. 

“TFR is one of the consumer-driven agendas in CML research because an increasing number of CML patients in Australia are going to live a long life, and they going to live well. But if they’ve got chronic side-effects for 20 years that are lifestyle-affecting and causing them to be miserablethey will ask, ‘Doc, when can I get off these dreadful pills?’ 

“A number of patients don’t have any side-effects and that’s fine, but still, a pill is a pill, and if you can tell them, “Mr Smith, there’s a 95 percent chance you won’t need this tablet again if you stop next year because of the clever test that I’ve done and the result shows this is what it is”, then Mr Smith can make his call. 

Second/third generation TKIs and side-effects 

The second generation TKIs are more potent than imatinib, with a lower likelihood of leading to the development of mutations. 

“They’re quicker to act and reduce the BCR-ABL leukaemia cell numbers more quickly compared to imatinib,” said Dr Yeung. 

But some patients may have unacceptable side-effects, which are “actually quite dangerous”. Dr Yeung said there was “a slightly higher chance” of problems in susceptible patients with blocked arteries that could lead to a stroke or heart attack from nilotinib, and fluid around the lungs [pleural effusion] that affects breathing, with dasatinib.  

Whereas the side-effects from imatinib are “annoying” – facial swelling, nausea, diarrhoea, vomiting, swelling of the ankles – “these tend to be less serious health consequences, but they are more common and affect quality of life”, said Dr Yeung.   

“When we treat CML, we’ve got to balance who goes on what drug, depending on the likelihood of our patients developing side-effects and how this may affect them – actively taking into account other chronic health problems patient may have.” 

Dr Yeung said another issue was that some patients developed disease resistant to the second generation TKIs, and five years after nilotinib and dasatinib, ponatinib (Iclusig®) became available through the PBS in 2015. 

“This is a drug we reserve in third line because, while it’s very potent against CML, it’s also got the highest chance of causing blocked arteries. We only use it under special circumstances when we have no other choice. This is reflected by current Medicare restrictions for its use in the third line (after patients are either resistant or intolerant of all other TKIs available in Australia).” 

Dr Yeung said the more potent BCR-ABL inhibitors can be used for increasingly resistant disease, and sometimes, when patients are intolerant to one drug, “we swap across to another drug and most of the time the side-effects resolve”. 

“So, it’s nice to have a choice, to have more than one agent to rely on.   

“We’re also working towards the goal of having a really potent BCR-ABL inhibitor without the side-effects. We’re always looking for a better agent to fill the gap,” said Dr Yeung about ongoing research. 

David Yeung in the lab 2
David Yeung: “having the two jobs, across the research institute and the hospital, enables me to combine these interests in my profession, translating the benchtop science to the patient in the clinic”.

Asciminib study as a frontline therapy 

Asciminib is a new drug currently undergoing clinical trials for CML. The results of the first clinical trial associated with its use was published in the New England Journal of Medicine last year, in a clinical trial led by Professor Tim Hughes.   

“In Adelaide, we’ve had access to asciminib for about six years because of our active clinical trials program in CML. There are a number of our patients who have had resistance or side-effects to all the TKIs that are currently available, and it’s great that have another option to offer these patients.  

“Even in this group of patients with resistant disease, we’ve been seeing some good results; there are patients with a very good reduction in their CML, and the side-effects profile seems quite favourable, although we still need long-term data.” 

Dr Yeung said preparations were being finalised for a Phase II Australasian study run through the Australasian Leukaemia & Lymphoma Group to test asciminib in newly diagnosed CML patients 

Recruiting for this trial, called ASCEND-CML, will start in late-2020, with at least 15 sites to open across Australasia, including at least one hospital in each state and territory. 

“What we hope to achieve is disease burden reduction and disease response as favourable as any other anti- CML drug currently available, but without the side-effects of the more potent TKIs, with the ultimate goal of getting more patients to the starting line of the  treatment free remission phase of the journey.” 

What the optimal patient journey looks like 

Dr Yeung said the patient journey “arguably, looks something like this in the optimal sense”. 

It starts off with “rapid diagnosis, which we have in Australia, where almost every state and territory has access to multiple laboratories and can diagnose CML well”. 

“Then, the patients need access to specialist physicians, and sometimes clinical nurses, for advice on diagnosis and to choose a drug to start therapy with. The patients will then have the drug,” he said.  

“They can then watch their CML leukaemia burden fall (using the BCR-ABL QPCR), with monitoring through a credited laboratory; and most patients have access to that. We want the CML burden, measured as the BCR-ABL level, to ideally drop to undetectable levels as soon as possible, allowing patients to have the option of TFR.  

“At the moment, patients who choose to have a TFR attempt have a ~50% chance of not needing therapy again, although there is no sure way to tell, ahead of time, what the success rate will likely be in any individual patient.  

“In the future, we will have a suite of tests that can tell if the patient can come off their drug and never have to go back on tablets, or not.”   

Treatment-free remission 

After reaching a deep and stable response to treatment, Dr Yeung said most patients, when offered a chance to discontinue TKI therapy, do choose to stop their treatment provided they have the information, the opportunity to think about it, and the support. 

When broaching the topic of TFR, Dr Yeung said, “almost invariably, patients show an interest and want to know more”. 

“We talk about the success rates, the possible side-effects of coming off their CML drug, and what to do if the disease comes back.  

“A number of patients prefer not to do it: the possibility that the disease may come back, and the uncertainty regarding the timing will place a psychological stress on certain patients.   

“They may defer that decision, but eventually most patients get to a point where they’re comfortable in considering a trial of cessation if the support network is there,” said Dr Yeung. 

“Patients want to know that yes, you are testing them regularly enough to look for signs of relapse, yes someone will check the reports when they come throughsomeone will tell them if the result is positive or not, and someone will tell them if they need to restart their drug.  

“If they’re reassured that… there’s someone to call, someone who’s checking, and that there’s nothing to lose by doing it, then patients are generally happy.” 

Dr Yeung said when patients come off their CML drug, they should, at a minimum, have a monthly blood test for six months, then every two months for the next six months, and then every three months thereafter and forever. 

“There have been rare cases around the world of patients where restarting the therapy doesn’t work so well, but the vast majority of patients do respond very quickly,” he said.  

Initial disease control critical 

Another of Dr Yeung’s colleagues in Adelaide, Professor Sue Branford, was one of the first people who developed an internationally standardised BCR-ABL monitoring assay to approximate the number of CML cells left inside a patient. Having an accurate assay is critical in telling patients and doctors how well their anti-CML therapy is working. There is now a series of treatment targets at various time points that patients should meet after starting treatment if they are to do well. 

“Sue has 20 years’ of BCR-ABL data in her lab. Her observations show: how the disease responds in the first three months is critical to longer term responses,” Dr Yeung explained. 

“Analysing that data and working with Sue, our colleague Dr Naranie Shanmuganathan, found that that if a patient starts therapy and their BCR-ABL (disease burden) falls like a lead balloon, that’s really good because it means you’ll get to your goal of zero CML faster, and when you are eventually advised to  stop the drug, you’re much more likely to not need to get back on it. 

“If the BCR-ABL falls slowly, even if you eventually get it down to undetectable levels, and your doctor says you can try coming off tablets, the disease is much more likely to relapse. 

“Whether it takes you three years or one year to get to the starting point of a trial of cessation, it’s still zero or close to it before you stop. But what is interesting, is the patient who had a fast disease response within the first three months of starting treatment and got to the TFR starting point much sooner, will have a higher chance of not needing treatment again, as compared to the patient who had a much slower rate of response in the first three months, and took longer to get to the starting point. Naranie is about to publish her paper on this,” explained Dr Yeung.  

“One interpretation of the data is that the initial disease control is critical, and getting a drug that is potent and non-toxic to actually bring the tumour load rapidly down in that initial period may actually set you up for success later on. 

When to have a go at treatment-free remission 

The current recommendations state that CML patients should achieve good control of the disease with their anti-CML therapy – also called deep molecular response – and have maintained this with therapy for at least two years, prior to being considered eligible for coming off therapy for a TFR attempt. The total duration of therapy should be at least three years prior to stopping. Patients are advised not to stop treatment if these conditions are not met, and never stop therapy without consultation with their doctor. 

“If a patient has had two years of undetectable BCR-ABL and more than three years of treatment overall, if they are happy to have a go at TFR, we would supervise them in a structured trial of cessation any time they are ready. Any additional year of treatment, whilst maintaining a deep molecular response, is likely to increase the success of stopping, though not by much.  

“Sue Branford published data about six years ago to say that if you start off with imatinib treatment, after eight years of treatment 42 per cent of patients will reach the point where you would offer a treatment-free remission attempt.  

“This may very well change in the future and the hope is that we can shorten this time significantly,” said Dr Yeung. 

“The expectation is that, with more potent drugs, we wouldn’t take eight years to get 42 percent to the starting line of stopping. It may take three or four years, and that’s what we’re seeing with the more potent drugs like nilotinib or dasatinib. Hopefully we can do better still.” 

Asciminib in combination with other CML drugs 

Since asciminib is in a completely different class of drug to imatinib, nilotinib, and dasatinib, Dr Yeung said, “arguably you can pair asciminib up with the drugs we currently have, to try to hit CML in two different places”. 

“We still don’t know how effective asciminib is in resistant disease. “There is ongoing work pairing asciminib with the other TKIs in those patients. Although the ASCEND-CML patients will enrol newly diagnosed patients, there is provision for them to access combination therapy if they fail to respond to asciminib alone. In that setting, asciminib may be paired with either imatinib, nilotinib, or dasatinib.  

“We think that combination strategy may work much better in patients with treatment resistance. How to optimise outcomes in resistant patients is another clinical research priority in CML. In this group, we think that combination is the way forward.” 

Four clinical research priorities 

Dr Yeung said the clinical research priorities in CML were: 

  • how to get better, safer, more effective treatments for the newly diagnosed  
  • how to improve salvage in those who have a suboptimal response and disease resistance 
  • how to increase the number of patients we can treat successfully, and predict when patients are ready to come off therapy and get off therapy, and 
  • improving the success of a second trial cessation. 

And biologically, there are a number of interesting research topics, such how the BCR-ABL gene forms in the first place; how CML cells take up oxygen and nutrients compared to other cells, and whether this can be exploited to develop new therapies; and how the immune system affect treatment responses.   

“These are some of the things we’re following up on, so watch this space,” said Dr Yeung. 

 Adding the microenvironment to the AML therapy mix improves efficacy   

Adding the microenvironment to the AML therapy mix improves efficacy

Ingrid Winker and Valerie Barbier

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.

Ingrid Winkler, Valerie Barbier, Joshua-Tay
A/Professor Ingrid Winkler, right, with co-authors, Joshua Tay and Valerie Barbier

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).