“Yeah, let’s give this a go. Let’s get these horrible drugs, that have saved my life, out of my system and see what happens.”
That was the decision Leanne Pitman and her husband, Ted, made together back in mid-2015 after her haematologist, Associate Professor David Ross, talked to her about stopping her CML treatment.
At first, she was “very scared”.
“I hadn’t heard of anyone else doing it, so it was a little bit scary not knowing what would actually happen,” said Leanne, 60, of Adelaide.
During the discussion, she was reassured that she would be monitored very closely–in fact, for the rest of her life–and if there was evidence of CML reappearing, she could restart her tyrosine kinase inhibitor (TKI).
“So that was part of the understanding when we decided to come off the medication… I knew it was there to go back to if anything happened,” explained Leanne about the option of restarting treatment.
She immediately stopped taking the nilotinib (Tasigna®) tablets she had taken religiously every day for five years. Prior to that she had been on imatinib (Glivec®) since her diagnosis with CML just before Christmas in 2006, aged 46,
The key reason Leanne chose to attempt treatment-free remission (TFR), under the supervision of her haematologist, was the extreme bone pain, fatigue, and other side-effects she had lived with for nine years.
“I started on Glivec and was on that for quite some time, about five years,” said Leanne, and she responded well to imatinib.
“I got to zero BCR-ABL on Glivec quite quickly, but I had a lot of trouble with side-effects. I was an absolute mess. I reckon I would have been in hospital at least once a month with it.
“Nausea was pretty bad to start with, but I seemed to manage that.
“Mostly the side-effects were bone aches. In the end, I couldn’t walk without a walking stick, I would be in that much pain continuously, vomiting from the pain. It was just really bad,” said Leanne.
“I was on Endone, Oxycontin, Panadeine. I was continuously taking painkillers, all the time.
“I can remember, when I was on Glivec, I was taking 18 tablets in the morning.
“At that stage I was still running a seven-day-a-week café.
“I’m very thankful that my daughter was in business with me, and I had some very good staff to help look after the café when I’d end up in hospital.”
At the time, the Pitmans were living at Penola, 400km from Adelaide.
“One of the hardest things, obviously, were the trips up to Adelaide all the time,” said Leanne about her regular appointments with her haematologist there.
These were initially monthly, then two-monthly, before being every three months.
“That was really hard, especially with my husband who was a truck driver. He’d have to take time off all the time,” said Leanne about Ted who had to drive her to and from Adelaide for her medical appointments.
“I couldn’t drive myself. I couldn’t drive any long distances at all.
They’d head off early in the morning and Leanne would still be her pyjamas so she could sleep on the trip.
Pain management lead to a change in therapy
Leanne was on so many painkillers that she was referred to a pain clinic in Adelaide where she was given a script for a different pain medication. When she went to fill it at Penola, the pharmacist said it would cost hundreds of dollars.
“He said he had something the same but not that brand,” said Leanne.
“Almost immediately the pain stopped. It was a miracle, and I remember handing in all my other painkillers at the hospital, because I didn’t need them.”
Leanne said, “it was fantastic”, she was just taking imatinib and the new drug… but not for long. After her next blood test, she got a call from her haematologist.
“He questioned me as to why I wasn’t taking my Glivec.
“I remember so clearly saying, ‘I swear on the lives of my children, I have not missed any of my medication’.
“Anyway, I had to go back to Adelaide again, and we worked out that the new pain medication wasn’t exactly what I had been prescribed and had counteracted the Glivec.”
As a result, there was no evidence of imatinib in Leanne’s blood and her leukaemia level had risen.
After this incident, Leanne was able to change her CML medication to nilotinib, and her side effects weren’t as bad.
“The pain came back but it wasn’t as severe, and the fatigue wasn’t as severe.
“I tolerated it [nilotinib] a lot better and I never had to go back to using the walking stick,” said Leanne.
Moving back to Adelaide was a necessity
She continued making her three-monthly trips to Adelaide until 2013 when she moved back to Adelaide, and the Leukaemia Foundation provided her with some financial support.
“In the end I had to sell my café,” said Leanne.
“It got to the stage, with the frequent trips to Adelaide and there was no doctor in Penola and having a locum meant having to go in an explain myself every time to get medication, that we decided it would be better for me to move to Adelaide permanently.
“I live 400km from my husband,” said Leanne.
“Fortunately, we’ve got a very good relationship. We talk every night on the phone.
“When he gets the opportunity to come to Adelaide, he will, and he tries to come up for family events because the rest of our family now lives in Adelaide as well, or I try and get down there to him.
“It’s only been in the last two years that I’ve actually been able to drive the 400km without being in immense pain.
“Ted and I bought a large house [in Adelaide] and my parents moved in with me, so I look after them a bit, and our son and daughter and our three beautiful grandchildren are 10-minutes away.
“So if anything happens to me, or anything happens to them, we’re close together.”
And, in a couple of years, when Ted retires, he will re-join Leanne and the family in Adelaide.
The lead-up to treatment-free remission
“I had a lot of trouble getting doctors to understand what was going on with me, because this was something new, saying I had bone pain,” said Leanne.
“I was on the CML Facebook pages and I wasn’t the only one going through bone pain. Others were going through the same thing.”
Then, in July 2015, Leanne’s haematologist had a conversation with her and Ted about stopping her CML medication.
“Because my BCR-ABL1 had been zero for so long, many years,” said Leanne.
When she decided to try TFR, it was just days before going on holiday to Darwin to visit a girlfriend, and her first query was, “do I take it [the nilotinib] with me?”.
Then, because she still had “a fair bit of nilotinib”, at least a month’s worth, she wondered, “do I give it to someone else, because of the cost?”.
“I was thinking surely David [Ross] would have someone who could use it.
“Even though it was unopened, apparently you can’t reuse medications,” said Leanne, who ended up throwing out her leftover nilotinib a couple of years later when it was out-of-date.
Leanne has had no change in her blood test results since stopping nilotinib more than five years ago.
“I’m still zero in treatment-free remission.”
“I’ve had other specialised blood tests,” she Leanne who had consented to her blood samples being used for research.
“I was asked to participate in these other blood tests that had to be done on a certain day and the results took a lot longer.
“What they found, when looking deeper, is that I still have CML cells deep in my blood,” said Leanne, who was told, “they’re just sitting there”.
“I’ve done two of those tests and both times the CML cells have been there.
“I’m quite aware that if anything ever happens, there’s always the medication to go back to and I know that will control it.”
For Leanne, that’s very reassuring.
It’s five years since Leanne went on TFR and she still has a lot of side-effects.
“I still have the pains in my legs. Fatigue’s the worst, but I get on with my life and live it the best I can.
“I’m on the TFR Facebook page and it’s quite upsetting when you’re watching people and it’s, ‘oh no, blood levels have come back up. I have to start medication again’.
“That’s always in the back of my mind every time I have my blood tests.
“The last time I saw David [Ross], because it’s been five years, he seems to think it would be very unlikely now that it would come back, but you just never know.”
Leanne said she doesn’t give coming out of remission a lot of thought anymore.
“But I still say to people, because of my pain and fatigue, that I’m a leukaemia patient.”
Visits to her haematologist have dropped back to once a year, but she still has blood tests every three months, and this will continue for the rest of her life.
Looking back, Leanne thinks going on TFR was “a good decision”.
“I’m not on as many drugs, I’m a lot better off now as far as the bone pain, and I think I’m coping a lot better.”
Her advice to others regarding TFR is, “give it a go, because it gives you a break off medication, and the medication’s always there for you to go back to. That was what made our decision so much easier.”
Expert interview series: Dr Susan Branford on molecular monitoring and drug resistance in CML
Professor Susan Branford is better known internationally than here in Australia where she heads a diagnostic lab in Adelaide, has research interests in CML, and is an NHMRC Research Fellow. Her work on the importance of molecular response in CML has been widely recognised and includes the International CML Foundation Prize in 2016 for outstanding contributions to the improvement of CML treatment in emerging economic regions, and the International Federation of Clinical Chemistry and Laboratory Medicine Distinguished Award in 2017 for significant contributions in molecular diagnostics.
Professor Susan Branford’s work on molecular monitoring and drug resistance, although largely behind the scenes, has underpinned many Australian and internationally significant developments in CML over the last 20 years.
The pathway to her current position as Head, Leukaemia Unit, Genetics and Molecular Pathology at SA Pathology, Centre for Cancer Biology wasn’t conventional. She started as a lab technician who worked in clinical chemistry for many years.
“That gave me a really good grounding in some of the key elements required to generate good diagnostic tests, which is what we are doing here in the lab now, as well as research,” said Dr Branford, also Professor, School of Pharmacy and Medical Science, at the University of South Australia.
In 2000, she took the opportunity to move to a new department–Genetics and Molecular Pathology–where her role was to develop methods using a new technique, real-time quantitative PCR* in various cancers. She worked with haematologist, Professor Tim Hughes, who had set up PCR when he was at Hammersmith Hospital in London.
“My role was to develop a technique and to start to monitor patients with chronic myeloid leukaemia, which we did. At that time imatinib [Glivec®] was first being tested,” said Dr Branford about the original, first generation tyrosine kinase inhibitor (TKI).
“After a few years of developing this method and being very interested in the research I was doing, Tim [Hughes] said, ‘look, I think the work you’re doing is at a PhD level, why don’t you apply to do a PhD?’, so I did.
“I’d already published papers at that stage and even though I didn’t have a primary degree, the university looked at my credentials and said ‘yes’ to my application, based on my publications and relevant background.”
Introducing molecular monitoring to the international stage
Dr Branford had an opportunity to participate in some exploratory research in patients who were treated with imatinib.
“Until imatinib was available, CML patients were either treated with interferon, which most patients couldn’t tolerate and only a few responded to, or patients had an allogeneic bone marrow transplant,” she said.
“Then imatinib, which is a targeted therapy, changed everything.”
“From the first trials, it was clear that patients were going to have very good responses,” said Dr Branford.
“Tim [Hughes] told Novartis that we had a method to monitor patients and we were able to perform exploratory molecular analyses for Australian and New Zealand patients enrolled in the IRIS international trial, that started in 2000.
“This trial enrolled over 1000 patients and was the first trial of newly diagnosed CML patients treated with imatinib.
“We worked with colleagues in London and Seattle who also had monitoring methods set up using real-time PCR for patients with CML. These labs performed the molecular analyses for the other patients enrolled in the IRIS trial. But our methods were all slightly different, which meant our results didn’t align. So we worked to standardise the results, and this was the first attempt to align data for CML patients generated by different labs.
“The trial protocol required that molecular analysis was only commenced once patients achieved a complete cytogenetic response.
“But we were lucky enough to get support to test all of the Australian and New Zealand patients at three-monthly intervals. This proved to be really informative because we monitored patients more intensively than a lot of the other patients on the trial,” she explained.
“We found that the achievement of a certain molecular response correlated with very good outcomes and the data was published in 2003,” said Dr Branford.
“Then we followed those patients who became resistant to imatinib, looking for their mechanisms of drug resistance. That’s really how it all started.”
Significance of Leukaemia Foundation funding support
The overall aim of Dr Branford’s research is to understand why some patients with CML don’t respond to therapy, given that most patients do extremely well.
“Patients can be treated with imatinib, the first generation drug and the least potent, and have very rapid responses. Some patients may eventually be able to stop therapy and maintain treatment-free remission,” she explained about a typical CML patient journey.
“But we know that some patients have a delayed response. By using molecular monitoring, we found that values very early into therapy are highly predictive of how patients are going to respond.
“A lot of our work is focused on trying to understand and to predict why some patients do well and why some patients have a poor response.”
Dr Branford, Professor Hughes, and Dr Deborah White received funding from the Leukaemia Foundation in 2008 that contributed to research with the primary goal of understanding the mechanisms of resistance and how to overcome this resistance to improve outcomes.
“At that time, we were very focused on mutations in BCR-ABL1. BCR-ABL1 is the primary genetic mutation that causes CML, and mutations in this fusion gene cause drug resistance. We were able to develop a very sensitive method to detect these mutations. We had some good publications from that work where we were able to show that low level mutations are clinically relevant.
“Any bit of funding we get means that we can do some analysis, even if it’s preliminary. We find these great preliminary results and we feed that back into our next grant application. It’s all been a fantastic support,” said Dr Branford.
Predicting treatment response
“We started off looking at BCR-ABL1 at diagnosis and found there was no predictive information; it didn’t matter what level you started with; it was what happened after treatment.
“By three months, if patients had a very rapid decline, they were going to do very well.
“We’ve always tried to find out what’s going on at diagnosis and it’s really starting to come together after many years of using new technology and looking outside of BCR-ABL1.
“We’re at quite an exciting spot.”
“We’re using new genomic and molecular techniques –whole exome sequencing**, or whole transcriptome sequencing–where we look at every gene at diagnosis.
“We did a pilot study that took us many years. We looked at patients who had the best responses and those who had the very worst responses. We found additional genomic abnormalities in some CML patients at diagnosis in addition to BCR-ABL1.
“Our study started in 2011 but even as far back as 20 years ago, scientists had detected the occasional mutation found in a highly mutated gene, like TP53.
“It wasn’t until the new sequencing technology came along that we could look at everything, and that we’ve really started to find these mutations.”
Dr Branford said the research has since been extended to an expanded cohort of CML patients, not just those with very poor or very good responses to imatinib. We are studying patients enrolled in the TIDEL II study, which was set up by Dr David Yeung and run out of Adelaide in conjunction with the Australasian Leukaemia & Lymphoma Group (ALLG). The results of that study were published in Blood in 2015. Blood is the top-ranking journal that publishes data on blood cancers.
“So far, in our preliminary work, it holds up that if patients have a mutation at diagnosis, then it puts them at a higher risk of treatment failure.
“PhD student and haematologist, Dr Naranie Shanmuganathan presented our preliminary data in early December  in an oral session at the American Society of Hematology (ASH) meeting, which was a virtual meeting last year.
“We tested the diagnosis samples of patients where we know their outcomes; we know which patients did well and which patients did poorly.
“We’ve looked at the genomics at diagnosis of about two-thirds of the patients so far and have found that having these mutational events at diagnosis is an independent predictor of poor outcome.
“At a live question time after Dr Shanmuganathan’s presentation, one of the questions was, ‘when is this going to be available in the clinic?’.
“That was quite exciting for us, to hear that there is interest from around the world.”
“There is still a lot of work to do. We need to find out if the poor risk conferred by mutations at diagnosis can be overcome with more potent inhibitors.”
Dr Branford said the next step now is to go back and test the tissue samples (usually peripheral blood) of other CML patient cohorts–those treated with the more potent inhibitors such as nilotinib (Tasigna®) and dasatinib (Sprycel®) as their first line of therapy–to see what their outcomes have been.
“That could be quite useful,” she said.
“If we find that a patient has a particular mutation at diagnosis and is treated with a certain drug that reduces the risk of treatment failure, then that could be really important. It could be practice changing in terms of helping clinicians decide the best drug to give at diagnosis.
“Our aim is to identify those patients who will do really well on the standard dose of imatinib, which is a safe drug, whereas the more potent inhibitors (nilotinib and dasatinib) have some toxicity and cardiovascular risk associated with them, so the patients who have those drugs need to be carefully selected.
“But that’s another year or so off until we get those results.
“We’ve got patient consent for this work, it’s just a matter of funding.
“Getting funding is becoming harder and harder and, unfortunately, there may be a time when we just aren’t able to pursue the things we would like to do, based on our preliminary data, because we just don’t have funds.”
Retrospective analysis using archived tissue samples
For a lot of this research, Dr Branford uses existing samples that have been collected and stored for many years in Adelaide.
“Patients with CML are routinely monitored for BCR-ABL1, and we do a lot of the molecular analysis for Australian clinical trials.
“We’ve got about 700 patients who we’ve followed in clinical trials.
“It’s a great resource,” she said.
“We correlate the data with the BCR-ABL1 values we’ve collected over time.”
Groups around the world are finding that tissue banks of stored patient samples, where the response to treatment is known, can provide a wealth of information.
“It’s a very nice retrospective analysis,” said Dr Branford.
“One of the initial mechanisms of drug resistance we found were mutations that occurred within the BCR-ABL1 gene itself, in the drug-binding site.
“Again, with this rich data source, we were able to go back, track, and correlate the emergence of these mutations with drug resistance.
‘We’ve moved on from there and are now looking more broadly at other mutations and other genes,” she said.
Several other groups around the world developed molecular monitoring techniques and established these rich data resources at around the same time; the Hammersmith in London; in Germany; and Jerry Radich’s group in at Seattle in the U.S.
World first trial for asciminib has opened
Hopefully, new samples will be added to the CML tissue bank in Adelaide from the 100 participants who are expected to enrol in a new national study that opened in late 2020.
“I think this is the first clinical trial in the world treating newly diagnosed patients with a new drug, called asciminib,” said Dr Branford about the ALLG CML13 study, also known as the ASCEND trial, run from Adelaide.
Asciminib, previously known as (ABL001) is another drug that targets BCR-ABL1, but it is different because its activity is very specific.
“It has limited off-target activity, so has limited toxicity. We’re very excited to be able to test and treat patients with asciminib as their first line of therapy.”
But Dr Branford said her research group doesn’t have the necessary funding to test these patients at diagnosis.
“We keep applying to various funding bodies to get the money to do the testing. The patients will all be consented to do the test, it’s just dependent on if we can get some funding,” she explained.
“This trial might recruit very quickly because, at the moment, this drug is not available outside of a clinical trial.”
Data on asciminib was presented at ASH in a late-breaking abstract session on the results of a large randomised Phase III trial, called ASCEMBL, for patients who had failed prior therapy; up to three different therapies.
“This drug met its primary endpoint, meaning it was superior to the other drug that was used in the trial – that’s very exciting,” said Dr Branford.
“It’s now gone in for fast track approval to the FDA [in the U.S.] as the second line therapy as a monotherapy.”
Dr Branford said we will have some idea how well patients respond to asciminib very early in the ASCEND trial and there is a treatment intervention timeline.
“By three months, if the patient hasn’t reached a certain level of BCR-ABL1, then the study has built in some treatment intervention at that stage.
Investigating the effect of mutations on therapy response
While Dr Branford heads a diagnostic lab, her focus is research, which involves grant writing and paper writing [for submission to journals], and involvement in clinical trials.
“We’ve worked with Novartis over a number of years. They have an interest in these mutations that cause resistance.
“Over the last few months, we have been testing samples of patients enrolled in the ASCEMBL trial at the time just before they start their asciminib; we’re looking at what mutations they have, and we’re starting to get data from this clinical trial.
“We will do an exploratory analysis, to see the effect of these cancer gene mutations on response to asciminib. This will be a companion analysis to that in the TIDEL II trial,” said Dr Branford who, since 2018, has been writing up the trial methodology and has performed validation studies.
“We’ve got a huge amount of data and we’re analysing the last of our data for the TIDEL II study. We’ll do the statistics on that, and that will be the next paper we work on.”
Rolling out molecular testing across the globe
Dr Branford considers her greatest contribution to science is developing the molecular techniques and being involved in rolling out the test globally.
“It is now accepted that this is how patients should be monitored,” she said.
“Over the last decade, once we demonstrated that there was a clinically relevant reason for doing molecular analysis, labs have taken this up. We had to work hard as an international community with collaborators to standardise methods.
“It took many, many years… a lot longer than we thought, because the technique is quite complex and lots of things can lead to variability.
“Now it’s routine that all labs offer molecular testing for CML, whereas if we look back five or six years ago, that wasn’t the case.
“It is much harder in undeveloped countries and we’ve been working with commercial groups, including Cepheid, which developed an instrument called the GeneXpert.
“Again, this has been a work in progress over the last decade.
“GeneXpert is a very rapid cartridge-based method that’s used in a lot of labs in places like Africa and India, where patients can’t access drugs unless they have a definitive CML diagnosis.
“GeneXpert has come to prominence in the COVID era because this instrument is being used for rapid COVID testing, but it also does rapid BCR-ABL1 testing.”
The importance of molecular monitoring
In the first molecular monitoring study Dr Branford did, in the IRIS trial, she found that if patients reached a certain level of BCR-ABL1 after 12 months of therapy, they were essentially protected from disease progression.
“It’s now known as a safe haven, and it’s got its own term, it’s called a major molecular response,” she said.
“It’s the equivalent of a three-log reduction from the diagnosis level. That was the first time that this was found to be an important response.
“Now, in most clinical trials, the primary endpoint is the achievement of a major molecular response and if that can be achieved within 12 months of therapy these patients will have a very good outcome.
“A lot of groups then looked at earlier time points and we’ve now found that if patients reach a BCR-ABL1 ratio of 10% at three or six months, then this has prognostic information. If patients don’t reach these levels, we know that those patients are at risk of treatment failure, disease progression, or even death.
“We now have molecular milestone values at three, six, and 12 months, and these are now our decision points.”
Dr Branford said that in 2013, international recommendations for monitoring patients with CML, published by the European LeukemiaNet, for the first time recommended that molecular milestone values are used for treatment decisions.
“Very early molecular monitoring is important because it can determine whether clinicians should change therapy so that patients have a chance of achieving an optimal response,” she said.
“If BCR-ABL1 values are greater than 10% at three months, the recommendation is to confirm the result by doing another test very rapidly. And if it’s still greater than 10, that’s a bad sign. That’s when the recommendations mandate a change of therapy. Otherwise those patients are at high risk of disease progression. It’s become very important.”
Greatest unmet need in CML
Dr Branford thinks the greatest unmet need in CML is finding appropriate therapy for patients whose disease advances to a rapidly fatal blast crisis. This only occurs in a small number of patients now.
“There are some patients who progress very rapidly,” she said.
“We recently had a young person here who was diagnosed in the chronic phase, started standard therapy, and unexpectedly went straight into blast crisis. Very sad. The patient will have an allogeneic transplant.”
“Tyrosine kinase inhibitors are not effective for patients with disease progression and there is no other effective drug therapy,” said Dr Branford.
“Their best chance is to have chemotherapy, to ablate the leukaemia, then go on to have a transplant. Fingers crossed for this most recent patient.”
Between five and 10% of patients fit into this category, depending on the drug they start their treatment with.
“There’s less progression if patients start with the more potent inhibitors, but these are associated with greater toxicity. There’re pros and cons, and these are the issues their clinicians are dealing with at the time of diagnosis; what’s the best drug for their patient?”
When Dr Branford finishes all the current preliminary work looking at diagnosis, she hopes to focus her research on this group of patients.
“Maybe, if we can introduce rapid genomics at diagnosis, we can work out what are these mutations that are leading to this very rapid progression.
“Maybe it will identify those patients who perhaps need a more potent inhibitor, and they should start to look for a [bone marrow] donor very early,” she said.
“If we can identify a mutation, like IDH1, which we’ve seen occasionally in CML, and which we know occurs in acute myeloid leukaemia, we know there are inhibitors for that.
“As more and more drugs are developed that target specific mutations, there may be effective treatment for these patients.”
Ongoing developments in CML
Dr Branford said that, in addition to the asciminib trial and the research using genomics, a “very exciting area of research is trying to understand how we can pick patients who are going to be successful when they stop therapy; that is, patients with treatment-free remission”.
“I’ve been fortunate enough to be involved in international patient advocate groups because of our international connections,” she said.
“Following on from our work, and other groups’, where we are looking at genomics in CML, Tim and I formed the International Genomics Alliance, which was launched in 2018, to eventually pool all of our data, and we are working closely with patient advocates.
One over-arching group, called the CML Advocates Network, has connected 125 CML patient groups worldwide, and is working with academics and pharmaceutical companies to work out goals and spread word of the latest research findings.
Dr Branford worked with two international patient advocates who are both in treatment-free remission and who helped review her most recent grant application.
“It’s becoming more and more important that we work closely with patients, and that they review our grant applications,” she said referring to what is acceptable to the patient community, such as the level of drug toxicity.
“There are some drugs that are highly toxic,” she said.
“Modification of our grant applications based on feedback from patients is going to be important to improve overall outcomes for patients.”
* Polymerase chain reaction (PCR) is a technique used to amplify small segments of DNA because significant amounts of a sample of DNA are necessary for molecular and genetic analyses.
** Whole exome sequencing sequences the 1.5% of the whole human genome that codes for proteins. Whole transcriptome sequencing sequences the RNA and can measure gene abundance.
The CML13 trial is evaluating the most appropriate treatments for CML patients and the purpose of this important clinical Phase II trial is to evaluate the efficacy of asciminib in newly diagnosed patients with chronic phase CML.
Asciminib (previously known as ABL001) is a novel allosteric inhibitor of BCR-ABL that has demonstrated good tolerance and efficacy in CML patients who are resistant or intolerant to the currently available tyrosine kinase inhibitor (TKI) drugs.
This trial is open to recruitment at the following sites:
Victoria – Peter MacCallum Cancer Centre
New South Wales – Concord Hospital
South Australia – Royal Adelaide Hospital.
More locations to open over coming months.
For more information on this and other current clinical trials in CML, visit the ALLG website, or speak to your treating haematologist.
* The ALLG is the only not-for-profit collaborative clinical trial group in Australia and New Zealand delivering research projects focused on blood cancers. The ALLG’s purpose is to achieve better treatments and better lives for people with AML and other blood cancers. ALLG clinical trials are taking place at 93 accredited hospital sites and cancer centres across the country and more than 800 physicians and haematologists, nurses, scientists, and professional support staff are ALLG members.
For many people living with blood cancer, their pets are an integral part of the family. They would be lost without the love and companionship pets add to their lives.
Your furry friends often can stay by your side during and after blood cancer treatment providing you consult with your treatment team and take the appropriate measures to reduce your risk of infection.
Read our top tips on how to safely care for your pets while undergoing and recovering from treatment.
Talk to your treatment team
After receiving a blood cancer diagnosis, speak with your treatment team about your pet and your routine for taking care of them. Not all pets pose the same risks, and not all blood cancer treatments do either. Your treating team can provide advise on how to safely interact with your pet throughout your blood cancer treatment.
Understand the risks
When undergoing chemotherapy or a bone marrow transplant, there will be times where you are immunosuppressed and more susceptible to an infection. Avoid bites and scratches at this time and if your pet plays rough it may be necessary for your family or friends to look after them until your immune system recovers.
Visit your vet
Consult with your veterinarian to ensure your pet is up-to-date with its immunisations and booster shots. Ask whether any of the vaccinations are ‘live’ and check with your treatment team before these are given to your pet. Your vet can also prescribe medicines to prevent heartworm, fleas and ticks in dogs and cats.
If you have a cat, have it tested each year for feline leukemia (FeLV) and feline immunodeficiency (FIV) viruses. While these viruses cannot infect humans, they can weaken your cat’s immune system which can put them at risk of other infections that can infect humans.
Make hygiene a priority
Wash your hands after petting, caring for, touching or feeding your pets, and remember to wash your hands before taking medicine, handling food or anything in your kitchen.
Several illnesses can be spread through pet faeces and urine. Have someone else clean up after your pet or clean the litter box, and make sure it is not kept in the kitchen or anywhere you consume food. If you must do the clean-up, wear disposable waterproof gloves and wash your hands afterwards.
Always keep your pet’s sleeping areas as clean as possible and ensure your pet does not come into your bed while you are recovering from treatment.
Keep your pet healthy
Try to keep your pet on your own property or indoors to minimise their risk of picking up an infection from other pets and animals. Cats that go outside and hunt birds or small rodents are at risk of getting a parasitic infection called toxoplasmosis. While this infection tends not to make the cat sick, it can be very serious, even fatal, for a human with a weakened immune system.
Try to avoid dog parks and walk your dog on a leash in places where they won’t encounter other animals of unknown health.
Adopting a pet during treatment
While it is not usually recommended, some people do choose to get a new pet while undergoing treatment. If this is a choice you make, it is best to adopt a healthy pet that is at least 12 months old and to have it checked by your vet. Puppies and kittens tend to ‘play rough’, bite, and scratch, and have more ‘accidents’ that need cleaning up during toilet training.
Animals to avoid during treatment
It is best to avoid contact with birds, reptiles, rodents, and other exotic pets when undergoing blood cancer treatment. These animals are common carriers of salmonella and other rare but serious diseases. Salmonella can cause diarrhoea, skin infections, and other serious viruses which can be lethal for people whose immune systems are weakened. This germ can live for some time on surfaces and objects that an affected animal has touched, which means it can be transmitted without you handling the animal.
If you do choose to keep these animals as pets during treatment, ensure you follow the precautions above when handling, feeding, cleaning up after them or handling objects the animal has touched.
Real stories about living with blood cancer and pets
Lyndell’s passion for her pets keeps her strong
Lyndell Wills is a bone marrow transplant recipient, has survived myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) and is mum to chickens, Sox the cat, and dogs, Meggs and Molly.
She was diagnosed with MDS in 2015 with it progressing to AML in late 2017.
“I was basically neutropenic from my first diagnosis, but things really ramped up when I got the AML diagnosis and was told I would need chemotherapy and a bone marrow transplant,” said Lyndell, who lives on Lake Macquarie (NSW).
“When we travelled to Sydney for my treatment, my husband and I had to leave the chickens, cat, and two dogs behind to be looked after by friends and family.
“For the first four weeks in hospital I was constantly asking my treatment team when I would be able to see them again.
“We did speak about bringing them to the side entrance of the hospital for a quick visit, but I decided that would just confuse them, with the different smells and environment.
“Throughout my whole treatment I kept photographs of my animals up on the walls of the hospital room, so they were with me in some way and gave me strength.”
Lyndell’s transplant, from an unrelated matched donor, was in December 2017.
‘’That was the most challenging time, having to be away from my two daughters and pets for so long, but we did manage a few short visits back home when I started feeling better.
“The chickens are obviously recognised as one of the high-risk animals for infections.
“We spoke to the haematologist who ran through how we can best manage that, and I certainly got out of cleaning chicken poop out of the cage for a good three years.
“But I would still sit and watch them, I just loved that when I was in the middle of treatment and feeling my weakest because they’re so busy, inquisitive, and very entertaining.”
Having dogs has also provided Lyndell with the motivation to get out and about again.
“Some days you don’t really feel like getting out of bed and want to bury yourself under the covers,” said Lyndell.
“But then you see that look in their eyes willing you to take them for a walk.”
“I now try and do something with the dogs most days. Some days it’s a shorter walk than others but it’s better than staying couped up all day.”
Lyndell encourages people to speak with their treatment team and practice good hygiene when handling their pets.
“You’ve just got to be sensible. After patting or feeding the animals, I always get up and wash my hands,” said Lyndell.
“If you’ve got an open wound, don’t let the pet near it, and avoid scratches.
“I would also highly recommend seeing a psychologist and talking about this adjustment to your lifestyle for the good of your health.
“You don’t realise what a big impact it can have on you mentally and the decision to keep pets, while it was non-negotiable for me, some people may need to work through that choice and understand what the best approach is for them.”
Lyndell also runs an online support group called, Transplant Tribe, for those who have had, or are planning to have, a bone marrow transplant, as well as their family and friends. Find out more at www.transplanttribe.com.au.
Pets ‘like therapy’ to Barb through treatment
Barb Vezos, who couldn’t imagine life without her beloved pets, prioritised hygiene and health so she can continue taking care of them safely.
Diagnosed with acute myeloid leukaemia (AML) in 2015, Barb underwent chemotherapy and a bone marrow transplant from an unrelated matched donor. At the time of her diagnosis, she was a single mum to two boys, and had four pets to care for.
“I’m so grateful for their support, it was really important to have my pets taken care of by people I know and trust.
“Unfortunately, one of the cats and dogs passed away while I was going through treatment which was really devastating…but I still returned home to Kitty the cat and my dog, Daphne, who were ecstatic to have me back.”
Before going home, Barb she spoke to her treatment team about caring for her pets safely and ensuring she minimised her risk of infection.
“I did have the option to re-home them, but I decided to just see how I went with them and if I ended up with an infection or allergies, then I would reassess,” explained Barb.
“My cat is really good, she’s not scratchy and she does her own thing most of the time.
“My dog, Sydney, was a new addition at the end of 2017. Both dogs are content to just sit by me, they don’t have to be all over me. Sometimes I look into their eyes and just know, they know what’s going on – they are so gentle.
“They can come inside, but I tend not to let them on the couch and bed now, and I am constantly washing my hands after touching and feeding them.”
Barb still remembers the week between chemotherapy and her transplant when she went home and could spend time with her pets.
“I think that was the most relaxed I had been the whole year. To just have that constant companionship was like therapy to me,” said Barb.
“I don’t know how to explain it, but the pets give me a sense of peace and are the best company in the world.
“I’ve always had animals and I couldn’t imagine my life without them.”
By Professor Susan Branford PhD, a medical scientist with the Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology and the University of South Australia and University of Adelaide.
My PhD research in biomedical science involved assessing people with CML to determine if monitoring the level of disease during therapy using a molecular marker could predict treatment outcome.
I also investigated the reasons for drug resistance that occurs in a small number of patients.
The tests I developed are now incorporated into routine patient monitoring along with the other blood tests a person with CML has on a regular basis after diagnosis.
CML is a genetic disease. A change in the structure of DNA within cells leads to the formation of a new gene that does not behave normally and causes CML. The new gene is formed from the fusion of two different genes and is called BCR-ABL1.
BCR-ABL1 is a molecular marker that can be measured during therapy. Importantly, a blood sample is required to measure BCR-ABL1 levels rather than bone marrow, the collection of which is associated with greater discomfort for patients.
In the past, there was a greater need for people with CML to have bone marrow biopsies to diagnose their disease and to monitor their response to therapy. Bone marrow collection is still necessary at diagnosis and is a very important part of patient management.
In Australia, however, molecular monitoring of BCR-ABL1 during therapy, using a blood sample, has largely taken over from bone marrow testing. The advantages of molecular testing include a shorter time for the result to be ready, and the test is 300-1000 times more sensitive for detecting low levels of leukaemia, compared with cytogenetic testing.
Our laboratory has been monitoring BCR-ABL1 levels in patients with CML for a long time and was one of the first laboratories in the world to develop this technique.
We monitored patients in early clinical trials for imatinib – the first drug that was truly effective for most CML patients and since then there have been many clinical trials of different and more powerful drugs.
All the trials have consistently shown that the molecular test can provide very useful clinical information for the prediction of response to drug therapy, and many labs around the world are now performing the test.
The molecular technique is not easy for new labs to develop and BCR-ABL1 values can vary from lab to lab. To overcome these differences, about 10 years ago it was decided that all labs adopt a common way to report the results, so a BCR-ABL1 value is similar no matter in which lab it is tested.
Working with many labs around the world, we developed a set of recommendations for the testing procedure and BCR-ABL1 values are now reported on an international reporting scale. This has improved the quality of the results.
A panel of experts recommended that BCR-ABL1 values reported on the international reporting scale be used to determine if a patient is responding well to therapy or if a change of therapy is necessary to improve response.
The critical timepoints to assess response is at three, six and 12 months of drug treatment. A value of 10% at three months, 1% at six months, and 0.1% at 12 months is an optimal response, and no change of therapy is necessary. Most patients reach these levels.
A small number of patients develop drug resistance and the main reason is a change in the DNA sequence of the BCR-ABL1 gene that can stop the drug working properly.
A rise in BCR-ABL1 level can indicate that drug resistance is occurring. When a rise occurs and the doctor suspects relapse, a blood sample can be used to check for a change in the DNA sequence of BCR-ABL1. The haematologist can then decide whether a change of therapy is necessary.
There is still a lot we don’t know about CML. At the time of diagnosis, we can’t identify those patients who will fail their therapy. But technology is rapidly advancing, and over the next 10 years, we hope to more thoroughly examine and understand the molecular changes that occur, which will lead to improved treatment and better outcomes for all patients.
Second drug treatment now controlling Leanne’s CML
This story was published in the December 2009 issue of CML News. Leanne now lives in Adelaide and has been in treatment-free remission since July 2015.
Leanne Pitman knew she wasn’t well, but it took seven months before she was finally diagnosed with chronic myeloid leukaemia (CML).
“I was tired, rundown and very cranky. I kept seeing my doctor and having blood tests,” said Leanne, 49, of Penola, 400km south of Adelaide.
Despite there being “something wrong” with her white blood cell count on each occasion, it was attributed to having just had a cold.
At around the same time, in July 2006, Leanne and her daughter, Kristy, 22, started a business together, running a café in Penola.
Six days before Christmas that year, Leanne had a blood test while in Adelaide seeing a specialist. As the result wasn’t clear she had another blood test that day (Friday) then returned to Penola.
The following Monday Leanne received a call from her specialist to say there was a problem with the result which showed her white blood count was very high. Arrangements were made for Leanne to see a haematologist in Adelaide the next day.
Leanne and her husband, Ted, had to get up very early to drive into the city for the 9am appointment.
“The haematologist was 99% sure of what I had, but he had to do another blood test to confirm it before he sat us down and told us about CML,” said Leanne.
Afterwards, Leanne’s parents, who live in Adelaide, followed the Pitmans back to Penola and they all spent a family Christmas together at home.
Leanne returned to Adelaide in early January to discuss treatment with imatinib (Glivec®) and to have a bone marrow biopsy, which was necessary to qualify for the drug to be available to her under the Pharmaceutical Benefits Scheme.
She began treatment in February 2007, 400mg of imatinib in a tablet, once a day. After a month on the treatment, Leanne started to have severe side effects including nausea, aching limbs, fluid retention, and puffy eyes.
She described the pain in her legs as debilitating: “I can remember my husband carried me into the hospital and I collapsed on the floor because my legs were so sore”.
Leanne said she had to take a lot of other tablets, in addition to the imatinib, to provide pain relief, and anti-nausea medication.
“The Glivec controlled the CML very well,” said Leanne. “But I had to consider whether I should continue to take it because of the side effects, and if I changed to a different CML medication, then the Government doesn’t let you go back onto the Glivec.”
Then, in May 2009, Leanne’s haematologist contacted her and asked if she had stopped taking the Glivec, because her latest blood test hadn’t shown any evidence of the drug.
“I said ‘no’ I’ve never missed taking it,” said Leanne, but her white blood cell count had gone up and there was no evidence of the drug in her system.
Leanne went back to Adelaide and her haematologist started her on a new drug, nilotinib (Tasigna®).
“It’s back to controlling the CML and it doesn’t have as many side-effects,” said Leanne who had been on this new treatment for more than three months as the December 2009 issue of CML News went to print.
“Now we hope the Tasigna will continue to control my blood levels, that eventually I will go into remission, then come off the medication after five years.
“I’ve got a positive outlook. I’m in good hands, I’m hoping for the best and am getting on with my life as best I can.
“I’m also feeling a lot better and people around me say how much better I am looking.”
Before her CML diagnosis Leanne worked full-time at the café. Now she is on a disability pension and helps out with a bit of bookwork for a few hours a week.
“Kristy has been a tower of strength for me,” said Leanne.
“And the Leukaemia Foundation had been fantastic.
“They have provided emotional support and are always there for me, letting me know what’s available. I’ve used the transport service to pick me up from the airport and take me to the doctor,” said Leanne who has participated in the Foundation’s CML telephone forum.
“I’ve learnt a lot more from talking to other people with the same problems.
“The CML Alliance has been good too.”
Leanne took part in the Foundation’s inaugural Light the Night fundraising event in Adelaide in 2008, and in 2009 she organised a team at Mt Gambier.
Read about Leanne’s experience with stopping treatment and being in treatment-free remission since July 2015.
The AMLM21 study is evaluating ponatinib (Iclusig®) in combination with 5-azacytidine (Vidaza®) in FLT3-ITD or CBL positive patients with AML who have failed prior therapy or are unfit for intense chemotherapy.
The trial is open to recruitment at the following sites: Victoria – Alfred Hospital, Barwon Health New South Wales – Liverpool Hospital, Calvary Mater Newcastle, Westmead Hospital Queensland – Royal Brisbane Hospital.
AMLM22 – leading doctor, Professor Andrew Wei
The most appropriate treatments for AML patients in their maintenance treatment phase are being evaluated in the AMLM22 platform trial.
This randomised, multi-arm study platform is comparing the efficacy of experimental therapies versus standard of care in patients with AML who are in first complete remission. The AMLM22 trial is an adaptive trial platform designed to compare the efficacy of novel therapies or combinations flexibly and efficiently to the current standard of care. Several treatment domains are proposed on the platform with patients randomised to the domain they are eligible to participate in, and then randomised to either an investigational or standard of care treatment arm.
This trial is open to recruitment at the following sites: Victoria – Alfred Hospital, Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Austin Health, Barwon Health, Monash Health New South Wales – Calvary Mater Newcastle, Border Medical Oncology, Prince of Wales Hospital, Concord Hospital, Gosford Hospital, Royal North Shore Hospital, Orange Health Service, Wollongong Hospital Queensland – Princess Alexandra Hospital, Townsville Hospital, ICON integrated Cancer Centre South Australia – Royal Adelaide Hospital Tasmania – Royal Hobart Hospital, Launceston Hospital Western Australia – Fiona Stanley Hospital, Sir Charles Gairdner Hospital, Royal Perth Hospital Northern Territory – Royal Darwin Hospital.
The HO150/AMLM23 trial is an international trial led by the Heamato Oncology Foundation for Adults in the Netherlands (HOVON).
This placebo-controlled study compares ivosidenib (Tibsovo®) or enasidenib (Idhifa®) in patients newly diagnosed with AML or myelodysplastic syndrome (MDS). The purpose of the study is to investigate the efficacy and safety of ivosidenib and enasidenib in patients with AML or MDS.
This trial is open to recruitment at the following sites: Victoria – Royal Melbourne Hospital, St Vincent’s Hospital, Alfred Hospital New South Wales – Royal Prince Alfred Hospital, Concord Hospital Queensland – Princess Alexandra Hospital, Townsville Hospital Tasmania – Royal Hobart Hospital Western Australia – Fiona Stanley Hospital.
AMLM25 – leading doctor, Professor Andrew Wei
The AMLM25 trial is a Phase II trial evaluating the most appropriate treatments for older AML patients.
AMLM25, also known as the INTERVENE study, is aimed at improving treatment for people aged 60 or older with adverse risk and non-adverse risk AML who have not already received previous chemotherapy (treatment-naïve), or those who are not able to receive intensive initial chemotherapy. It is hoped that the treatment will improve the initial response, prolong the duration of response, and increase overall survival.
The aim of the first part of the study is to determine the safest dose of the study drugs midostaurin (Rydapt®) or pracinostat when given in combination with venetoclax (Venclexta®) and cytarabine (LDAC).
The second part of the study will compare the effectiveness and safety of midostaurin and pracinostat when used in combination with venetoclax and cytarabine.
This trial is open to recruitment at the following sites: Victoria – Alfred Hospital, Peter MacCallum Cancer Centre, Royal Melbourne Hospital, St Vincent’s Hospital, University Hospital Geelong New South Wales – Calvary Mater Newcastle Tasmania – Royal Hobart Hospital Queensland – Townsville Hospital, Princess Alexandra Hospital South Australia – Royal Adelaide Hospital, Flinders Medical Centre Western Australia – Fiona Stanley Hospital.
For more information on current clinical trials in AML, visit the ALLG website, or speak to your treating haematologist.
* The ALLG is the only not-for-profit collaborative clinical trial group in Australia and New Zealand delivering research projects focused on blood cancers. The ALLG’s purpose is to achieve better treatments and better lives for people with AML and other blood cancers. ALLG clinical trials are taking place at 93 accredited hospital sites and cancer centres across the the country and more than 800 physicians and haematologists, nurses, scientists, and professional support staff are ALLG members.
The title of Dr Bray’s research project is Development of a translational bioengineered microenvironment model to advance pre-clinical acute myeloid leukaemia research and is supported through the Estate of Florence Brown.
Dr Bray said 3D tissue microenvironments can replicate many natural mechanical, chemical, and cellular processes that cannot be depicted in the 2D cell cultures currently used for most drug research.
“My fascination with 3D models began in 2009, during my PhD project at the Queensland Eye Institute. I was using tissue engineering to grow three-dimensional corneas for potential future applications in patients who needed a replacement,” said Dr Bray.
“I could see the remarkable potential then of these models as an alternative to animal or human testing.”
After being awarded her PhD, Dr Bray moved to Germany for on a three-year research fellowship and her focus shifted to AML.
“I had a real personal drive to bring my knowledge of tissue microenvironments back into the oncology field, as my family, friends and colleagues have been affected by cancer in many different forms,” she said.
“In the lab, when you’re using a standard culture of leukaemia cells, they are just floating around in a solution and we know it’s not replicating the way that leukaemia cells grow in the actual bone marrow environment. There are other cell types in the bone marrow, including blood vessels which act as a conduit to nutrients and flush out waste in the body.
“But these blood vessels can also act to protect leukaemia cells, giving them the ability to hide and become resistant to treatment.
“By developing these 3D bone marrow microenvironments, we hope to understand how these leukaemia cells interact with the surrounding natural cells, and hopefully develop new targets to stop them growing in that space.”
These models have the potential to be utilised as research platforms for fundamental biological studies and pre-clinical trials, as well as to study new targeted therapies for cancer patients.
Dr Bray is eager to see the study build on previous findings which her research group has already published.
“We were able to recreate part of a 3D bone marrow microenvironment and watch the leukaemia cells interact with it in real time,” she said.
“We then applied a certain drug that inhibits the ability of the cancer cells to adhere to the blood vessel and watched the cells successfully detach from the vessels in the model, showing that our models can reproduce quite complex biological processes.”
Having Leukaemia Foundation funding will enable Dr Bray to determine which cells will survive after certain treatments and then start to grow again.
“Over time we need to be able to identify these specific cells and then remove them out of the model to study what makes them resistant,” said Dr Bray.
“By being able to profile these cells, we can hopefully find some new targeted treatments.”
A major driver for developing these models is to reduce the number of animals used for drug testing, and in 2015, Dr Bray was awarded a Lush Prize for her work; the largest global prize fund in the non-animal testing sector.
“The regulatory structure in Australia stipulates that animal testing must be done prior to human trials,” she said.
“But we know that 95% of drugs that have positive results in a lab setting will fail in human clinical trials.
“We want to change that pipeline with these 3D models acting as a middle ground where those non-effective drugs can be weeded out.
“This will save time, money, and many animals from having to be sacrificed just to find out that the drug will not work on a human.”
Due to the COVID-19 pandemic, Dr Bray’s lab was closed for four months last year and was unable to source specialised blood vessel cells from the U.S. supplier during that time.
“That was really difficult as it takes a lot of time to build up these cell cultures,” explained Dr Bray.
“It takes a few months of work, either side, to wind it down and then start it up again, but hopefully we are through the worst of it now and the Leukaemia Foundation has been really understanding and permitted an extension to my grant funding period.”
Over the past few years, Dr Bray and her team have worked to promote the benefits of 3D models and encourage biologists at the bench to adopt the technology.
“Traditional 2D cultures are easy and they’re cheap, but we and others are trying to bring these 3D models into the mainstream research space.
“This project will certainly help our case with the dream to see these three-dimensional technologies applied across all diseases, not just blood cancer.”
Why Dr Morrison pays attention to his vitamin C intake
Internationally recognised leader in stem cell research, Dr Sean Morrison, makes sure he gets his daily requirement of vitamin C – not a lot more and definitely no less!
Why? Because his research has discovered a connection between vitamin C levels and leukaemia, and the importance of meeting daily requirements as opposed to taking megadoses.
Dr Morrison is director of the Children’s Medical Center Research Institute at UT Southwestern*, Dallas (U.S.). He was in Brisbane in 2019 to present at the International Society of Experimental Haematology (ISEH) meeting where he spoke to AML News.
His lab focuses on the blood forming system and studies stem cells in cancer.
“We study the mechanisms stem cells use to replicate themselves, which is how they persist throughout life in our tissues, and the ways in which cancer cells hijack those mechanisms,” said Dr Morrison.
“Cancer is a disease of dysregulated self-renewal, where cancer cells hijack the mechanisms that stem cells use to self-renew and over-activate those mechanisms to form tumours rather than normal tissues.
“We are trying to improve the treatment of disease, including cancer, by better understanding the underlying biology.
“Anything that promotes those mechanisms is a potential regenerative medicine therapy, and anything that inhibits those mechanisms is a potential anti-cancer therapy,” explained Dr Morrison.
“We have done a lot of work to characterise the micro-environment that maintains stem cells in the bone marrow.
“There are specialised cells in the bone marrow that help to maintain blood forming stem cells.
“One thing leukaemia cells do, is eliminate the normal cells partly by destroying those niche cells that help to maintain the normal cells.
“We discovered these leptin receptor positive cells that are the main source of factors that promote the maintenance of stem cells.
“Cancer cells kill off those normal leptin receptor positive cells and the normal stem cells, and by eliminating the competition from the normal cells it helps the leukaemia cells to progress more quickly,” he said.
Understanding the metabolic regulation of stem cells is another area of Dr Morrison’s research.
“We are looking very widely at whether there are metabolic pathways that are active in stem cells, more so than in other cells, and whether those pathways could be involved in supressing the development of leukaemia. And we found that they are,” he said.
“It turns out that haematopoietic stem cells take up more vitamin C than other haematopoietic cells.
“They have to take up vitamin C to regulate normal gene expression in the stem cells.
“Part of what vitamin C does is that it suppresses the development of leukaemia from blood forming stem cells.”
“You’ve heard your whole life… eat fruit to suppress the development of cancer,” said Dr Morrison.
“There were old epidemiological studies done, where it was seen that people with below average vitamin C levels get more cancer, but the underlying mechanisms were not at all clear.
“We’ve discovered some of the underlying mechanisms, where there is a particular tumour suppressor, called TET2, in the haematopoietic system that gets mutated in a lot of leukaemias.
“TET2 function requires vitamin C, and vitamin C is limiting for TET2 function,” he said.
“So, people who don’t get enough vitamin C in their diet don’t have adequate TET2 activity and they’re walking around with messed up stem cells in a way that predisposes them to leukaemia.
“That research has been published in the journal, Nature, and we’ve continued to refine and develop these methods for studying stem cell metabolism.”
Dr Morrison said another exciting discovery in recent years is that clonal haematopoiesis is more common than originally thought. This is where a haematopoietic stem cell (HSC) acquires mutations that allows it to outcompete normal HSCs and it starts to take over blood cell production.
“Normally, thousands of blood forming stem cells contribute to blood cell production, but as you get older, or if you have been treated for cancer, a surprisingly high fraction of people have clonal haematopoiesis.”
Dr Morrison said that by age 70, at least 10% of all people have clonal haematopoiesis, and about 30% of people who have been treated for cancer – who have received radiation therapy or chemotherapy – have clonal haematopoiesis.
“We are talking about a lot of people in the Western world, most of whom have no idea they have clonal haematopoiesis.
“This is a pre-leukaemic condition and in addition to increasing their risk of leukaemia, it predisposes to other diseases of aging, like cardiovascular disease,” said Dr Morrison.
“The people who discovered clonal haematopoiesis think the existence of this condition, along with the loss of TET2 function, causes the blood forming system to become more inflammatory.
“Inflammation makes us old and causes the changes that occur during aging.
“One of the most common mutations – the second most common mutation in clonal haematopoiesis – is loss of one allele** of TET2.
“While most people with clonal haematopoiesis never develop leukaemia, it is just a subset.
“We think the people who are most likely to develop leukaemia are those who have not only lost one allele of their copies of TET2, but who are also not getting enough vitamin C in their diet. If you are down to one good copy of TET2, you better get 100% of your daily vitamin C requirement in order to maximise the leukaemia-suppressive activity of the copy of TET2 that you have left,” he explained.
“And we know there is a dosage relationship, that the more you reduce TET2 activity, the more likely you are to get leukaemia.
“We are testing that in patients now, by offering to test vitamin C levels in everybody with clonal haematopoiesis. We are collecting that data over time to test our prediction that people with lower levels of vitamin c are more likely to progress to leukaemia.
“If it turns out that we are correct, and we can predict who is going to get leukaemia and who is not, based on their vitamin C levels, then it could have a major public health impact to insist that everybody with clonal haematopoiesis drinks a glass of orange juice every day or takes a multivitamin to ensure that they get 100% of their vitamin C.”
Dr Morrison said testing for clonal haematopoiesis involved sequencing and was not routinely done by doctors now.
“But I think, someday, it will start to be done routinely,” he said.
“In the future, when we hit 60 years old, or have been treated for cancer, we will be tested for clonal haematopoiesis. And then people will start paying attention to their vitamin C levels.
“After we saw from our experiments that blood cancer was particularly sensitive to vitamin C, we went back to the Centres for Disease Control and Prevention data and found that for most cancers, risk doesn’t change with vitamin C nutrition.
“There are only a few cancers that go up with low vitamin C and myeloid leukaemia is number one on the list.”
“If we could ensure that everybody with clonal haematopoiesis got optimal ascorbic nutrition, I bet we could cut down on the number (thousands) of people who would otherwise have got cancer,” he said.
So, does Dr Morrison pay attention to his vitamin C intake?
“Historically, I never did. I feel like I eat a pretty good diet. But after we published this paper, I was thinking that there are some days where I really don’t get 100% of my vitamin C, so I started taking a multivitamin.
“I don’t want people to misinterpret what I’m saying. I’m not suggesting people go out to the drug store and buy those megadoses of vitamin C,” emphasised Dr Morrison.
“I just think getting 100% of your daily requirement is good, and that doesn’t mean that 1000% is better. But getting 100% is good. That is why I take a multivitamin that has a little bit of vitamin C in it.”
Pre-COVID-19, Dr Morrison flew 200,000 miles (320,000 km) a year travelling the world to meetings like the ISEH meeting in Brisbane.
“I probably do travel too much,” he said.
“I prefer to be at home. It’s a healthier lifestyle to be at home, sleeping in your own bed, eating healthy food that you control, and getting exercise.
“But on the other hand, I almost never come to a meeting and feel like it’s a waste of my time.
“I learn something every time I come to meetings. I sit there, emailing questions back to people in the lab – ideas about doing new techniques or new ways of testing the things that we are working on. It does accelerate the science, and that undermines my willpower to say, ‘no’ more.”
Melanoma, in particular melanoma metastasis, is another area of study in Dr Morrison’s lab, which resulted in the discovery that melanoma cells are unusually sensitive to oxidative stress during metastasis.
“Let me give one piece of advice that your readers may not have heard elsewhere,” said Dr Morrison.
“The idea is so strong in people’s minds that antioxidants are good for you. For many years, there was this idea that if you ate antioxidants you would age more slowly and get less cancer.
“In fact, many clinical trials show that people who take antioxidants get more cancers, have worse outcomes with cancer, and are more likely to die of different causes,” said Dr Morrison.
“In our experiments with melanoma, we see that the cancer cells benefit more from the antioxidants than the normal cells do. If we take a mouse with melanoma and give it antioxidants, the melanoma progresses and kills the mouse faster.
“I worry that people who are diagnosed with a serious cancer and become very health conscious, then go to the drugstore and start buying all these supplements and antioxidants and things, are increasing their risk of dying because the cancer cells benefit more from the antioxidants.
“I’m not telling anyone to eat an unhealthy diet,” said Dr Morrison, who specifically mentioned people buying a pill that has 500% of the daily requirement of an antioxidant (vitamins A and E).
“In clinical trials, when people supplement their diet with large levels of vitamin A or vitamin E precursors, they have worse outcomes in terms of cancer.
“Now that people like us are finding the underlying molecular mechanisms, when combined with the earlier clinical trials that show worse outcomes, I think the scientific community is really flipping over to recognise that while it’s good to get 100% of your daily requirement of these things to be healthy, it’s not good to get 500%, especially if it is from a pill.
“If you eat a salad, those vitamins get released into your system over a period of time as you digest it. But if you eat a pill, your system gets blasted with these chemicals very quickly and the idea that if a little of something is good, more must be better, doesn’t turn out to be true,” said Dr Morrison, whose overall career goal is for a new therapy to emerge from his lab’s work that cures people who wouldn’t otherwise be cured.
* UT Southwestern is a premier academic medical centre in the U.S. that integrates pioneering biomedical research with exceptional clinical care and education.
Dr Traver’s fascination with how leukaemia happens
Dr David Traver is an experimental haematologist who specialises in haematopoiesis*. The Professor of Cellular and Molecular Medicine, and of Cell and Developmental Biology, at the University of California (San Diego, U.S.) spoke to AML News at the International Society of Experimental Hematology (ISEH) conference in Brisbane (Aug 2019), where he was awarded the Leukaemia Foundation-sponsored McCulloch and Till Award and gave the closing lecture on Decoding the molecular cues that regulate HSC specification.
How do you feel about receiving this award?
It was quite a surprise and an honour. This has always been my favourite meeting. I gave my first talk in science at this meeting when I was a graduate student, in Vancouver in 1997 or 1998. I was terrified. There were all of these big names in the audience who I had only read about as a third-year student. But everyone was so open and welcoming, and they were all very approachable. It has been my favourite meeting ever since.
And now you’re one of those famous people!
I guess [laughter] but I’ve never cared about being famous. I’d like to be rich, but I think I chose the wrong career for that. I generally don’t like to be the centre of attention, so I sometimes wonder why I chose this career. The idea of being the lab’s spokesperson was initially challenging for me, but I’ve learned over the years to enjoy it. I love the science and love to always be learning.
How did you become an experimental haematologist?
I joined the immunology program at Stanford University, where I had a choice of about 30 labs working on things related to immunology. I was attracted to Irv Weissman’s group because he was focused on haematopoiesis, meaning the study of how blood cells arise, how stem cells work, and how leukaemia happens. And those were the questions I found really fascinating, rather than classic immunology. I liked the process of blood formation, then became intrigued with development, genetics, and imaging, and fell in love with the zebrafish, which was an emerging system at the time.
What is your lab working on?
We are trying to understand how the stem cells that make the entire haematopoietic system are born. In other words, how they are first formed during development of the embryo. One of the big goals of regenerative medicine is to harness the technology of induced pluripotent stem cells [that have the potential to make all the cell types in our bodies], as discovered by Shinya Yamanaka, to make patient-specific blood cells. What we can’t do yet is make blood stem cells from this primitive precursor. A transplant for a person with leukaemia or a blood-based disease needs haematopoietic stem cells (HSCs), to provide lifelong regeneration of the lineages they need. Ultimately, the goal for many of us in the field is to try and take these human pluripotent stem cells and instruct them to generate HSCs. Despite attempts for 30 years, we’ve never been able to do it because we don’t yet know enough about how the embryo does it.
What are your big picture goals?
One is to understand how the embryo makes HSCs. That’s why we use zebrafish. They are born externally from their mother and are completely translucent for the first week of life. They develop into a free-swimming animal with a beating heart and stem cells within 24 hours of fertilisation. We can use fluorescent transgenes to light up the HSCs to watch how they behave inside a living animal in real time.
“We saw the HSCs being born out of one of the major blood vessels, just by watching to see what happened.”
There were several theories about where HSCs were born in the embryo. We imaged animals with fluorescent blood vessels and fluorescent HSCs via a 24 hour time-lapse and the evidence was irrefutable. That is what we’ve been working to better understand ever since.
What does this finding mean?
Once we knew, finally, where stem cells were coming from, we could then work to figure out how, genetically, those cells were born… how they are made, how the environment instructs them what to become. What we are working on now is to target single HSCs at the site of emergence [where they are born] and activate a single oncogene** in a single stem cell.
“This is how everyone thinks cancer starts.”
You take one hit, probably to a stem cell because it has to live long enough to accumulate more mutations. We can ask, is that sufficient? It is not thought that one mutation is ever sufficient to cause cancer, but it might be sufficient to start the process.
What questions are you asking now?
If a clone we are working on does give risk to leukaemia later on, how does it do it?
We can pull out those clones and ask every week… how does that clone change in a molecular way? We can activate an oncogene in a single stem cell in a hundred different embryos and pull out 10 embryos every week or month and ask… how are they changing? This is the five-year plan; what we are working to do now. You can only do these amazing experiments in zebrafish because everything happens ex utero. This approach cannot be taken in mouse models because you can’t effectively target those stem cells that early.
“And the powerful thing is that we’ve all come from a common ancestor.”
So, the things that we discover in zebrafish are almost always applicable to studies in mice, frogs, or humans, since our immune systems have all derived from a shared ancestral source. The zebrafish we work on are really beautiful. They’re remarkable little creatures. You can see every cell in their bodies and how they behave in real time. My talk [at ISEH] includes a few time-lapse movies people in the lab generated. We do a lot of our early work, genetics, imaging and stem cell biology in the zebrafish, and revalidate our findings usually in the mouse embryo, where my early training was. Then often we take what we’ve learned and test it in human pluripotent cell systems. I think, ideally, if we can show the same thing is true in systems as different as fish, a rodent, and us, then it is fundamental and a great foundation to move forward.
How is your work contributing to blood cancer treatment?
We are studying the genetic mechanisms of how stem cells are born and how are they are maintained, and a big part of that is self-renewal. The hallmark of the stem cell is how it can make copies of itself forever, without becoming cancerous. Stem cells and cancer cells are the flipside of the same coin because cancer cells should never self-renew but somehow can. There could be a lot in common with the normal self-renewal mechanisms of stem cells and how cancer cells become transformed. Once we can generate these models of leukaemia starting with a single cell, we can do chemical screens and rapidly discover compounds that specifically kill that cancer.
For children with translocations in the mixed-lineage leukaemia (MLL) gene there is no effective treatment and it [MLL] is invariably fatal. It is thought that these translocations happen very early in development, because if you find identical twins where one has the mutation, the other almost always does too – meaning it happened very early in development, when each shared a circulatory system. So, this particular translocation is intimately involved in HSC emergence. It happens very early, which is one reason we think if we can activate expression of the human oncogene in a single stem cell it may accurately model what happens in these children.
What happens in your lab day-to-day?
It depends on the day. We have lab meetings once a week, where my students and fellows present their work and receive feedback from myself and others in the lab. I like to have a lab of 10-12 people, that is my ideal size. We have a journal club where we talk about papers that are relevant to what we do. I meet individually with everyone for at least half an hour a week to talk about their projects, their results, and to troubleshoot. One of my main jobs is to facilitate – to know the bigger picture, and how the individual components connect. I teach a fair amount – classes in stem cell biology, and there are grant cycles that are never-ending. It usually takes a couple of submissions to land a grant these days. And there are lots of faculty meetings and different seminars to participate in each week. I don’t do much experimenting anymore, I’m too busy with writing, grants, travelling, teaching and everything else that comes with this often crazy job.
What advice can you offer people with a blood cancer like AML?
One thing to try and do is to stay on top of what’s developing. If you have a disease that is typically hard to treat, see what is out there in terms of trials, talk to your doctor, and talk to researchers. A lot of patient-specific immune therapy, like the CAR T-cells, have had amazing success. But it has only worked so far for a handful of cancers and leukaemias. The cancer immunotherapy field is moving fast.
“I lost my own mother to AML 10 years ago.”
It was very demoralising and disappointing to see her taken by something I felt I knew a lot about and should be able to understand. My mum had a perfect match for the bone marrow transplant, she just couldn’t handle the preparative regimen. Her body rejected the platelets that were transfused following the chemotherapy. I think we just still don’t know enough. The regimens used are very generic, and damages all systems in the body. We need to get better at finding regimens that are more specific for each disease type.
What is your holy grail?
I would love to contribute to the recipe on how to effectively build a blood stem cell from scratch. Then we can translate our findings, from our embryonic settings, to in vitro settings in human pluripotent stem cells. I think, in a couple of years, we and others in the field will figure it out… but I have thought that for a while [laughter]. In the second phase of my career I would love to contribute more directly to human health and to helping people, because what we do in basic science often takes a long time to find its way to helping patients.
*Haematopoietic stem cells (HSCs) are the stem cells that give rise to all blood and immune cells. This process is called haematopoiesis and occurs in the bone marrow, in the core of most bones.
**An oncogene is a gene that has the potential to cause cancer.