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 go 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 go will into remission, then come off the medication over 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.
Chronic blood cancer diagnosis sparks Mel’s passion for awareness
Since receiving a shock chronic myeloid leukaemia (CML) diagnosis in July 2020, Mel Harris has learnt quickly that the so-called ‘invisible cancer’ can have everyday impacts beyond what many would expect.
Mel had been feeling unwell for months in the lead up to her diagnosis, always cold to the bone, constantly tired, experiencing night sweats and “horrific” back pain.
“I just explained everything away – thinking it was menopause, maybe depression or just the huge year we were having with the global pandemic,” explained the 47-year-old from Canberra.
“The first week of July, things got worse and I couldn’t physically get out of bed. My 18-year-old daughter, Mackenzie said to me, ‘Mum, I’m really worried’.
“That was enough to kick me into gear and I went to the gym the next day. Not long after I started exercising, I passed out and was taken to hospital!”
“I spent the next couple hours Googling the disease, reading about poor prognoses and aggressive treatment regimens – that was really scary,” said Mel.
“I then got transferred to a different hospital in Canberra to have a bone marrow biopsy and the morning after, the haematologist was able to confirm that it was actually chronic myeloid leakaemia (CML).
“Within about 18 hours, I’d gone from feeling like I could smash out a gym session to being diagnosed with a blood cancer.”
Mel was relieved when the haematologist explained that CML was an entirely manageable blood cancer which most people live with for the rest of their life and rarely die from.
“I was just thanking god, because Mackenzie wasn’t quite 18 at the time, it’s just the two of us and she was in the midst of finishing grade 12,” said Mel.
“My haematologist has been really good, explaining the full history of CML drugs. He’s been around for a while and told me how he could remember when this ‘miracle drug’ called imatinib was in clinical trials.”
Since starting on imatinib, Mel has experienced minor side effects of night-time nausea, bone pain, fluid retention under her eyes, a swollen spleen and neck.
“But my GP and haematologist work well together to address those issues as soon as they come up,” she said.
“It’s not hard to manage and I actually feel really lucky because some of the side effects I’ve read on the online support groups sound horrific.
“I do find the groups good for connecting with others and information sharing. I ran out of my drug one day and I remembered that someone had posted about a great chemist in Canberra who would have stock – that was really helpful.”
A couple of months into treatment, Mel started to feel like herself again and went into her haematologist’s office thinking she would be told she had beaten the leukaemia.
“I had taken my tablet religiously every night at the same time, I’d been exercising again, not drinking alcohol and maintaining a really healthy diet,” said Mel.
“I was having regular blood tests, my white blood counts and haemoglobin were looking really good.
“It had completely eluded me that I would still need leukaemia tests every three months and I would need zero detection of leukaemia to be cleared.
“He said to me, ‘You must remember at the end of the day, you still have blood cancer. Just give yourself a break’.”
Mel works as a capability and change strategist at the Australian Trade and Investment Commission (Austrade) in Canberra.
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.
Expert interview series: Dr David Yeung discusses CML
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 rapidlyevolve 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 persistencefrom 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.”
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.
“If you didn’t havea 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 ofpotential 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 here, in 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 miserable, they 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 developingside-effects and how this may affect them – actively taking into account other chronic health problems a 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.
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 preparationswere being finalised for a Phase II Australasian study run through the Australasian Leukaemia & Lymphoma Group to test asciminib innewly 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 burdenfall (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.”
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 through, someone 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 therapyand 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.
Five-year prognosis unacceptable to CML warrior Rona
Rona Wall was diagnosed with CMLin January 2002 after noticing that a large black bruise on her arm hadn’t healed after six weeks.
She was living in Sydney at the time, working three part-time jobs, and she and her now late husband, Richard, had recently sold their home. They had plans to move to coastal Kiama, south of the city.
When Rona went to her GP to have her high blood pressure checked, just before Christmas 2001, she also asked him about the bruise. Even though her bloods had been “perfect” nine months earlier, her doctor ordered another full blood test, and Rona was shocked when he called her in the new year.
“He told me I had something wrong with my white cells,” said Rona, now aged 77.
“And straight away I said, ‘I’ve got leukaemia’.
“The line went dead silent, then he asked me, ‘how do you know that?’, and I told him my brother died from leukaemia when I was two.
“My father described it to us as, ‘the white cells ate the other cells’. His leukaemia had nothing to do with mine though, I’m told it’s not hereditary.”
Rona said her CML was untreatable with chemotherapy and, 59 years old at the time, she was classed as too old to have a bone marrow transplant, so she went on hydroxyurea (Hydrea®) to lower her high white blood cell count.
“At the time, it was mostly used to treat AIDS and I was given a prognosis of five years,” explained Rona.
“I’m a very strong person and I didn’t accept that. My late husband, daughter and I were very determined to find another treatment that would prolong my life.”
Self-advocating for imatinib
In 2005, Rona’s oncologist-haematologist mentioned a new CML drug, imatinib (Glivec®).
“He asked me; ‘you don’t have $6000 a month to spend on it do you?’,” said Rona.
“I didn’t have that type of money, but I was determined to get the drug.
“My daughter, Trenna-Ann and her husband, Rob, offered to sell their Sydney apartment to pay for it, but I couldn’t accept that.
“You’ve got to take responsibility for your own life.”
Rona called the drug’s manufacturer, Novartis, asking if there was a way she could get access to imatinib at an affordable price. And she continued to call every week for three months.
“I eventually got the name of a research doctor running an imatinib CML trial,” said Rona.
“I still struggled to get an appointment and was told patients were selected by the researchers, not by patients coming to them directly.”
Luckily, Rona’s oncologist-haematologist at the time was able to pull some strings to get her an appointment, and when she finally got into see the trial investigator, she told him how difficult it had been to get an appointment.
“Well, that really changed things,” explained Rona.
“He said to me, ‘that’s wrong, anyone should be able to access this whether you’re a vagrant on the street or the prime minister’,” said Rona.
“He really was my saving grace.
“Later, I told him how I thought I only had two years left when I first saw him, and he said, ‘no Rona, you actually only had three months!’.”
Imatinib revolutionised Rona’s blood results, and her only “real side-effect” was fluid retention.
Transitioning to nilotinib
Rona continued taking her imatinib tablets for almost a decade until allergies affected her so badly in 2015 that something had to change.
“I had terrible swelling on my eye lids and could hardly open my eyes,” said Rona. “I literally had to prise them open in the mornings.
“I was able to go on a new drug that didn’t have that side-effect, called nilotinib (Tasigna®).
“It was a bit of a risk changing over as I couldn’t go back on imatinib (Glivec®) if this failed.
“I really took a chance, but luckily it paid off. It keeps me in remission and I will be on it for the rest of my life,” said Rona who also takes medication for her thyroid, cholesterol, blood pressure and immune system.
She has blood tests every three months and sees her haematologist every six months for a check-up.
In 2017, Rona attempted to come off nilotinib in a government-led stopping treatment trial.
“Within a month I was incredibly fatigued and not myself at all,” said Rona.
“My leukaemia had become acute and they put me straight back on nilotinib; four tablets a day instead of one.
“I also had prednisone for three months to counteract my allergies from the strength of the nilotinib.
“Then I became terribly allergic to prednisone as well, with thrush in my throat and bad rashes, but slowly weaned myself off it.
“Interestingly, 60 per cent of people in that trial were able to remain off the nilotinib, I was just one of the unlucky ones,” said Rona.
Playing the carer
During most of her CML journey, Rona had also cared for her husband. Richard had been finally diagnosed with dementia in 2007 and he passed away in 2016.
“That whole time I really put my own leukaemia to the back of mind. He was my main priority,” said Rona.
“All I had to do was take my pills every day and keep up my appointments.
“I was very strong through that whole time. I took him to all the support meetings; we did everything together.”
Trenna-Annand a carer friend, Henne,werea great source of support during this time. They alternated going down to Kiamafrom Sydney each weekend.
“I was very lucky to have that extra support, especially with physical tasks like showering [Richard] because they tend to get very cranky with the person they love,” explained Rona.
“They don’t like you telling them what to do all the time, so that can be very challenging.
“We got through it though and there were some hysterically funny moments with the misunderstandings that went on.
“I was going write a book called, ‘It’s all not that bad’ filled with stories of the funny things he did.
“You really have to laugh through those tough times. That’s the biggest lesson I learnt through it all.”
Leukaemia Foundation support
Rona got in touch with the Leukaemia Foundation after her diagnosis and she was connected with another CML patient, to share their experiences.
“They put me on to a beautiful lady called Euniceand I even spoke to her last week,” said Rona.
“She has been a great friend and we’ve kept each other going. She had the same issue with her eyes on imatinib so we could talk through that – it’s just been fabulous.”
Rona also regularly attended the Leukaemia Foundation’s support groups prior to COVID-19.
“Snezana [a blood cancer support coordinator] from the Leukaemia Foundation has been so wonderful, giving up her Saturdays to run the groups. She even comes and picks me up from the train station,” said Rona.
“Those groups make a big difference. There’s not a huge amount of trusted information out there and you need to be sure you’re not going down a Google rabbit hole.”
In 2014, Rona participated in the Leukaemia Foundation’s World’s Greatest Shave raising $5,000 to support others going through a blood cancer diagnosis.
The future is bright
When Rona spoke to CML News, she was renovating her beachfront unit. She keeps busy with her groups of close girlfriends, in Sydney and Kiama. She loved going on cruises with Richard and then later, with her girlfriends.
“My girlfriend and I have a trip planned to the Cook Islands. It’s been on my bucket-list for ages and it will be bliss to get away after the year we’ve all had,” said Rona, who is always looking forward to the future.
Rick’s “very happy” with his decision to change to generic imatinib
Rick Razey, who was diagnosed with CML in 2015, didn’t hesitate to change his prescription to a generic imatinib a couple of years ago when he heard of its availability.
Then he made another change after hearing of a different brand of imatinib that donated profits from its drug, Cipla, to a charity – the Leukaemia Foundation.
“If you can take a drug that can do good for others… why wouldn’t you do that? It makes complete sense to me,” said Rick, 53, of Sydney.
When he was told he had CML, on 20 May 2015, his haematologist described him as the earliest case of detectable CML he’d seen in his career, and that that was “good news”.
Rick was having investigations into a cough he’d had for a few years when a blood test revealed some concerning numbers. The blood test was redone and when those results showed some of those numbers had worsened, Rick was referred to a clinical haematologist.
After more detailed tests, Rick’s haematologist explained, “the bad news is, you’ve got chronic myeloid leukaemia, but the good news is I think it is the earliest I have ever seen it detected in my career”.
“We can see from other blood tests you’ve had that there was not a hint of it then, so you’ve had it in your system for between one and three months and that is exceptionally early to detect CML,” said Rick’s haematologist.
He also said, “the earlier that you detect this sort of thing, the much better the prognosis”. But when Rick asked about life expectancy, he said “no change”.
Rick went straight onto imatinib (Glivec®) – four 100mg tablets a day – and he continued his active lifestyle, playing squash every week, and wakeboarding and waterskiing every weekend. He worked in the retirement living industry at the time and was studying nursing at university.
Just shy of 12 months later – on 16 May 2016 – Rick was told he had achieved a complete molecular remission.
Rick’s daily dose continued to be 400mg, but one tablet instead of four, and he has always been strict about adherence to his medication.
“I’m 99.9% compliant. I think I’ve missed one capsule in the last year. You’d say I’m 364 out of 365 days a year compliant,” he said.
“The day I missed was when I was away travelling and a flight got cancelled when I was in Airlie Beach. I had taken enough tablets for the time I was meant to be away and we got stuck there for an extra day.
“Now when I travel, I take one or two extra tablets with me.”
Rick said he “basically has no side-effects” from imatinib, “occasionally some toileting urgency and some very occasional cramps, but it’s very occasional”.
“I have noticed that if you don’t have enough in your stomach, you’re definitely prone to gastrointestinal (GI) upset with imatinib,” he said.
When Rick’s pharmacist mentioned that Glivec was about to go off patent, he decided to go on to a generic form of imatinib when it became available.
“I said to my pharmacist – let me know as soon as you get the non-branded product in and I’ll give it a go. The first generic imatinib came with a whole range of skincare products and it seemed okay.
“The next time I saw my haematologist I told him I’d changed from the Glivec. He said he had a brochure about another generic imatinib that apparently gave all the profits away to charity – the Leukaemia Foundation.
He gave Rick a copy of a For Benefits Medicine (FBM) brochure about the generic imatinib, Cipla, and said, “do some research yourself. Ring them up and have a chat”.
“And I did. I rang up and spoke to John [Hurley, an FBM Director] and asked him all about it and he explained what they did and what the story was.
“He said you just need to ask your pharmacist to order in Cipla imatinib.
“So I went in and asked the pharmacist. I said, ‘this is what I want you to order’ and he did that, and I changed. I’ve been getting it ever since and I’ve been very happy.
“That’s how I got on to it. I got the initial recommendation from my clinical haematologist.”
Rick had no concerns about changing to a generic imatinib.
“Cipla is a capsule, not a tablet, and I have found that the capsule is actually a bit better. It has reduced GI upset, compared to the tablet.
“I asked John and Barry [Frost, also an FBM Director] about that and they said they didn’t think there was any research about that.
“I said, well I reckon the capsules are fractionally better.
“I’ve had no problems and it’s been terrific, and the thing is, the profits go to the Leukaemia Foundation – that’s the very best thing.
“It’s a shame that Australians are fearful of generics,” said Rick. “It didn’t really concern me because the TGA has pretty high standards.”
When he spoke to CML e-News, Rick was about to begin a “brand new career”. He starts work next month (February 2020) as a registered nurse.
World leader in CML research, Professor Timothy Hughes has seen CML transform from “a universally fatal disease” in the 1980s, to a chronic disease requiring lifelong therapy in the 2000s, to a disease where treatment free remission is possible for many in the current decade. He is Cancer Theme Leader at the South Australian Health and Medical Research Institute (SAHMRI), Beat Cancer Professor at the University of Adelaide and has a host of accolades including the GSK Award for Research Excellence 2017.
Q. Why did you choose a career in CML?
I specialised in CML after having the privilege of working with [the late] John Goldman in London in the 1980s. He was the leader in the field at that stage. CML was such a fascinating and challenging disease. We knew a mutant gene caused the leukaemia but couldn’t convert that knowledge into treatment. I thought this was a worthwhile challenge to build my career on.
Q. How has CML treatment changed?
The first agent that had an impact on survival was interferon. It was very toxic, with severe side-effects and only benefitted about 25% of patients. When the tyrosine kinase inhibitors (TKIs) first became clinically available in Australia around 2000, we started seeing good responses in over 80% of patients. The responses were deeper and the tolerance of these oral agents was much better. This complete turnaround in both effectiveness and tolerance is important when you’re talking about a lifelong therapy. The first TKI was imatinib (Glivec®) and the responses were so dramatic that a couple of CML experts, including me, proposed that perhaps some patients could eventually stop their therapy.
Q. What was the initial response to treatment free remission?
French and the Australian groups pioneered the concept of treatment free remission (TFR) as a potential ultimate goal of CML treatment. For many years TFR was regarded as dangerous and inappropriate and something patients would find confusing, as on the one hand we tell them to take their drug every day, and on the other hand we tell them to stop taking their drug one day. There’s still a lot of concern about doing it properly, under the right conditions. The risk is that clinicians who aren’t very experienced at treating CML may misinterpret or only get half the message and stop their patient’s therapy after a couple of years when their responses have been good, but not as deep as you need to get successful TFR. That’s something we talk about a lot at meetings and workshops; the critical requirements that make TFR a safe thing.
Q. What stopping treatment trials have been held here?
We started a trial in 2006, as did the French, where patients who’d had the deepest response for at least two years actually stopped their therapy. Both trials made the same observation. Half the patients rapidly regained their leukaemia population, had to go back on therapy and got good [CML] control. And half remained in deep response, with no need for further therapy. Some patients have been off therapy for more than 10 years now and remain in remission. So, we’re starting to think of the possibility of actually curing some of these patients, but won’t know that for another 10-20 years. In Adelaide we have 80+ patients who have come off their drug and around half are still in remission. The other half have had to go back on their TKI drug and we’re now looking at other ways of getting them off their therapies.
Q. What are the latest results around TFR?
Our knowledge has rapidly evolved as we do more of these trials. The initial trials were only for patients who’d had a very long exposure to imatinib – at least eight years – and that’s when we found out it was safe to attempt TFR. Now there are two more potent kinase inhibitors (nilotinib and dasatinib) that can be used as frontline therapy. The question we wanted to address was – do you need to wait so long before stopping these more potent TKIs, because we’re achieving deep responses much earlier than we did with imatinib? We’ve conducted some studies and one was published last month [March 2018] in the Annals of Internal Medicine showing patients who’ve gone on a more potent TKI after switching over from imatinib are able to stop their therapy successfully as well. Another recent study shows that if you actually start [CML treatment] with the more potent drug, you can in many cases get them off their therapy within four to five years. That’s a very strong message to give to a young patient, particularly a young woman who wants to start a family but is aware that they can’t attempt pregnancy while taking TKI therapy because it’s teratogenic. This has been a real dilemma for many young women. Now, if they go on to more potent therapy right from the start, there’s a very good chance they’ll get a deep response in three to five years, and thus be eligible to attempt to achieve TFR.
Q. Why do half the patients who stop treatment relapse?
That’s something we’re actively investigating. It’s clear that the longer you keep a patient on their drug and the longer that they have achieved a deep response, the more likely it is that they will remain in TFR. There are competing hypotheses. One is that we’re gradually getting rid of the leukaemic stem cells capable of causing relapse and eventually you no longer need the drug because you no longer have the cells present that are capable of relapsing. The other hypothesis, with equally strong evidence, is that the immune system is capable of controlling the CML cells when you get down to a very low number in the blood and bone marrow, so you no longer need TKI therapy at that stage. If that is the case, the way forward is to stimulate the immune system to allow patients to stay off their therapy long-term. There are trials starting where we use immune stimulatory drugs to see if we can achieve better success. There’s a lot of interest in the checkpoint inhibitors being used in melanoma and lung cancer, which show remarkable activity because they awaken the immune system to see the cancer. There will be trials using those agents in this setting [CML] as well. The problem is, they are not without toxicity and you have to be very careful about using a toxic drug in a [CML] patient who has an excellent long-term chance of survival and whose only issue is whether they’re on their drug or not. The challenge is to find drugs that are very low in toxicity but can give a meaningful boost to the immune system, to increase the chances of success when therapy is stopped.
Q. What new drugs are in the pipeline?
We have 22 patients in Australia (and more than 200 people worldwide) on a Phase I trial for a very new drug, asciminib (previously called ABL-001). The TKIs (imatinib, nilotinib, dasatinib) work as small molecules that compete with ATP*, blocking kinase activity, and thus killing leukaemic cells because they are dependent on kinase activity for survival. In the process, there’s some spillover of their effectiveness and activity against other normal and important kinases, which lead to side-effects (e.g., diarrhoea, fatigue, bone pain and muscle cramps). There’s been a lot of interest in developing an inhibitor that doesn’t have these off-target effects. Asciminib is an allosteric inhibitor – a new class of inhibitor – designed not to compete with ATP but to block this overactive kinase by binding to a different site on the protein, so you gain this incredible specificity. For someone who has come on to asciminib because they can’t tolerate any of the TKIs or can’t achieve a good response, this is a last chance. We’ve been really excited by the results, which I first presented at the American Society of Hematology annual meeting in 2016. We plan to publish a major paper on the trial results, which demonstrate the drug is much better tolerated than any of the TKIs and is effective in many patients who don’t respond to the TKIs. Asciminib may become the big new development of this decade and take over from the TKIs as the preferred treatment. It is being developed by Novartis, the company that originally developed Glivec (imatinib) and they are now moving into Phase II and Phase III studies. We are about to start a Phase III study comparing asciminib to another TKI, so it’s rapidly moving towards clinical development as a mainstream drug in CML.
Q. Have many of your patients switched to generic imatinib?
Imatinib came off patent last year  in Australia, allowing generic forms of the drug to be marketed in Australia at a lower cost. There was concern amongst patients about switching from the trusted drug they’d had for the last decade (Glivec) and worry that other (generic) forms of imatinib would not be effective. Numerous trials, including careful studies from Canada and Eastern European countries, where these changes came in a couple of years earlier than here, demonstrate that patients who had received good responses on the Novartis form of imatinib (Glivec), were maintaining their response when they switched to the generic form of the drug. Clinicians in Australia are generally satisfied that the generic drugs available to our patients are of good quality. We’ve been communicating that to patients and most are now pretty comfortable. Gradually, patients are understanding that any new drug (e.g., cholesterol-reducing statins) progress to a phase where appropriate generics are the norm. We can have fair confidence that the TGA does due diligence on the generics that are licensed in Australia and that it is safe to switch across.
* a complex organic chemical that participates in many processes.
World leader in CML research, Professor Timothy Hughes has seen CML transform from “a universally fatal disease” in the 1980s, to a chronic disease requiring lifelong therapy in the 2000s, and now, to a disease where treatment-free remission is possible for many. He is Precision Medicine Theme Leader at the South Australian Health and Medical Research Institute (SAHMRI), a consultant haematologist at Royal Adelaide Hospital, and Chair of the International Chronic Myeloid Leukemia Foundation (iCMLf), along with other leading roles in the field of CML.
Q. If you were diagnosed with CML today, what would you do and what treatment would you choose?
That’s a difficult question to answer. There are really good choices today for the best drug to take if you’re diagnosed with CML. A lot depends on what your goals are of therapy. For younger people, there is a very strong focus on achieving treatment-free remission (TFR) as soon as possible. For older patients, there’s a much stronger interest in finding a drug they can tolerate and to get on with their life and not having it impair their quality of life too much, rather than focusing on TFR. It’s also very relevant to know the co-morbidities of the patients. If a patient has significant lung or vascular disease, that would push you in a certain direction. All those things need to be considered. There’s no right answer for every patient. For many patients, imatinib* (Glivec®), the original drug, is going to be the best choice because it’s incredibly safe and effective for most patients. But for the younger patient and also the patient with more aggressive disease, we try to assess the risk profile of the disease to decide which drug to use. If a patient has either a high priority to achieve TFR in as short a time as possible, or high-risk disease, in those settings I would tend to use the more potent second-generation drugs such as nilotinib (Tasigna®) and dasatinib (Sprycel ®). These drugs are generally well tolerated but both can have significant toxicities, which can be a concern for some patients, so I don’t tend to use them unless there’s a good reason.
Q. What are your key discoveries/achievements?
If you’re talking about what we’ve achieved in Adelaide [at the South Australian Health and Medical Research Institute (SAHMRI)], our major achievement was to lead the development of molecular monitoring (MM). That’s a way of determining whether a patient is responding well to a treatment or needs to switch therapies to something else. We really pushed for MM to be harmonised internationally, so if we talk about a certain result in Adelaide, it would mean the same as if that result is referred to in Seattle or London. And that required a lot of work, led by Associate Professor Susan Branford [the global leader in molecular monitoring for CML] who works here in Adelaide, developing the international standard for the PCR** test that we use to measure the response. That’s been one of our major contributions to the field and has allowed us to tell a patient that their response has been so good that they have an excellent chance of remaining alive and well in the long-term. That couldn’t be done before there was an accurate way of monitoring the response to disease, which is done by using the PCR assay that we standardised. It’s also the fundamental requirement to allow a patient to stop therapy – because you need to know that the patient has achieved a deep molecular response before you know it’s safe to have a try at stopping. If you try stopping before getting a deep molecular response (DMR), it can be very unsafe for the patient. So you needed to have a very sensitive and standardised way of measuring DMR and that’s the thing that we’ve been one of the drivers in developing in Adelaide.
Q. Do you have a holy grail… the one big thing you would like to achieve in your research career?
At this stage, I’d like to be able to completely understand treatment-free remission. If we could understand why we achieve TFR in one patient and not in another, it would allow us, firstly, to inform a patient as to when they can actually try stopping [treatment]. At the moment, all we can tell them is… it’s a 50% chance of success and that’s a tough call for a patient to make a decision to stop therapy based on having a 50% chance they’ll have to restart their drug somewhere in the next 6-12 months because their leukaemia is starting to come back. This is quite an emotionally difficult thing for them, so I would love to have the capacity to say to a patient – ‘your chances of success are 80% so let’s go ahead and give that a go’, or ‘your chances are just 20% so let’s hang on to your therapy, keep going for another year or two, and then we’ll reassess what your chances are like’. That’s what I’d love to be able to do, based on understanding how TFR is achieved.
I’d also like to greatly improve the number of patients who can achieve TFR. Today, it’s around about 25%. We think we can do a lot better by smartly using the second-generation drugs, and I think the new kinase inhibitor, asciminib, is going to give us an even greater capacity to achieve DMRs in more patients. I’m hoping that over the next decade we’ll be able to achieve TFR in the majority of patients.
If you look at the overall response of patients, about 50% achieve a stable DMR, and of those patients, about half, when they stop [their drug) remain in TFR. In Adelaide, about 25% of our overall patient cohort are in TFR; another 25% will have tried and not succeeded and now are looking for another way to get off their drug; and 50% would not have had a good enough response to even attempt stopping. We’re looking at new drugs like asciminib to try and get better outcomes for those patients. Asciminib is the first kinase inhibitor that only targets the leukaemic kinase and not other kinases, so it is very well tolerated, while being one of the most potent kinase inhibitors available today.
Q. Does everybody who relapses after trying TFR regain stability of their disease when they go back on their treatment?
I’d say more than 95% regain a deep molecular remission but not 100% because some patients get discouraged and stop taking their drugs as regularly as before, when they were only taking it every day without skipping doses because they were hoping to stop their therapy. And now, having failed, it’s hard to motivate them to be just as careful with taking their drug. In some patients, we have tried to stop a second time. Some patients have gone back on their drug for at least a couple of years and have achieved a deep response again. We’ve done that in about a dozen patients so far and the success rate there is about 50% as well. That means, we’re gradually getting more and more patients off therapy. It may well be that with second attempts and third attempts, you’ll eventually get a much higher percentage of patients off their therapy, but you’d like to do it the first time if you can.
Q. How important is it for people to take their drug at the same time every day?
It’s interesting. For most of the last decade, the focus we had in treating patients was persuading them to take their drug every day because it’s hard to do that. It’s okay for the first 12 months – you know you’ve got a life-threatening disease – but after 12 months, you’ve achieved a good response and your doctor tells you, ‘it looks as though you’re one of the lucky ones who can remain on this drug for the rest of your life and you’ll be fine’ and then they start losing their motivation to take it every day. They have unpleasant side-effects, so they tend to skip it on the weekend, to be more comfortable and enjoy themselves more. Some patients are just forgetful and don’t take it often enough. They lack the motivation, just like patients with hypertension or diabetes who don’t always take their drugs every day. That’s the same challenge, and we’ve found the patients who are not taking their drug every day are not getting the deep responses that the other patients are getting.
But in the new era, where patients are focused on TFR, it’s much easier to persuade a patient to take their drug every day because they now have a target. It’s not just ‘I’m stuck on this drug for life’, it’s ‘if I can take this drug every day now, I’ll achieve the sort of response that I need to achieve to give me the chance to get off it for good. There’s this huge motivation now.
I have an easier time now persuading patients to be remain compliant with their drug than I did 10 years ago.
Q. What aspect of your work excites you the most?
I’m excited the most by the fact that every week I see a lot of my CML patients and, in many cases, what we talk about is not so much their leukaemia, but their blood pressure and their cholesterol, because they’re going to live long and healthy lives and these [health concerns] become more the focus of our attention. So, I’m excited by the fact that I’m watching a whole lot of CML patients thrive and get on with their lives, whereas in the 1980s and 1990s I watched a lot of CML patients slowly decline, and in many cases, die.
It’s a very different scenario now and that excites me every time I go to my CML clinic.
Q. What do you consider to be the biggest research hurdle?
We have great support for funding from the Leukaemia Foundation, the NHMRC, and other organisations. But the hurdle for research in Australia is that it’s still a really tough ask to get someone to become a medical researcher. I see a lot of very talented young medical researchers who move away from research and go into other industries; ones with more security. We lose a lot of talent, because we can’t give these young scientists the sort of security and career path that we’d like to, and the most talented of them all will tend to go overseas, where they can get much better opportunities to do their research. It’s still a major hurdle for us to keep the talented young scientists and medical researchers in the field motivated and on satisfactory career paths. I know this is something the Leukaemia Foundation has been very supportive of in the past by providing fellowships. That’s really one of the critical things we need to maintain.
Several of the people I can see out in the lab right now were Leukaemia Foundation scholarship recipients, we’ve received funding for several projects that we’ve conducted here, and I’ve certainly had strong support from the Leukaemia Foundation over the last decade.
Q. What is the source of inspiration for you?
It is my patients. I’ve got about 350 patients with CML and I’m almost always asking them, when I see them, whether they’d be willing to join a study or willing to give us a sample of their blood so we can’t try and understand why they’ve succeeded or why they didn’t succeed if they’ve tried to stop [treatment]. And I can’t remember a single occasion when a patient has said ‘no you can’t have my blood’, ‘no I won’t join your study’. That is inspiring. Yes, I’ve had patients who’ve not joined clinical trials for good reasons, but they are willing to provide their information, their blood samples and to enter all sorts of research studies. Even studies where they don’t know what’s going to happen, like the first patient who stopped their drug. We had no idea what would happen, but they were willing to go into the trial. And, almost universally, they will say to me, ‘I don’t know if this is going to help me but I might be able to help someone else’. To me, that is such a universal response, one I hear from people from all walks of life and it reassures me that there is a widespread determination to help other CML patients that’s truly inspiring.
Q. What’s the story about the first person who stopped taking their CML drug?
Even before our stopping treatment trial, a person came to see us who just couldn’t bear the side-effects of imatinib therapy. This was before we had any choice but imatinib… we didn’t have second generation drugs. He said, ‘I’d rather die of this disease than have these awful side-effects’. Fortunately, he’d had a very good DMR for a couple of years. So, because he wanted to stop, he stopped, and we followed him very closely. He’s still negative after 14 years.
He was the first person who made us think… gee, maybe this can work, and from there we started a trial. But of course, the first person who entered the trial didn’t have that sort of motivation and did want to remain healthy long-term, so they were taking a risk when they joined that study.
Once we did the study and got more experience, it became easier and easier to discuss the idea of stopping because we had all that information from the preceding patients to give to them and to say how safe it was as long as it was done under the appropriate conditions.
It’s been 10 years since many of the patients on the TWISTER trial stopped. We want all our trial patients to keep having blood tests, to check the leukaemia doesn’t come back, because we don’t know when it might come back. Although I think it is likely that the CML will never return, it’s still possible that the CML will eventually come back in some cases, so we have monitor these patients for the rest of their lives.
We know that they are free of their drug, but they are not free of their blood tests – that’s an important message that we always tell our patients.
*Imatinib (Glivec®) is a targeted cancer drug (biological therapy). This cancer growth blocker is called a tyrosine kinase inhibitor (TKI).
** Polymerase Chain Reaction (PCR) testing for BCR-ABL has become the primary method used to monitor leukaemia levels in people with CML.
The Leukaemia Foundation has provided the following funding to Professor Timothy Hughes and members of his lab:
Characterisation of immune responses in CML patients on nilotinib and interferon alpha, primary grant recipient: Agnes Yong, 2013, $100,000; Developing a gene signature to predict the optimal front line kinase inhibitor for CML patients, primary grant recipient: Deb White, 2011, $100,000; Developing predictive assays to select second line therapy imatinib resistant CML, primary grant recipient: Timothy Hughes, 2008, $100,000.
“I was diagnosed with CML then found out I was pregnant”
When Elle Halliwell found out she was pregnant in early 2016 – two days after being told she had CML – a Leukaemia Foundation newsletter dating back to 2008 gave her hope.
It featured a story about Shelley Bell who was 10 weeks pregnant when the blood test that confirmed her pregnancy also showed she had CML. That was in 2007 and today her daughter Amelie is a thriving nine-year-old.
Elle’s husband, Nick Biasotto, found Shelley’s story on the Foundation’s website during a weekend of intense internet research prior to Elle’s first appointment with a haematologist on Monday May 2.
Their GP had already broken the news of Elle’s diagnosis on Thursday April 28.
Elle’s discovery that she had blood cancer, like Shelley’s, was a twist of fate.
Planning to start a family later that year, Elle, 31 of Sydney, who is the fashion editor of a Sydney newspaper, had a blood test to check her folate and vitamin D levels. These were fine, but she had an abnormally high platelet count.
Although Elle had a negative result from a pregnancy test two weeks earlier, she “had this weird feeling” that she needed to do another test.
“When I looked at the result and saw two little blue lines, I was just in shock. I was carrying my first child and thought – well, that’s not going to happen. How can someone with cancer carry a baby to full term?
“But Nick showed me some videos he’d found about pregnancy and CML, where doctors were open to the idea of continuing with a pregnancy in that situation although it was rare, and I read the story about Shelley.
“It instantly gave us hope that there was light at the end of the tunnel.”
The advice of the haematologist, who Elle met with two days later, was to terminate the pregnancy, have fertility treatment and freeze some eggs, go on TKI treatment for at least five years, then go off the treatment and try to conceive.
The Halliwells sought a second opinion, from internationally renowned CML specialist, Professor Tim Hughes in Adelaide.
“He gave us a vote of confidence that, although there were risks, I could see the pregnancy through, without the CML going to the accelerated or blast phase,” said Elle.
“My CML had been caught early. My Sokal (a prognostic evaluation of CML) level was right at the bottom, I felt great, my spleen was fine, my white blood cell count was okay and I had no other sign of CML other than high platelets.
“It was still so early and I didn’t know if I’d make it through the first trimester.
“We made the decision to go through with having the baby, and then we reached out to the Leukaemia Foundation to get in touch with Shelley.
“She agreed to have a chat and we had a really nice phone conversation about her experience and how she managed her eight-month pregnancy,” said Elle, who at that stage hadn’t begun treatment.
This gave her added hope and confidence, as did knowing that Shelly’s child was prospering, and that CML was not hereditary.
“We decided for the moment to continue as we were and felt that we had made the right choice and were not doing anything reckless,” Elle explained.
“This all made me feel a lot better about the decision, and that if I exercised and had a good diet, and had treatment, then my son had a good chance of being born and having a healthy start to life.”
In July, Elle started treatment on slow release pegylated interferon which she had intravenously once a week.
“I’ve responded very well, have hardly any side-effects apart from a bit of fatigue which could be from being pregnant, and I feel good.”
Elle said her BCR-ABL level was sitting stable at 15% (down from 18%) and her baby is thriving and at 23 weeks, was at the top end of the weight scale.
He is due on January 6 but is likely to be induced a month early, and Elle hopes to breastfeed for at couple of days, before she goes on to TKI treatment.
In August, Elle wrote a story for her newspaper about how she was coming to terms with having leukaemia and being pregnant with her first child. She continues to work full-time as a journalist, a couple of days from home, and is considering taking an additional six months on top of standard maternity leave.
“I’m taking things day-by-day and step-by-step,” said Elle.
“It’s hard to make plans when you don’t know what’s happening.
“Work has been a great support, and from day dot I’ve been really grateful to the Leukaemia Foundation which has been so helpful. It’s made a difference and it’s meant I haven’t felt alone.”