The greatest unmet need in CML is the ability to predict outcomes at the time of diagnosis according to Dr Naranie Shanmuganathan, a consultant haematologist at Royal Adelaide Hospital and SA Pathology.
“If we can find key predictive factors, earlier, as to which patients we need to be a lot more proactive with, we could ideally tailor their therapy very early on.”
And the next area of unmet need, she said, is identifying those patients likely to be able to stop therapy and stay off therapy successfully in a treatment-free remission (TFR) attempt.
Having completed a fellowship in chronic leukaemia, Dr Shanmuganathan is part of the world-leading CML research group at the South Australian Health and Medical Research Institute (SAHMRI) in Adelaide where she works alongside Professor Timothy Hughes, Dr David Yeung, and Dr Susan Branford.
“Tim’s track record was a key factor in my decision to participate with ongoing research,” said Dr Shanmuganathan who is completing her PhD in the genomics of leukaemia.
“It’s wonderful to be on the cutting edge, involved in primary lab research that has the potential to be translated straight into the clinic. It is inspiring.”
Her career goals are “to be a successful clinician researcher and to continue to publish high-level impact research in this field and in other areas of haematology as well”.
Predicting patients’ responses to therapy
The primary focus of Dr Shanmuganathan’s research is identifying the factors in CML that can predict how patients will respond to therapy, in other words, “who is going to do very well” and “who is going to do very badly”.
“To see if we can work that out from day zero, when they are diagnosed, so we can perhaps be preventative rather than reactive,” she said.
“If we can predict who is going to respond very well that would be ideal.
“There are some signs early on as to which patients are the most likely to be able to stop therapy many years down the track, but there are also signs about who are the patients more likely to progress to the more aggressive forms of CML.
“And for those that are predicted to be less successful, how can we maximise their chances in attempting to stop their tyrosine kinase inhibitor (TKI), which is the treatment for CML, and remain off therapy long-term.”
Dr Shanmuganathan said the overall goals of CML therapy are to prevent the disease progressing, minimise the toxicity of therapy as much as possible, and maximise the molecular response, to enable a TFR attempt down the track.
“Minimal residual disease refers to the traces of leukaemia that are only evident when you do a very sensitive molecular test,” she said.
“You can’t see it from a general blood test because the numbers have all normalised. What we’re looking for are traces of the mutation that causes CML, and seeing what the levels fall to, and ideally you want it to be undetectable or as close to undetectable as possible.
“This leads on to a treatment-free remission, which is basically an attempt to stop the TKIs.”
Those patients eligible for this need to have been on therapy [their TKI] for a number of years and for their CML to undetectable, or close to undetectable, “for at least two years at minimum, depending on which criteria you’re using”.
“About 50% of those patients who manage to stop treatment will be able to remain off treatment long-term, and that has the benefit of minimising the toxicities that are related to the treatment,” said Dr Shanmuganathan.
“For a lot of people, treatment-free remission has the opportunity to improve their quality of life and outlook on everything because they’re not having to deal with taking their tablet, the logistics to taking medication including fasting, and adjusting their lifestyle around their medication.
“And they’re not having to deal with the side effects related to therapy, although the alternative to not commencing therapy would be the higher potential for progression to more aggressive CML and side effects related to disease.”
CML has essentially changed from a blood cancer to a chronic illness.
And for those who have successfully stopped their therapy, Dr Shanmuganathan said they would be considered cured in that it’s “unlikely that their leukaemia will ever come back”.
“But they do need to keep being monitored, because on some occasions late recurrence does occur,” she said.
Early response to treatment leads to better long-term outcomes
Patients who have a very rapid decline of their leukaemia burden early on, in response to their therapy, are the patients who tend to do better in the longer term.
“They reach their molecular targets faster, they get into a deeper molecular response sooner, and they’re more likely to enter into these deep molecular responses which is a prerequisite for a TFR attempt,” Dr Shanmuganathan explained.
“They’re also more likely to be successful and remain in a treatment-free remission.”
What we do early has long-term implications for patients.
Dr Shanmuganathan said the strategies that can make a difference relate to “what TKI they start on to begin with” and “maintaining the dose intensity earlier on, assuming that toxicity does not impede this”.
But she said a lot more work was required, looking into “how we can improve early disease response where possible, for some patients”.
“That’s still a work in progress.”
Dr Shanmuganathan said which TKI a patient starts their treatment on is not standard, “it all depends on their underlying health, the specific side effect profile, what’s available, and what the ease of administration is”.
Each patient needs to be individualised.
When a person is first diagnosed with CML, they need to have regular blood tests to keep an eye on their blood count.
“And we also keep an eye on the mutation that characterises CML; we monitor the mutation levels very closely early on,” she said.
Dr Shanmuganathan’s research
In 2020, Dr Shanmuganathan won the Simpson Prize for Cancer Research which recognises outstanding research undertaken at the RAH or SA Pathology and is presented for the best paper published by an early career researcher. Dr Shanmuganathan’s paper, titled Modelling the safe minimum frequency of molecular monitoring for CML patients attempting treatment-free remission, was published in the journal, Blood.
“We’re fortunate in Australia that we can do regular monitoring without financial hardship because we have a public health system,” she said.
“There are other countries around the world where the number of tests that you can do in any calendar year is limited, or every test that is done has to be paid for by the patient or an insurance company.
“For patients attempting to stop their TKI therapy in a treatment-free remission, the ability to monitor patients can influence the possibility of whether they can actually stop the TKI or not, because if they can’t be monitored safely, they should not be stopping their drug.”
Dr Shanmuganathan’s research centred around the question… what’s the minimum a patient needs to be monitored to enable a safe treatment-free remission attempt, to ensure that all relapsing patients were captured?
“Can we monitor them less frequently and still capture them if they have a molecular relapse before the CML comes back, and can we do that safely?” she said.
“So, basically, instead of the 12 blood tests that would be required in a calendar year [according to current standard of care], can we do less tests and still capture the same number of molecular relapses? And the answer was, we could.
“In Australia, that means that maybe patients here don’t need to be monitored quite as frequently as they have been.
“We have very conservative monitoring strategies and, potentially, with this work, we could be a little less stringent, and that means less blood tests.
“We could go down to seven tests instead of 12 but the specific strategy is a little more complicated,” she explained.
“You could do monthly tests for six months, which is really critical, and then two-monthly thereafter for the next 12 months.”
Dr Shanmuganathan said that if someone relapses, they immediately restart their TKI and that again controls their CML, and there are “only rare cases where it does not work”.
Investigating the role of mutations in CML
The genomic mechanisms that underpin resistance in CML is another area of Dr Shanmuganathan’s research.
“Basically, we are doing next-generation sequencing at the time of diagnosis, looking at key cancer genes and seeing which patients have these potential mutations.
“Then evaluating these patients’ responses over four to five years and correlating the two bits of information together to see if there are any key associations… so what the implications for these mutations are long-term, and whether these mutations make any difference, or no difference whatsoever, and what outcomes they may influence,” she explained.
While Dr Shanmuganathan said she couldn’t talk much about the results, “there are changes that are present at diagnosis that do influence outcome”.
This research is being validated over the next year, “with the view to translating this work into clinical practice soon after”.
What Dr Shanmuganathan was able to share now was that “patients with mutations might be better off treated with more potent inhibitors earlier on. So, instead of first-generation drugs, maybe second-generation TKIs, or early consideration for stem cell transplantation” but this requires further research to validate .
“First-generation TKIs would be something like imatinib [Glivec®]. It was the first drug that was developed for CML,” said Dr Shanmuganathan.
“Second-generation TKIs are more potent, so that would be something like nilotinib [Tasigna®] or dasatinib [Sprycel®]. And then there is a new drug that is coming out, that is in clinical trials, called asciminib [Scemblix®] which has a potency of second generation TKIs but seems to have a less toxic profile.”
Dr Shanmuganathan said the next step was to see whether or not these negative influences, by mutation, can be turned off or reduced by having more potent TKIs, and that is at the cutting edge of CML research, with clinical trials underway.
“A few groups are looking at different perspectives, but at the moment I think, hopefully, we’ll be the first to report what this looks like in a clinical trial setting,” she said about the Phase II and Phase III studies that are underway across Australia.
Genomic testing and CML
While mass spectrometry can be used to identify specific mutations in CML, Dr Shanmuganathan said it was “a bit more obsolete and is becoming old technology”.
“The things it can tell you are limited compared to next generation sequencing (NGS) which looks at a multitude of genes, in the search for mutations or rearrangements that can influence outcomes, not just in CML, but in cancer in general.
“NGS is now being applied more frequently to CML, not so much in patients that are doing well, but as needed, mostly in patients if they are having poor outcomes such as those who are not responding to treatment as well as you’d like or who are losing response,” she explained.
“We’re looking for mutations and looking for additional causes of resistance because it is important to work out if there’s anything else that could influence the outcome.”
Dr Shanmuganathan said that while genomic testing was not necessarily done following a CML diagnosis, it could be used to profile patients considered higher risk. Clinical risk scores are used to estimate this based on a differential blood test that shows the types and amounts of white blood cells, and clinical parameters including the spleen size at diagnosis.
“Some patients acquire specific mutations which highlight their resistance to specific TKIs, but there is also a big proportion of patients that do not have these specific mutations,” she said.
These patients are still becoming resistant to therapy but the reason is unknown.
“We’re trying to find out these mechanisms to predict resistance.”
What to do when first diagnosed with CML
Dr Shanmuganathan said that, assuming a patient recently diagnosed with CML had been referred to and had consulted a haematologist, “they should be risk-stratified based on their clinical risk scores and commence on the tyrosine kinase inhibitor that suits their profile, based on the side effects and what associated medical conditions that they have”.
“It is important to start therapy immediately, stay on that therapy [compliance], and be regularly monitored,” she said.
There’s data to show that patients that have poor compliance are the ones that are also more likely to have poorer responses to therapy.
