Q&A: Professor Timothy Hughes – Part 1
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.