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. 

Here is the second instalment in a two-part series. (Read Part 1 here.)     

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.