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Jane’s survived a second cancer diagnosis while on watch and wait

Jane’s survived a second cancer diagnosis while on watch and wait

All Jane Blakeley knew about leukaemia – at the beginning, when she got the shock diagnosis of having a precursor to CLL – was that “people who have leukaemia die”.

“That was my understanding,” said Jane, 60, of Wilton, south west of Sydney.

And that’s why she didn’t tell anyone for a long time. She thought most people would think, ‘oh, God, you’re going to die’.

Jane Blakeley with her two Jack Russells
Jane Blakeley with her two Jack Russells

“It was only as I found out more information over a few years that I started to tell people,” she explained.

“I didn’t know leukaemia was a blood cancer and didn’t realise there were so many different types of leukaemia.

“And then the haematologist said, ‘if you’re going to get leukaemia, this is the one to get’.”

The call that changed everything

Jane’s cancer journey began in 2012, when she got a call from her GP one afternoon while babysitting. She’d had a full blood test to keep an eye on her cholesterol and blood sugars, etc.

“We need you to come in and talk to the doctor,” she was told, “we’ve picked up something in your bloods”.

“It was an absolute shock,” said Jane, who is married and has step children and grandchildren.

“So off I go. They said they’d been monitoring it [her B-cell count] for a while, and it had gone up enough to think it could go into CLL.

“From there it was off to the haematologist. I had monoclonal B-cell lymphocytosis*, a precursor to CLL.

“It was just monitored and eventually it crossed over to CLL in early-2013.”

Again, that was a shock for Jane, and equally for her husband, David.

“I had no symptoms, nothing. I’ve never had any symptoms. If it wasn’t for the blood tests, I would still not know about it probably, except for what else has happened.”

Jane and David at Uluru
Jane and David at Uluru in July 2019: “we travel a lot together”

Coming to terms with having CLL and finding out more

“At first, it was really, really scary… you’re waiting for something to happen to you.

“In the early days, if I got an ache or a pain or was particularly tired, I’d think, is this because of the CLL? It took me a good few years to get my head round it.

“I contacted the Leukemia Foundation to try and find out a bit more, because I’d just Googled stuff, as you do.

“I must admit the Leukemia Foundation was unbelievable. The more information I got, the better I felt about the situation.”

“They sent me all sorts of information,” said Jane, and she’s saved all of it in a file, which includes back copies of CLL News.

“They got me involved with a support group, then I went to a conference they had, and then another blood cancer conference.

“Over the years I’ve kept going to the support group meetings,” said Jane, initially at Liverpool Hospital (Sydney) and now at Bowral, which is closer.

“I think they’re good. You get to know people.

“At first, it was a great help to hear other people who had CLL, their experiences. And now I’ve been going long enough that I can help other people.

“You learn from others. You pick up how they deal with things, and you can talk about how you deal with things.

“And the more people I met, the more information I found out, the happier I’ve been.

“Knowledge is power and the more knowledge I had – about the research being done, the breakthroughs and the success with treatment – the better I felt about it.

“By the time I might need treatment, there might be a cure.

“I was told… a third of people [with a CLL diagnosis] will need treatment straight away, a third will need treatment at some stage, and a third will never need treatment.”

Jane and David in Europe
Jane and her husband, David, went to Europe for Christmas 2018 after she completed breast cancer treatment

Going from watch and worry to not worrying anymore

Seven years have passed, and Jane hasn’t had any treatment for CLL.

“It was diagnosed early and its progress is slow,” she said.

“My haematologist says… the way I’m going, its progress over the last seven years and looking at the markers in my blood, it will be a long, long time before I need treatment.”

So how does her CLL diagnosis affect Jane now?

“It doesn’t,” she said. “Not now.”

“At first, it was very hard to get my head around. But the more I found out, the more comfortable I felt.

“It used to be watch and worry, but I don’t worry about it anymore.

“I try to live more mindfully; doing things I’d like to do, rather than what I have to do. You realise that life is short.

“But I’ve had breast cancer as well, and that’s had a greater impact on me than the CLL diagnosis.”

Jane’s second cancer diagnosis

Two years ago, a mammogram detected breast cancer.

“That rocked me more than anything did, because that was immediate and needed to be dealt with straight away. Whereas with the CLL, I knew it was a long-term thing,” said Jane.

“I was diagnosed with breast cancer in late-January 2018. When I saw my haematologist the next month for my yearly check-up, I’d already had one operation.

“He said, ‘don’t worry about your CLL. You just do what you need to do to treat the breast cancer’, and he kept in contact with my oncologist.”

It’s 18 months since Jane finished her breast cancer treatment, which knocked her around, and it’s only been in the last couple of months that she’s felt herself again.

“It never quite leaves you because of ongoing medication, but I don’t live every day worrying about it,” said Jane.

“I just get on with things. I’m that sort of person.

“But I had trouble coming to terms with the breast cancer after it was all finished,” said Jane, who found herself waiting and wondering… what’s next?

“I had counselling for that, and that made a huge difference.”

The psychologist she saw treated people who’d had cancer.

“The aim was to try and focus on the good things and not on the ‘what might happen’.

Jane with her patchwork quilt
“I love sewing and have so many unfinished projects, I need to live until I’m about 500 to get them all done,” says Jane Blakeley working on her patchwork

Getting on with life and living with CLL

“Now I’m stuck at home, I love it,” said Jane about self-isolating during COVID-19.

“I get to do more of the things I want to do. I sew. That’s my happy place. And I meditate a lot and go for walks with my two Jack Russells [terriers].”

“I only see the haematologist once a year and he’s happy with progress so far. He’s always been very positive.

“He looks across all my bloods, says ‘this is a bit high, but that’s perfect, come back in another year and stay healthy’, and that’s about it.

“At the moment [during the COVID-19 pandemic] he says, ‘be careful to stay away from sick people’ because my immune system is still compromised.

“And I have to be proactive. If I get sick, I have to act on it straight away.

“His opinion is that there’s no need for any treatment at this time. And my understanding is that if they treat CLL too early, the side-effects are worse than the treatment.

“And having had chemotherapy, I can understand why they say that.”

Interestingly, the chemo Jane had for breast cancer also had a favourable effect on her CLL.

“It’s funny, the chemo actually knocked the CLL on its head,” said Jane.

“When I had to see my haematologist in March last year, he said there was no detection of CLL in my blood at all!”

“When I asked, does that mean I don’t have it anymore, he said, ‘no, but it’s not detectable in your blood at the moment’.

“But when I saw him in March this year, they could detect it again. It’s starting to creep up a bit.”

However, Jane says, “I’m in a good place with it now”.

“I have a wonderfully supportive and loving husband, and a great brother and sister who help put things into perspective. Extended family and close friends help as well.

“I try to stay positive, do things that I like doing, and try and be as healthy as I can.”

“I eat well, but I like red wine and sometimes drink more of that than I should. But at the end of the day, life’s short. I exercise and I’m an active person. I walk primarily, around where I live which is a beautiful semi-rural area.

“I’m lucky, we travel a lot. We’ve got a motorhome and travel overseas a fair bit. I always appreciate being able to travel,” said Jane.

But this year, their Easter trip to the South Coast, and the holiday they planned to Alaska and Canada in July, were both cancelled.

Jane’s advice to others on watch and wait

“For anyone at a similar stage to me, I’ve said, go to the Leukemia Foundation because they’re so good at providing information, try and look after yourself to the best of your ability, and eat as well as you can. Try to stay healthy, in other words.

“I’ve found by concentrating on things I enjoy, there’s not as much time in your head for the other stuff.

“The important thing is, you have to get on with life.”

* Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic precursor condition for chronic lymphocytic leukemia (CLL). It is defined by the presence of small clones of aberrant B-cells in the peripheral blood, with a total B-cell count below the threshold for diagnosis of CLL.

PBAC/PBS update on CLL/SLL therapies

PBAC/PBS update on CLL/SLL therapies

Here are updates on three novel therapies for the treatment of CLL and SLL.

Acalabrutinib as a first-line treatment

Acalabrutinib (Calquence®) has been available on the Pharmaceutical Benefits Scheme (PBS) for CLL and SLL since September 1 for the treatment of patients with relapsed or refractory CLL/SLL who are not suitable for treatment or retreatment with a purine analogue (also known as second line treatment of CLL/SLL).

Acalabrutinib: available on the PBS for relapsed/refractory CLL

At the July 2020 meeting of the Pharmaceutical Benefits Advisory Committee (PBAC), the decision was made not to list acalabrutinib for the first-line treatment of patients with CLL/SLL who are considered unsuitable for treatment with a purine analogue, either as a monotherapy or in combination with obinutuzumab (Gazyva®). The same decision also was applied for the first-line treatment of patients with CLL/SLL who harbour a 17p deletion.

Ibrutinib as a tablet for more dose flexibility

This month’s PBAC meeting considered a minor submission by Janssen requesting that ibrutinib (Imbruvica®) tablets have the same listing conditions as already applies to ibrutinib capsules. The Leukaemia Foundation took this opportunity to provide the PBAC with feedback sought from consumers via its disease-specific Facebook pages on their experiences with ibrutinib.

These responses about side effects and improvements to quality of life were as follows:

  • A CLL patient, when treated with obinutuzumab, had experienced lethargy. Following relapse, this patient was placed on ibrutinib and saw a dramatic improvement in energy levels and did not experience any side effects. The patient said, “my energy level has been restored and I am happier in myself”.
  • Another CLL patient who said it was likely that they would need to be placed on ibrutinib in the near future expressed concern that without subsidy they would not be able to afford the medication.
  • A SLL patient who manages a SLL-specific online support group noted that those eligible for ibrutinib praised its effectiveness on improving quality of life. This person further stated that, “by having ibrutinib added to the PBS, my potential for my quality of life to drastically improve in an affordable manner means that not only is my life extended, but the time I have with my wife and kids is too.”
  • Another patient who has been taking ibrutinib for eight months noted that they had not experienced any negative side effects and believed it had improved their blood test results.

The Leukaemia Foundation understands from information provided that ibrutinib capsules are currently available in a single dosage (140 mg), whereas the proposed tablets would be available in four different dosage strengths: 420 mg and 560 mg that would provide patients with a more convenient dosing regimen that reduces the pill burden, from three capsules daily to one tablet daily and which also may improve adherence; and 140 mg and 280 mg to allow for dose adjustments that may be required by patients to manage any adverse effects, improve tolerability, and/or be used when patients are receiving concomitant CYP3A inhibitors.

Venetoclax as a first-line therapy for CLL

On 1 March last year, venetoclax (Venclexta®) was listed on the PBS for CLL patients who have relapsed or are refractory to at least one prior therapy and who are unsuitable for treatment or retreatment with a purine analogue.

Another outcome from the PBAC’s July meeting this year was a positive recommendation for the PBS listing of venetoclax, and scheduling is expected by the end of the year. This listing is for venetoclax in combination with obinutuzumab for first-line treatment of patients with CLL who have coexisting conditions and are unsuitable for fludarabine-based chemoimmunotherapy.

The PBAC was satisfied that venetoclax plus obintuzumab provides, for some patients, an improvement in efficacy over current first-line CLL therapies in delaying progression.

Deborah’s one of the first Aussies to have CAR T-cell therapy for CLL

Deborah’s one of the first Aussies to have CAR T-cell therapy for CLL

Deborah Sims and children
In February 2019, when Deborah Sims and her children participated in the announcement that venetoclax would be listed on the PBS

Deborah Sims, one of the first Australians to have CAR T-cell therapy for CLL, was back at work within a month of having the new form of immunotherapy in hometown Melbourne.

And now, the mother of three is officially ‘a genetically modified human being’ after having an infusion of her own re-engineered T-cells in September to treat her aggressive CLL.

Diagnosed at 38, Deborah, now aged 47, had failed chemo (FCR), failed a novel therapy (venetoclax [Venclexta®], and was on her second novel therapy (ibrutinib [Imbruvica®) when she went on an international CAR T-cell therapy trial.

CLL News 2016“I’m at Day… at 37,” said Deborah when she spoke to CLL News in late-October.

“I’ve lost track of how many days because I’m not even counting anymore, because my life’s back to normal.”

This is the story of how Deborah got on that trial, due largely to her own self-advocacy efforts.

But first, read about Deborah’s diagnosis and early treatment, including a monthly commute to the UK on a venetoclax/obinutuzumab (Gazyva®) trial.

The previous time CLL News spoke to Deborah was in 2016, a year she describes as “all a bit of a blur from permanent jet lag”.

When her appointments stretched out to being three-monthly, in 2017, this “took a bit of pressure off” for her.

“I would fly to London, mainly to get the drug, three months’ supply. I’d get a blood test, see my consultant, then fly home,” said Deborah.

“Then, in 2018, I was told the trial was ending; they’d got the data they needed.”

At her last appointment in London in April 2018, she was given two months’ supply.

The drug’s manufacturer, AbbVie, then granted Deborah compassionate access to venetoclax in Australia… right at the time when the drug stopped working for her.

When she went to the Peter McCallum Cancer Centre in Melbourne to pick up her venetoclax, she had a blood test.

“That test showed I was no longer MRD negative; they found some CLL,” said Deborah.

She was devastated by this finding.

Deborah Sims with her children at Light the Night
Deborah with her three children at Light the Night at Melbourne’s Federation Square in 2018

“I was really sad because I was the beacon of hope for this disease.

“Venetoclax is an amazing drug and I’d had so little side effects from it. I was truly grateful it had given me a four-year remission and had beaten my disease down in a way chemo had never achieved.

“I’d had a completely normal life for four years on that drug, with the exception of having to fly to the UK so much to get it.”

On March 1 last year, ventoclax became available through the Pharmaceutical Benefits Scheme (PBS) for Australians with relapsed/refractory CLL.

“I was delighted to help with the campaign to get it listed on the PBS. My children and I were with Health Minister Greg Hunt the day it was listed,” said Deborah.

“It’s so important that patients can get this treatment. I still think it is the most powerful drug we have in our arsenal (apart from CAR T-cell therapy),” said Deborah.

“I’d like to see venetoclax/obinutuzumab front line.”

“And I’d really like to see the end of FCR*, which is chemotherapy, except for people with the right [genetic] markers to respond well to it, which is a very small proportion of CLL patients.

“I was one of the earliest people on venetoclax,” said Deborah, but some people had been on it since the first trial in 2011.

“Unfortunately, because of all the patient journalism I’ve ended up doing, when I went to an international conference for CLL in November 2017 in New York and saw Dr Mary Ann Anderson presenting her research, I discovered that resistance [to venetoclax] was developing in some of the early patients.”

Read an interview with Dr Mary Ann Anderson about the development of venetoclax in Australia

Deborah stayed on venetoclax for four years because she didn’t have any side effects and it wasn’t known what would happen if she stopped it.

“But the standard of care now is that you’re on venetoclax for two years,” explained Deborah.

Deborah Sims and her children at Brighton Beach
The family together at Brighton Beach in 2019

“There’s a theory that because I stayed on drug for four years, maybe that’s why the resistance developed. Other people haven’t relapsed after the two years, and those who have relapsed have actually responded again to the drug when they’ve had it [again, after a break].

“I don’t want people to hear my story and go, ‘Oh, but I’m going to relapse’, because that’s not the case.

“I have very aggressive disease. I was already relapsed and refractory when I started it.

“I got one of the deepest remissions they’d seen on this treatment, and I got no detectable disease in the bone marrow for two years on it.

“Dr Piers Blombery and Dr Mary Ann Anderson have identified a gene that has developed in patients while they’ve been on venetoclax that has made their disease resistant to it.

“Basically, ventoclax turns off a pathway, and CLL is so smart it finds a way around that pathway to start growing again in some patients with aggressive disease.”

Deborah’s relapse and what happened next

When venetoclax stopped working for Deborah, she had a “very slow relapse”.

“We’re talking a tiny amount of disease. They were finding it at the molecular level, but knowing my disease doesn’t stay molecular very long–it really takes off–they were trying to find out how quickly it was progressing before deciding to switch treatments, because I had done so well on venetoclax,” said Deborah.

In February 2019, the decision was made for Deborah to try four cycles of rituximab (MabThera®), as an experiment, to see if that would help the venetoclax hold the line a bit longer.

“It wasn’t going to be a cure for me, but I was really running out of options as to what we’d do next.

“It gave me two months where the disease was knocked back a bit, but it was pretty unpleasant.

“It was the third time, I’d had a monoclonal antibody and I think I was starting to develop resistance to that. I struggled with a lot of pain. I’d had a nice easy ride on venetoclax and it was quite a shock having a treatment that was hurting me and causing all these side effects,” said Deborah.

“By August the CLL was really coming back and I was planning to go to the American Society of Hematology (ASH) conference in Orlando in the U.S. that December,” said Deborah who has been going to the European Hematology Association meetings, the International Workshop on CLL, and to ASH each year.

“I interview doctors from a patient perspective about scientific research and clinical trials, and tailor that information for Australians,” Deborah explained.

“The way I see it is… patients don’t have to read scientific papers, but they need to be aware of what science is doing because at some stage, especially with CLL, they are going to need the latest treatment.”

Joining the Blood Cancer Taskforce

Motivated by the lack of a standard of care practice for CLL and her annoyance at people not being referred on to clinical trials, Deborah accepted an invitation to join the Federal government’s Blood Cancer Taskforce in September 2019.

During a flight to Canberra to attend a Taskforce meeting, she sat next to Dr Michael Dickinson, a haematologist who specialised in aggressive lymphoma, who asked how she was going.

“I said I’d relapsed on venetoclax and all I really had left was a BTK inhibitor, that I could get ibrutinib on the PBS, but I’d much prefer acalabrutinib, and zanubrutinib was in trials, and we’re discussing which one to put me on,” she said.

He asked if she knew of the CAR T-cell trial** that was opening soon at the Peter MacCallum Cancer Centre and explained that, to qualify, trial participants had to have been on ibrutinib for six months. Deborah knew about this one-off treatment. She had met people who’d had the new form of immunotherapy in America and whose disease had not relapsed.

Then, in early-December last year, Deborah set off once again to the ASH conference in the U.S.

“I did all these interviews with CAR T experts including with Professor Tanya Siddiqi of the City of Hope National Medical Centre (California) and decided if I couldn’t get to the Peter Mac [trial] I would go to the City of Hope and have my CAR T-cell product there, although that was going to cost a million dollars, so I wasn’t sure how I was going to do that.”

Deborah doesn’t know why, but the decision was made to take her off venetoclax the week before she went to ASH.

“So I get to America and my disease is going off.

“My neck is suddenly swollen. I’ve got lymph nodes under my armpits. I’m actually panicking because I was not expecting to get bulky disease immediately,” she said.

“It’s not something you see when you come off venetoclax, so my disease obviously decided it’d had enough.

“But luckily I’m with every great haematologist in the world and I’m interviewing them.”

“I said to [Professor] Miles Prince, ‘before we do the interview, can you just feel my neck, tell me what you think?’, and he’s like, ‘you’ve definitely got some lymphadenopathy but I don’t know what your neck was like before, I’m not the person to ask’.

“Basically, I got 40 opinions at this conference,” said Deborah.

When she returned to Australia, she spoke to her lead haematologist, Professor Con Tam, and although he wasn’t sure if she’d get on the CAR T-cell trial in Australia, he put her on ibrutinib in January this year.

“I didn’t tolerate it as well as I had venetoclax. I had quite a lot of side effects–joint pain, bruising–but it worked, and my disease started going back into remission.

“We got to June and, in the meantime, COVID happened and the CAR T-cell therapy trial had been put on hold.

“I asked about the CAR-T trial and Con checked with Michael.

“It had reopened, and Con said, ‘let’s get you on it’, so screening [a bone marrow biopsy, CT scan, ECG, and bloods] was booked for the day after I’d been on ibrutinib for six months!

“And the way the trial works is that they do the leukapheresis [the T-cell harvest] before you even know if you’re on the trial.”

It’s a three-hour process that involved “a massive needle” and an anti-blood clotting drug that made Deborah vomit.

“I thought… I’ve got stable disease, I could have had years of ibrutinib, what am I doing?

“Anyway, it just happened really quickly.”

Deborah’s T-cells were sent to America to be re-engineered, but there was a hold-up due to COVID, and she waited seven weeks for them to be returned.

This meant she needed another round of screening to provide a new baseline for the trial.

“It showed very little detectable disease and the CT scan was clear. I was very well,” said Deborah who at the time was having “major second thoughts”.

“I could not get my head around what I was doing.”

Deborah Sims and Michael Dickinson in hospital
Deborah with Dr Michael Dickinson when he visited her in hospital after her CAR T-cell therapy procedure

The anguish of having CAR T-cell therapy while well and healthy

“A private counsellor helped me reason that this was about long-term survival, rather than waiting for another drug to fail, then running out of treatment options, or having a bone marrow transplant as salvage therapy, which was the last thing I wanted to have.

“My mental anguish was about the decision to do something which could have killed me.

“Even though the doctors said, ‘you’ll be fine, you’ve got little disease, we’re not expecting you to have side effects, I’ve lost two friends within hours of having their CAR-T transfusion.

“They were very much like me, patient advocates campaigning for the best treatment, and they got those treatments first.”

On top of this, Deborah was getting a CAR T-cell product that was new.

“Anything new is scary, and you don’t really want to be the first patient having something. But equally, this was such an amazing opportunity for me. My disease was in its best state ever to have this. My doctors were confident it would work, and if it didn’t work, that it wouldn’t harm me.

“With CAR-T, it really does either work, or it doesn’t. And if it doesn’t, there’s a risk of mortality,” said Deborah.

Deborah Sims being monitored in hospital
Being closely monitored when Deborah was in hospital after having her CAR T-cell infusion

“I’m on an international CAR-T patients Facebook group. There’s 2000 of us on it and every day you’re hearing great news from someone, then devastating news from someone else. It’s that black and white.

“What scared me was that first month after infusion; what I was going to go through? I was very scared about how sick I might get.

“It was the first time in 10 years of having this disease that I’ve done an advanced care directive and sorted my will out. I prepared everything in case I died.

“So mentally, to go into something where you really thought you might die, when you’re well, was incredibly difficult.

“I’ve always been a pioneer. I genuinely think it’s the bravest thing I’ve ever done, but I was worried that it was also the most reckless. I was very scared that I wasn’t being brave as much as reckless with my good health.

“But I’ve spent years making sure I’ve had the best doctors and I’ve trusted them. That’s always been my mantra to patients; find doctors you trust.”

Once Deborah’s cells had been re-engineered, she decided to go ahead with the procedure.

“This is a $600,000 treatment and I was getting it free, and a lot of people had gone to a lot of effort to make sure I got it.”

Three days after her T-cells arrived back in Australia, Deborah had three days of lympho-depleting chemotherapy, just enough to wipe out her immune system. After having the weekend to recover, Deborah went to the apheresis ward on a Tuesday.

“A nurse infused a vial of my engineered T-cells and that was it. It was so weird.”

“This was a really expensive, amazing product and thousands of people had been involved in getting it into me and this senior nurse just infused it, then did a flush, and that’s it.

“Then I spent three days just watching Netflix, and writing, and reading, and nothing at all happened to me,” said Deborah, and she went home on the Friday.

She was told that Day 11 was when they could expect to see some activity.

“But because I have CLL and very little disease they weren’t expecting much of a reaction and they certainly weren’t expecting something called cytokine release syndrome, which causes fever and can become serious.

“They know how to manage it better now, than when my friends died.”

On Day 10 Deborah started getting a “massive amount of pain” in her bones, “like someone was giving me a bone marrow biopsy all over my body”. The pain worsened, she started getting a fever and started shaking. When the fever spiked, she spent the night of Day 11 in the high dependency ward at Royal Melbourne Hospital and on Day 12 she was pleased to see the haematologist was Dr Mary Ann Anderson who until then she had admired but never met, and she was transferred back to the Peter Mac.

“She was pretty sure I had cytokine release syndrome,” said Deborah.

“They said I might have had more disease than they thought.”

Mild pain continued for another week.

“I swear I could feel the CAR T-cells going around my body mopping up the CLL cells.”

Con Tam, Carly Burgess and Deborah Sims
Deborah Sims, centre, with Professor Con Tam and her trials nurse, Carley Burgess

“I’d get a pain suddenly in my armpit, which was where my lymph nodes would always grow the most, and hang around there for the day, then it went up to my jaw, on to the lymph nodes in my face, and the back of neck, which was sore for a few hours.

“It was like going around, just cleaning out everything. It was incredibly exciting.”

Deborah doesn’t think CAR T-cell therapy should be a salvage or last-ditch treatment.

“I think if you’re as well as you can be going into it, the outcomes are better. That’s what I’ve found talking to CAR T-cell therapy doctors. Tanya Siddiqi, in particular, wants to see it become second line treatment.

“Patients like me put themselves on the line, not for unselfish reasons, but we’re the ones that are going to make it a lot easier for the patients in a few years’ time, like with me now saying, ‘I went around the world to get venetoclax and obinutuzumab’.

“There are so many really good trials out there that are better than standard of care and patients really need to ask their doctors about them.

“It’s really up to everyone to say, ‘are there any new treatments I should be aware of? Is there a clinical trial, even if it’s not in my state?’.”

You can read Deborah Sims blog, abtandme.

* Fludarabine, cyclophosphamide, rituximab

** An international trial, with four sites in the U.S. and one in Australia (at the Peter MacCallum Cancer Centre). The trial has three arms, for CLL, DLBCL, and ALL.

Deborah Sims and children
Before Deborah has her CAR T-cell treatment, at home with Cameron, Natasha and Marlowe



Expert Series Q&A: with Dr Mary Ann Anderson

Expert Series Q&A: with Dr Mary Ann Anderson

Mary Ann Anderson
Dr Mary Ann Anderson: “The thing that gets me up in the morning is finding new and better ways to help people.”

This story was first published in CLL News June 2018 

At the Leukaemia Foundation-hosted New Directions in Leukaemia Research (NDLR) conference in Brisbane in March 2018, Dr Mary Ann Anderson, a clinician scientist at the Walter & Eliza Hall Institute of Medical Research (Melbourne), shared a story about the development of venetoclax (Venclexta®). It involved research by thousands of people over 30 years resulting in a paradigm shift in the treatment of CLL that is “tangibly changing people’s lives”.

How did you become interested in blood cancer research?

What struck me as a haematology registrar was – we have great treatments and can cure some people but there are many diseases where patients don’t have good outcomes. I found it particularly challenging when we didn’t have therapies for people and couldn’t help them. The natural next step in my career was working to get better treatments for those people. The only way to do that is through research, so I went into a PhD. I’ve been extremely fortunate to be involved in the development of a new drug that has helped a lot of people and I’ve fulfilled my career goal doing that. Sadly, we still have unmet areas of need that means I’ll be employed for some time in the search for better treatments.

What was your presentation at NDLR about?

I shared a wonderful story about the development of a new drug called venetoclax (formerly known as ABT-199) that I’ve only been involved in for the last seven years but which started in 1984 when a protein called BCL2 was discovered. Over the 80s and 90s, BCL2 was shown to be pivotal in driving cell survival, keeping cancer cells alive inappropriately, making cancers develop and being insensitive to chemotherapy. Researchers at WEHI, in collaboration with AbbVie and Genentech, developed a molecule that selectively binds to the abnormal BCL2 protein to take out its function. I started my PhD in 2011 and together with Professor John Seymour and Professor Andrew Roberts at Peter Mac and Royal Melbourne we gave venetoclax to the first three patients in the world. We knew within hours that this drug worked. They all had dramatic and rapid clinical responses.

Describe your role in the discovery process.

I started my PhD six months before we dosed the first patient. In the laboratory, I tested CLL cells against venetoclax and they died very sensitively, suggesting the drug may be effective. I also looked at how the cancer cells were dying and found evidence this was a result of BCL2 being inhibited by the venetoclax. That’s what we call an ‘on-target’ effect. Then we gave it to a person and saw almost instantaneously that it was working. As well, using translational cells taken from these trial patients prior to dosing, then 8 and 24 hours after dosing, we could see the cells were dying via apoptosis (through the inhibition of BCL2), so we recapitulated in the lab what we were seeing in the clinic and vice versa.

How did you feel when you saw the ventoclax response in the lab?

It’s important you don’t get carried away. To me it’s… ‘ok, it works in the lab, that’s great; will it work in people?’ It was only when we gave it to the first few people, and saw their white cell counts falling from 40 to 2 in a matter of eight hours, that I allowed myself to think – ‘wow, we really might be on to something here’. I was really lucky, it was only a matter of six months from seeing it work in the lab to actually seeing it work in a person. There was also a lot of work at AbbVie to test its safety and a lot of other work by colleagues to underpin the safety of the drug.

What was your involvement in the first venetoclax studies?

Looking after patients was my main role in the early phase studies where safety is the primary consideration and end-point. Patients must be monitored really closely and often have other health issues as well. It was day-to-day medical work, made richer by the fact I was taking cells from my patients and looking at how they died in the lab in response to this drug. I’d see the patient and look at their cells in the lab, then see the patient again the next day. For me the two really played off each other, so I was hopefully better informed about my patients and how they might respond by my laboratory work, but at the same time I was being driven to do my laboratory work by seeing the patients and how well they were responding. These patients voluntarily agreed to donate their cells for research purposes. Without many patients over decades donating their cells so we could study them in the lab, we would not have these drugs. That’s something that should never be underplayed, the importance of patients altruistically donating their samples for science that has given us these new discoveries.

What was the outcome of that first venetoclax trial?

It was a very successful Phase I clinical trial. In contrast to most Phase I studies, we showed venetoclax works in about 80% of CLL patients and we can get rid of all evidence of disease in 20% of them. The way we think about CLL is radically changing as a result of this new therapy. We no longer just want to control the disease. For the first time people are wondering if we can cure CLL with tablets rather than going on to allogeneic transplant. The main side-effect we identified was that all three of the first patients who received this drug developed a complication called tumour lysis syndrome (TLS) – where cancer cells are destroyed too quickly. While you never want to see complications, for a first-in-human trial, this was both worrying and extremely exciting, and an incredibly powerful indicator that the drug was working too well. We’ve got protocols to manage the risk of TLS now and it is rarely seen.

What’s happened since?

Many patients relapse after about two years on venetoclax as a monotherapy. In the next suite of trials we combined venetoclax with monoclonal antibodies such as rituximab or obinatuzumab, or with other novel agents such as ibrutinib. Patients on combination therapy achieve deeper responses. Rather than a partial response, they’re achieving a complete response, and instead of just achieving a complete response, they’re actually clearing all evidence of disease; a state we term minimal residual disease (MRD) negative. These deeper responses correlate with longer periods before patients relapse. In some patients, we can actually stop treatment and some have enjoyed prolonged periods without treatment, where the disease has not come back. It’s starting to remind us of what happened with CML*. It’s very early days, we don’t yet have strong evidence that it’s safe or the right thing to do, but it’s something we’re starting to explore in our clinical trials.

What other areas of research are you are working on?

In the lab I’m trying to identify which patients are more likely to have good responses and also those who are more likely to have bad responses. We are doing a series of molecular tests to see if there’s a way we can prospectively identify the patients who aren’t going to do as well, and selectively target those patients for more intensive therapy. I’m also interested in trying to understand why resistance develops so we can look at targeting it more effectively. We don’t yet have a good biomarker (a laboratory test that predicts for a poor outcome) so another approach is looking at the micro-environment. CLL can sit in the bone marrow, lymph nodes and blood. There’s strong evidence that CLL in a lymph node is protected from death by any agent due to its environment. The stroma (tissue) and blood vessels help to keep the CLL cells alive and sustain them. When we look at CLL cells on an artificial stroma, in an artificial micro-environment, they are resistant to death by venetoclax. Early evidence from my colleagues suggests you can overcome this effect of the microenvironment niche by combining venetoclax with ibrutinib.

What aspect of this research excites you the most?

The thing that gets me up in the morning is finding new and better ways to help people. A few years ago I’d have to say – “I have nothing for you”. Now I’m saying to more and more of my patients – “I actually have something that can help you, a new drug, with good evidence that your disease will respond”.

What is the role of clinical trials?

They are essential and have different roles in different patient groups. When patients get to a point where there aren’t any conventional therapies, then a Phase I trial is particularly attractive. They are always ethically approved, based on evidence the drug is likely to be safe and effective. That doesn’t mean they will be and sadly sometimes they’re not. But we offer Phase I studies to people who have no other options and occasionally we find a venetoclax and we give people a prolonged period of disease-free survival. We always hope the next venetoclax is around the corner. To people asking if they should go on a clinical trial, I say: “it may help you and we really genuinely hope it does but if it doesn’t help you it will help people down the line”. Knowing a drug by itself doesn’t work is still valuable information, so we don’t use it on other people going forward. For patients on a trial, there are elements of ‘there is something in it for me’ because they might get a drug that will work, as well as altruism because they’re helping science and those people who come after them. It’s often easier to sell larger Phase II and III studies to patients where the drug has good safety evidence and a signal of efficacy. But as a basic scientist I find Phase I studies the most inspiring. They’re the ones where people are in the most need and that are bringing the next big thing to our attention.

What is the next big thing?

I think it’s going to be combinations. We’re already doing trials of combination therapies – monoclonal antibodies with novel agents, dual novel agent therapies, and potentially the holy trinity, as John Seymour puts it – two novel agents and a monoclonal antibody, or potentially down the track, even combining chemo-immunotherapy with novel agents. That’s where I think we’ll end up, with these very deep responses and potentially options of cure. There are always new drugs in the pipeline and it remains to be seen how they all fit together. A challenge is integrating evidence from lots of different trials, to find out where in a patient’s journey we should use these agents. They’ve been used traditionally in the relapsed/refractory setting but maybe they’ll be more effective in the frontline setting.

Venetoclax – a 30-year story

1984: BCL2 protein discovered

2011: First patient dosed with venetoclax

2016: Venetoclax FDA-approved in the U.S.

2017: Venetoclax TGA-approved in Australia

1 March 2019: Venetoclax listed on the PBS in combination with rituximab for relapsed/refractory CLL

“It’s decades and decades of work by very many clever and very intelligent people – chemists, structural biologists, basic science biologists, translational scientists and clinicians,” said Dr Anderson.

“It’s work at places like the WEHI and by industry like Abbvie and Genetech and in academic research hospitals like Peter Mac and Royal Melbourne.

“It’s a body of work that’s taken thousands of people, in a rich variety of backgrounds, to come to fruition.”

* Treatment-free remission is possible for many people with CML.

“Mummy’s magic medicine” has made Deborah better

“Mummy’s magic medicine” has made Deborah better

This story was first published in CLL News May 2016

The hardest thing Deborah Sims has ever done was kiss her three young children goodbye last August [2015] and move to London – hopeful of getting on a clinical trial.

“I didn’t know if I’d come back,” said Deborah from Melbourne last month [March 2016], during her first trip home to Australia since starting the trial in November [2015].

Deborah Sims and her children
In September 2015, before getting on the venetoclax trial, Deborah Sims with her children, Cameron, Natasha and Malowe, in the Hampton Court Palace gardens, London

The Phase I trial for a combination of venetoclax (Venclexta®, formerly known as ABT-199)] and obinutuzumab was considered a chance of a cure for the aggressive form of CLL/SLL she was diagnosed with in December 2011.

Back then, just days before Christmas, when Deborah took her two-year old daughter to the doctor, it was happenstance that her GP asked about her health.

She’d seen a different GP about a lump in her neck earlier that year. When she got the “all clear” for an ultrasound and blood test, Deborah got on with her busy life, forgetting about the follow-up due six weeks later.

“When my GP said, ‘I see you came in six months ago, is the lump still there?’ I said ‘yes and there are a few more too’. She examined me, gave me a hug, and asked if I had private health insurance.”

Then she told Deborah to go directly to an appointment with a haematologist. The next day she had a lymph node biopsy and the following week was told she had CLL, which is rare in someone her age. She was 38 at the time.

“It came totally out of the blue and I had the worst Christmas of my life, said Deborah. “I mourned myself for two weeks and went into my shell.”

Deborah went on ‘watch and wait’ and, expecting to have lots of time to think about treatment options, began her own in-depth research into CLL while continuing to work full-time.

“I’m a journalist and I needed information. I joined forums, subscribed to medical journals, and was referred to a number of specialists for second opinions.

“It was highly likely I’d need a stem cell transplant (SCT) at some stage in the future.

Deborah Sims and nurse Sam
Deborah and nurse Sam during her first night on the venetoclax and obinutuzumab trial

“My youngest sister is a perfect match, so I knew early that I had that option. But the more you know about stem cell transplants, the less you want one. I’m doing everything I can to avoid having one,” said Deborah, then aged 42.

“I’m always doing a risk assessment to give myself the best chance of being here to care for my children.”

This included paying for a genetic test that is not the standard of care in early diagnosis.

“I wanted to know how bad my markers were, and I have the type of CLL* you don’t want to have.”

One of her three consulting specialists talked about clinical trials and some of the drugs in the pipeline, in particular ibrutinib and ABT-199 (venetoclax).

“I did everything I could to avoid chemo and even looked at importing bendamustine from Germany.

“By October 2012 I was really sick and very tired. I couldn’t schedule afternoon meetings at work,” said Deborah.

In January 2013 she started the FCR chemo regimen.

“From the first day, I wished I’d had it (FCR) earlier. I had no side-effects apart from a sudden feeling of wellness and I responded really well.”

Three months later, even though Deborah still had a trace of residual CLL in her bone marrow it was suggested that she stop FCR after three (of six) cycles, to avoid the extra toxicity from continuing the treatment.

She returned to watch and wait, with three-monthly bone marrow biopsies, but at six months it was evident she was relapsing and her specialist talked about when she’d have a transplant.

“I was so well, and in mid-2014 was doing more research into clinical trials,” said Deborah, whose relapse was very slow.

Her appointments were extended to six months, but by her next appointment, in December 2014, she was starting to feel sick, the lumps had returned and she was losing weight.

A transplant was earmarked for early-2015 and Deborah had her hair cut short in preparation, but she needed more treatment to reduce the bulky disease prior to the SCT.

Motivated by wealthy businessman, Ron Walker’s success with Keytruda® in treating his melanoma, Deborah dipped into her superannuation fund to attend a patient conference on CLL clinical trials in the U.S. in April last year [2015]. While there she had a consultation with Professor Thomas Kipps, an international CLL expert.

“He said ‘you should not have a transplant. We are on the verge of a cure. We just have to work out what the best drug is. You need something to buy yourself some time’.”

The next day, at the conference, it was fortuitous that one of the guest speakers, Dr John Gribben from the UK, sat next to Deborah. They chatted and he told her about a clinical trial in London that would be the best possible treatment for her at that stage.

It was with ABT-199 [venetoclax], which ironically was developed in Melbourne. The only way Deborah could access ABT-199 in Australia was through a Phase III randomised trial that meant a 50% chance of getting the new drug, as the other arm of the trial was chemo.

“I’d already had chemo, so I couldn’t take that risk,” said Deborah.

She asked one of her Australian specialists – “if you were me, what would you do?” and he answered – “I’d get on a plane to London”.

“It knocked me that the best trial was 10,000 miles away,” said Deborah, who used her super again to go the UK. She had previously lived in London for 10 years, and had friends there, but getting on the trial was not for the faint-hearted.

“I had to be sick enough to go on the trial, well enough to tolerate a Phase I trial, I had to go back to work there, get a national health scheme number, and a referral to Barts (St Bartholomew’s Hospital). There was a lot of paperwork and no guarantee I’d get on the trial,” Deborah explained.

“There were only 40 places in the world for this trial – two at Barts and none in Australia which was very frustrating.

“According to my risk assessment, this could buy me a long remission and possibly a cure,” said Deborah.

She went back to work at the BBC as a freelance reporter and started writing a blog:

“When I heard the great news I was on the trial, I was so excited, it felt like I’d won the lottery.”

The first six weeks of the trial were “full on” with lots of monitoring and blood tests as the dose of ABT-199 was gradually increased until she reached the full daily dose (four tablets) in January. The obinutuzumab was given in monthly infusions that finished after six months (in April).

She has had no side-effects from the combination treatment and a CT scan in February showed she was in partial remission.

“My blood work is completely fantastic. I’m working again and going out. It’s given me my life back again.”

Deborah’s children, Cameron, 11, Marlowe, nine, and Natasha, six, and her husband, Robert, arrived in London for nine weeks in November to coincide with her starting what they call ‘mummy’s magic medicine’.

“They left at the end of January and by mid-February I wasn’t coping.”

Since January, Deborah has only needed to go to Barts one day a month. The length of the trial is three years and to stay on the trial Deborah is committed to her monthly appointment in London.

“When I get to no detectable disease I can go off the treatment although I may need to stay on ABT-199 on an ongoing basis.”

In February, she came home to Australia for three weeks. She returned to London in mid-March and is still working for the BBC. She has another flight home booked in April and while she’s here, she’ll have a bone marrow test to see if she has achieved complete remission after six months on the trial.

“I’m hoping it will show there’s very little disease left and that I’ll stay on ABT-199. I’m loathed to come off the drug. It could be the Glivec** of CLL.”

While on the trial, ABT-199 is free, but Deborah’s treatment odyssey has cost her $400,000 in lost income, flights, accommodation and living expenses. She has applied to have the drug dispensed in Australia.

* stage IV CLL, unmutated with del 6q, which is associated with more rapid disease progression.

** a daily tablet used to treat people with CML.

Expert Series interview with Professor Constantine Tam on CLL–now and into the future

Expert Series interview with Professor Constantine Tam on CLL–now and into the future

Professor Constantine (Con) Tam is a Melbourne-based expert in CLL and low-grade lymphoma whose sights are focused on curing these blood cancers. He is Clinical Lead for CLL and Low-Grade Lymphoma at Peter MacCallum Cancer Centre/Royal Melbourne Hospital and Professor of Haematology at the University of Melbourne where he teaches and supervises PhD students. Prof. Tam is the global lead for the novel BTK inhibitor, zanubrutinib, and he completed the world’s first study combining ibrutinib and venetoclax. Born in Hong Kong, he came to Australia as an 11-year-old and after completing his undergraduate degree, trained in medicine and haematology and worked at St Vincent’s, Peter Mac and Alfred hospitals before heading overseas for a two-year CLL fellowship at the MD Anderson Cancer Center in Texas (U.S.).

The latest news on CLL research are the small molecules–the BTK and BCL-2 inhibitors–and there’s a resurgence of interest in CAR T-cell therapy in CLL, says Prof. Con Tam.

Professor Constantine Tam
Professor Constantine Tam: while yet to be proven, CAR T-cell therapy “probably gave the best chance of giving someone a cure in the long term”

“There are now many studies to show that we can combine BTK and BCL-2 [inhibitors], and those combinations are tolerable and get very deep responses,” he said.

“The most recent clinical trials have shown that these drugs, as either monotherapy or in combination with an antibody, are better than standard chemotherapy.

“But I think the next generation of trials will look at whether the combinations of both a BCL-2 and a BTK inhibitor will be even better than single agents.”

He is referring to ibrutinib (Imbruvica®) and the newer generation BTK inhibitors, zanubrutinib (BGB-3111) and acalabarutinib (Calquence®), which have all been studied in combination with the BCL-2 inhibitor, venetoclax (Venclexta®).

“Adding venetoclax to the regimen gives the advantage of patients potentially being able to come off these drugs.

“At the moment, you go on the BTK inhibitor and you’re pretty much stuck on it forever, because you never clear minimal residual disease (MRD),” explained Dr Tam.

“Whereas in combination with venetoclax, it seems most people can be cleared of MRD and can potentially stop taking both drugs; take a drug holiday.

“That’s quite an exciting prospect… being able to take tablets for a fixed duration–12 to 24 months of therapy–that will clear MRD. Then, just like after having chemotherapy, having a break.

“And CLL being CLL, we anticipate that the majority will eventually relapse and will be retreated. Hopefully, it will be years before that will happen.”

CAR T-cell therapy for CLL

Dr Tam said, “the other exciting thing” is the resurgence now of interest in CAR T-cells in CLL”.

CLL was one of the first diseases to respond to CAR T-cells in early trials.

“The first major report from the University of Pennsylvania was in fact in CLL, where three patients were successfully treated with CAR T-cells, and to my knowledge they remain cured.

“The attention has shifted since then to diffuse large B-cell lymphoma [DLBCL] and ALL [acute lymphoblastic leukaemia] because they’re more urgent diseases.”

Another reason is that in CLL patients, the quality of the CAR T-cells is not as good as in DLBCL and ALL patients, due to both the CLL itself and the cumulative effects of previous therapy.

“Often the CAR T-cells don’t work as well in CLL because the T-cells are less fit,” explained Dr Tam.

Ibrutinib has been used to improve the quality of the T-cells before they are collected for CAR T-cell therapy, and Dr Tam said it was time CAR T-cell therapy was used “in a more intelligent manner” to treat CLL; not as a “Hail Mary manoeuvre” when all other treatment options had stopped working and when a patient had a lot of CLL onboard.

“Under those circumstances, CAR T-cells are probably not expected to work well,” he said.

But if, for example, for patients in stable remission on ibrutinib, the T-cells are a lot more fit and there is a lot less CLL onboard to be treated, and CAR-T cells may be applied as a ‘curative’ procedure to achieve MRD clearance and terminate the need for indefinite ibrutinib therapy.

“You might be able to provide someone with a permanent cure to consolidate a good response to some other therapy,” said Dr Tam.

In other words, use CAR T-cell therapy more effectively by using it as an earlier line of treatment.

“If trials, like the one Deb’s [Deborah Sims] on are able to show that people can get off indefinite ibrutinib therapy with CAR T-cells, then this might be quite worthwhile because CAR T-cells are expensive–$500,000 for the procedure–but that’s only about three years’ of having ibrutinib, in terms of costs,” said Dr Tam.

“And if you can have CAR T-cells, and no longer need ibrutinib, you are saving money in the long-term for the government.

“Also, ibrutinib doesn’t last forever, so you are circumventing the problem of future ibrutinib resistance and the side effects that may be associated with ibrutinib.

“These drugs are so expensive. CAR T-cell therapy is an expensive procedure and so are the drugs CLL patients are on [like ibrutinib and venetoclax].

“It may work out that this [CAR T-cell therapy] is a worthwhile thing, for both quality of life reasons and economic reasons,” he said.

The availability of CAR T-cell therapy

Dr Tam pointed out, however, that CAR T-cells for CLL are currently only available on a clinical trial.

“No government anywhere in the world has approved the use of CAR T-cells in CLL.”

Access to this immunotherapy for CLL patients depends on the nature of the trials that are open and what sort of CLL patients those trials are looking to enrol.

“In the past, they have enrolled patients with active CLL who had failed other therapy, and those trials have not resulted in such good outcomes, because these patients, like I said, had poor T-cells anyway, and quite a lot of disease to be treated,” said Dr Tam.

“The newest generation of trials is looking to consolidate an incomplete ibrutinib response, to try and convert someone who has got residual disease on ibrutinib to someone who is MRD negative.

“These trials are moving in the right direction; they’re using CAR T-cells as consolidation and as an earlier line of therapy, not necessarily frontline, but as an earlier line of therapy. I think this is an intelligent way to use this technology.”

Dr Tam said the reason CLL was not an approved indication for CAR T-cell therapy was because it was not yet proven.

“We know using CAR T-cells in just any old-fashioned CLL doesn’t produce such great response rates. They are far lower than in DLBCL and ALL, and cures are probably achieved in less than one in five people with CLL.

“That’s probably because we’re using the CAR T-cells in the wrong way. So, until we’ve proven that the CAR T-cells can be used in a more effective way, in different settings, through clinical trials, the government is not going to approve CAR T-cells for CLL.”

Dr Constatine Tam
Constantine Tam, in 2007, with a poster when he was a Fellow at MD Anderson

CLL diagnosis and treatment

Dr Tam said CLL was the most common leukaemia in the western world, with about 1000 new cases of CLL diagnosed in Australia each year.

On average half these patients would go on watch and wait and never require treatment in their lifetime. For them the disease doesn’t worsen or cause problems.

“The best thing to do is to just watch very carefully, to get a feel for the pace of the disease for the individual patients, and to wait for a better treatment to come along,” he said.

For those whose disease progresses and needs to be treated, he said access to prognostic panels that helped to define very precisely the subtype of a person’s CLL was important.

“All our patients undergo a FISH¹ study, an IgVH² mutation study, and next-generation sequencing³ to identify gene mutations, so we know which patients are not suitable for chemotherapy.

“These are patients who have p53 deletions and mutations, and we stream those patients towards clinical trials on novel therapies.

“We also know which patients are really suitable for chemotherapy. For example, there is a small subset of patients with a 13q deletion, and more importantly, a mutated IgHV status, that get FCR chemotherapy and will be cured of CLL in the long-term.

“Then we have a big group of patients where the disease is not curable with chemotherapy but who potentially may respond to chemotherapy; they’re not chemo-resistant but they’re not curable [with this treatment].

“We tend to favour putting these treatment-naïve patients on clinical trials that compare chemotherapy with a combination of novel agents, such as a BTK inhibitor and a BCL-2 inhibitor.

“For patients who have relapsed after chemotherapy, often we’ll put them on either an ibrutinib- based regimen or a venetoclax-based regimen, depending on patient preferences and the logistics of a situation.

“Ibrutinib is very easy to start, but you’re stuck on it pretty much forever, and you have to put up with the low-grade side effects forever, versus venetoclax, which is trickier to start because of tumour lysis⁵ risk, but tends to have a limited duration; in the frontline it’s 12 months, and in the relapsed setting it’s 24 months.

“It’s a question of whether you put in the work right from the start and you’ve got a difficult tumour lysis monitoring period, for a chance at a fixed duration of therapy, or whether you take the easy option, which has got less work to do in the start but treatment needs to be continued indefinitely.”

Dr Tam said CAR T-cell therapy, which is not proven and is just a principle “probably gave the best chance of giving someone a cure in the long term.”

What’s next on the treatment horizon?

Next generation “reversible” BTK inhibitors are coming online and “they are all looking quite active”, said Dr Tam.

“At the moment, all the BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) bond to the same site on the BTK enzyme, so once you get a resistant mutation at the site where the drugs bind, you’re resistant to all the current BTK inhibitors.

“But the next generation drugs, like ARQ-531 and LOXO-305, don’t bind to that site and they bond differently.

“They look quite active in patients who have failed ibrutinib. They’re also looking quite active in themselves, and they might start to come to the frontline or may end up being used ahead of ibrutinib, if the clinical trials show that they are more effective and/or better tolerated than ibrutinib.”

“And there are new versions of venetoclax coming. It’s very hard to improve on this really good class, but we’re now starting to get new drugs within that class that overcome some of the problems with the previous class, and include drugs that are 10 times more potent than venetoclax.

The importance of clinical trial participation

Dr Tam said clinical trials were “very worthwhile” to go on for several reasons.

“From a patient point of view, when you go on a clinical trial, you’re usually seeing an expert who’s got a particular area of interest and these doctors are highly skilled in that particular disease.

“Some are early-phase trials which have a single arm, and others are randomised trials.

“Now in randomised trials, the control arm–the arm we’re comparing against–is chosen carefully as the most active treatment in that disease. So you can be assured when you go on a trial you’re getting the best available treatment anywhere in the world for your disease. Or, you might get a treatment that is even better than standard of care, on the experimental arm.

“So I think, from a selfish point of view, patients get very good medical care when they join clinical trials.

“The other thing about being on a clinical trial is that you are monitored very closely, so you get better than the usual monitoring, as well as access to new drugs that are potentially five to 10 years ahead of the time.”

But there are drawbacks and you have to be prepared to accept uncertainty, Dr Tam said.

“There’s no guarantee that the new drug on the experimental arm is better. The experts think it is, but we do the clinical trial to help us to determine whether that’s true or not.

“And sometimes you have to travel, because all the scans and blood tests need to be done at the hospital where the trial is based. That may be an issue for patients who live in the countryside and where standard therapy may be easier for them.

“The last thing about clinical trials that I often describe to my patients is an altruistic view. It is the “warm and fuzzy” feeling that by helping us do the research, you’re helping advance the cause of medicine in general.

“By participating in a trial, you’re helping us understand the disease better, you’re helping us develop the next generation of treatments, and you may be the reason why the next generation of patients gets even better therapy.

“People on a clinical trial not only get treatment that might benefit them, they were contributing to the body of knowledge that may benefit many generations in the future.”

“All the new exciting treatment we’ve got at the moment, which is doing a better job in controlling leukaemia than we’ve ever done before, with less side effects, have all occurred because previous patients volunteered their time and their trust by going on a clinical trial 10 years ago.

“There are many clinical trials and the most exciting ones are comparing chemotherapy, which is still the frontline standard of care, against combinations of new agents. Hopefully, in five years these will show that new drugs and new drug combinations would do a better job of treating CLL frontline than chemotherapy.

“And that might effectively end chemotherapy as we know it.”

That’s Dr Tam’s holy grail; to develop a permanent natural, meaning nonchemotherapy, solution with treating CLL. To work out a way that the immune system not just controls but is a cure for CLL for all patients.

“That is an achievement I would be extremely proud of. It’s probably 10 years away. I might be out of a job!”

¹ Fluorescence in situ hybridization (FISH) analysis is the single most common cytogenetic abnormality in patients with CLL.

² The immunoglobulin variable region heavy chain (IgVH) gene encodes antibodies that function in the immune response.

³ Next generation sequencing (NGS), massively parallel or deep sequencing, are related terms that describe a DNA sequencing technology which has revolutionised genomic research.

⁴ FCR regimen is a combination of fludarabine, cyclophosphamide, and rituximab .

⁵ Tumour lysis syndrome can occur as a complication during the treatment of cancer, where large amounts of tumour cells are killed off (lysed) at the same time by the treatment, releasing their contents into the bloodstream.

Expert Series Q&A with Professor Judith Trotman

Expert Series Q&A with Professor Judith Trotman

Professor Judith Trotman
“I’ve been very privileged to be a haematologist over the last 25 years,” says clinician researcher, Prof. Judith Trotman

Professor Judith Trotman, MBChB, FRACP, FRCPA, Grad. Cert. Clinical Trials, is Head of Haematology at Concord Repatriation General Hospital, Sydney.

A clinician researcher, she was the Founding Director of the Clinical Research Unit at Concord Hospital (Sydney) 2005 -2019. She provides global leadership in charting the role of PET scanning in lymphoma and, based on her data, was successful in obtaining an MBS listing of PET for indolent lymphomas. She has developed digital research initiatives in collaborations with patients, including ClinTrial Refer and the WhiMSICAL study, and is currently developing the My Hodgkins, My Health app. Recently, she started the new international collaborative group, Women in Lymphoma. She is a Board Member of the Australian Clinical Trials Alliance and the Foundation for A Bloody Great Cause.

Professor Judith Trotman
Professor Judith Trotman

Q. Why did you study medicine and specialise in haematology?

“I’d wanted to do medicine since I was a teenager. I had a serious motor vehicle accident at the age of 13 and, although I don’t remember much of the intensive care stuff, I found it fascinating being in the hospital setting. I had great training in New Zealand and was interested in HIV medicine. After doing a paediatric HIV elective in New York in 1992, I decided to come to Sydney to do HIV medicine at St Vincent’s Hospital. I found HIV absolutely tragic, but an incredibly fascinating multi-system medicine. Then I really enjoyed my haematology term and inspired by fantastic mentors I thought, ‘I’ll do haematology and HIV medicine together’. Fortunately, there became very little HIV, and I ended up doing just haematology. Lymphoma has always interested me, but I’ve always wanted to remain a generalist haematologist because I love the variety.

What really motivated me to do clinical research, as a registrar at St Vincent’s Hospital, was a woman my age, in her 20s, who had Philadelphia positive acute lymphoblastic leukemia and we battled for a couple of years to keep her alive. Back then, we had just started to get a sense of the importance of the tyrosine kinase inhibitor, imatinib, and 25+ years ago we had just started using email, through which we contacted our U.S. colleagues and desperately tried to get our hands on imatinib for this young woman, but she died before we could get it.

I remember thinking, if I was to practise as a haematologist, it would be within a big clinical research setting that was at the cutting edge, so I could access emerging new drugs for my patients. Back then, rituximab (MabThera®) was just coming out, and I remember, as a registrar, supervising a patient having their first rituximab infusion because we were so nervous about infusion reactions to rituximab. It was my first exposure to what has since been an explosion in targeted immunotherapies and biologics for blood cancers.

I’ve been very privileged to be a haematologist over the last 25 years, when there’s been so much change. Incrementally building our clinical research unit was jolly tough, but also incredibly rewarding and gave us the opportunity to contribute to global change and to be at the cutting edge for our patients, accessing Bruton tyrosine kinase (BTK) inhibitors for so many CLL and Waldenström’s patients and the PD-1 inhibitors for Hodgkin’s, immune therapies for myeloma, close molecular monitoring for CML patients, and of course PET scanning and then PET-adapted therapies for lymphoma patients. It’s just been amazing, and I couldn’t imagine practising haematology outside of a really active clinical research unit. With Dr Jane Estell’s fresh leadership at Concord Haematology’s Clinical Research Unit, we are expanding our Phase I portfolio and accessing the promising new bi-specific antibodies for myeloma and lymphoma.

A real change for me was having a year “off” in France, in 2009, when I immersed myself in the clinical trials unit at Hospital Lyon-Sud and the operations of the now French Lymphoma Study Association (LYSA). Lyon-Sud was one of the biggest lymphoma research units in Europe, but I realised that just a decade earlier it had been establishing itself like us at Concord. Being in that sort of environment makes you realise anyone can be a clinician researcher if you’ve got the will and the commitment, the people with the shared commitment beside you, and by making international connections with many colleagues.”

Concord Haematology team
Prof. Trotman, centre, surrounded by the Concord Haematology team

Q. What is Women in Lymphoma and how is this group instigating change?

“Things are changing. It’s increasingly recognised that whether viewed with a social justice or a business lens, gender equality is imperative. There’ll be a huge amount of change with this amazing group of women from all over the world who will increasingly collaborate. Women in Lymphoma (WiL) may have been catalysed by Australians, I’m the Chair and Eliza Hawkes from Monash also is on the steering committee, but it is a global initiative. Our mission is to support and advocate for greater leadership of women in lymphoma by inspiring and empowering women in lymphoma care, research, and teaching. We plan to map the metrics of their engagement and, with wit and grit, be a collective voice to encourage productive diversity in lymphoma leadership internationally, not just on behalf of women in lymphoma, but all lymphoma clinicians, researchers, and patients. Some British colleagues emailed WiL about the European School of Haematology’s How to Diagnose and Treat Lymphoma series; only one of the 42 speakers was a woman. That’s 2.5%! The WiL initiative, which had by then formed a steering committee, established governance, a website ( and 130 members, wrote to the ESH. Nothing changed, so we set up our own free WiL Education Series. Our first five-week series, in early-September, was on diffuse large B-cell lymphoma (DLBCL), and our first lecturer was Professor Sonali Smith (Chicago), and 86 people attended via Zoom. The entire series was a huge networking and educational success, to be followed by a Hodgkin Series in 2021.”

Q. What do you consider your career highlights?

“There are so many individual patient highlights with milestones achieved, but career-wise it would be my global leadership in PET lymphoma, in particular PET in follicular lymphoma (FL), and establishing PET as the gold-standard imaging modality for staging and response assessment of FL. It provides a platform for PET-adapted trials, designed to improve outcomes and develop an individualised approach for patients. Being able to translate the global data into access to PET locally for patients with low grade (indolent) lymphoma in Australia was just as important to me. Kiwis to follow, hopefully.

Being a part of enhancing and increasing the Australasian Leukaemia & Lymphoma Group’s international collaborations. I’ve really enjoyed our collaboration with the RATHL (Response Adapted Therapy in Hodgkin Lymphoma) study, with the UK National Cancer Research Institute, and the REMARC study with the French lymphoma group, LYSA. It’s been an absolute privilege to participate in the iNNOVATE Phase III trial with ibrutinib, the first BTK inhibitor for Waldenström’s, and then in the trials with zanubrutinib, the second-generation BTK inhibitor. It was amazing to see these patients, exhausted and unwell with relapsed/refractory disease, who were running out of options, take these incredibly well-tolerated oral agents and literally get up off their beds and live healthy lives.

The first BTK inhibitor had minor side-effects. But compared to a life living with or dying from refractory Waldenström’s, any of us would be happy to put up with a bit of bruising, arthritis and diarrhoea. And the second-generation BTK inhibitors, like zanubrutinib (Brukinsa®, formerly BGB-3111), have an even better toxicity profile. It changed the whole mentality around progression-free survival (PFS) being the most important (surrogate parameter) for overall survival (OS) because these drugs are a switch; they switch off the activity of the Waldenström’s or CLL. Studies like MURANO, and accessing venetoclax (Venclexta®) for our patients with CLL, have also been a privilege, to access all these incredibly well-tolerated and potentially time limited oral therapies that are keeping people out of hospital, keeping people alive, and living well; not just flogging people with repeated rounds of salvage chemotherapy. I’m so pleased I haven’t had to use toxic drugs like fludarabine for years.

Getting access to either brentuximab vedotin (Adcetris®), an anti-CD30 antibody-drug conjugate, or the PD-1 inhibitor, pembrolizumab (Keytruda®), an immunomodulatory antibody which harnesses the patient’s own immune response, in the KEYNOTE studies for Hodgkin lymphoma (HL). (Our lead investigator at Concord was Dr Robin Gasiorowski). It was quite amazing to witness young patients with refractory (resistant) HL respond so well and tolerate these smarter treatments so much better than blunderbuss chemotherapy. I don’t want to sound like a Pollyanna–we still have to use pretty intensive chemotherapy for many lymphomas–but there’s a real recognition of the fact that we’re getting a better understanding of the biology, and how we can interfere with the pathways that are driving the lymphoma proliferation. With greater sub-classification of lymphomas though collaboration between clinicians and patients, niche clinical trials for specific lymphomas will be even more important. And the immune revolution for patients is not restricted to lymphoma; our patients have accessed so many new antibodies for myeloma (daratumumab, elotuzumab) through the myeloma trial portfolio lead by Dr Jane Estell.”

Haematology Clinical Research team
Prof. Trotman, second right, with members of the Haematology Clinical Research team

Q. What do you consider is the greatest unmet need in lymphoma?

“Every different lymphoma histology has its own unmet need. Every different patient has their own unmet need and different priorities. In DLBCL, being able to identify and get better therapies for the poor prognosis patient is certainly an issue. We have various prognostic indices, but they’re not perfect. That’s clearly an unmet need. In FL, we’ve got this real focus on ‘progression-free survival’ as we develop new therapies. But I think that while PFS is absolutely a really important metric, it’s not always a surrogate for OS as the key metric, and with patients living so much longer, we can’t even easily and rapidly map PFS differences out with short-term clinical trials. We need a better surrogate for OS. I think it’s also about patients’ quality of life, and I think, finally, there is a growing recognition that patient reported outcomes measures are really, really important.

While we focus on PFS, because obviously that’s a key priority for industry and it’s a key priority for us too, we’ve got to have more of the patient voice engaged in setting the priorities. That’s why we (Ibrahim Tohidi-Esfahani and I, with the WMozzies and IWMF patient investigators) created WhiMSICAL. That’s why Gajan Kailainathan, Janlyn Falconer and I are building the My Hodgkin My Health App for long-term follow-up of patients. The challenge is that the patient voice is not just one voice; there are so many different unmet needs and different priorities. While a cure is priority #1 for many, for other patients, controlling their disease is the main priority; particularly for some older patients if they can control their lymphoma while living well without, or with minimal, side-effects of therapy. Yet, other older patients may say that’s very paternalistic/maternalistic of me to say that; they want cures too! Balancing the efficacy and toxicity of novel therapies was a key aspect of Dr Emma Verner’s ALLG IRiC study of Ibrutinib and Rituximab-Mini-CHOP in elderly patients with DLBCL. It’s really hard to say what’s the greatest unmet need.”

Q. What’s the most important news in lymphoma research at the moment?

“You know what? I don’t know. Perhaps the data showing that patients on the PD-1 inhibitor pembrolizumab are doing even better than brentuximab (another great antibody-driven therapy) in the relapsed Hodgkin’s setting, so I eagerly await the final KEYNOTE publication which shows that patients with relapsed and resistant HL are surviving for years on pembrolizumab. Our own Phase I-III zanubrutinib data, developed with our colleagues across Australia and globally, is now published in the journal Blood, revealing the very high (96%) response rates and long-term excellent tolerance of zanubrutinib for the treatment of patients with WM, is of course a favourite of mine. It’s really hard to know, particularly because everyone’s so focused on COVID at the moment. People haven’t been attending meetings as much.

COVID has completely transformed the whole way we manage our patients. And everyone’s tired, not just the Melbourne clinicians. And the patients are so fearful; so many of them have just gone into lockdown. They’re shielding themselves. COVID changed the way we operate, with telehealth. You can do a few telehealth appointments, but after a while you do need to see the patient face-to-face. You need to feel their lymph nodes and see their reactions and get a sense of what their anxieties and their worries are. Most patients are needing treatment for lymphoma, that’s the overriding priority, not COVID. But I expect, particularly for a lot of patients in certain hospitals in Melbourne, and in Europe and around the U.S., there are huge anxieties in coming in and having treatment. We had our own patients fearful of coming in when we had a very small, (and I’m proud to say), well contained outbreak at Concord. I recently reviewed a large overseas cohort of lymphoma patients infected with COVID and there are specific factors that may be associated with higher mortality risks, but I can’t share the data yet because it’s in press.” We are learning on the run with COVID.

Judith Trotman and colleagues
Dressed up in red at last year’s fundraiser for A Bloody Good Cause, Judith Trotman, second right, and colleagues

Q. The NHL30* (PETReA) study is part of the Leukaemia Foundation’s Trials Enabling Program. How is it progressing?

“This is a 1200-patient study using a PET response to adapt ongoing treatment for patients after their induction therapy for what’s called high tumour burden FL. It’s a UK-linked study and the principal investigators in Australia are Dr Anna Johnston, in Tasmania, at the Royal Hobart, and me.

It’s effectively two clinical trials in parallel. After a patient has received antibody and chemotherapy treatment for their FL, they have a PET scan. On the basis of data in other clinical trials, for 80% of those patients the PET scan will become negative, and there will be no signs of any metabolic activity of the lymphoma in their body. Now in those patients, we are randomising them to antibody maintenance (rituximab/obinutuzumab [Gazyva®]), compared to no antibody maintenance. We predict that antibody maintenance given every two months for the following two years, even in the PET-negative will prolong PFS, but not their OS. It will keep the patient in remission for longer. But it comes at the price of increased toxicity, particularly increased troublesome infections like sinusitis, bronchitis, and respiratory tract infections. FL is generally seen as an incurable lymphoma, and when the patient relapses after antibody maintenance they don’t have as long a remission the second time round because they’ve already been exposed to a lot more antibody. So there are swings and roundabouts, there are trade-offs from this antibody maintenance. Firstly, what we’re wanting to do is to quantitate that trade-off in the patients who have the best prognosis, those who have become PET-negative after their initial antibody chemotherapy treatment. Secondly, less than one in five (<20% of the patients) will still have signs of glucose uptake attributed to the lymphoma on the PET scan, and we know these patients who remain PET-positive have a much worse prognosis. We know they are more likely to relapse much earlier and are >5 times more likely to die earlier because of their lymphoma. This is one of the real appeals of the PETReA NHL30 study, because in this PET-positive population, half of them are receiving the (rituximab or obinutuzumab) antibody maintenance, and half of them are going to have lenalidomide (an immune modulatory agent which harnesses the activity of their own immune system to fight the lymphoma) added to the antibody maintenance.

So, to summarise PETReA, we’re measuring the benefits and toxicities of maintenance in patients who become PET-negative, and the likely benefit and toxicity of additional lenalidomide in patients who are PET-positive. We’re trying to work out a PET-adapted approach; a specific personalised medicine approach for individual patients, rather than one-size-fits-all, where you give everybody intensive antibody-chemotherapy and ongoing treatment with antibody maintenance, which we know has significant toxicity.

So, significant benefits, but significant toxicity, and indeed in the very old, people over the age of 70, they’ve got a much higher risk of dying on antibody maintenance after drugs like bendamustine (Treanda®). There’s no point getting a complete response of your lymphoma and then dying of an infectious toxicity because of the treatment.

We’ve been in the study for about a year now and we’ve recruited 30 patients in Australia out of about 150 patients worldwide. We put it on hold initially with COVID, then we realised, with COVID, this study is even more important, because there’s potentially an even higher risk of toxicity of the maintenance antibody in the COVID setting. We genuinely don’t know, and that’s the setting where clinical trials are vital to advancing lymphoma care.”

Q. How important is the funding from the Leukaemia Foundation for the NHL30 study?

“The Leukaemia Foundation funding was a great enabler. While we got some funding for the study from the MRFF [Medical Research Future Fund], to get access to the trial for a decent number of patients across 15 sites, we needed more funding. And this helps not just current but future patients access clinical trials. By being able to contribute well patients to the UK RATHL study, we have had access to PETReA and soon we hope the RADAR study for patients with early stage HL, in 2021. We also then get access to new studies and new treatments for our patients. Maintaining these international collaborations is how you get access to new treatments. They really are.”

A previous study Professor Trotman was involved in received a $340,000 grant from the Leukaemia Foundation titled: RATHL – Randomised Phase III trial to a assess response adapted therapy using PET in newly diagnosed advanced HL, the results of which were published in the world-leading New England Journal of Medicine in 2016 – the day of the Brexit vote!

“You come back, and you get back into life” – that’s how Patrick lives with two lymphomas

“You come back, and you get back into life” – that’s how Patrick lives with two lymphomas

Patrick Devine with Ros walking
Patrick Devine “walking again” with Ros in February 2020 (Photo: Anna Carlile)

Patrick Devine has two extraordinary physical aims – to walk the 10 kilometres from Melbourne Central to Camberwell where he lives, and to swim 200 metres butterfly!

Extraordinary, because this time last year he couldn’t walk or talk after miraculously surviving a sepsis infection that saw him spend 11 weeks in hospital, 27 days unconscious in ICU, and 15 days on a ventilator.

“My wife was told many times to say her goodbyes,” said Patrick, 73.

The recently retired pharmacist is living with two different types of incurable lymphoma. Sézary Syndrome (SS), an aggressive form of cutaneous T-cell lymphoma which he’s had for 10 years, and since mid-2018 he’s also had Waldenström’s macroglobulinaemia (WM), a B-cell lymphoma.

“I live with cancer, accept the best treatment available and live in the best way that my body will allow.”

That’s Patrick’s philosophy and it steers him through the dramas and traumas inherent in having blood cancer so he can get on with and appreciate “a very ordinary life”.

When he spoke to Lymphoma News, the COVID-19 restrictions in Melbourne was the only thing holding him back from reaching his two goals.

Patrick Devine learning to walk December 2019
In December 2019, when Patrick was learning to walk again

Sézary Syndrome – diagnosis and treatment

While Patrick’s diagnosis with SS was in November 2010, he says the condition began 15 years earlier, when he started having skin rashes.

“Skin rashes can be eczema or psoriasis, but in the case of Sézary a cancer forms in the body which manifests itself in the skin and affects the lymph nodes and blood,” he explained.

“Initially it appears like eczema, but the skin can get covered with patches, plaques and tumours. When or if the skin gets broken, you become very susceptible to infection,” explained Patrick, a competitively successful swimmer for most of his life, who has spent a lot of time in the pool.

“In the last year [2009] before diagnosis, I was training quite a lot and my skin got worse and worse. I got a secondary infection over this eczema-looking rash and went to the doctor.”

After a blood test, his GP called that night saying his white blood cells were “off the scale” and the haematology registrar at a Melbourne hospital was waiting for him.

Patrick spent the next four days in hospital having tests, treatment for his skin infection, and he was diagnosed with SS – a rare condition that while incurable is treatable.

He was treated with extracorporeal photopheresis, which enhances the immune system and helps it cope with the SS. It requires access to a machine that takes blood out of the body, treats it with ultraviolet light, then returns the blood to the body.

The availability of some treatments, such as extracorporeal photopheresis (ECP), is not widespread, said Patrick who is concerned about people with rare cancers who live in remote areas.

“The rarer the cancer, the more difficult it is for treatment to be available at all major hospitals and to have specialists familiar with state-of-the-art knowledge and facilities to treat those cancers.

“Extracorporeal photopheresis is available in Melbourne, but at the time I had it, it wasn’t available in Sydney and is still not available in most other major centres today.”

Patrick Devine at the launch of the Blood Cancer Taskforce September 2019
Patrick Devine at the launch of the Blood Cancer Taskforce, September 2019

Next – a clinical trial for brentuximab vedotin

The ECP treatment “loses its potency after a while” so when an international clinical trial testing the drug brentuximab vedotin (Adcetris®) became available in 2015, Patrick participated. He was randomly assigned to the other arm of the trial and the treatment he received was bexarotene.

“When I wasn’t responding, they graciously transferred me to the brentuximab arm and I responded well to that,” said Patrick.

“Sezary syndrome is caused by a mutation in the genes and brentuximab is a monoclonal antibody designed to destroy specific proteins in the cancer cell.

“I was one of the few patients in the trial that could sustain the full dose – an infusion every three weeks for the 45 weeks of the trial.”

Patrick’s rashes responded “very very well” to the brentuximab and his lymph nodes “reduced in size and are fine”. But he got severe peripheral neuropathy and this side-effect made it difficult for him to walk, hold things, and he had a lot of gastrointestinal symptoms.

“So it wasn’t comfortable, but at the same time you could say it [brentuximab] saved my life,” said Patrick.

Over the following 18 months, he gradually got better and during this time he could swim more easily than he could walk, and he continued to swim competitively*.

He was drug-free after the trial and gradually his peripheral neuropathy improved, assisted by a series of gentle exercises and weights.

A second lymphoma diagnosis

Then, in June 2018, Patrick got another lymphoma, WM, which, astoundingly, he said “was fine”.

“I’m a pharmacist and I’ve worked with people with cancer all my life. I’ve counselled them, I’ve seen them die. I’ve made friends with them and many have continued living, and I’ve admired the way they have travelled their journeys.”

“You take what strengths you have, work out the best way to live, get the best treatment you can, and accept the result.”

“Emotion coming into it doesn’t help, does it?” he added.

Patrick’s treatment for WM was a combination of two drugs, rituximab (MabThera®) and bendamustine (Ribomustin®). He was to have six doses, but after the fifth he developed sepsis (septicaemia) and ended up in hospital.

“I completely lost all my motor skills and came out weakened by it, but I got back into life straight away, in the best way that I could manage,” said Patrick.

“I couldn’t walk well but I got back into swimming 3-4 km a week and coaching swimming, and I was working as a consultant pharmacist, part-time, which I’d done since 2015,” said Patrick.

But he no longer swam competitively: “My last serious competition was in 2017”.

The WM has since been “behaving itself well”, but in February 2019 his SS was “coming back” and the decision was made for Patrick to have total body electron beam radiation; 21 sessions in July and August plus other appointments.

“It was fairly intensive in terms of time and this is where public transport was important because I live near a station and the thing is… parking at hospitals in incredibly expensive,” said Patrick.

Despite his weakened immune system, Patrick doesn’t hesitate to catch public transport to his medical appointments and treatment, but he’s “fairly careful”. Using it is a statement of living a normal life.

“Even though your immune system is compromised, you still have to expose yourself to society,” he said.

“I don’t have fear. Fear is not a thing that helps.”

In October last year, Patrick, who is an active member of a car club, displayed his car [a 1956 Mercedes 300 SL that he restored from a wreck] at the Motorclassica exhibition in Melbourne.

“I was there for three days, talking to people from all over the world.”

The next day, Patrick and his wife, Ros, celebrated their 50th wedding anniversary, and only three days later he collapsed, and Ros called an ambulance. By the time he got to Emergency, he had lost consciousness.

Patrick Devine and Ros at a car rally
Patrick and Ros at a car rally in 2019 (Photo: Stephen Skok)

A second near-death brush with sepsis

Patrick Devine in ICU
Patrick when he was in ICU and ventilated in November 2019

This was his second sepsis episode. He was ventilated, his heart, lungs, kidneys and liver collapsed, and Ros was told, “sorry, he’s not going to make it, say your goodbyes”.

Patrick had no idea what a dire situation he had been in until he became semi-conscious and Ros said, “hey, it’s November”. All sorts of things had happened, which he had no knowledge of including Melbourne Cup.

He was moved to the palliative ward.

“The thing was, I was sent up there to die, and Ros was rearranging the house so they could put a hospital bed in our bedroom, because I may have ended up dying at home.”

One day, during the three weeks Patrick spent in the palliative ward, a doctor noticed he had produced a “thimble full of urine”, the colour of shiraz wine.

“And I noticed a tiny little bit of excitement in his voice… things were just starting to work,” said Patrick.

Gradually, over many weeks, Patrick’s systems started to recover and he was moved to a rehabilitation hospital.

Having big lungs, from a lifetime of swimming, was “probably the reason I survived”, he said, along with Ros’ unending support, and “an amazing group of people with different skills and abilities” who saw him throughout this period.

Getting back into life

Patrick Devine with Ros and Scott Morrison
Patrick and Ros Devine with Prime Minister Scott Morrison in April 2018 when he was “lobbying for patients from remote areas who have rare blood cancers”

He left rehab on January 3 and went home with a wheelchair, walker and shower stool, “but I never used any of them”. By February, Patrick was “reasonably active” and took his car to a garage day and two exhibitions.

But he did find it “very hard” to walk the gentle 15m slope, from his car to the backdoor.

“One day I even crawled,” said Patrick.

“I also crawled around house and tried to sing.

“This was my idea. It was very hard for me to stand up. Crawling is very good as a limb coordination exercise and it was something I could do with the state of my body.

“I mixed crawling with walking, and I tried to sing, for my lungs.

“Even now my speech is not quite what I would like it to be, because my tongue was damaged from the ventilation tubes,” said Patrick, who speaks slowly, and very clearly.

“Sometimes, if I speak quickly, I’ll start one word, then say another word because the tongue has gone into the wrong sequence.

“But I’m back to where I chaired a Zoom meeting in September for the annual meeting of my car club with 204 members.”

Patrick Devine at the pool
Back in 2016, when Patrick was at the pool

Patrick’s two physical aims

“Eventually, I’ve rebuilt. I can now walk several kilometres and I have two physical aims at present.”

But there are a couple of caveats, thanks to COVID-19.

“I want to do the walk before it gets too hot. Ros will come along as a support team, but at present we have a five-kilometre radius in Melbourne that we’re not allowed to go outside.

“And the pools have been locked down and I haven’t been able to book a swim yet,” said Patrick when he spoke to Lymphoma News in early-October.

“Of course, it will take me a while to work up to the 200m butterfly.”

And there’s another “thing”.

“My Sezary isn’t going very well and I’m back on brentuximab,” said Patrick. He had just had his fourth dose, with another 12 infusions to go.

So he also wants to do both his walk and swim before he builds up too much peripheral neuropathy – a cumulative side-effect of this treatment.

PBS listing of brentuximab

Back in April 2018, when brentuximab vedotin was approved by the Pharmaceutical Benefits Committee (PBAC) to be funded on the Pharmaceutical Benefits Scheme (PBS), Patrick was involved in the announcement with the Minister for Health, Greg Hunt.

At that time a course of brentuximab treatment cost $300,000.

“It’s hugely expensive and I’m forever grateful to the Australian taxpayers who pay for that to keep me alive,” said Patrick who is an avid consumer advocate for blood cancer.

A few days after the PBAC announcement Patrick was asked to meet the Prime Minister.

“We talked about brentuximab and I gave him a letter outlining the difficulties of people who live in remote areas and have a rare lymphoma or leukaemia,” he said.

That’s Patrick’s biggest advocacy concern and his passion – how those people manage, from being diagnosed by their GP, to accessing treatment, and the role of the various state-based health jurisdictions.

He was actively involved in the launch by the Leukaemia Foundation and the Australian government of the Blood Cancer Taskforce last year and the National Action Plan that was released in September, and more recently, he advocated for another expensive cutaneous lymphoma drug, mogamulizumab, to be recommended by the PBAC for listing on the PBS.

Enjoying the “nice things of now”

“I don’t know what will happen when this cycle of brentuximab stops working. I’ve got 12 more treatments, and it’ll sustain me for a while, but I’d like to live well into my 80s or 90s,” said Patrick.

He doesn’t worry too much about the future though, “because worry stops you enjoying the nice things of now”.

“So, I’ll enjoy my swim. I know how weak I’ll be, but it’ll still be fun.“

Exactly 12 months after being admitted to ICU, on October 19, 2020, Patrick had his first swim since then of one kilometre.

“And the next time the car club has something, it will be nice to go on it. And I’ve got motoring articles to write [for the club magazine that Patrick edits].

“Believe it or not, I don’t mind having the lymphomas at all. The things that are fantastic in normal life – they’re absolutely garnished, garnished more than you could ever imagine. They become much more important.

“What happens… you appreciate the finest and the nicest things and sometimes the very ordinary things. They just become more highlighted in your life.

“There are certain traumas that have happened and it’s quite amazing that I’ve got through them. You have to put those bits aside and just be completely normal,” said Patrick.

* Patrick, who started swimming at 11, has broken four Australian records in Australian swimming championships and has many gold medals amongst his trophies for Royal Life Saving. He started competing in Masters’ competitions at the age of 50 and has eight gold medals in international lifesaving and three golds swimming at international level. “The second year after I was diagnosed, which was 2011, I could still make the top 10 in the world in Masters’ swimming in my age group,” said Patrick.

COVID has been beneficial to some WM patients

COVID has been beneficial to some WM patients

Andrew Warden and Judith Trotman
Professor Judith Trotman helped train Andrew Warden to give himself subcutaneous immunoglobulin which has now replaced his previous monthly intravenous immunoglobulin that was administered in a hospital setting

“COVID’s been good to me and quite a few other patients”, says Andrew Warden, who volunteered to be a “guinea pig” on a program initiated by Professor Judith Trotman.

It was for a new treatment procedure, subcutaneous immunoglobulin (SCIg), which can be self-administered at home on a weekly basis, thereby replacing the previous intravenous immunoglobulin (IVIg) method which involved going to a cancer centre every four weeks.

“In recent years there’s been subcutaneous immunoglobulin replacement therapy, given every week rather than every month, and the patient can be trained to give it to themselves at home,” explained Prof. Trotman.

Andrew was among the first of a group of around 20 patients at Concord Repatriation General Hospital who, when asked if they would like to self-inject at home, agreed. After a couple of training sessions, he made the change to SCIg back in June.

Andrew Warden self-injecting at home
Andrew Warden self-injecting his weekly dose of subcutaneous immunoglobulin at home

That means Andrew, who has Waldenström’s macroglobulanaemia (WM) and lives at Coasters Retreat, which has no road or land access, saves hours of travel time and this results in superior social distancing.

“For me, it saves three hours for each treatment. Return travel time for me from Coasters Retreat to Concord involves 2½ hours in my car and ½ hour in my boat,” said Andrew.

“Concord Cancer Centre gave me practical training in SCIg in three weekly sessions at the centre. This has now been streamlined to two training sessions at the centre, with the third session being held virtually at home.

“This results in superior social distancing during the COVID-19 pandemic but also saves the travel time to and from the clinic typically every four weeks,” he said.

“I self-inject at home, which saves travelling for three hours and going into a risky hospital environment. It’s been a winner,” said Andrew.

According to data from the WhiMSICAL Registry survey, 14% of WM patients receive IVIG treatment.

Prof. Trotman said the subcutaneous immunoglobulin program had been very successful for patients with reduced antibody production who need immunoglobulin replacement therapy.

“Dozens of our patients at Concord now can self-administer or their carer can administer the immunoglobulin to them at home.

“The patients don’t have to come into hospital, which is convenient and particularly relevant to patients who live far away, and for patients when they don’t want to be coming into ambulatory care settings,” said Prof. Trotman.

Mogamulizumab being considered again by PBAC

Mogamulizumab being considered again by PBAC

This month the Pharmaceutical Benefits Advisory Committee (PBAC) will consider a resubmission from Kyowa Kirin for mogamulizumab (Poteligeo®) for relapsed or refractory (R/R) cutaneous T-cell lymphoma.

The Leukaemia Foundation made comments to the July 2020 PBAC meeting for a previous submission for mogamulizumab (when the PBAC made a first-time decision not to recommend) and again for the November 2020 PBAC meeting.

The requested listing is a Section 100 (Efficient Funding of Chemotherapy) Authority Required (Written) listing for patients with R/R CTCL who have been previously treated with at least one prior systemic therapy.

Mogamulizumab illustration The sponsor (Kyowa Kirin) provided the Leukaemia Foundation with summary information on the target population, specifically patients with the mycosis fungoides (MF) or Sézary syndrome (SS) subtypes of CTCL, how the condition is currently managed in Australia, where mogamulizumab sits in the current standard of care, information on the MAVORIC clinical trial, common side-effects of the treatment, and how it is administered.

The Leukaemia Foundation’s Head of Policy and Advocacy, Emily Forrest, said, “we understand that patients with early-stage MF are treated primarily with skin-directed therapies, whereas patients with treatment-resistant early-stage MF, advanced-stage MF, or SS require systemic drugs including vorinostat, or cytotoxic chemotherapeutic drugs”.

“We understand that in the MAVORIC clinical trial, mogamulizumab significantly prolonged progression-free survival compared with vorinostat. Also, patient-reported outcomes, as measured by the Skindex-29 and FACT-G, showed significantly greater symptom reduction and improved functional status in favour of mogamulizumab versus vorinostat in early cycles and throughout treatment.

“We also requested consumer feedback via the Leukaemia Foundation’s disease-specific Facebook pages, which included a link to the Patient Voice Initiative ‘Tip sheet for submitting consumer comments to the PBAC’,” said Ms Forrest.

The Leukaemia Foundation received one response to its request for feedback for the July meeting from consumers: Donna, a CTCL patient in Queensland who we understand has not undertaken treatment with mogamulizumab: I’ve not been given any drugs and I’m asking WHY when I’m at Stage 4 … .

“A second request, for the November meeting, did not receive any consumer comments, which may reflect the small population of patients for this therapy to date,” said Ms Forrest.

Information provided by the Leukaemia Foundation to the PBAC in support of the two submissions included: “CTCL is a rare type of lymphoma, and rarer still for specific subtypes of the disease such as MF and in particular SS. Smaller patient populations with rare diseases face significant hurdles in accessing new treatments in a timely manner. It is for precisely this reason that patients and clinicians need access to new therapies to treat the disease.

“We therefore urge the PBAC to consider the high unmet needs of this patient population in its decision making and in making a recommendation to government for listing this therapy on the PBS.”

More PBAC news on CTCL

In other PBAC news, on 1 November 2020, methoxsalen (Uvadex®) was listed on the Pharmaceutical Benefits Scheme (PBS) for patients with erythrodermic CTCL who have not responded to other treatments.

Methoxsalen was approved for listing by the PBAC at its May 2020 intracycle meeting. It was considered as part of a streamlined co-dependent dual-review process with the Medical Services Advisory Committee’s consideration of Medicare funding of extracorporeal photopheresis (ECP) for CTCL, based on a favourable clinical and cost-effectiveness comparison.

Approximately 75 patients annually are expected to benefit from this listing. ECP also will be funded through Medicare for use in combination with methoxsalen.

ECP involves attaching a patient to a machine that removes some of their blood, separates the white blood cells (WBC) and returns the red blood cells and platelets to the body. The WBC are mixed with methoxsalen, exposed to ultraviolet light, then administered to the patient, to activate their immune system to fight the blood cancer.