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Daratumumab – first new myeloma agent PBAC-recommended in years

Daratumumab – first new myeloma agent PBAC-recommended in years

For the first time in 13 years, a new agent with a different mode of action against myeloma, daratumumab (Darzalex®), has been recommended for Pharmaceutical Benefits Scheme (PBS) reimbursement.

At the July 2020 meeting of the Pharmaceutical Benefits Advisory Committee (PBAC), daratumumab received a positive recommendation for PBS listing as a second line treatment, in combination with bortezomib (Velcade®) and dexamethasone for patients with myeloma.

In a submission to the PBAC in June 2020, the Leukaemia Foundation provided consumer comments in relation to daratumumab, based on the everyday experiences of people living with myeloma.

Peter, a myeloma patient from Western Australia, said:

Darzalex “This drug is proving revolutionary in the fight against this terminal blood cancer and should be available as a permanent line of therapy [as] it can extend or save lives.”

The Leukaemia Foundation’s submission also stated that, based on the summary clinical trial information provided, “we understand daratumumab-based combinations have demonstrated efficacy in comparison to other agents tested in head-to-head relapsed or refractory myeloma trials in terms of delaying disease progression and response rates, and have also been shown to lead to molecular remissions in a greater number of patients with relapsed multiple myeloma”.

The PBAC noted in its recommendation that daratumumab monotherapy would be provided by the sponsor (Janssen), on a compassionate basis, to all eligible relapsed and/or refractory (R/R) myeloma patients who have no other PBS-funded treatment options.

A study, published in an August 2020 online issue of Journal of Hematology & Oncology, confirmed and extended the previously known effectiveness and tolerability of daratumumab plus standard of care (bortezomib/dexamethasone) as a treatment for R/R myeloma.

The Leukaemia Foundation also made a submission to the PBAC for carfilzomib (Kyprolis®).

“We received eight responses to the request for feedback on this submission,” said Emily Forrest, the Leukaemia Foundation’s Head of Policy and Advocacy.

“Views amongst patients and their families/carers were mixed, with some concerned about the side-effects of the treatment,” said Emily.

“There is a high unmet need for new treatments for myeloma, which is currently an incurable disease which becomes progressively harder to treat after each relapse as patients become refractory to different treatments.

“We believe that the listing amendment for carfilzomib would provide clinicians with additional choice in therapy regimens for patients with refractory myeloma.”

Carfilzomib also received a positive recommendation to amendments to the dosing regimen and a change to a streamlined authority level, as sought by the sponsor (Amgen Australia).

Emily said the Leukaemia Foundation would provide submissions to the PBAC for consideration at its November 2020 meeting for elotuzumab (Emplicit®) and ixazomib (Ninlaro®) for patients with R/R myeloma.

Read Shirley Irwin’s experience with myeloma and a range of treatments including carfilzomib and daratumumab. (add link to story)

You stepped up for Jack and his family in their darkest hour

You stepped up for Jack and his family in their darkest hour

Jack Mcilvar in May 2020

Stem cells are primitive cells likened to ‘baby’ cells, yet to decide what they want to be when they grow up. They turn into all the different blood cells, including the cells of our immune system.

But people with blood cancer or related blood disorders often need their stem cells replaced because of their disease or toxic treatments like chemotherapy.

Most stem cells donated to Australians actually come from overseas. So, what happens when unprecedented travel restrictions during a pandemic strangle the vital supply of stem cells?

Jack Mcilvar was 22 years old when he was diagnosed with a dangerous blood disorder called aplastic anaemia. He needed a stem cell transplant this year to save his life.

His father and carer, James, recalls how his son had battled aplastic anaemia for many months, spending weeks in intensive care and coming close to death. But there was light at the end of the tunnel: a stem cell donor had been found in Europe and Jack was finally well enough for a transplant.

His new live cells were prepared for a trip to Australia, to be accompanied by a necessary human courier. Meanwhile, Jack’s doctors in Adelaide began the normal process of destroying what was left of his immune system ahead of the transplant.

But then COVID-19 began to spread. Borders closed, couriers could no longer travel, transplants were deferred. Jack’s life-giving cells remained thousands of kilometres away.

“We just couldn’t believe our luck,” James recalled.

“Our son had no immune system left and was now one of the most vulnerable people in the world.

We’d got through so much and were at last ready for a transplant, but now there was a global pandemic.

“Doctors had to stop treatment because his stem cells were no longer guaranteed to arrive.

“Our family was in complete turmoil. Who could we reach out to? It was a feeling of utter helplessness.”

Then a chance encounter in hospital. One of our team, visiting other families with blood cancer, overheard James in the patient lounge and offered to help.

Jack’s stem cells did make it through.

“We’re still not sure how it happened but Jack’s transplant arrived, we think on one of the last flights in carrying cells,” James explained.  “We were lucky. It was such an incredible relief to us.”

Jack Mcilvar after his transplant

After weeks of difficult recovery following his transplant, and against all the odds, we’re thrilled to report Jack is now on the verge of going home. Thank you so much for being there for families like Jack’s during the coronavirus pandemic.

There are lots of challenges ahead but with Jack and thousands of others like him catalysing our efforts, we’re ready to take them on together.

What’s CAR T-cell therapy?

What’s CAR T-cell therapy?

Bruce Levine

For more than 25 years, Dr Bruce Levine has worked alongside Professor Carl June – the doyen of immunotherapy – on the development of CAR T-cell therapy*, which he describes as “a living and dividing drug”. 

In his role as Deputy Director of the Center for Cellular Immunotherapies at the Perelman School of Medicine (Philadelphia, U.S.) Dr Levine’s focus is on technology innovation and assessment.

“CAR T-cells FDA version 1.0 is approved but how do we get to version 2.0 integrating new technologies?” he says.

Dr Levine’s analogy is that CAR T-cells are now at the Model T stage. “It takes a lot of effort to make them.”

“It took decades for car manufacturers to integrate automation systems, and now we’re moving into the era of Tesla and Google self-driving cars. That’s where we want to be, thinking of these T-cells not only as tumour killers and drug delivery vehicles, but self-driving drugs. Smart drugs.”

Dr Levine spoke to Lymphoma News when he was in Australia last year to present at the Leukaemia Foundation-hosted New Directions in Leukaemia Research  (NDLR**) conference in Brisbane.

What in simple English is immunotherapy and how does it work?

It’s the manipulation of the immune system to fight disease. In simple terms, the earliest immunotherapy was the vaccine for small pox and the next generation of immunotherapy began to look at chemical messengers that the immune system uses to communicate amongst cells. The thinking was… could we repurpose some of those that could be manufactured in laboratories to administer to patients to fight disease, cancer among them.

More recently, beginning in the 1980s and 1990s, this concept of cellular immunotherapy began to emerge out of what may have been the first cell therapy – bone marrow transplantation and stem cell transplantation (SCT). We’ve taken that a step further in that we’re manipulating immune cells to redirect them, to endow them with functions they would not ordinarily have – to see antigens, and targets they would not ordinarily have, and potentially to carry drugs or to be resistant to HIV or to fight off or reverse auto-immunity, and so we’re creating a new type of immunotherapy to treat disease.

 

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Can you summarise your NDLR presentation?

What we’ve been able to do is take patients’ immune cells and modify them using genetic technology to express a receptor (chimeric antigen receptor, CAR) that redirects those cells to kill cancer.  The CAR is composed of a cell external portion that is an antibody directed towards a tumour antigen, and a cell internal portion designed to signal and activate immune cells. This is a living therapy that in many cases has durable benefit. It’s unique in that it is a bespoke therapy; we are using each patient’s own cells.

It’s a new class of drugs, even though it is a cell, and it is viewed by regulatory authorities as a drug.

CAR T-cell therapy is used in a type of acute lymphoblastic leukaemia (ALL), in paediatric and young adults up to the age of 25, and in non-Hodgkin lymphoma (NHL) – diffuse large B-cell lymphoma.

We’re also developing this therapy in other blood cancers – in adult ALL, and chronic lymphocytic leukaemia (CLL), and myeloma. In myeloma, there’s a different target, called BCMA (B-cell maturation antigen). We’ve conducted a pilot trial targeting CD123 in AML and there’s more work to be done there using another target, CD33, and we have a new technology to integrate into that trial. And in solid cancers, there’s a panoply of targets depending on the type of cancer. The challenge in solid cancers is finding a target that covers all cancer cells but is not expressed on other tissues.

When you move to a new target, you just swap out the antibody portion of the CAR but the rest of the design and the production of this therapy is the same. It’s a platform technology in that sense.

How well does the public understand CAR T-cell therapy?

When [data on] our first three patients were published in 2011, some journalists were confused with the role of HIV in this cancer therapy. We use a disabled form of HIV as a gene vector. Its only purpose is to convey the genetic material and coding the chimeric receptor inside the cell, and that’s all it can do.

What I have found fascinating about genetically modified organisms is the misrepresented fear of people, for example, who buy GMO-free breakfast cereal, thinking it’s better, but if you’re genetically modifying an organism to treat their cancer, then that’s ok. Speaking to one of our patients over dinner, I said – ‘how do you feel about being a genetically modified organism?’ She said she’d never thought about it. Sometime later, I said ‘you should buy a T-shirt that says, “I’m a GMO”, and she did!

That is what it is, because the CAR transgene lentivirus insertion into the genome is permanent for that cell and all the daughter cells, so the CAR is carried forward in the progeny of every T-cell. It’s durable activity from one dose. We don’t know how long one dose will last but the data we have in HIV is 10 or 11 years, and the data in cancer with our first treated patients is 8.5 years. So, in some patients, those CAR T-cells continue to exist. In others we can’t detect them. They may be there, but they are inaccessible or beyond the level of detection.

How many patients worldwide have been treated with CAR T-cell therapy?

At the University of Pennsylvania, we’ve treated over 600 patients, and Novartis, in their clinical trials and commercial setting, is now well above that number. Then there are all the other industry developers – Kite/Gilead’s Yescarta®(axicabtagene ciloleucel), for example– and academic institutions around the world. To hazard a guess, I’d say 2000-3000 patients.

What is the survival rate of CAR T-cell therapy?

That depends on the disease. The best response is in paediatric ALL. At one month (after CAR T-cell therapy) in relapsed/refractory ALL, there is an 83% complete response rate – it’s really striking compared with any other therapy. In lymphoma and CLL, the response is lower – generally in the 45-50% range – but keep in mind these are patients who are relapsed and refractory, with no other options.

Are CARS likely to be used as a front-line treatment?

I think that’s some ways away. We’re working at shortening the manufacturing and simplifying things. I think the next leap will be in second-line therapy, and then we’ll see.

How do you see CAR T-cell therapy, which is very expensive, having a wider application to more patients?

I think the key is the setting and right now we’re in the relapsed/refractory setting. If you look at expenditure on patients in the leukaemias and lymphomas, the ones that are eligible for CAR- T-cells are at the very top of the curve. Whether it’s multiple rounds of high-dose chemo or a SCT, if you look at the cost to the health system for those patients, especially those who go to SCT, and the cost of CAR T-cells, it’s really not that unfavourable, especially when you look at a one-time infusion for durable benefit. Are they expensive? Yes, but I would argue, it’s financially complex because it’s expensive up front, but the longer a patient responds, the lower the expense per quality of life year gained.

Do you expect this new type of living drug to have application across the other blood cancers?

Yes.

What’s it like being involved in the first-in-human trials of CAR T-cell therapies?

We’ve done a number of first-in-human trials, and with the first patient you’re never sure what’s going to happen. It could be nothing, it could be a glimmer of something, and it could be what you draw up on the board as your dream for what’s the best that could possibly happen. So, I remember quite well the first patient we treated, in August 2010. We were excited to give him the cells and then you wait. You wait for the blood counts, and you wait for the bone marrow biopsy, and the pathology on the bone marrow biopsy.

The pathology report emailed by the study investigator, David Porter, to Carl June, me, and others said: ‘shows no evidence of leukaemia’. Carl June wrote back and said, ‘I don’t believe it. Do it again’. Dr Porter had to go back to the patient and say, ‘the lab screwed up your sample, we’re going to have to take another bone marrow biopsy’, which is not very comfortable. The patient agreed fortunately, and it came back again with ‘no evidence of leukaemia’. So then, you say, ‘okay. It’s one patient. It could be a fluke, let’s see what happens the next time’. Then it happened again, and it happened again in patients with heavy leukaemia burden, and eventually you begin to see something very special is happening.

But you’re not quite believing how good this could be. And then we had a run of patients who didn’t respond, and it was… why is this happening, are we making the cells differently? But it just turned out that the first three patients were responders and others weren’t, and in the end the CLL response was what it was – around 45-50%. At that point, we made the decision to move into ALL and that’s really where we’ve seen the most amazing results to date – in paediatric ALL.

And there was the event with Emily [the first paediatric patient to be treated with T-cell therapy, on 17 April 2012], where she got very very sick with cytokine release syndrome (CRS). So sick that her physicians told her parents to call the family in because she wasn’t going to be around in the morning. Fortunately, at Carl June’s suggestion, administering an antidote – tocilizumab – was the cause of her recovery from CRS. If that had not happened, that would have set back the field immensely. We are indebted to Emily and her family, and we are as investigators, and I think the field is extraordinarily fortunate – that that antidote to this side-effect of the T-cells being very active was discovered.

In 2017, Kymriah® (tissagenleclelucel) received Breakthrough Designation status and FDA Approval in the U.S. and is now in commercial development. How did you feel about this achievement?

It’s hard to put into words, when something you’ve worked on for 20+ years you see as an FDA-approved therapy. I attended the FDA hearing of the oncology drug advisory committee in July 2017 and Emily [Whitehead] and her parents were there, and other parents were there and testified. At that hearing the advisory committee voted to recommend FDA approval. It was a unanimous vote and I’m getting choked up now…

How did you get involved in blood cancer research?

My father was a cell biologist, and as an undergraduate, thinking of what area of science to go into, I asked my professors “what will be ‘the’ field in 15-20 years?”.Their answer was ‘immunology.’

I applied to graduate schools in immunology and infectious diseases and did my thesis on signalling in T-cells when I was at the bone marrow transplantation research lab at Johns Hopkins Hospital (Maryland, U.S.). I’d read articles by a guy called Carl June. I applied for and was accepted for a post-doctoral fellowship in his lab in 1992 and we’ve worked together ever since. When he asked if I’d like to run a lab that grew cells for an immunotherapy trial (in HIV) I said, “sure, that’s exactly what I want to do”.

When we had data from the trial (in HIV) showing we could increase CD4 T-cell counts and increase immune function, the natural application was in cancer after high-dose chemotherapy and after stem cell transplantation. In 1999, at the University of Pennsylvania’s clinical cell and vaccine production facility, we started doing trials in cancer – first in leukaemia and lymphoma.

Carl directs the Center for Cellular Immunotherapies – a collection of laboratories and translational and clinical scientists and a manufacturing facility with about 250 staff. I was the director of the cellular production facility and in 2017 I took a new position in the centre focusing internally on new technologies for manufacturing, and externally focusing on national and global engagement. I am now the President-Elect of the International Society for Cell and Gene Therapy.

What does your role as Deputy Director involve?

To facilitate the development of the new technology, so we have wider access for patients inpaediatric and adult ALL and NHL, other blood cancers and beyond, including solid tumours. Some of them will work quite well and some won’t work, and there’ll be new technologies that we bring in, and combination treatments.

One thing that is encouraging in our lymphoma work is that we do have patients who don’t respond but when we give them checkpoint antibodies, then they do respond, and the T-cells wake up. So, by combining CAR T-cells with checkpoint antibodies, or with tumour vaccines, or with oncolytic viruses, or other agents, we have opportunities for increased responses than if we were only operating in isolation.

What is the main area of your work?

It’s several-fold. The Centre’s internal effort focuses on technology assessment and integration in manufacturing immune cell therapies directed at cancer, infectious disease and autoimmunity.

Next is coordinating efforts at our centre and at the Institute for Regenerative Medicine and other investigators and institutes at Penn including the engineering, business and vet schools. We have a CAR T-cell trial in dogs at the vet school. People can enroll their companion animals and what we learn in humans we can take to dogs, and what we learn in dogs we take back to humans.

The outer ring of my current effort is global – speaking at conferences like this (NDLR*) and participating in professional societies and in a leadership capacity in private consortia, moving the field as a whole forward. I can speak not only to manufacturing, testing the impact, the regulatory landscape and patient access, but also communicating to the public, so the public understands what we are doing and that it’s not a mystery or that we are creating some genetic adverse event or Frankenstein type of thing!

What are some of your major accomplishments?

The first-ever FDA approved gene therapy to treat people with untreatable cancers – that’s a highlight of my career. We were also the first centre anywhere in the world to use a lentivirus vector, using disabled HIV, to deliver a gene to cells, and that was a trial in HIV. And we were the first centre in the world to do any type of gene editing, that was also in HIV, using zinc finger nucleases. So, before CRISPR there was zinc finger nucleases and we used those to knock out a co-receptor that HIV needs to get inside a T-cell, and in effect, generate HIV-resistant T-cells. So, we took T-cells from HIV patients, generated HIV-resistant T-cells and gave them their own resistant immune system back. That work is continuing. A spin-out from the University of Pennsylvania, called Tmunity, takes our T-cell technology as a platform to further develop in oncology and infectious disease and auto-immunity. We’ve received funding for clinical trials in myeloma and prostate cancer and there will be others that we’re excited about.

What is the most exciting thing you are currently working on?

We are using a gene editing tool, called CRISPR combined with delivering a tumour targeting T-cell receptor, to create redirected T-cells that are resistant to one of the main immunosuppressive mechanisms that tumours use to evade the immune system. So we’re redirecting T-cells but we’re using CRISPR to knock out a receptor on T-cells, called PD-1, that tumours use to suppress T-cells. PD-1 is one of the targets of checkpoint antibodies that have been approved in solid cancers and some other cancers, and in this case, we’re making those T-cells resistant to one of the main tricks that tumours use to evade the immune system.

What is the Holy Grail for you – the one thing you’d like to achieve in your career?

The really big one occurred with the FDA approval [of CAR T-cell therapy]. What I’d like to see now is success in solid cancers and sustainability of this therapy so that we have as wide access to as many patients as possible. We’re really building a new pillar of medicine if you think about surgery, radiotherapy, chemotherapy, even targeted therapies with the kinase inhibitors. This is a new class of therapies that is more different than any of the others were. I would like to especially thank the patients who enroll in our clinical trials. They place their faith and hope in us, and we have an obligation to them to develop these new therapies in the safest and most practical and expeditious way possible. Without them volunteering for clinical trials, we could not develop new medicines.

* In CAR T-cell therapy, T-cells – a key part of the immune system – are removed from a patient, genetically modified in the laboratory to target a specific cancer and infused back into the person.  

** NDLR, considered one of the best haematological science meetings in the world, brings together scientists and clinicians to discuss and debate current concepts in our understanding of the molecular basis of leukaemia and other haematological malignancies, emerging paradigms and breakthroughs at the forefronts of research in these areas, and new therapies emerging in the clinic.

Cancer-related fatigue – what it is, how it can affect you and how to manage it

Cancer-related fatigue – what it is, how it can affect you and how to manage it

For many people living with blood cancer, cancer-related fatigue (CRF) is a side-effect that has an enormous impact on their quality of life.

What is fatigue?

Managing fatigue.

In these videos, a Leukaemia Foundation Blood Cancer Support Coordinator, Andrew Smith talks about fatigue: what it is, how it can affect your life, and what you can do about it, including practical tips and strategies.

CRF is very different from normal, everyday tiredness and fatigue, where a good night’s sleep means you feel energised and refreshed the next day.

Despite sleeping for long periods, people with CRF wake feeling exhausted and don’t have enough energy to face the things they need or want to do in their everyday life. This type of fatigue has a negative impact on their day-to-day life.

Physically, CRF can feel like a heaviness or weakness, or a cognitive or mental feeling of fogginess, and of not being ‘switched on’.

The cause is not usually just one thing, but several. The blood cancer itself and cancer treatment can contribute to CRF, as can your previous level of fitness, overall health, previous medical issues, or a medical condition such as having a low red blood cell count.

It is important to get the latest up-to-date information to understand what CRF is and isn’t.

The effect of CRF can be mild, moderate or severe in how it affects you. Work out where you sit on this spectrum and whether it’s affecting your work or daily life.

If it’s highly-moderate to severe, consider asking one of our blood cancer support coordinators to connect you with a relevant health professional in your local community, such as an occupational therapist, exercise physiologist or a physiotherapist, who is good at managing this side-effect.

Also, map your energy levels throughout the day and across the week, to identify persistent low energy levels, and look for patterns in your energy levels.

Then you can apply the ‘three Ps’ – planning, prioritising and pacing – an energy conservation technique to maintain your health and well-being.

There’s always something you can do for yourself to improve your quality of life and lessen the effect of CRF. This includes getting quality information, connecting to the right people, and getting specialised support.

News flash: The Leukaemia Foundation has a new blood cancer information and education YouTube channel – the home of trusted information about blood cancer.

Addressing knowledge gaps in immunoglobulin therapy

Addressing knowledge gaps in immunoglobulin therapy

Dr Khai Li Chai is working to improve the prevention and treatment of infection in blood cancer patients with antibody replacement therapy.

Khai Li Chai
Dr Khai Li Chai

Dr Chai is a specialist clinical and laboratory haematologist based at the Transfusion Research Unit at Monash University (Melbourne). She was awarded a PhD scholarship from the Leukaemia Foundation and the Haematology Society of Australia and New Zealand (HSANZ) in early-2020.

Working with Associate Professor Zoe McQuilten and Professor Erica Wood, her project, Immunoglobulin therapy to prevent and treat infections in patients with blood cancers: who, why, when and how? will evaluate the evidence base, current practise and clinical outcomes of immunoglobulin therapy.

People diagnosed with CLLnon-Hodgkin lymphomamyeloma and those who have undergone an allogeneic stem cell transplant, frequently develop low immunoglobulin (antibody) levels (hypogammaglobulinaemia) due to their disease or as a result of treatment.

In hypogammaglobulinaemia, low levels of antibodies can be associated with serious and/or recurrent infections. Immunoglobulins made from donated blood products and containing vital antibodies can be given to patients to help keep infections at bay.

New technologies, plus an increased understanding of the immune system, mean scientists and clinical teams now have the capacity to create detailed immune profiles of individual patients. Dr Chai will analyse these immune profiles to better understand the capacity of an individual’s immune system to fight off viral and bacterial infections.

She hopes this analysis will help identify new immune markers that can be used to guide and monitor optimal dosing and duration of immunoglobulin therapy. This approach will identify high-risk individuals who may benefit from ongoing treatment and those who are at lower risk and can come off treatment sooner.

“We know that people with blood cancers are at increased risk of infection,” explained Dr Chai.

“As clinicians, we often administer antibiotics and antibody replacement therapy to reduce this risk. A lot of what we do requires more up-to-date information.

“My project goals are to reduce this knowledge gap and ensure that the therapy we provide is not only effective, but safe and sustainable for the future.”

While she enjoys treating patients working as a clinician and pathologist, being able to learn and delve more deeply into the field of research and contribute to better understanding blood cancers is very important to Dr Chai.

“The main thing I want to achieve with my research is to produce findings that make a significant impact in delivering individualised therapy – sustainable therapy that is able to support improved quality of life for people living with blood cancer,” she said.

“The beautiful thing about research is the unpredictability of each day.  

“It can range from reviewing patients in hospitals, examining samples in the laboratory, teleconferencing with other researchers across the world, learning and discussing new concepts in biostatistics and epidemiology with other students at university, or learning more effective ways of performing literature searches from the librarian.

“Each new day brings new learnings, challenges and skills.”

Dr Chai is most excited by sharing and presenting her research findings to her peers.

“We do this virtually now, and we will do this in person again soon,” she said, during the COVID-19 restrictions.

“It is a great feeling to find out that your research is supported and respected by your peers.

“I thank the Leukaemia Foundation, HSANZ and everyone who has made this funding possible for giving me this opportunity.”

Multi-Million Dollar Research Program to fight GVHD

Multi-Million Dollar Research Program to fight GVHD

Professor David Gottlieb

Chief Australian Investigators:  Professor Geoff Hill, Dr Siok Tey, Professor David Gottlieb (pictured), Professor David Ritchie, and Associate Professor David Curtis

Location: The Centre for Blood Transplant and Cell Therapy, National

Research Aim: To meet the urgent need for new approaches to better prevent and treat the potentially deadly graft versus host disease.

Graft versus host disease (GVHD) is one of the most significant contributors for transplant related deaths. In Australia, an alarming 50 to 70 per cent of stem cell transplant (SCT) recipients will develop GVHD.

GVHD occurs when donated cells (the graft) see your body cells (the host) as foreign and attack them. Chronic GVHD severely compromises a person’s quality of life, causing severe abdominal pain, mouth ulcers, muscle or joint pain and extreme damage to vital organs such as lungs and liver.

Twenty percent of stem cell transplant recipients will develop severe acute GVHD that does not respond to conventional treatment, resulting in more than half of these individuals dying.

The Centre for Blood Transplant and Cell Therapy (CBTCT) will receive $1 million over five years from the Leukaemia Foundation to invest in better outcomes for people living with GVHD. The Leukaemia Foundation is a major partner and the only non-government organisation to support the CBTCT project.

About the CBTCT

The CBTCT aims to improve the prevention and treatment of GVHD by:

  • Changing the clinical practice for treating transplant recipients who have GVHD.
  • Discovering biomarkers with diagnostic, prognostic and predictive power, to prevent GVHD.
  • Using novel agents, such as chimeric antigen receptor (CAR) T-cells therapy, immunomodulatory and immunotherapy agents and genetically modified T-cells, to reduce blood cancer relapse and improve patients’ survival.

“The potential from this research has been very promising in theory, and we are optimistic that we can replicate them into reality in the coming years,” Prof David Gottlieb said.

To do so, the CBTCT project will include prevention studies that will investigate new therapies for GVHD and relapse. The studies will comprise of a pilot study, a Phase I, a Phase I/II, and two Phase III randomised trials. There also are treatment studies with three early Phase I, a Phase I/II, and a Phase III trial.

To ensure patients have equitable access to the research and trials conducted by the CBTCT, the Leukaemia Foundation also will provide some additional funding for eligible patients for their transport and accommodation needs.

This research and clinical trials will be conducted at the BMT/SCT units in Brisbane (Royal Brisbane and Women’s Hospital), Sydney (Westmead Hospital) and Melbourne (Royal Melbourne Hospital, The Alfred Hospital), with involvement from SCT units in Adelaide and Perth.

The CBTCT project is led by world leaders in transplant research. Chief Australian Investigators include Professor David Gottlieb, Professor Geoff Hill, Dr Siok Tey, Professor David Ritchie, and Associate Professor David Curtis. International Chief Investigators on the team are Professor Bruce Blazar (University of Minnesota, US) and Professor James Ferrara (Icahn School of Medicine, Mount Sinai, US).

The CBTCT’s scientific partners are Queensland Institute of Medical Research, University of Sydney, University of Melbourne and Monash University in Australia, and the international centres are the University of Minnesota and Icahn Centre School of Medicine at Mount Sinai in New York, both in the US.

National Health and Medical Research Council CBTCT logo

Bruce has found his pot of gold – acalabrutinib

Bruce has found his pot of gold – acalabrutinib

Bruce Wood and family
Bruce Wood, centre, with his family last Christmas, from left, Luke, Emily, Belinda and Ella

Bruce Wood chose to delay starting chemotherapy last year while he “desperately waited” for an international CLL study to open in Australia for the targeted therapy, acalabrutinib (Calquence®).

When it became available, he was quick to sign up and was the first patient in Adelaide to join the Phase III acalabrutinib trial, ASSURE.

The utilities project coordinator, 56, of Adelaide, was “over the moon” at having access to this new second-generation BTK inhibitor, and it was well worth the wait.

He describes acalabrutinib, the tablet he started taking in November 2019, “as very effective” and he has had “almost nil” side-effects. Within the first six weeks his spleen had reduced from 21cm below his lower rib (very large) to normal size, and now his platelets and haemoglobin counts are back to normal.

Bruce Wood and his wife, Belinda Wood
Bruce Wood and his wife, Belinda Wood

Seven years of watch and wait

Bruce was on watch and wait for seven years following his diagnosis with CLL in late-2012, at the age of 48. The blood cancer was picked up when a routine prostate awareness blood test showed his white blood cells were slightly elevated. He was called in for further tests, then informed he had CLL.

“It was certainly a blow,” said Bruce, whose twin brother had been diagnosed with acute myeloid leukaemia earlier that year and passed away in 2013.

The advice Bruce received after his CLL diagnosis was “just go on the watch and wait process and try and live without thinking about it pretty much”.

“It’s always in the back of your mind but without any symptoms, still reasonably fit and working full-time, it didn’t really change my life at all,” he explained.

Educating himself

At the time, Bruce knew “nothing at all” about CLL.

“I got some very basic info from my GP and one or two calls early on from the Leukaemia Foundation helped with information,” he said.

“Then, I’m a bit of a researcher, so I spent a lot of time on the internet, reading blood cancer journal papers from around the world.

“I was always looking into the disease itself and what’s the best way to go forward.

“I watched a video one day from an American CLL specialist. He said – and it’s always stuck with me – the most successful CLL patients are the ones that have a smart specialist, and educate themselves from day one.

“I talked to specialists, to find out who knew the most and who were considered the best in Australia,” he explained.

“I was referred to a very good haematologist in North Adelaide, who I saw for a year or two, then decided after doing a lot of reading to visit a haematologist/professor that specialises in CLL, in Melbourne.

“I flew over for an initial appointment, and then back for a potential trial enrolment.

“The trial he thought would suit me, based on my situation and markers, was the ACE trial. It had two arms; FCR*, and acalabrutinib with two other drugs.

“Then I found out this same trial was opening in Adelaide, so he referred me to the haematologist at Flinders I’m seeing now.

“I didn’t end up going on the trial. It’s a long story,” said Bruce, who went through “the whole trial process”.

Bruce Wood with furniture he made
Bruce Wood with his labour of love – a blackwood tallboy

This involved CT scans and having 22 vials of blood taken and sent overseas for testing. Then, right at the end, he was randomised to the FCR arm, “the drug you could get anywhere”.

His decision not to have FCR

Based on what he had learnt, Bruce had already decided not to have chemotherapy (FCR), so when asked if he wished to proceed with the [ACE] trial, he declined.

While on watch and wait, Bruce had “done a whole lot of tests” and this genetic and molecular testing showed his CLL had NOTCH1 mutations and unmutated IGHV status.

“These markers suggest that chemo doesn’t give a long remission,” said Bruce.

“I was looking to go on a trial, and hopefully it would be soon, because my numbers were increasing reasonably quickly.

Accessing acalabrutinib on a trial

“I had done a lot of research on ibrutinib [the first BTK inhibitor], that had been available in the U.S. for some years, with very good results. Acalabrutinib wasn’t available off the shelf and the only way to get on it was to enrol in a trial.”

Bruce had talked to his haematologist about the ASSURE acalabrutinib trial, but it wasn’t until 12 months later that it started recruiting.

“That was a period of treading water,” said Bruce, and by mid-2019 his health was deteriorating.

“I was concerned because I’d been waiting a long time and I was getting sicker and sicker.

“I probably should have been on treatment six months before starting this trial. If it hadn’t opened when it did, I would’ve had to do something rather than choose to do nothing.

“It was a very difficult time. My options were closing fast and pointing to having to start chemo,” said Bruce, but he knew he couldn’t go on the trial if he had a pre-treatment.

“My spleen was huge, almost the size of a football. It was full of CLL cells and I could only eat half-size meals. My platelets and haemoglobin were dangerously low, and I was at a point where something had to be done,” said Bruce.

Bruce Wood and his EH carBruce Wood and his EH car
Bruce heading out in his EH

Then, in November, he got the call that the trial had opened, and he successfully enrolled in the treatment-naïve group, one of three cohorts**.

“This is a particularly good trial because it’s only a single arm, there’s no placebo. If you qualify, you get acalabrutinib as a single tablet taken twice a day.”

When Bruce started taking the drug his white blood cell count was around 250. It then shot up to 400 over the first couple of months as the CLL cells in his organs were released into his blood and then excreted. His white blood cell count gradually slid down over the next few months.

“I think I’m sitting somewhere around 70 at the moment, which is high, but not 400.”

Acalabrutinib received a positive recommendation from the Pharmaceutical Benefits Advisory Committee in April (2020), which Bruce said was “fantastic”.

“For people in my situation, with the same markers, I think they should be given the option to avoid chemo at all costs,” said Bruce, who had contributed to the Leukaemia Foundation’s submission to the PBAC in February 2020.

Despite acalabrutinib’s future availability through the Pharmaceutical Benefits Scheme, once listed, Bruce will stay on the four-year trial.

“There’s more testing and closer contact with the specialist and that has always been important to me. So, it’s good for me and it’s beneficial for everyone with CLL as well, to find out just how long these drugs work.

“There’s been resistance in previous trials with ibrutinib over some years. That’s what they are looking at for acalabrutinib, to see how we go long-term. When you compare ibrutinib and acalabrutinib side by side, acalabrutinib has far less side-effects. It’s a much easier drug to take and still as effective.”

Bruce takes his two acalabrutinib tablets 12 hours apart, at 7am and 7pm each day.

“I don’t ever go off it, and because I don’t really have any side-effects, it’s not a hindrance on how you live. It’s like taking a blood pressure tablet.

“I’m really happy to be included on the trial.

“I was always wondering whether something would be approved that was frontline, to avoid FCR; that was my goal.

“I saw venetoclax approved, but only as second treatment for relapsed CLL I think.”

Bruce Wood and his newborn granddaughter
Bruce with his brand new granddaughter, Lilly Wood, who was born in February 2020

Life is steadily returning to normal for Bruce 

“The first few months on the trial were a fair bit slower than normal. I was a bit of a lounge person and wasn’t very active because I was quite ill.

“I struggled to push the wheelie-bin to the gutter when I was not feeling the best,” he said.

“It takes a bit of time to recover when your blood counts are as low as mine. But for the last month or two, I’m pretty much 80% of what I was before I was feeling ill.

“This COVID thing has made a few things complicated. BTK inhibitors can play with your immune system a bit and the CLL does that anyway. My immune system isn’t as good as it could be, so I’ve got far more risk of some complications with this virus,” said Bruce, and he has applied added precautions against contracting it.

His employer “has been really good” and Bruce was given a few months off work to “stay home and focus on getting well, to give the drug the best chance of doing the job”.

“So that’s what I did which was important. The main risk being a secondary infection from being exposed to industry and lots of people.

When Bruce spoke to CLL News, in April 2020, he had just returned to full-time work.

“I’m working from home and have pretty much zero face-to-face contact,” said Bruce, and that includes socially distancing from his wife, Belinda, and their 15-year-old daughter, Ella.

“We’ve split our house into two areas. We’re lucky enough to have a couple of bathrooms and Belinda and Ella come and go from their area.”

Bruce Wood with daughter Ella and their dog
The Woods have two boxers and here’s Bruce and Ella with the youngest, Bailey

As he has recovered, Bruce has returned to his creative pursuits. A fitter and turner by trade, he has made a beautiful blackwood bedroom suite which he describes as a labour of love, and he tinkers with the old Holden EH he’s restoring.

What he no longer spends much time doing, now that he’s on the trial, is researching CLL.

“I found the pot of gold I was looking for,” he said.

* FCR: a chemotherapy combination of fludarabine, cyclophosphamide and rituximab.

** The other two cohorts: people with relapsed/refractory CLL; and those who had prior Bruton tyrosine kinase inhibitor (BTKi) therapy.

Decisions from the March PBAC meeting for CLL/SLL

Decisions from the March PBAC meeting for CLL/SLL

Acalabrutinib (Calquence®) will be added to the therapy arsenal for CLL and SLL after receiving a positive recommendation by the Pharmaceutical Benefits Advisory Committee (PBAC) at its March 2020 meeting.

Two treatments for SLL and/or CLL were considered at the meeting for listing on the Pharmaceutical Benefits Scheme (PBS). Venetoclax (Venclexta®) was given a first-time decision not to recommend in a particular indication and acalabrutinib received a positive recommendation.

Acalabrutinib was recommended 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). The PBAC considered that acalabrutinib may provide a different toxicity profile compared to ibrutinib for some patients.

In its decision not to recommend venetoclax in combination with obinutuzumab for the first-line treatment of CLL patients with coexisting conditions and who are unsuitable for fludarabine-based chemoimmunotherapy, the PBAC accepted that venetoclax + obinutuzumab was clinically superior to current first-line therapy for CLL in delaying progression. However, the cost effectiveness ratio and financial estimates needed to be reviewed.

When the PBAC meets again, in July 2020, it will consider new submissions for acalabrutinib for CLL/SLL patients with a 17p deletion, and a resubmission for venetoclax in combination with obinutuzumab for patients with CLL.

In submissions to the PBAC in February 2020, in support of the availability of new treatment options for this blood cancer, the Leukaemia Foundation included consumer comments, sourced from our disease-specific community groups on Facebook. Australia’s patient population for these yet-to-be-listed therapies is small and we received two consumer responses in relation to acalabrutinib and venetoclax.

The Leukaemia Foundation also contacted the pharmaceutical sponsors who made the submissions, AstraZeneca (acalabrutinib) and AbbVie (venetoclax), for information to help inform our consumer comments. This included details about the target patient population/subgroup, current treatment pathways, how the medicine works, its efficacy relative to other medicines available to treat CLL/SLL, how the medicine is administered, side-effects and their management, and quality of life impacts.

In the Leukaemia Foundation’s submissions, CEO, Bill Petch, urged the PBAC to recommend the treatments be listed on the PBS for eligible patients, “given the high unmet needs of people living with CLL who are unable to tolerate the current standard of care”.

“People want choices,” he said.

“They want access to a range of treatments to help them fight the disease with fewer side-effects, to help them not only to survive but also to live well, and to provide them with greater options for remission and ultimately improved quality of life.

“Our priority is to ensure all Australians living with blood cancer have timely access to the best therapies and treatments available, to improve time spent in remission, survival and quality of life,” said Mr Petch.

Acalabrutinib for r/r CLL or SLL

AstraZeneca sought a listing of acalabrutinib for people with r/r CLL or SLL who were unsuitable for treatment with a purine analogue (e.g. fludarabine) and who have had a least one prior therapy for CLL/SLL.

Based on summary information on the ASCEND clinical trial, use of acalabrutinib versus current standard of care demonstrated a statistically significant reduction in the risk of death or disease progression for patients – including those with high risk features such as 17p deletion, 11q deletion, TP53 mutation, and unmutated IGHV. The usual dose (of acalabrutinib) is a capsule taken twice daily and which can be taken from home, which is convenient for patients and their families.

Bruce Wood, from South Australia, who is living with CLL provided the following input to the PBAC for its consideration of this submission:

I have been taking acalabrutinib for 6 weeks now via a clinical trial at Flinders Medical Centre for CLL. 

My white cell count is rapidly decreasing and my spleen has reduced from 21cm below my lower rib to a normal size. It is a very effective drug with minimal side effects. 

“If it was available to the general public as frontline treatment for CLL it would make a huge improvement to current treatment regimes,” said Bruce.

Venetoclax/obinutuzumab combination as a first-line treatment

AbbVie had requested a streamlined listing of venetoclax in combination with obinutuzumab as first-line treatment for people with CLL with coexisting conditions and who are unsuitable for fludarabine-based chemotherapy such as FCR (fludarabine, cyclophosphamide and rituximab). The venetoclax/obinutuzumab regimen is administered orally, on a daily basis, and can be taken at home after an initial five-week treatment phase where the patient is closely monitored.

Patients who aren’t eligible for intensive chemoimmunotherapy, such as FCR, are currently treated with obinutuzumab in combination with chlorambucil.

Based on summary clinical trial information, AbbVie believes venetoclax in combination with obinutuzumab to be superior to the current standard of care (obintuzumab combined with chlorambucil) for these patients.

A Victorian patient with CLL responded to our request for input on this submission, saying they would be prescribed venetoclax combined with obinutuzumab when they started treatment.

PBAC reconsidered plitidepsin for myeloma 

PBAC reconsidered plitidepsin for myeloma 

The Pharmaceutical Benefits Advisory Committee (PBAC) considered four blood cancer treatments at its March 2020 meeting including a drug for myeloma – plitidepsin (Aplidin®).

Plitidepsin was given a subsequent decision not to recommend. This is the second time the drug was not recommended for listing on the Pharmaceutical Benefits Scheme (PBS) for this particular indication, having been previously considered by the PBAC at its July 2019 meeting.

The submission from Specialised Therapeutics was for plitidepsin in combination with dexamethasone for people with relapsed or refractory myeloma who have had three prior treatment regimens*.

Summary clinical trial information indicated that plitidepsin, which is administered in hospital as an IV therapy, was well tolerated and may reduce the risk of disease progression and death.

However, in its decision not to recommend plitidepsin for listing on the PBS in this indication, the PBAC noted that it considered the claim of non-inferiority versus the comparator drug (pomalidomide) was not demonstrated in the third-line setting and that the cost-effectiveness of plitidepsin was not demonstrated in the fourth-line setting.

The PBAC also considered the treatment comparison against dexamethasone as a monotherapy demonstrated only a marginal benefit in terms of progression free survival (PFS) without progressive disease (PD) confirmation, and the clinical benefit attributed to PFS with PD confirmation was not reliable.

The Leukaemia Foundation provided consumer comments to the PBAC in February 2020. These comments reflect the everyday experiences of people living with myeloma, sourced from our disease-specific community groups on Facebook.

A Victorian patient made the following comment:

“Very excited to hear of new drugs coming from nature – powerful bio-active agents have proven to wildly useful in medicine to date, and have only heard good things about the prospects of this drug for myeloma, which is known to be strongly relapsing to treatment. So while I’m not using it as yet, to have it in the arsenal of available drugs in the future is very encouraging.”

In its submission, the Leukaemia Foundation said: “the benefits of more effective and well tolerated treatments on the lives of individuals with myeloma cannot be underestimated. We assist myeloma patients over the course of their experience with this blood cancer and we know they would welcome the availability of a new treatment option”.

“The impact of this incurable cancer and the cytotoxic effects of treatment have an immeasurable impact on people’s lives and the lives of their families and carers.

“Giving clinicians more options in their ‘toolbox’ in the fight against myeloma, and removing barriers so patients can commence treatments tailored to their disease without any undue delays, is vitally important.”

The Leukaemia Foundation also made comments to the July 2019 PBAC meeting for a previous submission for plitidepsin for myeloma.

*   At least three treatments including both a proteasome inhibitor (PI) and an immunomodulator (IMiD), or in patients who have received two prior lines of therapy, if the patient is refractory and/or intolerant to both a PI and an IMiD.

5,000 new stem cell donors by September 2020

5,000 new stem cell donors by September 2020

Jack Jacobsen

More than 600 Australians have a potentially life-saving stem cell transplant each year and of those needing a matched unrelated donor, more than 80% of their donors are sourced overseas. 

While almost a third of bone marrow transplant recipients find a match within their family, for the remaining 70%, the Australian Bone Marrow Donor Registry (the Registry) matches patients to unrelated donors, both in Australia and around the world.

Unfortunately, some people miss out because they can’t find a suitable donor.

An allogeneic transplant is a potentially life-saving or curative therapy for several types of blood cancer including non-Hodgkin lymphomaMDSAML and ALL.

Currently, the Registry can’t meet the needs of Australian patients requiring an allogeneic stem cell transplant. And, with less than 5% of registered Australian donors being considered ideal (aged 18-30 and generally male), most donors are being sourced from overseas, mainly Germany and the U.S.

There is an urgent need for new donors to meet demand and to help recruit new donors and increase awareness, the Leukaemia Foundation has partnered with the Australian Bone Marrow Donor Registry (ABMDR) for a 12-month trial which runs until September 2020.

We will assist the Registry to achieve its goal of adding 5,000 new Australian donors, aged 18-30, to the registry by September 2020.

Supporting people living with blood cancer through the transplant process and providing information and education on stem cell transplants is an important part of the Leukaemia Foundation’s services. This partnership enable us to pursue opportunities to improve donor matches and increase the pool of viable donors.

Younger donors result in better outcomes for patients, hence the need for 18-30 year-olds to register, which increases the chances of finding the best possible match.

Ethnic diversity is also important as patients are more likely to find a match with a donor from the same ethnic background.

And young men make particularly important donors as they often weigh more, so they literally have more (stem cells) to give!  But this group only makes up 4% of donors on the registry.

To add someone to the Registry’s database and potentially result in saving someone’s life, it takes just five minutes to do the initial screening, through a cheek swab.

Go to lf.strengthtogive.org.au and register – answer a few questions and wait for your swab kit to arrive – easy!