People with chronic lymphocytic leukaemia (CLL) are immunocompromised* and for that reason attention and a sense of urgency is needed whenever they see their GP or present at hospital.
That’s according to clinical haematologist and researcher, Associate Professor Nada Hamad, Director of the Haematology Clinical Research Unit at St Vincent’s Hospital in Sydney.
She has a passion for CLL being a priority in haematology, and since medical school, when “people would say, ‘people die with CLL not from CLL’, A/Prof. Hamad has thought slightly differently. And she “hasn’t quite subscribed to this notion that CLL doesn’t necessarily kill people”.
“Often CLL patients have the disease for a very long time,” says A/Prof. Hamad.
“Although there’s this notion that as a disease CLL is slow, it’s grumbling, and people don’t die immediately from it, in my mind it’s a disease that’s punctuated by events in a patient’s life; by presentations to hospital with infections and immune complications that we don’t see quite as often outside of CLL, in other haematological conditions.
“Every time a CLL patient comes into hospital, they have the potential to end up in ICU sometimes with unusual opportunistic infections or presentations that can be baffling to most people. But as a haematologist, you understand that these patients are immunocompromised and need that attention and that urgency every time they are in hospital.”
Research in CLL benefits other blood cancers
When novel agents emerged on the treatment landscape in haematology, in A/Prof. Hamad’s mind, “CLL was the perfect disease for studying lymphoma treatments more broadly”.
CLL is clearly a ready-made laboratory of investigation.
“As a researcher it conceptually drew me in because if you can treat a slow-growing lymphocytic disorder, you could potentially affect how a fast-growing lymphocyte would grow.
“So, whatever you learn in CLL you could potentially leverage in other lymphoid disorders.
“I remember thinking this when I was just a registrar. And sure enough, that’s where we are now, with all of the novel agents that emerged out of CLL studies, and the benefits have been seen for patients well outside that domain, in high-grade and low-grade lymphomas as well.
“While my interest in CLL as a researcher in the clinical trial space is modest compared to my other areas of interest, I feel that if you do CLL well from the patient’s journey perspective, a clinical quality perspective, and a research perspective, the rest of haematology benefits from that a great deal.
“And that includes the concept of integrating quality of life and patient experience into clinical research, which is yet to catch on in other areas where patients are considered to have a short lifespan.”
The greatest unmet needs in CLL
A/Prof. Hamad says there are two areas of unmet need in CLL. The first is that while the therapeutic landscape is improving, it’s not 100%.
“There’s still a group of people whose CLL impacts their lives quite dramatically and they run out of therapeutic options. So the more therapeutic options, the better. Therapeutic options that are deliverable and help people maintain their quality of life.
“The second is an understanding of the impact of CLL on a patient’s life. COVID really brought this to life in a way that I’m very grateful for, but I wish we didn’t need a pandemic to prove.
“These patients are so vulnerable to infections. They are so vulnerable to what the rest of us take for granted.
Everybody with CLL belongs in the vulnerable group.
During COVID-19, everybody was told “don’t spread your germs around, stay home if you’re sick” which highlighted the fact that CLL patients, as one of the most vulnerable groups, didn’t have that kind of protection before.
People with CLL had to live in a world where they were invisible and vulnerable.
“I’d have CLL patients with children, or grandchildren, who’d bring everything home with them from school or daycare. Their parent or grandparent would have to go on antibiotics for sinusitis but would struggle to get antibiotics from their GP, who would say, ‘you don’t need antibiotics, it’s viral’, without accounting for the specific circumstances of an immune-deficient state.
“CLL patients have always had to work really hard at advocating for themselves around what they needed to do to travel, what kind of support they needed with their vaccinations, additional vaccination approval, and the financial toxicity of having to pay for all of those things.
“We didn’t have a clear consistent strategy that was supportive of the struggles they would experience out in the world.”
A/Prof. Hamad’s advice to GPs is, “please consider their unique needs and that these patients do need more investigation and treatment for bacterial infections”.
“It’s not just their responsibility to stay at home and protect themselves. We have a responsibility as a community, from a public health point of view, to ensure that we are responsible for people in our community who are immunocompromised.
COVID really showed us how that works. We need to learn from that and build a future where it’s not up to the patient to demonstrate their vulnerability but up to a society to support them without too much effort.
Exciting CLL treatments are coming
A/Prof. Hamad is a world leader in the field of bone marrow transplantation and cellular therapies. She is excited about a future where potentially curative treatments that harness the immune system reduce the likelihood of CLL patients needing to have an allogeneic stem cell transplant.
“Although transplantation can be done safely, for those high-risk patients who need them, a transplant carries a lot of complication risk and potential for a reduced quality of life,” she said.
“CLL patients are not easy to deliver this kind of treatment (transplant) to. They are often quite vulnerable because they’re immune-compromised because of their disease and also because they’ve usually had a lot of prior treatments.
“We’ve had really amazing growth in the targeted agents that work on the specific intra-cellular mechanisms in CLL like the BTK inhibitors [acalabrutinib and zanubrutinib] and BCL-2 inhibitors [venetoclax], which have revolutionised CLL management.
(For more information, see the ‘Latest developments in CLL research’ section of the article, Expert Series: Professor John Seymour)
“The next step is to find additional treatments, and ideally ones that are potentially curative. Additional targeted therapies, CAR T-cell therapy, and possibly bi-specific agents, and I say possibly, because it’s still unproven.
“And then treatments that are less labour-intensive for patients, that don’t require as much follow-up; oral treatments that can be taken anywhere, at any time, which frees patients from needing to be attached to hospitals or clinics on a regular basis.”
A/Prof. Hamad said bone marrow transplantation is one of the few potentially curative treatment options in CLL because it offers a new immune system that lives with the patient and surveillances their body when the CLL tries to relapse, although it is only appropriate for a relatively small proportion of patients.
“The idea is that the immune system will prevent relapse long-term. That’s the real advantage of bone marrow transplantation but that potential for cure comes with ongoing issues that patients have to deal with – immunosuppression and potential complications of infection, and graft versus host disease.
“CAR T-cell therapy has the potential for cure – although that has not been demonstrated yet – without the toxicities of bone marrow transplantation because, like bone marrow transplantation, it’s a living kind of treatment, called a cell therapy.
“But how long these cells live and how long they last in maintaining that remission status is yet to be seen.
“We’ve seen this happen in some lymphoma patients, but not yet in CLL, and because CLL cells usually grow slowly, you might need those CAR T-cells to be alive for a very, very long time to be able to do their job properly.
“Bone marrow transplantation is tried and true but can only be offered to a very small population of people who have really high-risk disease, and who have well-controlled CLL. That combination is difficult, and you also have to have a suitable donor, so a very small number of CLL patients actually go into transplantation.
“CAR T-cell therapy is still in the clinical research phase, so although there is promise, it is yet to be integrated into routine care.
“It is only available in a clinical trial setting, which is exactly where it needs to be, so we can understand more about the long-term implications of CAR T-cell therapy in CLL patients.
“I know patients who have had CAR T and have had good results, and that’s very reassuring.
“There are some interesting studies with CAR T that might be coming to Australia but they aren’t confirmed yet, and there are some novel agents that are under investigation and reaching the level of comparison to more traditional targeted therapy.”
CLL patients and COVID-19
Associate Professor Nada Hamad was a guest speaker for the Leukaemia Foundation webinar, COVID-19 developments: Fact or fiction which you can watch here.
COVID-19 is a higher risk to CLL patients than any other disease group and data supports how vulnerable these patients are, and more so than all other blood cancer patients.
“The risk of death from COVID early in the pandemic was in the realm of 30-50% internationally in that population [CLL] and that far exceeded the rates of death in aged care facilities.”
A/Prof. Hamad and a colleague, Professor Stephen Mulligan, felt the arguments around who should be protected first did not take into account that critical piece of information.
“People kept talking about aged care facilities and all the elderly being vulnerable, forgetting who else in the community is actually also just as vulnerable, if not more.
“We needed to articulate this point based on data which is clear as day and therefore could not be ignored.
“The challenge for us was to understand how to effect that change; how do we speak to the right people and be in the right room, so the decision-makers heard us?
“I’ve never had to do that before. I’m just a haematologist; I don’t work in politics, policy or in public health.
“And I’ve had to learn very quickly because I knew that in the scramble of COVID it was very difficult for policymakers to think about who else was missing [from the vulnerable group].”
In 2021, A/Prof. Hamad, Prof. Mulligan, and CLL patient, Ms Deborah Henderson Sims presented a case to the vaccine taskforce at Cancer Australia. This resulted in the parameters of the Phase 1B rollout of the COVID-19 vaccine being changed to include bone marrow transplant recipients, those on CAR T-cell therapy, people on immune suppressive therapy for graft versus host disease, and people with haematological diseases and blood cancers.
“Stephen and I felt this was worth doing because this was our domain. We’ve known our CLL patients a very long time, in some instances for half their lives, if not more.
“I was also fortunate to be part of advocacy groups and had led guidelines on the management of CLL, lymphoma, and myeloma during COVID which gave me the support of my colleagues in understanding and recognising the importance of what we needed to do as a profession during COVID for our patients.
“In terms of COVID right now, the lack of restrictions has put us in a very similar situation to early on in the pandemic, where we are forgetting there are some people that will remain vulnerable, if not more vulnerable now than ever, because restrictions have been pulled back.
“And what struck me, that is unique to CLL patients, is the fact that they don’t respond to vaccines as in an immune-competent patient.”
In the CLL population, vaccine responses are very limited – with much lower and slower antibody production. Therefore, it’s important that having been vaccinated, CLL patients don’t get a false sense of security, and likewise, the people around them.
“There can be complacency around them that CLL patients really need to challenge constantly. They need to tell their family and friends and employers that, ‘no, for me, it’s [COVID’s] not gone, it’s not over yet. I’m still vulnerable because vaccination will not work for me like it does for you’.
“Also, the emergence of variants means we have to be very cautious about resistance and varying efficacy of the treatment options that we have available.
“Evusheld** was a preventative drug that we were able to offer CLL patients knowing that they would not respond to a vaccination as well as patients who are immune-competent. That medication is losing its efficacy in the face of the new variants emerging, so we’re losing more protection than we are gaining, leaving these patients with very few options.”
And, as the world opens up, FOMO [fear of missing out] is very real.
“I personally have long-COVID, and the fear of missing out on the world is really quite something,” A/Prof. Hamad explained.
“Friends are going out, they’re all traveling, and people are doing things, going to events, going to dinners, going to concerts, and without any precautions.
“For me and others who are vulnerable, we can’t quite do that. So there’s that peer pressure of, ‘you’ve got to live life, you’ve got to move on, you’ve got to forget about this COVID business’ that is really quite psychologically difficult to manage on top of everything else.
“I know, and so do my CLL patients know, their vulnerability has probably increased again. But it’s very hard to expect them to constantly have to push back against societal pressures around forgetting COVID exists.
“I think the struggle will be supporting patients in that advocacy, making sure that they have letters to their employers, and letters to their schools, and whoever may be looking after them, that explain that they are still vulnerable, and to please treat them as such without giving them a hard time.
That’s what I think clinicians can do, and what I hope CLL patients can get.
“Certainly, it’s a lot to face this far down in the pandemic.”
The Leukaemia Foundation has developed a My COVID Action Plan for people living with blood cancer to help:
- plan what you want to discuss with your treatment team
- know what to do if you test positive with COVID-19
- seek treatment while symptoms are mild and improve recovery
- care for your health if you become unwell.
* When immunocompromised, the body’s immune system’s defences are low which affects its ability to fight off infections and diseases.
** Evusheld® (tixagevimab and cilgavimab) by AstraZeneca Pty Ltd was the first medication for the pre-exposure prophylaxis of COVID-19 in Australia.
