Managing chronic leukaemias

Welcome to the Australian Prescriber Podcast. Australian Prescriber, independent, peer-reviewed and free.

Hi, I'm Jo Cheah and this is the Australian Prescriber podcast. Joining me today is Dr Eric Li. Eric is an Advanced trainee in haematology, in Sydney. Yeah, thanks for joining us, Eric. Welcome to the podcast.

Thanks Jo. I'm very glad to be here.

That's great. So, haematology is a very specialised area of medicine and depending on our clinical rotations, some health professionals may not have worked in the area or dealt with haematological malignancies before. So, in your article Eric, you talk about chronic leukaemias that are increasingly being managed in the community. So, for those of us who may not have a good understanding of haematology, could you give us a really basic rundown on the conditions that you've discussed in the article? Firstly, chronic myeloid leukaemia and secondly, chronic lymphocytic leukaemia.

Yeah. So, CML and CLL are a couple of the most common leukaemias we see in the community. There's things common between them and also things quite different between them. So, the common things are, they're both considered haematological malignancies, and they're both called leukaemias, in the sense that they both predominantly manifest in the blood, as well as the bone marrow. The chronic word that comes in the CML and CLL is the fact that, the natural history is, they progress over years before advancing to a more aggressive phase that can potentially be lethal. Many of these patients are diagnosed when they’re asymptomatic and essentially picked up incidentally. And, many of the GPs essentially refer to haematology for review because of unexplained raised white cells.

Then the difference between CML and CLL is that one is of a myeloid lineage and the other one is a lymphoid lineage. So, the myeloid lineage, essentially things that make your neutrophils, platelets, red cells, and more rare things like basophils and eosinophils which you don't see too much, but it's characteristic in CML. Whereas CLL is lymphoid lineage in a sense that these are specialised white cells that go to lymphoid tissues, such as the spleen and the lymph nodes, which can sometimes manifest in CLL as well. When we dig deeper they're genetically and molecularly quite different. So CML, we think of it as a genetically simple disease in a way, there's one single mutation that pretty much characterise this disease and that is the chromosome 9 and 22 translocation, also known as the Philadelphia chromosome; whereas, CLL there’s no single mutation that defines them and that's why they're quite heterogeneous and the treatments can vary as well.

That was a great summary. Thank you. So in your article, there's a really great table that summarises targeted oral therapies for CML and CLL, and in the table, there are drug names, dosages, and complications to look out for. So, since treatments for both CML and CLL differ, can we talk about CML treatment first? So, let's start by talking about the traditional way of CML and perhaps where we're going to at the moment.

Yeah. So, it's quite a fascinating history with CML and how we got to where we are at the moment. We initially treated this condition 70 years ago, let's say 1950s with nonspecific cytotoxic drugs, like busulphan and hydroxyurea. And, these are fairly good at reducing the leukaemic load initially and might help with the patient's symptoms. But, essentially it doesn't change the natural course of the disease and patients eventually will succumb to this condition. The first cure we have for CML is the advent of allogeneic stem cell transplant, which was available between the 1970s and 80s. And the problem with that is not everyone has a donor for a stem cell transplant and quite a lot of patients, unfortunately, are unfit for the procedure as well.

We also have available, later, a treatment called interferon alpha in the 1980s. And interestingly, this was effective and gave a remission to about 10% of the patients, but 90% of the patients, they don't respond very well to this treatment and again, succumb to the disease. So, it was only the invention of a drug called imatinib, which I think many people may be familiar with now. It was on Time Magazine and there was only two drugs in Time Magazine, it's imatinib and Viagra; so it was actually a marvellous invention. So yeah, this is essentially, now we're here, that's transformed the management of CML. So now, with the invention of imatinib, which is a first-generation tyrosine kinase inhibitor, we have now second-generation tyrosine kinase inhibitors, dasatinib and nilotinib, and third-generation as well called ponatinib, and these are more and more specific. And they also, unfortunately, come with unique side effects. That's a trade-off with the specificity of these drugs.

Great. So, what are tyrosine kinases and what is their significance in the progression of CML?

So, tyrosine kinases in general are essentially enzymes, which carry signals throughout the cell. And for many cells, it functions as a way that cells deliver signal for survival and growth. So, normally, it can be switched on and off in appropriate times. But the problem in CML is that, with the mutant translocated gene, so combination of a gene in chromosome 9 and chromosome 22, you essentially create a malignant tyrosine kinase that's continuously switched on. So, after discovering that to be the problem with CML, the ability to inhibit, essentially turn off these aberrant cells, has led to its transformation.

So, in regards to CLL, the treatment's a little different here. So, how do we treat CLL?

So, we think of the treatment of CLL in different eras. So, we started with the chemotherapy era where we treated the condition with chlorambucil in the 1950s and more recently fludarabine in the 1990s. This followed by the addition of rituximab in the 2000s. So, we combined chemotherapy and immunotherapy, so you hear the term chemoimmunotherapy, that's the most recent era before the development of the targeted therapies, which we talked about in the article. So, which only really became mainstream treatment in the last decade.

Okay. In the article, you've mentioned one of the targeted therapies, venetoclax, and that's used in combination with rituximab. So, can you comment on other combination treatments for CLL and when those would be prescribed instead?

So, the combination of targeted therapies with monoclonal antibodies is relatively common, but it's not universal. And, it really depends on what clinical trial was able to show to be of benefit. And, some studies have shown the addition of rituximab or newer generation monoclonal antibody called obinutuzumab to be beneficial in combination, but some did not show a positive benefit and may actually increase the risk of complications. So in Australia, what’s standard at the moment, as you mentioned, venetoclax and rituximab. There's a third agent, which we didn't really discuss in the article was idelalisib, which is also used with rituximab and it's not used very frequently. Whereas for ibrutinib, it is frequently used as a single agent, but some other centres overseas may use it in combination with rituximab.

Excellent. And, this is more general now for both conditions. Could you talk about how the newer oral targeted therapies have impacted life expectancy for these patients?

So, the benefit for CML is remarkable. If you were diagnosed with CML, let's say 20 to 30 years ago, and you were not eligible for a stem cell transplant, we commonly advise that the life expectancy is about two to seven years, depending on how aggressive the condition was diagnosed. And now, with the advent of imatinib for a majority of patients, we essentially tell them that they have a normal life expectancy. And one interesting fact, that I'd like to share is, there was a study, I think in Scandinavia, that patients with low-risk CML actually have a longer life expectancy than the matched controls because these patients are seeing their doctors more and get all the other risk factors managed better, so it was an interesting finding.

The answer for CLL is a bit more complex. An example of the long-term follow-up is that only recently we've got some data for the immunochemotherapy FCR and a follow-up of six years showed median survival was not reached at the time. And, the previous standard of care, which was just for fludarabine and chlorambucil, was 86 months, so these are quite long. If you compare that to 1970s, when in advanced CLL, the survival was only one to two years. And, regarding targeted therapy, survival is very difficult because there's all these new treatments coming out very quickly, but some of the more recent data with it, ibrutinib compared to FCR at three years, you've got, you have a survival of 98.8% in newly diagnosed patients. So it's quite remarkable.

Keeping on the topic of treatments, what are some major side effects, or drug–drug or drug disease interactions that we should be aware of?

So, from the CML perspective, the most common drugs that you might see on the ward or in the community is imatinib, dasatinib and nilotinib. With imatinib, we consider that to have a very safe profile. The difficulty with them is actual side effects that can really impair the function of the patients, but usually they’re not life threatening. And they include gastrointestinal symptoms like nausea, vomiting, and oedema. So, it's frequent that they have an oedema, lower limb oedema, they might have periorbital oedema, and it can be quite tricky to manage. And, sometimes dose adjustment is guided by the haematologist, is required for the management of these side effects. With respect to the second-generation tyrosine kinase inhibitors, they can be associated with significant cardiovascular and pulmonary adverse events. Nilotinib, that has been shown to have increased risk of cardiovascular events, such as myocardial infarction, cerebrovascular accident and peripheral vascular disease. And, these patients can sometimes have worsening of their hypertension, hyperglycaemia as well as hypercholesterolaemia.

So, with dasatinib, we are more worried about their pulmonary complications. So, there's a slight risk about 5–10% per year of pleural effusion. So, essentially they can accumulate fluid in the lung and that can sometimes land them in hospital and require drainage and cessation of the drug, at times as well. And, there's a very rare complication called pulmonary arterial hypertension associated with dasatinib that, once diagnosed, we have to stop. Whereas, for CLL drugs, we talked about ibrutinib and venetoclax. Ibrutinib’s main side effects are interestingly increased risk of bleeding, because it can cause platelet dysfunction as well, due to nonspecific targeting other than the Bruton’s tyrosine kinase. So, watching out for increased risk of bleeding, bruising, and in particular, in patients that are also prescribed aspirin and clopidogrel, which should be avoided where possible, have higher risk of significant haemorrhage.

Ibrutinib can also cause worsening of hypertension. And, interestingly patients can have a higher incidence of atrial fibrillation as well, which can be quite tricky because, as you might know, the recommendation for those patients is anticoagulation, which is very tricky because they already have an increased risk of bleeding. Venetoclax, one of the most concerning side effects initially is something called tumour lysis syndrome, where due to rapid death of the CLL cells, they release all the uric acid, release other toxic substances causing electrolyte disturbance, renal failure, seizures, and possibly death. So, that's why most of the patients are started with strict monitoring in the hospital setting and the dose of venetoclax is gradually increased from 20 mg to 400 mg. So, by the time many of these patients are in the community, they would have had to escalate their therapy to 400 mg a day. But, with both of these, ibrutinib and venetoclax, they further immunosuppress patients who are already immunosuppressed from CLL unfortunately, so infection is a major adverse event to watch out for.

Great. And, you did mention some drug interactions in that. Were there any others that we should be aware of?

So, we talked about the CYP3A4 interactions, which I think a lot of pharmacists and GPs can pick up and avoid where possible, and with the warfarin and anti-platelets for ibrutinib is another interaction.

You've mentioned in the article that suboptimal drug adherence can lead to treatment failure and poor clinical outcomes. So, could you explain the mechanism of this? For example, is it due to some kind of drug resistance that the cancer cells develop?

Yeah, look, so that's a very important point and it's a major challenge for haematologists managing these conditions. For CML in particular, we know patients who are not adherent and that's something like more than 10% of tablets missed, can dramatically increase the risk of disease progression. And, some studies actually show, and this is the main reasons why patients fail treatment. So in CML, we know the tyrosine kinase can mutate and gives the ability to resist the drug itself. So, when we have a subtherapeutic dosage from either drug interactions or poor adherence, you essentially select out the muting clones, and that's one of the suspected reasons why patients progress and become resistant to therapy.

No worries. So I guess, discussing management in the community, how do you suggest specialists, GPs, community pharmacists, and the patient work together to ensure the high compliance and good monitoring of that patient?

So, I think everyone working together is important and understanding that, most of the time, these patients are followed up with a haematologist from three months to sometimes six monthly basis; and in between a lot can happen, especially these patients are living longer. So, keeping a good communication between the community health professionals, as well as the haematologist is very important. And, many of the haematologists I've worked with, are more than happy to be engaged in conversation, if there is something concerning that occurred to the patient. And for example, if they detect interaction or noncompliance or suffer from adverse events, most of the haematologists I work with are very keen to know about that.

And, as I described earlier, cardiovascular events is becoming more of an issue for these patients, who are living longer and the therapies themselves are essentially exacerbating those risk factors. So, managing the traditional cardiovascular risk factors is very important. Hypertension, hypercholesterolaemia, obesity, smoking; so these things I'm sure GPs can do very well. And, everyone can be vigilant for drug interactions and encouraging good adherence. And, I’ll also mention here, that vaccinations are recommended for these patients, in particular the Fluvax, the Pneumovax in CLL patients. Some major guidelines also recommend them for CML patients, although their immune suppression status is not as high as patients with CLL. And, I’ll also mentioned for CLL patients it's contraindicated to give live vaccines and people have died from vaccines, such as the varicella zoster in the past.

Very interesting. And apart from reading your article, where else can we learn about CML and CLL?

So, a very good website that gives a broader overview of the condition and can be used by patients and encouraged for use by patients is the Leukaemia Foundation. It has a broad scope of different common and rare haematological diseases. If we want to look more into the treatments in terms of what the patients go through, so to understand the journey better, we use a website called eviQ, E V I Q, that you can see treatment protocols and some adverse events as well.

Yeah. You can also do some continuing education through the eviQ website as well. But yeah, thank you, Eric. That was really informative and I learned a lot. So, thank you so much for your time.

Thanks, Jo. And, I just want to give a special thanks for my co-authors, Professor Stephen Fuller, as well as Dr David Yeung, for helping me write this article.

[Music]

The views of the hosts and the guests on the podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm Jo Cheah, and thanks for listening to the Australian Prescriber Podcast.