Noemi Horvath is a highly reputed consultant haematologist at Royal Adelaide Hospital who has dedicated most of her life to her work and her special interest has long been amyloidosis.

To her, amyloidosis is “almost like a detective novel”.

“You’re waiting to get to the last page to see who’s done it. So, we’re waiting for the next development – to see if we can develop a test that identifies ‘clonal’ light chains when the light chain level is within the normal range, and whether those amyloid removing agents which are currently undergoing clinical trials are going to work,” she explained.

Dr Horvath’s medical background in haematology and amyloidosis

After studying medicine “because I have no imagination and both my parents were doctors”, Dr Horvath graduated with a Bachelor of Medicine and Bachelor of Surgery from New Zealand’s Otago University.

Then, after being rejected for radiology and deciding that if she did laboratory medicine, “I wouldn’t have to deal with people”, she started her specialist training in haematology in Christchurch, which she completed in Adelaide after moving to Australia in 1975.

“I’ve ended up spending most of my time dealing with people, and I’ve tried to be nice to them,” she said with her characteristic dry sense of humour.

Dr Horvath tells an interesting story about how she got into amyloidosis.

“As a sixth-year student, in 1969, we used to participate in admitting patients and looking after them on the wards. On a Saturday morning, my registrar told me to do an ECG on a patient, which I did, and the ECG looked very much like a flat line, but he was obviously still alive!

“I went back to the registrar and said, ‘I don’t know what I did wrong, but this ECG looks like he should be dead’, and he abused me, saying, ‘you stupid girl, don’t you know he’s got amyloidosis?’

“Amyloidosis wasn’t very prominent in my thinking when I was a sixth-year student. It wasn’t an important part of our teaching because it was rarely diagnosed,” explained Dr Horvath.

“I decided I didn’t want to have anything ever to do with amyloidosis, but at one of the European Hematology Association meetings many years later, I went to a Meet the Expert talk, which happened to be with Philip Hawkins* on amyloidosis, and I decided, maybe it’s vaguely interesting after all. So that’s how I got involved in it.”

Later, when Dr Horvath was in London, she visited Professor Hawkins, who is a rheumatologist and she asked him, “how come you’re interested in such a hopeless disease?”.

“At that time there was really no treatment for any form of amyloidosis,” she said.

“He was mostly involved in the AA type and that’s become relatively rare nowadays because there are such good treatments for many of the rheumatological diseases, and we don’t get nearly as many chronic infections that can’t be resolved.

“Once AA faded off the scene, AL (amyloid light-chain) amyloidosis was thought to be the most common type.”

And, as a haematologist, that’s the type of amyloidosis Dr Horvath predominately treats.

“Until recently, haematologists got referrals for all kinds of amyloid, because sometimes the amyloid hadn’t yet been typed,” she explained.

“I have seen at least four different kinds of amyloid, and I was the principal investigator for one of the transthyretin amyloidosis trials because it was thought that I knew a little bit about amyloid. That particular type of amyloidosis is not a haematological disease, but in South Australia they thought that I might be an appropriate person to treat it,” said Dr Horvath.

But looking ahead, she predicts transthyretin wild-type cardiac amyloidosis (ATTRwt), which is diagnosed and treated by cardiologists, “is probably going to be much more common even than the AL type”, and for renal physicians too.

Dr Horvath emphasised the importance of a histological diagnosis for amyloidosis.

“You have to have a piece of tissue that shows amyloid, and in most cases, you also have to type that amyloid,” she said.

“Amyloidosis is one of those diseases where you have to think of it to actually make the diagnosis.”

“Every meeting you go to about amyloidosis, they say ‘early diagnosis, early diagnosis’, and they’ll show you how many doctors someone has seen before a diagnosis is made and how many different tests they’ve had before that diagnosis was made.”

About AL amyloidosis and its diagnosis

The organs commonly involved in AL amyloidosis are the heart, kidney, and liver.

“Any organ can be involved, but not the brain, and sometimes multiple organs are involved,” said Dr Horvath.

“There was a lovely paper written by an Italian cardiologist a few years ago, entitled, I think, Cardiac Amyloidosis – the Creepy Killer, because it can sneak up on you as you’re getting a bit older, but sometimes you’re not very old at all and I’ve got a couple of youngish patients who have cardiac AL amyloidosis.

“But the damage to the organ takes a while to build up, and people don’t usually present until the organ is significantly damaged.

“So, depending on the dominant organ involved, people can present with heart failure or with what’s called proteinuria, where they’ve got a massive amount of protein in their urine that usually comes from kidney involvement. I also have a lady who has predominantly skin involvement – every time she rubbed her eyes, she has bruising around her eyes.

“One reason why amyloidosis is often diagnosed late is because the presentation can be very different in different people. It’s still not known why, in some people, it affects one organ more than the other, but the prognosis is mostly determined by how much the heart is involved,” said Dr Horvath.

“GPs usually look at the way the patient presents, then send them to the appropriate specialist and certainly the cardiologists and the renal physicians now have an increasing index of suspicion [of amyloidosis].

“We’re getting to the stage where we’re approaching early diagnosis, but patients have to admit to themselves that there is something wrong.

“I recently had a man who unfortunately died very quickly because he just didn’t seek medical attention when it was clear that he was getting very short of breath and his legs were grossly swollen. By the time we saw him, he had very severe heart failure that we couldn’t get him out of.

“Nowadays, if you present with any kind of heart failure, the cardiologist will almost certainly do at least a cardiac echo which will show if the heart walls are thickened which is one of the signs of heart involvement.

“There are some very characteristic appearances with the way the heart moves in people with amyloidosis.”

“When they look at the echocardiogram, they will almost certainly think… has this person got amyloidosis? Then they might do the haematological test that would suggest that it is the AL type – blood protein electrophoresis and serum light chains. If they’re abnormal, then they’ll shift the patient along to the haematologist.

“And when someone sends us a referral saying, ‘could this be amyloid?’, we usually see those patients pretty urgently, and once we’ve diagnosed someone, we need to get on and treat their disease.”

Dr Horvath said amyloidosis comes on gradually and she gave the example of “a reasonably young male patient who used to cycle to work every day”.

“He found a very slight incline when he was going home was more difficult, and then he found that it was a lot more difficult, and he had to get off the bike and push it. As a previously healthy young man, it took a while for him to realise that something was really, really wrong.”

When going through the amyloidosis diagnostic and treatment process with her patients, Dr Horvath always tells them, “treatment is similar to the treatment given for myeloma”.

“We have to be a lot more careful with patients with amyloidosis because they’ve got damaged organs. They’re a lot more delicate,” she said.

AL amyloidosis treatment is aimed at reducing the light chains

Dr Horvath said AL amyloidosis treatment reduces the supply of “the nasty” protein that makes amyloid.

“The protein that makes amyloid in AL is the immunoglobulin light chains, which are made by what we call clonal plasma cells. If the patient is unfortunate enough, then that particular protein has the propensity to join together in amyloid fibrils and with other proteins to make amyloid, and it gets laid down in the organs.

“That can take many months and we don’t know why some of these ALs prefer the heart and some of them prefer the kidney,” said Dr Horvath.

“When we treat people with AL amyloidosis, we try to get rid of those clonal plasma cells from their bone marrow by giving them chemotherapy, which is essentially the same as you would give them if they had a cancer called myeloma.

“Some people have both amyloidosis and myeloma but people who have myeloma alone don’t usually have the kind of organ dysfunction that affects amyloidosis patients, particularly not affecting their heart, but they can have kidney dysfunction,” she said.

“Treatment cuts down the supply of the protein, which means they will stop laying down amyloid if we can get that protein level down to normal or basically as low as possible.”

Dr Horvath said the haematological response to treatment was categorised “pretty much the same way as in myeloma” as well.

“If they get down to normal light chain levels and their paraprotein goes, they’re considered to be in complete remission, but you have to remember that the organ response is way behind that,” she said.

“Also, at the moment, we don’t have a test that tells us if light chain levels that are normal still have a component of clonal light chains.

“Everyone has circulating light chains in their blood, so there is a normal range.

“For the amyloidosis patient, if their light chain level is normal, is all of that normal light chain? Or is some of it still the light chain that is capable of making amyloid?”

Dr Horvath said there are plans in Australia to develop a test, “but these things take a while”.

“People who have analysed the survival in amyloidosis have shown that if your light chains get back into the normal range, then you survive better than if it doesn’t. But again, if we could eliminate all the light chains that make amyloid, then presumably you would do even better.”

Treating AL amyloidosis with daratumumab

Dr Horvath said bortezomib (Velcade®), which has only been available since about 2005 and which was initially used for myeloma, is usually used in first line treatment for amyloidosis and “is effective in most patients”.

More recently, daratumumab (Darzalex®), which is an antibody against the plasma cells, has been very effective at attacking and eliminating them, and Dr Horvath said the level of the nasty protein can drop quite quickly, “but sometimes it would be appropriate to combine it with chemotherapy”.

“But in Australia, there is no approved treatment for AL amyloidosis, so in theory, if a patient has AL amyloidosis but does not have diagnosable myeloma, you can’t treat them,” she explained.

“So funnily enough, it turns out that everyone who’s got AL amyloidosis has myeloma.”

Daratumumab could be the first therapeutic agent to be approved as a treatment for AL amyloidosis as it is going before the Pharmaceutical Benefits Advisory Committee [PBAC] for consideration this month.

“On its own, daratumumab may not be as effective as daratumumab along with something like bortezomib,” said Dr Horvath.

“If I believe a patient is fit to receive chemotherapy as well as daratumumab, then that’s what I’d like to give them because the quicker I can get them to respond, the better.

“I believe this approval [under consideration by the PBAC] is going to be for subcutaneous daratumumab, which is a very small volume, injected into the abdominal wall.

“A problem with using intravenous daratumumab in someone with severe cardiac amyloidosis is that a large amount of fluid is infused, and you may make their heart failure worse.

“It is very delicate treating someone with amyloidosis.”

Dr Horvath knows of amyloidosis patients who have been on daratumumab for three to four years.

“At the moment, we don’t know whether it’s appropriate to stop it,” she said.

“I have several patients who are on it and I accessed it for them by going cap in hand to the company that makes it, telling them that either the patient had failed attempts at other treatment, or they weren’t suitable for other treatment.”

Dr Horvath said another possible side effect of daratumumab is an allergic reaction, “so you have to give them drugs that reduce the possibility of allergy and you have to keep a very close eye on them”.

“That applies to all patients who are getting almost any kind of antibody,” she said.

“Daratumumab is also very immunosuppressive because it doesn’t just select out the nasty amyloid making plasma cells, it kills off all your plasma cells, so patients don’t make antibodies against infection very well.

“It also sticks to red blood cells, which means that if your patient needs a blood transfusion, it makes the cross-matching of the blood very difficult.

“Therefore, you have to make sure you have sufficient information about the patient’s blood group and red cell antigens to, in theory, be able to pull a bag of blood off the shelf and give it to them if they need it.

“And the patient has to be aware of that as well, because if they happen to be driving across the Nullarbor and have a car accident, it’s a good idea to have information about their blood group somewhere.”

The greatest unmet need in AL amyloidosis

Dr Horvath tells her patients, “aren’t you lucky you’ve got myeloma”.

“This is pretty cynical, when you’re telling them they’ve got cancer, but it means they get access to treatment. Until there is an approved treatment, everybody who has AL amyloidosis somehow has myeloma.”

The classification of these diseases has an important role, particularly for monoclonal gammopathy of clinical significance (MGUS) which Dr Horvath said means you don’t have myeloma, but you’ve got these plasma cells making a protein that can harm you.

“In theory MGUS doesn’t need treatment, but it does if it’s damaging a patient’s organs,” she said.

“And there’s a category called smouldering myeloma, and these people have more plasma cells in their bone marrow than people with MGUS. Normally you would watch them carefully.

“But if a patient has amyloidosis, you need to treat them.”

“That needs to be recognised by the people who make decisions about the drugs, and that’s not just for amyloidosis. A very small amount of protein can do a lot of damage,” said Dr Horvath.

“MGUS is a precursor for myeloma, and it’s a precursor for amyloidosis, but not everyone who gets MGUS develops either myeloma or amyloidosis.

“You can have what otherwise would be classified as MGUS but have that nasty protein that makes amyloid.

“So when you see someone with MGUS, then it’s one of the things you have to think about and try and make sure that you’ve excluded it with appropriate tests to diagnose it.”

And there’s another thing, says Dr Horvath.

“If you’ve treated an amyloidosis patient and they’ve done well, it is unfortunately still very likely to come back and there’s been a lot of discussion about when you should restart treatment.

“The consensus is… as soon as you are convinced the disease is active again, because if you wait until those light chains get to even a little bit above normal then you may have missed the boat because they’ve already laid down quite a lot of amyloid.”

Removing amyloid deposits from the organs

Dr Horvath said the body doesn’t have very good mechanisms for removing the amyloid that’s already there.

“It can take many months, sometimes years, and sometimes it’s incomplete, so their heart walls will continue to be thick, and their heart will continue not to work very well,” she said.

Several agents, looking at ways of removing the amyloid that’s already deposited, are currently in international clinical trials and are available at Australian centres that treat amyloidosis.

“If successful, that will be a great leap forward, as long as they don’t have horrendous side effects,” said Dr Horvath, because several years ago, a clinical trial for an earlier agent, developed in the UK, was stopped when it was found to be too toxic.

These current trials are for newly diagnosed patients with cardiac involvement. Two are for the monoclonal antibody, CAEL-101, and the third is birtamimab.

They are used along with chemotherapy because Dr Horvath said, “just removing the amyloid is not enough” unless further production is also stopped.

“If we had a newly diagnosed cardiac amyloidosis patient, I would recommend these trials,” said Dr Horvath.

Each of these studies has different inclusion criteria, which means they apply to slightly different subgroups of patients, offering a broader spectrum of trials.

What would Dr Horvath do if she was diagnosed with amyloidosis?

“I’d come and see someone like me who specialises in amyloidosis,” she said.

“And, depending on what the organ involvement was, I would want to see a renal physician or a cardiologist or a neurologist.”

 

The  Australian Amyloidosis Network is an amalgamation of four multi-disciplinary medical amyloidosis clinics, in Sydney, Brisbane, Melbourne and Perth, that are dedicated to the diagnosis and management of Australian patients with all types of amyloidosis.

 

* Professor Hawkins is a Professor of Medicine at University College London and Clinical Director of the NHS National Amyloidosis Centre at The Royal Free and is a leading authority on amyloidosis.