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Unlocking Myeloid Dyplasias and Malignancies: Insights into Diagnosis and Treatment

• Dr Gavin Nimon • Season 5 • Episode 68

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This episode explores the complexities of myeloid conditions, including myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukaemia, with insights from Dr. Joanna Czerwinski. Host, Dr Gavin Nimon (Orthopaedic Surgeon) interviews Dr Czerwinski about classification, symptoms, diagnostic approaches, and the latest treatment strategies for managing these conditions effectively.

• Overview of myeloid conditions and their prevalence 
• Explanation of the myeloid stem cell line and its relevance 
• Classification of myeloid disorders: acute vs. chronic 
• Common symptoms and their diagnostic implications 
• Key diagnostic tests and investigations required 
• Intensive treatment approaches for acute myeloid leukaemia 
• Management strategies for chronic myeloid conditions 
• Importance of genetic testing in guiding treatment 
• Future perspectives on myeloid malignancies and ongoing research

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Dr Gavin Nimon:

Did you know that conditions like myelodysplastic syndrome, myeloproliferative neoplasms and acute myeloid leukemia affect thousands of people each year, often with vague symptoms like fatigue, infections or unexplained bruising? These myelodysplastic conditions not only pose diagnostic challenges, but also have significant implications for treatment and prognosis. Understanding them is crucial for any clinician aiming to provide timely and effective care. G'day and welcome to Aussie Med Ed, the Australian medical education podcast designed with a pragmatic approach to medical conditions by interviewing specialists in the medical field. I'm Gavin Nimon, an orthopaedic surgeon based in Adelaide, and I'm broadcasting from Kaurna land. I'd like to remind you that this podcast is available on all podcast players and is also available as a video version on YouTube. I'd also like to remind you that if you enjoy this podcast, please subscribe or leave a review or give us a thumbs up, as I really appreciate the support and it helps the channel grow. I'd like to start the podcast by acknowledging the traditional owners of the land on which this podcast is produced, the Kaurna people, and pay my respects to the elders, both past, present and emerging.

Dr Gavin Nimon:

Today we're visiting an important area of hematology with a very special guest, Dr Joanna Czajwinski. She's returning to the podcast. Last time, Dr Czerwinski provided us with a comprehensive overview of lymphoid malignancies. This time we're shifting our focus to explore the fascinating and complex world of myeloid dysplastic syndromes and malignancies. Whether you're just curious about the role of genetic testing or the complexities of managing these conditions or symptoms should prompt a referral to a hematologist. This episode promises to be informative and engaging, so grab your coffee, take a seat and let's dive into the world of myeloid malignancies with Joanna Chwinski on AussieMedEd.

Dr Gavin Nimon:

I'd like to remind you that all the information presented today is just one opinion and that there are numerous ways of treating all medical conditions. It's just general advice and may vary depending on the region in which you are practicing or being treated. The information may not be appropriate for your situation or health condition and you should always seek the advice from your health professional in the area in which you live. Also, if you have any concerns about the information raised today, please speak to your GP or seek assistance from the health organizations such as Lifeline in Australia. Thanks, Joe. Thank you very much for coming back on Aussie Med Edge.

Dr Gavin Nimon:

This time we're going to talk about myeloid conditions. I believe there's two sort of different pathways the haematology conditions can undertake. We've talked about lymphoid conditions previously which went down the pathways of the cells that form T cells and B cells. Now we're going to talk about myeloid conditions, which are the stem cells that produce red cells, platelets, etc. Perhaps you can just explain what the myeloid stem cell line is like and how it divides and how it's affected as well. Start off and down that pathway, Jo.

Dr Joanna Czerwinski:

Yeah, of course. Thank you for having me again. So with the myeloid malignancies it does produce most of the blood components. So we originate again from the hematopoietic stem cell and then, as we mentioned in our previous podcast, it divides into either the lymphoid stem cell or the myeloid stem cell, and so it quite easily goes on to the chronic and the acute conditions, like we had previously. But in the myeloid stem cell components there are the red cells, the granulocytes, which are things like neutrophils, eosinophils, basophils, and there are the platelets, and so you can quite easily see that any damage to the myeloid stem cell can affect quite a lot of the blood components and is what causes a lot of the cytopenias as well as the cytoses.

Dr Gavin Nimon:

Right, and are there many things that can affect those sort of pathways? Is it more just aging and genetic elements, or what are the main factors that affect them?

Dr Joanna Czerwinski:

So most of the times it's due to older age and genetic damage. So most of the conditions are diagnosed above the age of 65. But in particularly the younger cohorts under the age of 50, there are additional risk factors that we look out for. These can be things like exposure to previous chemotherapy and radiotherapies. It can be radiation exposure just in general, and it can also include certain medications that we don't really think about as chemotherapeutics but fall under the class of, like your disease, modifying agents for rheumatoid arthritis and other inflammatory conditions. There is also a small group that it can be inherited conditions passed along through generations.

Dr Gavin Nimon:

What's your main ways of classifying these conditions and how do the classifications affect the presentations? Perhaps?

Dr Joanna Czerwinski:

So certainly I start off with acute and chronic, because in the acute category you've got acute myeloid leukemia and acute promyelocytic leukemia. Those are your only two acute entities, realistically. And then majority of the other myeloid conditions falls under the chronic banner. And in the chronic banner you've got the myelodysplastic syndromes and the key word there is dysplasia, meaning that the cells don't look or act normally. And then you have the myeloproliferative neoplasms where the key word is the proliferative part, because most of the time the cells are in overdrive and there's far too much production, and these are further subclassified as well. So in the myeloproliferative neoplasms you may have heard of polycythemia vera, where you make too many red cells. Essential thrombocythemia, where you make too many platelets.

Dr Joanna Czerwinski:

Chronic myeloid leukemia, where you make too many of the granular sites, particularly the neutrophils and precursors of neutrophils, and myelofibrosis, which is in a way a burnt out version of these myeloproliferative neoplasms, where it initially starts with high numbers of cell counts across the board, but then it burns out and it actually causes cytopenias as the bone marrow scars over.

Dr Joanna Czerwinski:

And we finally also have an overlap syndrome, where you've got a component that is dysplastic and a component that is proliferative, and this is called myelodysplastic, myeloproliferative overlap syndrome. It's a bit of a mouthful. One of the problems that we have with the dysplastic syndromes is that you may not have adequate cell counts so they may have cytopenias and with the remaining counts they could be quite dysfunctional. So they are at risk of immunodeficiencies, immunocompromised states In the myeloproliferative neoplasms, the polycythemia and essential thrombocythemia conditions where there's too many of the red cells and platelets respectively, you end up having dysfunction from either bleeding or clotting perspective. So usually it's not so much that they can't carry oxygen or can't go and make a clot formation, but it's that they try and overwhelm the system a bit too well.

Dr Gavin Nimon:

So is that how most of them will present then with bleeding and bruisings or DVTs and things?

Dr Joanna Czerwinski:

Most of them do present either through incidental blood tests and you can see an elevated platelet count or an elevated hemoglobin. But you can also see them in terms of having VTE events, and some of the VTE events can be in strange locations like splanchnic vein. They don't necessarily have to be your traditional DVT or PE.

Dr Gavin Nimon:

We talked about lymphoid malignancies that had some splenic conditions and other lumps and lymph node conditions occurring. Do you get any of that occurring in myeloid conditions or is it all purely in the bone marrow?

Dr Joanna Czerwinski:

So when the bone marrow is dysfunctional and either doesn't have the capacity to make cells anymore or has completely scarred over, a lot of the production is taken over by the spleen. So a lot of the particularly in the myeloproliferative conditions, you end up getting extra medullary creation of these cells, and this is predominantly in the spleen. So you can certainly get splenomegaly in these cases, and in the vast majority of the myeloproliferative cases it's in myelofibrosis, Because in that condition your bone marrow ends up being like one big scar tissue where there's no capacity for cell generation.

Dr Gavin Nimon:

I understand. Also you can sometimes present with shortness of breath. Now, is that from PEs or is that from the actual cells developing and occurring in the lungs?

Dr Joanna Czerwinski:

So it's in three parts, depending on the condition. So if they're anemic then the shortness of breath can be attributed to anemia. If they have something like a VTE, a PEE event, then they certainly can have shortness of breath from that standpoint. But the chronic myeloid leukemias and conditions where the granulocytes can be quite elevated you get this sometimes in the acute myeloid leukemias as well, where the total white cell count is over 100 and what can happen in the lungs is that you have a whole host of neutrophils around the lung tissues and their granular products. So things like histamine and other cytokines they can release in the lung area and it can present like an acute pulmonary edema situation.

Dr Gavin Nimon:

Or it could also probably look a little bit like asthma, could it in that scenario?

Dr Joanna Czerwinski:

Yeah, it can. And when we go into acute promyelocytic leukemia, I'll also talk about differentiation syndrome, which can present like an acute pulmonary edema as well.

Dr Gavin Nimon:

I understand also you can get acute pulmonary edema as well. I understand also you can get some skin itchiness as well. Is that from the same sort of process as you get occurring in the lungs, or is it a different sort of pathway?

Dr Joanna Czerwinski:

It's a similar pathway. It's due to cytokine release and sometimes it can be due to the thickness of the blood as well. So you often get, in particular in polycythemia vera, you can get itchiness, you can get a redness discoloration of the face.

Dr Gavin Nimon:

People look often quite flushed and they can get quite sweaty as well. Okay, so obviously the name polycythemia vera makes you think of redness. Is that not just purely because of the actual cells affected, but it's actually the appearance of the person is it?

Dr Joanna Czerwinski:

Yes, it is Quite plethoric.

Dr Gavin Nimon:

So the vast majority of cases. You see, though I think I said previously when we're talking about lymphoid malignancies. They were incidental on blood tests. Is that still?

Dr Joanna Czerwinski:

the same case with myeloid conditions as well. So in the myelodysplastic syndromes most of these occur above the age of 65, 70, and it's usually on routine blood tests that are done for other reasons and you might only get hints of this condition developing like they may have an anemia of 120 for a male, which is still anemic but is very mild, and the only real symptom that they may have is fatigue and in some ways it can be hard to say you know a 75-year-old that is otherwise fit that this condition is causing a lot of their fatigue. In the myeloproliferative neoplasms there's some of my patients where it's identified because they are again fatigued for different reasons or they have developed a VTE event. But we do see some of them come in with hemoglobins of 170, 180, and you can't determine whether that figure on its own is the polycythemia vera that comes from the bone marrow or whether it's secondary to diuretics, dehydration, chronic airways diseases, sleep apnea.

Dr Gavin Nimon:

Okay, Of the particular different classifications. Obviously you talked about acute versus the chronic episodes. How does the acute presentation vary to a chronic presentation?

Dr Joanna Czerwinski:

The way that it presents is often florid in emergency department and it usually only has a prodromal illness of maybe one to two months at most. So one of my cases that I'd had had been having back-to-back viral infections or sinus infections for a period of seven weeks before he presented to his GP and at that point he had a white cell count of over 100. So he was called in from SA Pathology. He was called in to present to emergency department and get quickly worked up and he ended up having an acute myeloid leukemia and the clue was that he was getting recurrent infections and not getting over them.

Dr Gavin Nimon:

Right and a chronic one is more just, purely a slow, insidious sort of presentation which is picked up more on blood tests.

Dr Joanna Czerwinski:

Yeah, so most often it's anemia that's been there for say 12, 18 months for the myelodysplastic ones or the myelofibrosis cases and conversely, on the other, myeloproliferative neoplasms like the polycythemia vera and essential thrombocythemia. Again it will be mildly above the mark but chronic, and the GP has done a few different tests and can still not figure out why this is. Platelets of 500 to 600, hemoglobin of 170 to 180. In those sort of mild categories where you could attribute it to they were a bit dehydrated or they've recently had an infection you could attribute it to they were a bit dehydrated or they've recently had an infection.

Dr Gavin Nimon:

So we've got these patients presenting with some vague symptoms and they're picked up on an abnormal blood test. Once the abnormal blood test is standard, I presume complete blood examination is performed. What other investigations are required? Are they the same as lymphoid type conditions or are there anything specific you'd do? Let's just go through them all again, just to remind me as well.

Dr Joanna Czerwinski:

Yeah, absolutely so. A complete blood examination with a blood film is a key, particularly for the myelodysplastic syndromes and the acute leukemias, because that's going to be pretty diagnostic quite early on if they have these conditions, and particularly the acute myeloid leukemia. If you have a blood test at nine in the morning, it gets sent through to SA Pathology. You've got someone looking at it a few hours later and bringing a patient into hospital later that afternoon. So it's quite a rapid turnaround for the acute leukemia. For the myelodysplastic syndrome, there might be the appearance of dysplastic neutrophils, for instance, and that will be the first clue to the diagnosis. So blood film is definitely essential For both the myelodysplastic syndromes and the acute leukemias. I do flow cytometry because that helps to determine what the blasts are. Are they myeloid origin or are they lymphoid origin? Now, if we're going down the acute leukemia pathway, that is usually managed in hospital and investigated in hospital. But the things that we want to know is what is their kidneys doing, what is their liver doing and what is their cardiac health like? Because those three things determine their ability to tolerate intensive chemotherapy. For the myelodysplastic syndromes it is helpful to have creatinine and is helpful to have liver function tests predominantly because the main treatments involve the kidney in the filtration system. So we need to have adequate renal function to be able to deliver treatments. For the myeloproliferative neoplasms, the renal function and the liver function are less required in terms of being able to deliver treatments, but it is still a good thing to help with your differentials as to what may be causing, for instance, your polycythemia vera. If you've got an appearance of dehydrated kidneys, then it might be due to diuretic effect, as an example. So the other tests that have become more recently available that a hematologist could order includes the karyotyping or the cytogenetics, and that's usually done on a bone marrow biopsy specimen. And they may also do a genetic panel looking at molecular mutations and again, that's predominantly done on the bone marrow. Having said that, in some of my older frail patients where I don't think I'll be able to adequately give them treatment, I can do the same genetic panel from their peripheral blood as a bit of a prognostic indicator as to how long I've got with the patient and what else I can do to improve their quality of life. So certainly, the acute leukemics, we all do bone marrows.

Dr Joanna Czerwinski:

On the myelodysplastic syndrome you need to have a bone marrow to access treatment. If you're going down a treatment pathway and for most of the myeloproliferative neoplasms it's good to have bone marrow, but not essential. The only essential ones that you need is myelofibrosis, because, again, treatment is reliant on that diagnosis being confirmed, and the chronic myeloid leukemia because it is a way that you can monitor effectiveness of treatment over time. But the majority, like the polycythemia vera and the essential thrombocythemia, it's good to have at diagnosis but not essential to begin treatment.

Dr Gavin Nimon:

Excellent. Are there other tests you might do as well, like apart from the bone marrow or the blood picture? Are there things like CTs or ultrasounds that are also required?

Dr Joanna Czerwinski:

So a good clinical examination for splenomegaly is important for the myeloproliferative neoplasms and in clinical trials they will always use splenic size to determine how people are responding, particularly for myelofibrosis. So a lot of people have a CT scan or an ultrasound at baseline and then serially performed to track response. But if you can feel the spleen at the beginning and you can measure, you know, for my fingers something starts out as four finger breaths and goes down to two finger breaths. I know that they're responding to treatment and I don't need radiology to tell me that. So it's not required to have a CT scan. If they're going to have intensive induction chemotherapy for the acute leukemia we often get a CT sinuses because they're at a lot of risk of sinus infection and particularly invasive fungal. So we may sometimes in hospital also do a chest CT as part of that.

Dr Gavin Nimon:

Right. So that's really the full workup. Then you can actually do fairly straightforward investigations. Then with the bone marrow biopsy and a few other investigations you can get the baseline of what you really need.

Dr Joanna Czerwinski:

Absolutely.

Dr Gavin Nimon:

How do you progress from there then? What's the next step, Once you've got your biopsies and you've got your blood picture?

Dr Joanna Czerwinski:

you've done your examination, what's the next step? So I guess if we're looking down the pathway of treatment, I need to get the infectious serologies ticked off, like your hepatitis B, c and HIV, and for the acute leukemias it's helpful to have a uric acid for tumericis response, particularly because the myeloid cells are generally bigger than lymphoid and when these guys break apart and burst they do release toxic products similar to the lymphoid cells. So we still need to think about tumor lysis syndrome in the acute leukemia status. With the chronic conditions, again, if I'm embarking on treatment I want to know their infectious serology. And then it's determining their age and fitness and putting in the different characteristics into like a prognostic scoring system to determine what treatment is best. And this can be different for whether they're young or old, whether they have transfusion dependency or not and whether they've had a VTE event or not when we're talking about the chronic one.

Dr Gavin Nimon:

I might just stop you there for two seconds and just ask you, because you've just raised some great thoughts that I didn't know about. So tumor lysis syndrome is that? I presume that you can get gout from that because of the release of uric acid. What else does it involve?

Dr Joanna Czerwinski:

So tumor lysis syndrome. I like to think of the acronym of CUP C-U-P-P, where your calcium goes down by 25% from baseline, your uric acid goes up by 25%, your potassium goes up by 25% and your phosphate goes up by 25%. So these are the early markers of tumericis and it's what we generally monitor twice to three times a day in an inpatient setting. When it's quite deteriorated it will involve the kidneys and you will see renal failure and you will also see complications such as acute pulmonary edema when the tumor lysis syndrome further progresses. So having those blood tests twice to three times a day during the early inpatient stay during their initial course of treatment, that's where you're going to be able to pick it up early and give them treatments to reduce their uric acid and reduce those toxins. So most patients get commenced on allopurinol and it's 300 milligrams a day and they continue it for the first seven days of intensive induction treatment.

Dr Gavin Nimon:

Why is it important to know about the infection status, the hep B, C and HIV. Why is that important?

Dr Joanna Czerwinski:

Because they become so heavily immunocompromised with their treatments. You want to detect whether they've got a chronic hepatitis that you can treat simultaneously or just prior to initiating your induction treatment, and the prophylaxis may also change. So, for instance, if you have a HIV patient, you want to be putting them on antiretrovirals and you want to make sure that they don't interact with your treatment plans.

Dr Gavin Nimon:

So, jo, moving back on to talking about the treatment plan, once you've done your standard workup looking for infections and also checking for tuberculosis syndrome and being prepared for it, what's the next steps? How do you progress with treatment following that?

Dr Joanna Czerwinski:

If we focus initially on the acute leukemias, if they have a stock standard acute myeloid leukemia the first things that we want to do is bring down their white cell count. If it's elevated down to less than 25 so that we can start induction chemotherapy, and this is to try and reduce that risk of tumerosis as well as to try and reduce the risk of any acute pulmonary edema or any other complications from things like differentiation syndrome or, again, the tumerosis effect. So what treatment is determined is based on patient age and fitness. So if they're an under 70 year old, we're usually offering intensive induction therapy, which is what we colloquially call 7 plus 3, which involves seven days of citarabine and three days of dawnerubicin or other anthracycline chemotherapy. So the way that this is delivered is simultaneous seven and three, so it's a total of seven days duration of chemotherapy. But because this is such an intensive chemotherapy and aims to clear out everything from the bone marrow and start from scratch, it does take about two to three weeks for recovery from this kind of intensity of chemo, and so most patients will be admitted for the entire month during their induction therapy and they will have to work through any complications, most commonly infections, after the seventh to tenth day and upon recovery of their blood counts at day 25 plus, they're usually scheduled for another bone marrow to see how well that job was done in clearing out their leukemia. And if they have achieved a remission so less than 5% blasts in their bone marrow then they go on to consolidation therapy and then the following steps after that is dependent on what risk category of leukemia they have.

Dr Joanna Czerwinski:

So if they have a high risk leukemia where they've got multiple mutations or very bad mutations, these patients will generally try and get onto the allogeneic stem cell transplant pathway. And most of the time we don't cap it by age. But generally speaking there are not many 75-year-olds that would be able to tolerate that kind of treatment. Broadly speaking, somewhere between 70 and 75, with their fitness level and their comorbidity index. That will determine who gets allowed to go to an allogeneic transplant. And that process involves usually high doses of chemotherapy to completely wipe out the bone marrow. And then you have a replacement bone marrow stem cell environment from another donor, usually a sibling, sometimes it's an unrelated donor, sometimes it can be a parent or a child.

Dr Gavin Nimon:

With transplants in the myeloid conditions, do you have to go on long-term immunosuppression for the use of them, like you do with kidney transplants?

Dr Joanna Czerwinski:

So I like to think of allogeneic transplants as the only circumstance where you are usually not on long-term immunosuppression. You are certainly on immunosuppression for the first 100 days, and it's usually things like cyclosporine, tacrolimus, the usual anti-rejection medications, and then after day 100, when that risk of acute graft versus host disease has subsided. That's when, if things are going well, they generally start to taper it down over the subsequent three months, so usually by six months. If it's gone all well, patients are usually able to come off of their anti-rejection meds and their new bone marrow and their new blood type is completely ingrained into their own bone marrow space.

Dr Gavin Nimon:

Does that mean that's really interesting? Does that mean like you might start off as an A negative and become back as a B positive?

Dr Joanna Czerwinski:

Absolutely. That's what exactly that means. That's crazy. There's obviously a lot of high-tech involvement with regards to that because, if you can imagine, we talk about transfusion reactions being incompatible blood and we're talking about incompatible bone marrow sources of blood.

Dr Gavin Nimon:

Wow, that's amazing. Okay, all right. Well, it's one of the most interesting facts I think I've learned in the whole four years. Truly All right. So that's for the acute stage, the acute conditions. What happens in those patients over 70 or 75? In the acute stage, they're unfortunately not going to tolerate the treatment very well.

Dr Joanna Czerwinski:

So a few years ago there became available this protocol called azacitidine and venetoclax. Now azacitidine I'll speak about again later because it's involved in myelodysplastic syndromes, but it's a hypermethylating chemotherapy agent that is given as a subcutaneous injection for seven days every cycle, and each cycle is usually 28 days, and this is paired with a BCL-2 inhibitor, so an anti-apoptotic marker, and that is a tablet therapy that is taken continuously. And even I think my oldest patient is in their mid-80s and is tolerating that treatment protocol. So again you would go through this induction treatment where you're very quickly ramping up to the maximum dose of venetoclax and you're also simultaneously giving the azacitidine and it's a standard treatment course for everyone for cycle one.

Dr Joanna Czerwinski:

At the end of cycle one you do a repeat bone marrow and again you're seeing how much of cycle one. You do a repeat bone marrow and again you're seeing how much of the leukemia you've cleared out. Now in most cases the leukemia has been cleared in that first cycle. Some additional people need a second cycle of similar intensity and then, once you have cleared out the leukemia, then you can adjust the doses for better tolerability, because most of the time it is an outpatient protocol, it is not needing to remain in because it is that gentler level. I've used this protocol also for people that are Jehovah's Witnesses and are not accepting of blood transfusions, because the former the 7 plus 3, renders everyone in need of transfusion, whereas this provides an option for if transfusions are not in that person's religion and also is much more tolerable for the older or frailer person.

Dr Gavin Nimon:

So this is more like a long-term suppressive type of treatment as opposed to a trying or a curative type treatment.

Dr Joanna Czerwinski:

Absolutely the longest person that I think has been on that combination has been more than 15, 18 months. So it is something that treatment protocol for 12 months and they've cleared the bone marrow of the leukemia and they're in a complete molecular remission where you can't detect their genetics from their presentation. Whether those patients can actually safely come off of treatment and have a drug holiday.

Dr Gavin Nimon:

We've got obviously using suppressive agents or chemotherapy agents. Are there any other types of agents you might use?

Dr Joanna Czerwinski:

Something that we'll again be talking about, mostly with the myeloproliferative neoplasms. But we do use hydroxyurea or hydroxycarbamide as a tablet treatment to cytoreduce or to bring down all of their cell counts. So it is a very old-fashioned, very indiscriminatory chemotherapy agent and it's tablets, and it will bring down not only the white cells that you're trying to bring down, but it will also render them anemic and thrombocytopenic. So you can only realistically do that for a few days, but that's all you're trying to achieve is a much more tolerated white cell count, so that then you can initiate the effective treatment.

Dr Gavin Nimon:

And this is purely for the acute myeloid leukemia, like promyelocytic leukemias. So that's purely the white cell type leukemias Do you get. I'm a little bit confused here. For a second, can you get acute leukemias involving red cells or platelets as well, or is it purely white cells? I'm not making it too hard for myself here.

Dr Joanna Czerwinski:

It is only with the granular sites, so it is predominantly the neutrophils gone bad essentially. So we are dealing with the myeloid precursors, but the white cell versions there. Technically is an acute proerythroid leukemia very rare. You only hear case studies about it. But they are nucleolated red cells that you see in the bone marrow and it has undergone multiple reclassifications so it's now more thought about as an acute myeloid leukemia with a predominance of those red cell precursors. And there is an acute megakaryoblastic leukemia and again it's very rare. It's very bad news if it occurs in an adult and the prognosis is better if it's in a child with Down syndrome, where there's an increased number of cases in that particular cohort of children with Down syndrome.

Dr Gavin Nimon:

Okay, so the red cell condition, the platelet conditions, are really more on the myelodysplastic or the chronic conditions that we're talking about then.

Dr Joanna Czerwinski:

Absolutely.

Dr Gavin Nimon:

Is there anything else that you'd want to say about the acute conditions before moving on to the chronic conditions, then?

Dr Joanna Czerwinski:

I guess the acute promyelocytic leukemia does not get treated the same way as the acute myeloid does so with the acute promyelocytic leukemia does not get treated the same way as the acute myeloid does so with the acute promyelocytic leukemia. It's treated with a combination of all transretinoic acid or ATRA, and combined with arsenic. And it is because of the particular translocation of the genetic proteins in that particular leukemia and it was discovered more than 10 years ago that this combination of the ATRA and the arsenic can actually break apart that fusion protein and cause those blast cells or those promyelocytic cells, the leukemia cells, to differentiate into proper neutrophils at the end stages. And it is a highly curative condition, highly curative treatment and most patients go through it and the survival is something like 95% long term without relapse.

Dr Gavin Nimon:

Wow.

Dr Joanna Czerwinski:

The most severe part of their induction program is the first three weeks, because there is a high risk of differentiation syndrome, where that process of going from leukemic cells to neutrophils occurs very instantaneously and degranulates all their cytokines and causes that acute pulmonary edema syndrome. The other thing that can happen, of course, is DIC, which is disseminated intravascular coagulopathy. So whenever we see an acute leukemia present into emergency department we're always asking for the extended coagulation parameters to include the fibrinogen and the D-dimer and you would see DIC if the fibrinogen is quite low, so less than 1.5, and the D-dimer is above 30,. We're much more different than your VTEs where your D-dimer is 1.

Dr Gavin Nimon:

Right, yes, how many of these sort of cases would you treat each year?

Dr Joanna Czerwinski:

So the acute promyelocytic leukemia is less common, so we probably get a handful each. Thinking back over the last few months we probably had two or three in the last three-ish months Whereas the acute myeloid leukemia in adults is much more common than lymphoblastic leukemia, and particularly now that we've got an older population, we're picking these things up. We now have treatments available for the older patient. We're seeing maybe one every week or two.

Dr Gavin Nimon:

We talked about the causes. We talked about just degeneration or age-related changes to the cells, but also talked about radiation exposure and medications. Is there a greater percentage of one over the other for causes?

Dr Joanna Czerwinski:

So certainly most of them is due to aging and bad luck. You can get acute myeloid leukemia even as a teenager and I've had very few cases of pediatrics that we've seen through the laboratory, but certainly we have had 18-year-olds, we've had 20-year-olds with acute myeloid leukemia. The ones where they've occurred post-chemotherapy or other treatments generally, are associated with more high-risk features because they've already had their DNA damaged from the other treatment and they're now coming in with high-risk features. So those patients are very, very likely to go to an allogeneic transplant unless they're unfit for one.

Dr Gavin Nimon:

Because that'd be like a field change. I presume the whole, all the cells are being damaged along the way.

Dr Joanna Czerwinski:

Absolutely, and usually, like the most common circumstances that we see, it is post-anthrocycline and similar intensity chemotherapy. So I haven't seen many from prostate cancer, but I have seen a few after breast cancer treatments with chemotherapy, as an example.

Dr Gavin Nimon:

If we move on to the chronic type conditions, then you've divided those up into the dysplastic syndromes, often as being pre-malignant conditions. Is there a particular type of classification of those particular syndromes?

Dr Joanna Czerwinski:

Yeah, so it used to be that the myelodysplastic syndromes would be divided up into appearances and the bone marrow technical comments of you know is it a high blast count? Is it a low blast count? How many of the red cell, white cell and platelet lineages are affected? So is it a multi-lineage dysplasia or a single lineage dysplasia? And there are certain mutations that it used to be classified by as well. So a deletion 5q would be in the old classification systems. These days it's excess blasts or not, multi-lineage or single lineage, and sometimes there will be key other features as well. So they might be defined by their molecular abnormalities or their genetic abnormalities as well. But by and large most of the myelodysplastic syndromes that come in to see me are what I would deem as low risk. They're very mild. They're, incidentally, picked up over serial blood tests. And you go and do a bone marrow and you find maybe they have single lineage myelodysplasia. Very low blast counts, low blast counts. And when you pop in those kind of numbers into the prognostic scoring system we'll tell you that their low risk and their average overall survival is 10 years, meaning that in a population where you're predominantly seeing 70-year-olds their average survival is going to be another 10 years For the more intermediate to high risk. Those patients usually have started having blasts in their blood tests, so you can immediately tell that you're dealing with a more aggressive case and they're often needing blood transfusions much earlier. So those are the patients that I would try and encourage them to get a bone marrow sooner, because that will affect how I'm going to treat them and when I think about the four different types of treatment for your myelodysplastic syndrome. The earliest is the watch and wait, where you're monitoring their bloods every two or three months and you're looking for changes over time. And when you do see those changes, that's when you would do a bone marrow to see what has molecularly changed or what's changed under their bone marrow. The next is supportive treatments. So these are things like blood transfusions, antibiotics, vaccinations and in some cases you can even get things like E2 bring up the hemoglobin. Obviously that's not on the PBS.

Dr Joanna Czerwinski:

The next third treatment is standard chemotherapy and that is indicated for your intermediate to high-risk players and it's to try and prevent the myelodysplastic syndrome from progressing into acute myeloid leukemia, because there is a percentage chance and it's in those same prognostic scores that I was talking about a few minutes ago. There is a chance that it will convert over to acute leukemia and you want to capture them before they make that transition so that you can offer them chemotherapy. And the chemotherapy is again that same azacitidine that I spoke about earlier in combination with the venetoclax. But you are using just azacitidine by itself for the myelodysplastic syndromes. And then the fourth and final treatment is usually reserved for, again, those really young players. But if you've developed myelodysplastic syndrome and you're under 50, you probably have genetics that are poor risk and you probably want to be thinking about a transplant early in the piece.

Dr Gavin Nimon:

So obviously the supportive treatments. We're talking about using blood transfusions. That's why it's so important to be donating blood and giving products for people who are undergoing this sort of treatment. And I presume they divide those cells up into whether red cells, platelets or neutrophils. Is that correct when they give transfusions? In that scenario? And if they're in a single lineage, they just need one or the other.

Dr Joanna Czerwinski:

Kind of mostly correct.

Dr Joanna Czerwinski:

So when someone goes and donates blood they generally donate whole blood and that is split up into its components of red cells, platelets and plasma and the plasma contains all the different proteins.

Dr Joanna Czerwinski:

But generally we don't transfuse granulocytes because that would run the risk and it's a very hefty risk of graft-versus-host disease where the donor's granulocytes are attacking the host.

Dr Joanna Czerwinski:

There are very rare circumstances where that's done and it's usually in a plastic anemia, which is a non-malignant condition. But you're certainly right that if a myelodysplastic patient predominantly plastic anemia, which is a non-malignant condition, but you're certainly right that if a myelodysplastic patient predominantly has anemia, they're predominantly going to be transfused just red cells and in the chronic transfused patient cohort they might be booked in for an outpatient transfusion every two or three weeks and it might be two units at a time. So when patients are being transfused for these chronic myelodysplastic syndrome conditions we're also thinking about their iron overload because that comes with those transfusions and there are iron chelators on the PBS which are available to those patients. So there is a requirement for a certain amount of transfusion every two months and a certain level of anemia and a certain level of ferritin before you can commence one of these treatments, and the treatment is only advantageous if the problem is more than two years, because it takes a very long time to chelate the blood from that iron.

Dr Gavin Nimon:

I presume so you're trying to prevent secondary hemochromatosis. Then in that scenario, In that scenario.

Dr Joanna Czerwinski:

Yes, you're trying to prevent other organ damage from their iron load.

Dr Gavin Nimon:

Right. Okay, there are other different types of treatments. I remember hearing about doing splenectomies for ITP and things like that. Is that done in this sort of conditions as well?

Dr Joanna Czerwinski:

It's generally reserved for the myelofibrosis cases where the spleen can get quite big, and some palliative measures can include splenic radiation as a treatment option. But these are usually when you've tried every other therapy and the spleen is still huge and still causing a lot of drama.

Dr Gavin Nimon:

So okay. So these are the main types of treatments you use for the chronic myelodysplastic conditions, and that's the sort of intermediate sort of chronic conditions we're talking about. Then you've got these chronic myeloproliferative disorders, which is really the next stage.

Dr Joanna Czerwinski:

Yeah. So I think about the myeloproliferative neoplasms as a condition where the gas pedal is fully firm to the floor and we're overproducing too many cells. So if we take polycythemia as the best example, most of those cases again we can see, incidentally, on routine blood tests. We can see it in the circumstances of VTE and we can see them in circumstances of they come to their GP complaining of fatigue and itchiness and they're red in the face, they're quite sweaty and in these conditions, whenever a polycythemic patient comes to me, I try and establish a few things quite quickly. I try and establish the chronicity of how long this has been over. I try and see do they have any respiratory or cardiac issues that might be causing them to need more red cells and need more oxygen, because that's the polycythemic drive? And I try and establish are they on any diuretics or having multiple coffees a day with not enough water intake? And if I can't find anything obvious then I'm sticking them on aspirin, unless they've got anticoagulants for other reasons. And the reason behind it is that aspirin prevents a lot of the complications of polycythemia vera when it comes to thromboses, because the thromboses are mostly VTE, but they can have arterial events like MI and stroke as well. So I will put them on aspirin until I've seen their genetic result. And polycythemia is associated with two mutations both in the JAK2 gene, and 95% of the polycythemics will have one or the other mutation. And that mutation study takes about three weeks to get results. So if I'm on the phone with a GP and they're telling me about a polycythemic case, I will say stick on aspirin, send them through to us, we'll do the genetic testing and then we'll talk to the patient about what we found. So then again, it's a bit determined by age as to what kind of treatment and whether they're of childbearing age in particular. So if I've got a young patient under the age of 50 and they're interested in having more family, then I would do venesections and my aim is to get their hematocrit down to normal, so the hemoglobin will come down. If I'm focusing on getting that hematocrit to the correct values In females it's less than 45% and in males I'm targeting 48% those venous sections might have to be quite frequent initially, so maybe weekly or fortnightly.

Dr Joanna Czerwinski:

But as you're getting further control you can spread those venous sections further and further apart. One of the ways that I can tell if a patient has polycythemia, even before I've begun venous sections is what their iron levels are doing, because polycythemia even before I've begun venesections is what their iron levels are doing. Because polycythemia, the pedal on the gas will only be limited by how much iron fuel you're giving those red cells. So by venesecting them it's not actually removing the red cells, that's part of the process, but you're actually trying to limit how much iron those red cells have in reserve to further procreate. So I would often try and get them to as low a ferritin as they can tolerate. Sometimes that means a ferritin of 20. So technically they're iron deficient by that point. So long as they can manage with the symptoms of that mild iron deficiency by offsetting their polycythemia vera, then that determines their venesection frequency. So it's a bit of a balance.

Dr Joanna Czerwinski:

The other type of treatment that can be available for young persons is pegylated interferon, which is a weekly subcutaneous injection.

Dr Joanna Czerwinski:

But we don't like to do that for currently pregnant female.

Dr Joanna Czerwinski:

We like to do that as a lead-in prior to pregnancy planning and they may need to be on it for a year or two to get their numbers under adequate control and then we can have that luxury of allowing them the nine to 12 months of trying to fall pregnant and then being pregnant. The treatment for the older patient involves hydrea, which we mentioned before as a cytoreducing agent. Now, the main risks of hydrea is that it gives you a risk of skin cancers. So I usually have all of my patients checked over quite thoroughly before initiating that treatment and then regular, at least annual, checks thereafter, and it causes wounds to heal quite poorly. Since a diabetic with polycythemia and their diabetes is out of control, I'm not likely to initiate that treatment straight away because I might be doing more harm than good. Diabetic ulcers are never going to heal properly. So those are broadly the three treatments that we've got available. So the venous sections, the interferon, the hydroxyurea and then the aspirin or the anticoagulation as a preventative of thromboembolic events.

Dr Gavin Nimon:

All right, so that's polycythemia. How do the other conditions vary compared to the polycythemia?

Dr Joanna Czerwinski:

So essential thrombocythemia is a bit harder to treat because venous sections don't work as well for them, so it's usually just isolated platelet count that's elevated. So in the very extreme ET cases where the platelets are greater than 1000, there is platelet phoresis, which is done in hospital where when people go to donate blood they can sometimes go and donate just platelets or just plasma and they get placed onto this machine which looks like a big dialysis or centrifuge machine where they have blood pulled into a machine. It's spun around so they're separated by different weights of cells and then you can remove the platelet level of the different weights being separated. And that's the same process that happens for platelet phoresis, where you're just removing the platelet layer from that centrifuge and that's to try and rapidly bring down platelet levels to prevent bleeding and bruising and clotting complications. But you can't obviously go in and have that treatment indefinitely and so most patients with ET get put on hydroxyurea.

Dr Gavin Nimon:

Okay, and then moving on to the myelofibrosis stuff, that's just where. It's just worn out.

Dr Joanna Czerwinski:

Yeah.

Dr Gavin Nimon:

So is there any particular treatment for that? I presume you're just getting an allogeneic transplant for those sort of conditions, are you, or how is that one treated?

Dr Joanna Czerwinski:

So for the young patients certainly allogeneic transplant is an option for really severe myelofibrosis where they've got splenomegaly or symptoms of fatigue, tiredness, shortness of breath, itch. Those patients I encourage them to have a bone marrow to confirm the diagnosis because then they can access ruxolitinib, which is a tablet therapy on the PBS. It's a form of a JAK inhibitor and it has improved quality of life scores in the trials that were done with it. So it improves spleen size and as a result it improves the cytopenias. It also improves those symptoms of the itch, postprandial fullness, the fatigue.

Dr Gavin Nimon:

Okay, that brings us down to the last type of condition, the myelodysplastic slash myeloprolutative overlap syndromes. Is it really a combination of what we've already talked about, or are these separate all again as well?

Dr Joanna Czerwinski:

They're a combination of what we talked about. Most patients I treat very similar to the myelodysplastic syndrome. You've got the watch and wait approach, the supportive care approach. The active treatment approach can be azacitidine if they're looking more like a myelodysplastic patient, or it could be hydrea if it's a proliferative. Look to it and then allogeneic transplant is an option for those younger patients, but generally the myelodysplasticastic, myeloproliferative overlap syndromes are above the age of 70.

Dr Gavin Nimon:

Well, that's a fair bit to go through. Is there anything you'd like to say to wrap up with that whole sort of process? Is there anything that comes to mind? There's a lot we've gone through already so far tonight.

Dr Joanna Czerwinski:

Well, I guess, out of all the cases that we've discussed today, I guess the thing that I would inform GPs is, if you've got a mild anemia, a mild thrombocytopenia, a mild elevated hemoglobin, elevated platelet count, is to monitor that over time, because if it's at the very mild stages, most of the cases can be monitored. But if you've got a mild proliferative neoplasm, you want to know is it because of their bone marrow or is it a secondary event? And in most cases, thankfully in this day and age, most of the treatments are oral, and particularly when it comes to the chronic conditions.

Dr Gavin Nimon:

Where do you think the future holds for hematologists in these two areas? What's the next steps? What do you want to see down the track?

Dr Joanna Czerwinski:

Well, I guess a lot of the particularly the chronic conditions in this space are diagnosed at much older ages and we're predominantly doing treatment to prolong survival and improve quality of life, but there's nothing that realistically prolongs it by years and years and that's the hardest thing to talk to patients about. But if there are treatments that are in clinical trials to try and extend that survivability even further, because I'm seeing patients that have just hit retirement go to their GP for the first time and then they're landed with this sort of a diagnosis because the previous 10 years they were busy working, doing other things, not necessarily seeing their GP at that point.

Dr Gavin Nimon:

It must be very hard in that scenario. Thank you very much, Jo, for coming on Aussie Med Ed and explaining these conditions for us. I really appreciate your time.

Dr Joanna Czerwinski:

You're welcome.

Dr Gavin Nimon:

It's really interesting to learn about it and I've learned some of the most amazing facts tonight. So thank you very much.

Dr Joanna Czerwinski:

You're very welcome. Thanks for having me again, me again, thank you, thanks, joe.

Dr Gavin Nimon:

Thanks again for listening to the podcast and please subscribe to the podcast for the next episode. Until then, please stay safe.

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