February 9, 2025 • 52 mins
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
Aussie Med Ed is sponsored by -HealthShare is a digital health company, that provides solutions for patients, General Practitioners and Specialists across Australia.
Aussie Med Ed is sponsored by Avant Medical Indemnity: They state that they offer holistic support to help the doctor practice safely and believe they have extensive cover that's continually evolving to meet your needs in the ever changing regulatory environment.
Mark as Played
Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Dr Gavin Nimon (00:00):
Did you know that conditions like
myelodysplastic syndrome,myeloproliferative neoplasms and
acute myeloid leukemia affectthousands of people each year,
often with vague symptoms likefatigue, infections or
unexplained bruising?
These myelodysplasticconditions not only pose
diagnostic challenges, but alsohave significant implications
for treatment and prognosis.
Understanding them is crucialfor any clinician aiming to
(00:21):
provide timely and effectivecare.
G'day and welcome to Aussie MedEd, the Australian medical
education podcast designed witha pragmatic approach to medical
conditions by interviewingspecialists in the medical field
.
I'm Gavin Nimon, an orthopaedicsurgeon based in Adelaide, and
I'm broadcasting from Kaurnaland.
I'd like to remind you thatthis podcast is available on all
podcast players and is alsoavailable as a video version on
(00:43):
YouTube.
I'd also like to remind youthat if you enjoy this podcast,
please subscribe or leave areview or give us a thumbs up,
as I really appreciate thesupport and it helps the channel
grow.
I'd like to start the podcastby acknowledging the traditional
owners of the land on whichthis podcast is produced, the
Kaurna people, and pay myrespects to the elders, both
past, present and emerging.
(01:04):
Today we're visiting animportant area of hematology
with a very special guest, DrJoanna Czajwinski.
She's returning to the podcast.
Last time, Dr Czerwinskiprovided us with a comprehensive
overview of lymphoidmalignancies.
This time we're shifting ourfocus to explore the fascinating
and complex world of myeloiddysplastic syndromes and
malignancies.
Whether you're just curiousabout the role of genetic
(01:24):
testing or the complexities ofmanaging these conditions or
symptoms should prompt areferral to a hematologist.
This episode promises to beinformative and engaging, so
grab your coffee, take a seatand let's dive into the world of
myeloid malignancies withJoanna Chwinski on AussieMedEd.
I'd like to remind you that allthe information presented today
is just one opinion and thatthere are numerous ways of
treating all medical conditions.
(01:45):
It's just general advice andmay vary depending on the region
in which you are practicing orbeing treated.
The information may not beappropriate for your situation
or health condition and youshould always seek the advice
from your health professional inthe area in which you live.
Also, if you have any concernsabout the information raised
today, please speak to your GPor seek assistance from the
health organizations such asLifeline in Australia.
(02:06):
Thanks, Joe.
Thank you very much for comingback on Aussie Med Edge.
This time we're going to talkabout myeloid conditions.
I believe there's two sort ofdifferent pathways the
haematology conditions canundertake.
We've talked about lymphoidconditions previously which went
down the pathways of the cellsthat form T cells and B cells.
Now we're going to talk aboutmyeloid conditions, which are
(02:26):
the stem cells that produce redcells, platelets, etc.
Perhaps you can just explainwhat the myeloid stem cell line
is like and how it divides andhow it's affected as well.
Start off and down that pathway, Jo.
Dr Joanna Czerwinski (02:38):
Yeah, of course.
Thank you for having me again.
So with the myeloidmalignancies it does produce
most of the blood components.
So we originate again from thehematopoietic stem cell and then
, as we mentioned in ourprevious podcast, it divides
into either the lymphoid stemcell or the myeloid stem cell,
and so it quite easily goes onto the chronic and the acute
(03:02):
conditions, like we hadpreviously.
But in the myeloid stem cellcomponents there are the red
cells, the granulocytes, whichare things like neutrophils,
eosinophils, basophils, andthere are the platelets, and so
you can quite easily see thatany damage to the myeloid stem
cell can affect quite a lot ofthe blood components and is what
(03:25):
causes a lot of the cytopeniasas well as the cytoses.
Dr Gavin Nimon (03:30):
Right, and are there many things that can
affect those sort of pathways?
Is it more just aging andgenetic elements, or what are
the main factors that affectthem?
Dr Joanna Czerwinski (03:38):
So most of the times it's due to older age
and genetic damage.
So most of the conditions arediagnosed above the age of 65.
But in particularly the youngercohorts under the age of 50,
there are additional riskfactors that we look out for.
These can be things likeexposure to previous
chemotherapy and radiotherapies.
(03:59):
It can be radiation exposurejust in general, and it can also
include certain medicationsthat we don't really think about
as chemotherapeutics but fallunder the class of, like your
disease, modifying agents forrheumatoid arthritis and other
inflammatory conditions.
There is also a small groupthat it can be inherited
(04:19):
conditions passed along throughgenerations.
Dr Gavin Nimon (04:22):
What's your main ways of classifying these
conditions and how do theclassifications affect the
presentations?
Perhaps?
Dr Joanna Czerwinski (04:28):
So certainly I start off with acute
and chronic, because in theacute category you've got acute
myeloid leukemia and acutepromyelocytic leukemia.
Those are your only two acuteentities, realistically.
And then majority of the othermyeloid conditions falls under
the chronic banner.
And in the chronic banneryou've got the myelodysplastic
(04:50):
syndromes and the key word thereis dysplasia, meaning that the
cells don't look or act normally.
And then you have themyeloproliferative neoplasms
where the key word is theproliferative part, because most
of the time the cells are inoverdrive and there's far too
much production, and these arefurther subclassified as well.
(05:11):
So in the myeloproliferativeneoplasms you may have heard of
polycythemia vera, where youmake too many red cells.
Essential thrombocythemia,where you make too many
platelets.
Chronic myeloid leukemia, whereyou make too many of the
granular sites, particularly theneutrophils and precursors of
neutrophils, and myelofibrosis,which is in a way a burnt out
(05:33):
version of thesemyeloproliferative neoplasms,
where it initially starts withhigh numbers of cell counts
across the board, but then itburns out and it actually causes
cytopenias as the bone marrowscars over.
And we finally also have anoverlap syndrome, where you've
(05:54):
got a component that isdysplastic and a component that
is proliferative, and this iscalled myelodysplastic,
myeloproliferative overlapsyndrome.
It's a bit of a mouthful.
One of the problems that wehave with the dysplastic
syndromes is that you may nothave adequate cell counts so
they may have cytopenias andwith the remaining counts they
(06:15):
could be quite dysfunctional.
So they are at risk ofimmunodeficiencies,
immunocompromised states In themyeloproliferative neoplasms,
the polycythemia and essentialthrombocythemia conditions where
there's too many of the redcells and platelets respectively
, you end up having dysfunctionfrom either bleeding or clotting
(06:37):
perspective.
So usually it's not so muchthat they can't carry oxygen or
can't go and make a clotformation, but it's that they
try and overwhelm the system abit too well.
Dr Gavin Nimon (06:50):
So is that how most of them will present then
with bleeding and bruisings orDVTs and things?
Dr Joanna Czerwinski (06:56):
Most of them do present either through
incidental blood tests and youcan see an elevated platelet
count or an elevated hemoglobin.
But you can also see them interms of having VTE events, and
some of the VTE events can be instrange locations like
splanchnic vein.
They don't necessarily have tobe your traditional DVT or PE.
Dr Gavin Nimon (07:18):
We talked about lymphoid malignancies that had
some splenic conditions andother lumps and lymph node
conditions occurring.
Do you get any of thatoccurring in myeloid conditions
or is it all purely in the bonemarrow?
Dr Joanna Czerwinski (07:29):
So when the bone marrow is dysfunctional
and either doesn't have thecapacity 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 inthe myeloproliferative
conditions, you end up gettingextra medullary creation of
these cells, and this ispredominantly in the spleen.
(07:50):
So you can certainly getsplenomegaly in these cases, and
in the vast majority of themyeloproliferative cases it's in
myelofibrosis, Because in thatcondition your bone marrow ends
up being like one big scartissue where there's no capacity
for cell generation.
Dr Gavin Nimon (08:07):
I understand.
Also you can sometimes presentwith shortness of breath.
Now, is that from PEs or isthat from the actual cells
developing and occurring in thelungs?
Dr Joanna Czerwinski (08:16):
So it's in three parts, depending on the
condition.
So if they're anemic then theshortness of breath can be
attributed to anemia.
If they have something like aVTE, a PEE event, then they
certainly can have shortness ofbreath from that standpoint.
But the chronic myeloidleukemias and conditions where
the granulocytes can be quiteelevated you get this sometimes
(08:40):
in the acute myeloid leukemiasas well, where the total white
cell count is over 100 and whatcan happen in the lungs is that
you have a whole host ofneutrophils around the lung
tissues and their granularproducts.
So things like histamine andother cytokines they can release
(09:04):
in the lung area and it canpresent like an acute pulmonary
edema situation.
Dr Gavin Nimon (09:10):
Or it could also probably look a little bit like
asthma, could it in thatscenario?
Dr Joanna Czerwinski (09:13):
Yeah, it can.
And when we go into acutepromyelocytic leukemia, I'll
also talk about differentiationsyndrome, which can present like
an acute pulmonary edema aswell.
Dr Gavin Nimon (09:25):
I understand also you can get acute pulmonary
edema as well.
I understand also you can getsome skin itchiness as well.
Is that from the same sort ofprocess as you get occurring in
the lungs, or is it a differentsort of pathway?
Dr Joanna Czerwinski (09:32):
It's a similar pathway.
It's due to cytokine releaseand sometimes it can be due to
the thickness of the blood aswell.
So you often get, in particularin polycythemia vera, you can
get itchiness, you can get aredness discoloration of the
(09:53):
face.
Dr Gavin Nimon (09:53):
People look often quite flushed and they can
get quite sweaty as well.
Okay, so obviously the namepolycythemia vera makes you
think of redness.
Is that not just purely becauseof the actual cells affected,
but it's actually the appearanceof the person is it?
Dr Joanna Czerwinski (10:01):
Yes, it is Quite plethoric.
Dr Gavin Nimon (10:04):
So the vast majority of cases.
You see, though I think I saidpreviously when we're talking
about lymphoid malignancies.
They were incidental on bloodtests.
Is that still?
Dr Joanna Czerwinski (10:14):
the same case with myeloid conditions as
well.
So in the myelodysplasticsyndromes most of these occur
above the age of 65, 70, andit's usually on routine blood
tests that are done for otherreasons and you might only get
hints of this conditiondeveloping like they may have an
anemia of 120 for a male, whichis still anemic but is very
(10:36):
mild, and the only real symptomthat they may have is fatigue
and in some ways it can be hardto say you know a 75-year-old
that is otherwise fit that thiscondition is causing a lot of
their fatigue.
In the myeloproliferativeneoplasms there's some of my
patients where it's identifiedbecause they are again fatigued
(10:58):
for different reasons or theyhave developed a VTE event.
But we do see some of them comein with hemoglobins of 170, 180
, and you can't determinewhether that figure on its own
is the polycythemia vera thatcomes from the bone marrow or
whether it's secondary todiuretics, dehydration, chronic
(11:21):
airways diseases, sleep apnea.
Dr Gavin Nimon (11:23):
Okay, Of the particular different
classifications.
Obviously you talked aboutacute versus the chronic
episodes.
How does the acute presentationvary to a chronic presentation?
Dr Joanna Czerwinski (11:34):
The way that it presents is often florid
in emergency department and itusually only has a prodromal
illness of maybe one to twomonths at most.
So one of my cases that I'd hadhad been having back-to-back
viral infections or sinusinfections for a period of seven
weeks before he presented tohis GP and at that point he had
(11:58):
a white cell count of over 100.
So he was called in from SAPathology.
He was called in to present toemergency department and get
quickly worked up and he endedup having an acute myeloid
leukemia and the clue was thathe was getting recurrent
infections and not getting overthem.
Dr Gavin Nimon (12:17):
Right and a chronic one is more just, purely
a slow, insidious sort ofpresentation which is picked up
more on blood tests.
Dr Joanna Czerwinski (12:24):
Yeah, so most often it's anemia that's
been there for say 12, 18 monthsfor the myelodysplastic ones or
the myelofibrosis cases andconversely, on the other,
myeloproliferative neoplasmslike the polycythemia vera and
essential thrombocythemia.
Again it will be mildly abovethe mark but chronic, and the GP
(12:46):
has done a few different testsand can still not figure out why
this is.
Platelets of 500 to 600,hemoglobin of 170 to 180.
In those sort of mildcategories where you could
attribute it to they were a bitdehydrated or they've recently
had an infection you couldattribute it to they were a bit
dehydrated or they've recentlyhad an infection.
Dr Gavin Nimon (13:07):
So we've got these patients presenting with
some vague symptoms and they'repicked up on an abnormal blood
test.
Once the abnormal blood test isstandard, I presume complete
blood examination is performed.
What other investigations arerequired?
Are they the same as lymphoidtype conditions or are there
anything specific you'd do?
Let's just go through them allagain, just to remind me as well
.
Dr Joanna Czerwinski (13:25):
Yeah, absolutely so.
A complete blood examinationwith a blood film is a key,
particularly for themyelodysplastic syndromes and
the acute leukemias, becausethat's going to be pretty
diagnostic quite early on ifthey have these conditions, and
particularly the acute myeloidleukemia.
If you have a blood test atnine in the morning, it gets
(13:45):
sent through to SA Pathology.
You've got someone looking atit a few hours later and
bringing a patient into hospitallater that afternoon.
So it's quite a rapidturnaround for the acute
leukemia.
For the myelodysplasticsyndrome, there might be the
appearance of dysplasticneutrophils, for instance, and
that will be the first clue tothe diagnosis.
So blood film is definitelyessential For both the
(14:09):
myelodysplastic syndromes andthe acute leukemias.
I do flow cytometry becausethat helps to determine what the
blasts are.
Are they myeloid origin or arethey lymphoid origin?
Now, if we're going down theacute leukemia pathway, that is
usually managed in hospital andinvestigated in hospital.
(14:29):
But the things that we want toknow is what is their kidneys
doing, what is their liver doingand what is their cardiac
health like?
Because those three thingsdetermine their ability to
tolerate intensive chemotherapy.
For the myelodysplasticsyndromes it is helpful to have
creatinine and is helpful tohave liver function tests
(14:51):
predominantly because the maintreatments involve the kidney in
the filtration system.
So we need to have adequaterenal function to be able to
deliver treatments.
For the myeloproliferativeneoplasms, the renal function
and the liver function are lessrequired in terms of being able
to deliver treatments, but it isstill a good thing to help with
(15:13):
your differentials as to whatmay be causing, for instance,
your polycythemia vera.
If you've got an appearance ofdehydrated kidneys, then it
might be due to diuretic effect,as an example.
So the other tests that havebecome more recently available
that a hematologist could orderincludes the karyotyping or the
cytogenetics, and that's usuallydone on a bone marrow biopsy
(15:37):
specimen.
And they may also do a geneticpanel looking at molecular
mutations and again, that'spredominantly done on the bone
marrow.
Having said that, in some of myolder frail patients where I
don't think I'll be able toadequately give them treatment,
I can do the same genetic panelfrom their peripheral blood as a
(15:57):
bit of a prognostic indicatoras to how long I've got with the
patient and what else I can doto improve their quality of life
.
So certainly, the acuteleukemics, we all do bone
marrows.
On the myelodysplastic syndromeyou need to have a bone marrow
to access treatment.
If you're going down atreatment pathway and for most
(16:18):
of the myeloproliferativeneoplasms it's good to have bone
marrow, but not essential.
The only essential ones thatyou need is myelofibrosis,
because, again, treatment isreliant on that diagnosis being
confirmed, and the chronicmyeloid leukemia because it is a
way that you can monitoreffectiveness of treatment over
time.
(16:38):
But the majority, like thepolycythemia vera and the
essential thrombocythemia, it'sgood to have at diagnosis but
not essential to begin treatment.
Dr Gavin Nimon (16:48):
Excellent.
Are there other tests you mightdo as well, like apart from the
bone marrow or the bloodpicture?
Are there things like CTs orultrasounds that are also
required?
Dr Joanna Czerwinski (16:57):
So a good clinical examination for
splenomegaly is important forthe myeloproliferative neoplasms
and in clinical trials theywill always use splenic size to
determine how people areresponding, particularly for
myelofibrosis.
So a lot of people have a CTscan or an ultrasound at
baseline and then seriallyperformed to track response.
(17:19):
But if you can feel the spleenat the beginning and you can
measure, you know, for myfingers something starts out as
four finger breaths and goesdown to two finger breaths.
I know that they're respondingto treatment and I don't need
radiology to tell me that.
So it's not required to have aCT scan.
If they're going to haveintensive induction chemotherapy
(17:41):
for the acute leukemia we oftenget a CT sinuses because
they're at a lot of risk ofsinus infection and particularly
invasive fungal.
So we may sometimes in hospitalalso do a chest CT as part of
that.
Dr Gavin Nimon (17:56):
Right.
So that's really the fullworkup.
Then you can actually do fairlystraightforward investigations.
Then with the bone marrowbiopsy and a few other
investigations you can get thebaseline of what you really need
.
Dr Joanna Czerwinski (18:08):
Absolutely .
Dr Gavin Nimon (18:09):
How do you progress from there then?
What's the next step, Onceyou've got your biopsies and
you've got your blood picture?
Dr Joanna Czerwinski (18:20):
you've done your examination, what's
the next step?
So I guess if we're lookingdown the pathway of treatment, I
need to get the infectiousserologies ticked off, like your
hepatitis B, c and HIV, and forthe acute leukemias it's
helpful to have a uric acid fortumericis response, particularly
because the myeloid cells aregenerally bigger than lymphoid
and when these guys break apartand burst they do release toxic
(18:45):
products similar to the lymphoidcells.
So we still need to think abouttumor lysis syndrome in the
acute leukemia status.
With the chronic conditions,again, if I'm embarking on
treatment I want to know theirinfectious serology.
And then it's determining theirage and fitness and putting in
the different characteristicsinto like a prognostic scoring
(19:08):
system to determine whattreatment is best.
And this can be different forwhether they're young or old,
whether they have transfusiondependency or not and whether
they've had a VTE event or notwhen we're talking about the
chronic one.
Dr Gavin Nimon (19:23):
I might just stop you there for two seconds
and just ask you, because you'vejust raised some great thoughts
that I didn't know about.
So tumor lysis syndrome is that?
I presume that you can get goutfrom that because of the
release of uric acid.
What else does it involve?
Dr Joanna Czerwinski (19:37):
So tumor lysis syndrome.
I like to think of the acronymof CUP C-U-P-P, where your
calcium goes down by 25% frombaseline, your uric acid goes up
by 25%, your potassium goes upby 25% and your phosphate goes
up by 25%.
So these are the early markersof tumericis and it's what we
(20:02):
generally monitor twice to threetimes a day in an inpatient
setting.
When it's quite deteriorated itwill involve the kidneys and
you will see renal failure andyou will also see complications
such as acute pulmonary edemawhen the tumor lysis syndrome
further progresses.
So having those blood teststwice to three times a day
(20:24):
during the early inpatient stayduring their initial course of
treatment, that's where you'regoing to be able to pick it up
early and give them treatmentsto reduce their uric acid and
reduce those toxins.
So most patients get commencedon allopurinol and it's 300
milligrams a day and theycontinue it for the first seven
days of intensive inductiontreatment.
Dr Gavin Nimon (20:45):
Why is it important to know about the
infection status, the hep B, Cand HIV.
Why is that important?
Dr Joanna Czerwinski (20:50):
Because they become so heavily
immunocompromised with theirtreatments.
You want to detect whetherthey've got a chronic hepatitis
that you can treatsimultaneously or just prior to
initiating your inductiontreatment, and the prophylaxis
may also change.
So, for instance, if you have aHIV patient, you want to be
putting them on antiretroviralsand you want to make sure that
(21:13):
they don't interact with yourtreatment plans.
Dr Gavin Nimon (21:17):
So, jo, moving back on to talking about the
treatment plan, once you've doneyour standard workup looking
for infections and also checkingfor tuberculosis syndrome and
being prepared for it, what'sthe next steps?
How do you progress withtreatment following that?
Dr Joanna Czerwinski (21:31):
If we focus initially on the acute
leukemias, if they have a stockstandard acute myeloid leukemia
the first things that we want todo is bring down their white
cell count.
If it's elevated down to lessthan 25 so that we can start
induction chemotherapy, and thisis to try and reduce that risk
of tumerosis as well as to tryand reduce the risk of any acute
(21:55):
pulmonary edema or any othercomplications from things like
differentiation syndrome or,again, the tumerosis effect.
So what treatment is determinedis based on patient age and
fitness.
So if they're an under 70 yearold, we're usually offering
intensive induction therapy,which is what we colloquially
(22:17):
call 7 plus 3, which involvesseven days of citarabine and
three days of dawnerubicin orother anthracycline chemotherapy
.
So the way that this isdelivered is simultaneous seven
and three, so it's a total ofseven days duration of
chemotherapy.
But because this is such anintensive chemotherapy and aims
(22:39):
to clear out everything from thebone marrow and start from
scratch, it does take about twoto three weeks for recovery from
this kind of intensity of chemo, and so most patients will be
admitted for the entire monthduring their induction therapy
and they will have to workthrough any complications, most
commonly infections, after theseventh to tenth day and upon
(23:03):
recovery of their blood countsat day 25 plus, they're usually
scheduled for another bonemarrow to see how well that job
was done in clearing out theirleukemia.
And if they have achieved aremission so less than 5% blasts
in their bone marrow then theygo on to consolidation therapy
and then the following stepsafter that is dependent on what
(23:27):
risk category of leukemia theyhave.
So if they have a high riskleukemia where they've got
multiple mutations or very badmutations, these patients will
generally try and get onto theallogeneic stem cell transplant
pathway.
And most of the time we don'tcap it by age.
But generally speaking thereare not many 75-year-olds that
(23:52):
would be able to tolerate thatkind of treatment.
Broadly speaking, somewherebetween 70 and 75, with their
fitness level and theircomorbidity index.
That will determine who getsallowed to go to an allogeneic
transplant.
And that process involvesusually high doses of
chemotherapy to completely wipeout the bone marrow.
(24:13):
And then you have a replacementbone 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 (24:27):
With transplants in the myeloid conditions, do
you have to go on long-termimmunosuppression for the use of
them, like you do with kidneytransplants?
Dr Joanna Czerwinski (24:35):
So I like to think of allogeneic
transplants as the onlycircumstance where you are
usually not on long-termimmunosuppression.
You are certainly onimmunosuppression for the first
100 days, and it's usuallythings like cyclosporine,
tacrolimus, the usualanti-rejection medications, and
then after day 100, when thatrisk of acute graft versus host
(24:58):
disease has subsided.
That's when, if things aregoing well, they generally start
to taper it down over thesubsequent three months, so
usually by six months.
If it's gone all well, patientsare usually able to come off of
their anti-rejection meds andtheir new bone marrow and their
new blood type is completelyingrained into their own bone
(25:19):
marrow space.
Dr Gavin Nimon (25:20):
Does that mean that's really interesting?
Does that mean like you mightstart off as an A negative and
become back as a B positive?
Dr Joanna Czerwinski (25:26):
Absolutely .
That's what exactly that means.
That's crazy.
There's obviously a lot ofhigh-tech involvement with
regards to that because, if youcan imagine, we talk about
transfusion reactions beingincompatible blood and we're
talking about incompatible bonemarrow sources of blood.
Dr Gavin Nimon (25:46):
Wow, that's amazing.
Okay, all right.
Well, it's one of the mostinteresting 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 patientsover 70 or 75?
In the acute stage, they'reunfortunately not going to
(26:06):
tolerate the treatment very well.
Dr Joanna Czerwinski (26:08):
So a few years ago there became available
this protocol calledazacitidine and venetoclax.
Now azacitidine I'll speakabout again later because it's
involved in myelodysplasticsyndromes, but it's a
hypermethylating chemotherapyagent that is given as a
subcutaneous injection for sevendays every cycle, and each
(26:31):
cycle is usually 28 days, andthis is paired with a BCL-2
inhibitor, so an anti-apoptoticmarker, and that is a tablet
therapy that is takencontinuously.
And even I think my oldestpatient is in their mid-80s and
is tolerating that treatmentprotocol.
So again you would go throughthis induction treatment where
(26:53):
you're very quickly ramping upto the maximum dose of
venetoclax and you're alsosimultaneously giving the
azacitidine and it's a standardtreatment course for everyone
for cycle one.
At the end of cycle one you do arepeat bone marrow and again
you're seeing how much of cycleone.
You do a repeat bone marrow andagain you're seeing how much of
the leukemia you've cleared out.
Now in most cases the leukemiahas been cleared in that first
(27:16):
cycle.
Some additional people need asecond cycle of similar
intensity and then, once youhave cleared out the leukemia,
then you can adjust the dosesfor better tolerability, because
most of the time it is anoutpatient protocol, it is not
needing to remain in because itis that gentler level.
I've used this protocol alsofor people that are Jehovah's
(27:40):
Witnesses and are not acceptingof blood transfusions, because
the former the 7 plus 3, renderseveryone in need of transfusion
, whereas this provides anoption for if transfusions are
not in that person's religionand also is much more tolerable
for the older or frailer person.
Dr Gavin Nimon (27:58):
So this is more like a long-term suppressive
type of treatment as opposed toa trying or a curative type
treatment.
Dr Joanna Czerwinski (28:04):
Absolutely the longest person that I think
has been on that combinationhas been more than 15, 18 months
.
So it is something thattreatment protocol for 12 months
and they've cleared the bonemarrow of the leukemia and
(28:27):
they're in a complete molecularremission where you can't detect
their genetics from theirpresentation.
Whether those patients canactually safely come off of
treatment and have a drugholiday.
Dr Gavin Nimon (28:38):
We've got obviously using suppressive
agents or chemotherapy agents.
Are there any other types ofagents you might use?
Dr Joanna Czerwinski (28:44):
Something that we'll again be talking
about, mostly with themyeloproliferative neoplasms.
But we do use hydroxyurea orhydroxycarbamide as a tablet
treatment to cytoreduce or tobring down all of their cell
counts.
So it is a very old-fashioned,very indiscriminatory
chemotherapy agent and it'stablets, and it will bring down
(29:08):
not only the white cells thatyou're trying to bring down, but
it will also render them anemicand thrombocytopenic.
So you can only realisticallydo that for a few days, but
that's all you're trying toachieve is a much more tolerated
white cell count, so that thenyou can initiate the effective
treatment.
Dr Gavin Nimon (29:25):
And this is purely for the acute myeloid
leukemia, like promyelocyticleukemias.
So that's purely the white celltype leukemias Do you get.
I'm a little bit confused here.
For a second, can you get acuteleukemias involving red cells
or platelets as well, or is itpurely white cells?
I'm not making it too hard formyself here.
Dr Joanna Czerwinski (29:46):
It is only with the granular sites, so it
is predominantly the neutrophilsgone bad essentially.
So we are dealing with themyeloid precursors, but the
white cell versions there.
Technically is an acuteproerythroid leukemia very rare.
You only hear case studiesabout it.
(30:07):
But they are nucleolated redcells that you see in the bone
marrow and it has undergonemultiple reclassifications so
it's now more thought about asan acute myeloid leukemia with a
predominance of those red cellprecursors.
And there is an acutemegakaryoblastic leukemia and
(30:28):
again it's very rare.
It's very bad news if it occursin an adult and the prognosis
is better if it's in a childwith Down syndrome, where
there's an increased number ofcases in that particular cohort
of children with Down syndrome.
Dr Gavin Nimon (30:45):
Okay, so the red cell condition, the platelet
conditions, are really more onthe myelodysplastic or the
chronic conditions that we'retalking about then.
Dr Joanna Czerwinski (30:52):
Absolutely .
Dr Gavin Nimon (30:53):
Is there anything else that you'd want to
say about the acute conditionsbefore moving on to the chronic
conditions, then?
Dr Joanna Czerwinski (30:57):
I guess the acute promyelocytic leukemia
does not get treated the sameway as the acute myeloid does so
with the acute promyelocyticleukemia does not get treated
the same way as the acutemyeloid does so with the acute
promyelocytic leukemia.
It's treated with a combinationof all transretinoic acid or
ATRA, and combined with arsenic.
And it is because of theparticular translocation of the
(31:17):
genetic proteins in thatparticular leukemia and it was
discovered more than 10 yearsago that this combination of the
ATRA and the arsenic canactually break apart that fusion
protein and cause those blastcells or those promyelocytic
cells, the leukemia cells, todifferentiate into proper
(31:39):
neutrophils at the end stages.
And it is a highly curativecondition, highly curative
treatment and most patients gothrough it and the survival is
something like 95% long termwithout relapse.
Dr Gavin Nimon (31:55):
Wow.
Dr Joanna Czerwinski (31:56):
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 neutrophilsoccurs very instantaneously and
degranulates all their cytokinesand causes that acute pulmonary
edema syndrome.
(32:16):
The other thing that can happen, of course, is DIC, which is
disseminated intravascularcoagulopathy.
So whenever we see an acuteleukemia present into emergency
department we're always askingfor the extended coagulation
parameters to include thefibrinogen and the D-dimer and
you would see DIC if thefibrinogen is quite low, so less
(32:40):
than 1.5, and the D-dimer isabove 30,.
We're much more different thanyour VTEs where your D-dimer is
1.
Dr Gavin Nimon (32:48):
Right, yes, how many of these sort of cases
would you treat each year?
Dr Joanna Czerwinski (32:52):
So the acute promyelocytic leukemia is
less common, so we probably geta handful each.
Thinking back over the last fewmonths we probably had two or
three in the last three-ishmonths Whereas the acute myeloid
leukemia in adults is much morecommon than lymphoblastic
leukemia, and particularly nowthat we've got an older
(33:12):
population, we're picking thesethings up.
We now have treatmentsavailable for the older patient.
We're seeing maybe one everyweek or two.
Dr Gavin Nimon (33:22):
We talked about the causes.
We talked about justdegeneration or age-related
changes to the cells, but alsotalked about radiation exposure
and medications.
Is there a greater percentageof one over the other for causes
?
Dr Joanna Czerwinski (33:33):
So certainly most of them is due to
aging and bad luck.
You can get acute myeloidleukemia even as a teenager and
I've had very few cases ofpediatrics that we've seen
through the laboratory, butcertainly we have had
18-year-olds, we've had20-year-olds with acute myeloid
(33:53):
leukemia.
The ones where they've occurredpost-chemotherapy or other
treatments generally, areassociated with more high-risk
features because they've alreadyhad their DNA damaged from the
other treatment and they're nowcoming in with high-risk
features.
So those patients are very,very likely to go to an
allogeneic transplant unlessthey're unfit for one.
Dr Gavin Nimon (34:17):
Because that'd be like a field change.
I presume the whole, all thecells are being damaged along
the way.
Dr Joanna Czerwinski (34:22):
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 fromprostate cancer, but I have seen
a few after breast cancertreatments with chemotherapy, as
an example.
Dr Gavin Nimon (34:40):
If we move on to the chronic type conditions,
then you've divided those upinto the dysplastic syndromes,
often as being pre-malignantconditions.
Is there a particular type ofclassification of those
particular syndromes?
Dr Joanna Czerwinski (34:51):
Yeah, so it used to be that the
myelodysplastic syndromes wouldbe divided up into appearances
and the bone marrow technicalcomments of you know is it a
high blast count?
Is it a low blast count?
How many of the red cell, whitecell and platelet lineages are
affected?
So is it a multi-lineagedysplasia or a single lineage
(35:13):
dysplasia?
And there are certain mutationsthat it used to be classified
by as well.
So a deletion 5q would be inthe old classification systems.
These days it's excess blastsor not, multi-lineage or single
lineage, and sometimes therewill be key other features as
well.
So they might be defined bytheir molecular abnormalities or
(35:35):
their genetic abnormalities aswell.
But by and large most of themyelodysplastic syndromes that
come in to see me are what Iwould deem as low risk.
They're very mild.
They're, incidentally, pickedup over serial blood tests.
And you go and do a bone marrowand you find maybe they have
(35:55):
single lineage myelodysplasia.
Very low blast counts, lowblast counts.
And when you pop in those kindof numbers into the prognostic
scoring system we'll tell youthat their low risk and their
average overall survival is 10years, meaning that in a
population where you'repredominantly seeing
70-year-olds their averagesurvival is going to be another
(36:16):
10 years For the moreintermediate to high risk.
Those patients usually havestarted having blasts in their
blood tests, so you canimmediately tell that you're
dealing with a more aggressivecase and they're often needing
blood transfusions much earlier.
So those are the patients thatI would try and encourage them
(36:38):
to get a bone marrow sooner,because that will affect how I'm
going to treat them and when Ithink about the four different
types of treatment for yourmyelodysplastic syndrome.
The earliest is the watch andwait, where you're monitoring
their bloods every two or threemonths and you're looking for
changes over time.
And when you do see thosechanges, that's when you would
(36:59):
do a bone marrow to see what hasmolecularly changed or what's
changed under their bone marrow.
The next is supportivetreatments.
So these are things like bloodtransfusions, antibiotics,
vaccinations and in some casesyou can even get things like E2
bring up the hemoglobin.
Obviously that's not on the PBS.
(37:19):
The next third treatment isstandard chemotherapy and that
is indicated for yourintermediate to high-risk
players and it's to try andprevent the myelodysplastic
syndrome from progressing intoacute myeloid leukemia, because
there is a percentage chance andit's in those same prognostic
(37:39):
scores that I was talking abouta few minutes ago.
There is a chance that it willconvert over to acute leukemia
and you want to capture thembefore they make that transition
so that you can offer themchemotherapy.
And the chemotherapy is againthat same azacitidine that I
spoke about earlier incombination with the venetoclax.
(38:00):
But you are using justazacitidine by itself for the
myelodysplastic syndromes.
And then the fourth and finaltreatment is usually reserved
for, again, those really youngplayers.
But if you've developedmyelodysplastic syndrome and
you're under 50, you probablyhave genetics that are poor risk
(38:21):
and you probably want to bethinking about a transplant
early in the piece.
Dr Gavin Nimon (38:26):
So obviously the supportive treatments.
We're talking about using bloodtransfusions.
That's why it's so important tobe donating blood and giving
products for people who areundergoing this sort of
treatment.
And I presume they divide thosecells up into whether red cells
, platelets or neutrophils.
Is that correct when they givetransfusions?
In that scenario?
And if they're in a singlelineage, they just need one or
the other.
Dr Joanna Czerwinski (38:46):
Kind of mostly correct.
So when someone goes and donatesblood they generally donate
whole blood and that is split upinto its components of red
cells, platelets and plasma andthe plasma contains all the
different proteins.
But generally we don't transfusegranulocytes because that would
run the risk and it's a veryhefty risk of graft-versus-host
(39:10):
disease where the donor'sgranulocytes are attacking the
host.
There are very rarecircumstances where that's done
and it's usually in a plasticanemia, which is a non-malignant
condition.
But you're certainly right thatif a myelodysplastic patient
predominantly plastic anemia,which is a non-malignant
condition, but you're certainlyright that if a myelodysplastic
patient predominantly has anemia, they're predominantly going to
be transfused just red cellsand in the chronic transfused
(39:33):
patient cohort they might bebooked in for an outpatient
transfusion every two or threeweeks and it might be two units
at a time.
So when patients are beingtransfused for these chronic
myelodysplastic syndromeconditions we're also thinking
about their iron overloadbecause that comes with those
transfusions and there are ironchelators on the PBS which are
(39:58):
available to those patients.
So there is a requirement for acertain amount of transfusion
every two months and a certainlevel of anemia and a certain
level of ferritin before you cancommence one of these
treatments, and the treatment isonly advantageous if the
problem is more than two years,because it takes a very long
(40:19):
time to chelate the blood fromthat iron.
Dr Gavin Nimon (40:22):
I presume so you're trying to prevent
secondary hemochromatosis.
Then in that scenario, In thatscenario.
Dr Joanna Czerwinski (40:27):
Yes, you're trying to prevent other
organ damage from their ironload.
Dr Gavin Nimon (40:31):
Right.
Okay, there are other differenttypes of treatments.
I remember hearing about doingsplenectomies for ITP and things
like that.
Is that done in this sort ofconditions as well?
Dr Joanna Czerwinski (40:40):
It's generally reserved for the
myelofibrosis cases where thespleen can get quite big, and
some palliative measures caninclude splenic radiation as a
treatment option.
But these are usually whenyou've tried every other therapy
and the spleen is still hugeand still causing a lot of drama
.
Dr Gavin Nimon (40:59):
So okay.
So these are the main types oftreatments you use for the
chronic myelodysplasticconditions, and that's the sort
of intermediate sort of chronicconditions we're talking about.
Then you've got these chronicmyeloproliferative disorders,
which is really the next stage.
Dr Joanna Czerwinski (41:13):
Yeah.
So I think about themyeloproliferative neoplasms as
a condition where the gas pedalis fully firm to the floor and
we're overproducing too manycells.
So if we take polycythemia asthe best example, most of those
cases again we can see,incidentally, on routine blood
(41:33):
tests.
We can see it in thecircumstances of VTE and we can
see them in circumstances ofthey come to their GP
complaining of fatigue anditchiness and they're red in the
face, they're quite sweaty andin these conditions, whenever a
polycythemic patient comes to me, I try and establish a few
things quite quickly.
(41:54):
I try and establish thechronicity of how long this has
been over.
I try and see do they have anyrespiratory or cardiac issues
that might be causing them toneed more red cells and need
more oxygen, because that's thepolycythemic drive?
And I try and establish arethey on any diuretics or having
(42:14):
multiple coffees a day with notenough water intake?
And if I can't find anythingobvious then I'm sticking them
on aspirin, unless they've gotanticoagulants for other reasons
.
And the reason behind it isthat aspirin prevents a lot of
the complications ofpolycythemia vera when it comes
to thromboses, because thethromboses are mostly VTE, but
(42:37):
they can have arterial eventslike MI and stroke as well.
So I will put them on aspirinuntil I've seen their genetic
result.
And polycythemia is associatedwith two mutations both in the
JAK2 gene, and 95% of thepolycythemics will have one or
the other mutation.
And that mutation study takesabout three weeks to get results
(43:00):
.
So if I'm on the phone with aGP and they're telling me about
a polycythemic case, I will saystick on aspirin, send them
through to us, we'll do thegenetic testing and then we'll
talk to the patient about whatwe found.
So then again, it's a bitdetermined by age as to what
kind of treatment and whetherthey're of childbearing age in
(43:21):
particular.
So if I've got a young patientunder the age of 50 and they're
interested in having more family, then I would do venesections
and my aim is to get theirhematocrit down to normal, so
the hemoglobin will come down.
If I'm focusing on getting thathematocrit to the correct
values In females it's less than45% and in males I'm targeting
(43:43):
48% those venous sections mighthave to be quite frequent
initially, so maybe weekly orfortnightly.
But as you're getting furthercontrol you can spread those
venous sections further andfurther apart.
One of the ways that I can tellif a patient has polycythemia,
even before I've begun venoussections is what their iron
levels are doing, becausepolycythemia even before I've
begun venesections is what theiriron levels are doing.
(44:04):
Because polycythemia, the pedalon the gas will only be limited
by how much iron fuel you'regiving those red cells.
So by venesecting them it's notactually removing the red cells
, that's part of the process,but you're actually trying to
limit how much iron those redcells have in reserve to further
procreate.
(44:25):
So I would often try and getthem to as low a ferritin as
they can tolerate.
Sometimes that means a ferritinof 20.
So technically they're irondeficient by that point.
So long as they can manage withthe symptoms of that mild iron
deficiency by offsetting theirpolycythemia vera, then that
(44:45):
determines their venesectionfrequency.
So it's a bit of a balance.
The other type of treatment thatcan be available for young
persons is pegylated interferon,which is a weekly subcutaneous
injection.
But we don't like to do that forcurrently pregnant female.
We like to do that as a lead-inprior to pregnancy planning and
(45:06):
they may need to be on it for ayear or two to get their numbers
under adequate control and thenwe can have that luxury of
allowing them the nine to 12months of trying to fall
pregnant and then being pregnant.
The treatment for the olderpatient involves hydrea, which
we mentioned before as acytoreducing agent.
Now, the main risks of hydreais that it gives you a risk of
(45:31):
skin cancers.
So I usually have all of mypatients checked over quite
thoroughly before initiatingthat treatment and then regular,
at least annual, checksthereafter, and it causes wounds
to heal quite poorly.
Since a diabetic withpolycythemia and their diabetes
is out of control, I'm notlikely to initiate that
treatment straight away becauseI might be doing more harm than
(45:53):
good.
Diabetic ulcers are never goingto heal properly.
So those are broadly the threetreatments that we've got
available.
So the venous sections, theinterferon, the hydroxyurea and
then the aspirin or theanticoagulation as a
preventative of thromboembolicevents.
Dr Gavin Nimon (46:10):
All right, so that's polycythemia.
How do the other conditionsvary compared to the
polycythemia?
Dr Joanna Czerwinski (46:15):
So essential thrombocythemia is a
bit harder to treat becausevenous sections don't work as
well for them, so it's usuallyjust isolated platelet count
that's elevated.
So in the very extreme ET caseswhere the platelets are greater
than 1000, there is plateletphoresis, which is done in
hospital where when people go todonate blood they can sometimes
(46:38):
go and donate just platelets orjust plasma and they get placed
onto this machine which lookslike a big dialysis or
centrifuge machine where theyhave blood pulled into a machine
.
It's spun around so they'reseparated by different weights
of cells and then you can removethe platelet level of the
(46:59):
different weights beingseparated.
And that's the same processthat happens for platelet
phoresis, where you're justremoving the platelet layer from
that centrifuge and that's totry and rapidly bring down
platelet levels to preventbleeding and bruising and
clotting complications.
But you can't obviously go inand have that treatment
(47:19):
indefinitely and so mostpatients with ET get put on
hydroxyurea.
Dr Gavin Nimon (47:25):
Okay, and then moving on to the myelofibrosis
stuff, that's just where.
It's just worn out.
Dr Joanna Czerwinski (47:30):
Yeah.
Dr Gavin Nimon (47:30):
So is there any particular treatment for that?
I presume you're just gettingan allogeneic transplant for
those sort of conditions, areyou, or how is that one treated?
Dr Joanna Czerwinski (47:36):
So for the young patients certainly
allogeneic transplant is anoption for really severe
myelofibrosis where they've gotsplenomegaly or symptoms of
fatigue, tiredness, shortness ofbreath, itch.
Those patients I encourage themto have a bone marrow to
confirm the diagnosis becausethen they can access ruxolitinib
(47:58):
, which is a tablet therapy onthe PBS.
It's a form of a JAK inhibitorand it has improved quality of
life scores in the trials thatwere done with it.
So it improves spleen size andas a result it improves the
cytopenias.
It also improves those symptomsof the itch, postprandial
fullness, the fatigue.
Dr Gavin Nimon (48:20):
Okay, that brings us down to the last type
of condition, themyelodysplastic slash
myeloprolutative overlapsyndromes.
Is it really a combination ofwhat we've already talked about,
or are these separate all againas well?
Dr Joanna Czerwinski (48:31):
They're a combination of what we talked
about.
Most patients I treat verysimilar to the myelodysplastic
syndrome.
You've got the watch and waitapproach, the supportive care
approach.
The active treatment approachcan be azacitidine if they're
looking more like amyelodysplastic patient, or it
could be hydrea if it's aproliferative.
(48:53):
Look to it and then allogeneictransplant is an option for
those younger patients, butgenerally the
myelodysplasticastic,myeloproliferative overlap
syndromes are above the age of70.
Dr Gavin Nimon (49:05):
Well, that's a fair bit to go through.
Is there anything you'd like tosay to wrap up with that whole
sort of process?
Is there anything that comes tomind?
There's a lot we've gonethrough already so far tonight.
Dr Joanna Czerwinski (49:14):
Well, I guess, out of all the cases that
we've discussed today, I guessthe thing that I would inform
GPs is, if you've got a mildanemia, a mild thrombocytopenia,
a mild elevated hemoglobin,elevated platelet count, is to
monitor that over time, becauseif it's at the very mild stages,
(49:35):
most of the cases can bemonitored.
But if you've got a mildproliferative neoplasm, you want
to know is it because of theirbone marrow or is it a secondary
event?
And in most cases, thankfullyin this day and age, most of the
treatments are oral, andparticularly when it comes to
the chronic conditions.
Dr Gavin Nimon (49:55):
Where do you think the future holds for
hematologists in these two areas?
What's the next steps?
What do you want to see downthe track?
Dr Joanna Czerwinski (50:02):
Well, I guess a lot of the particularly
the chronic conditions in thisspace are diagnosed at much
older ages and we'repredominantly doing treatment to
prolong survival and improvequality of life, but there's
nothing that realisticallyprolongs it by years and years
and that's the hardest thing totalk to patients about.
(50:23):
But if there are treatmentsthat are in clinical trials to
try and extend thatsurvivability even further,
because I'm seeing patients thathave just hit retirement go to
their GP for the first time andthen they're landed with this
sort of a diagnosis because theprevious 10 years they were busy
working, doing other things,not necessarily seeing their GP
(50:45):
at that point.
Dr Gavin Nimon (50:47):
It must be very hard in that scenario.
Thank you very much, Jo, forcoming on Aussie Med Ed and
explaining these conditions forus.
I really appreciate your time.
Dr Joanna Czerwinski (50:54):
You're welcome.
Dr Gavin Nimon (50:55):
It's really interesting to learn about it
and I've learned some of themost amazing facts tonight.
So thank you very much.
Dr Joanna Czerwinski (51:00):
You're very welcome.
Thanks for having me again, meagain, thank you, thanks, joe.
Dr Gavin Nimon (51:03):
Thanks again for listening to the podcast and
please subscribe to the podcastfor the next episode.
Until then, please stay safe.
Did you know that conditions like
myelodysplastic syndrome,myeloproliferative neoplasms and
acute myeloid leukemia affectthousands of people each year,
often with vague symptoms likefatigue, infections or
unexplained bruising?
These myelodysplasticconditions not only pose
diagnostic challenges, but alsohave significant implications
for treatment and prognosis.
Understanding them is crucialfor any clinician aiming to
(00:21):
provide timely and effectivecare.
G'day and welcome to Aussie MedEd, the Australian medical
education podcast designed witha pragmatic approach to medical
conditions by interviewingspecialists in the medical field
.
I'm Gavin Nimon, an orthopaedicsurgeon based in Adelaide, and
I'm broadcasting from Kaurnaland.
I'd like to remind you thatthis podcast is available on all
podcast players and is alsoavailable as a video version on
(00:43):
YouTube.
I'd also like to remind youthat if you enjoy this podcast,
please subscribe or leave areview or give us a thumbs up,
as I really appreciate thesupport and it helps the channel
grow.
I'd like to start the podcastby acknowledging the traditional
owners of the land on whichthis podcast is produced, the
Kaurna people, and pay myrespects to the elders, both
past, present and emerging.
(01:04):
Today we're visiting animportant area of hematology
with a very special guest, DrJoanna Czajwinski.
She's returning to the podcast.
Last time, Dr Czerwinskiprovided us with a comprehensive
overview of lymphoidmalignancies.
This time we're shifting ourfocus to explore the fascinating
and complex world of myeloiddysplastic syndromes and
malignancies.
Whether you're just curiousabout the role of genetic
(01:24):
testing or the complexities ofmanaging these conditions or
symptoms should prompt areferral to a hematologist.
This episode promises to beinformative and engaging, so
grab your coffee, take a seatand let's dive into the world of
myeloid malignancies withJoanna Chwinski on AussieMedEd.
I'd like to remind you that allthe information presented today
is just one opinion and thatthere are numerous ways of
treating all medical conditions.
(01:45):
It's just general advice andmay vary depending on the region
in which you are practicing orbeing treated.
The information may not beappropriate for your situation
or health condition and youshould always seek the advice
from your health professional inthe area in which you live.
Also, if you have any concernsabout the information raised
today, please speak to your GPor seek assistance from the
health organizations such asLifeline in Australia.
(02:06):
Thanks, Joe.
Thank you very much for comingback on Aussie Med Edge.
This time we're going to talkabout myeloid conditions.
I believe there's two sort ofdifferent pathways the
haematology conditions canundertake.
We've talked about lymphoidconditions previously which went
down the pathways of the cellsthat form T cells and B cells.
Now we're going to talk aboutmyeloid conditions, which are
(02:26):
the stem cells that produce redcells, platelets, etc.
Perhaps you can just explainwhat the myeloid stem cell line
is like and how it divides andhow it's affected as well.
Start off and down that pathway, Jo.
Dr Joanna Czerwinski (02:38):
Yeah, of course.
Thank you for having me again.
So with the myeloidmalignancies it does produce
most of the blood components.
So we originate again from thehematopoietic stem cell and then
, as we mentioned in ourprevious podcast, it divides
into either the lymphoid stemcell or the myeloid stem cell,
and so it quite easily goes onto the chronic and the acute
(03:02):
conditions, like we hadpreviously.
But in the myeloid stem cellcomponents there are the red
cells, the granulocytes, whichare things like neutrophils,
eosinophils, basophils, andthere are the platelets, and so
you can quite easily see thatany damage to the myeloid stem
cell can affect quite a lot ofthe blood components and is what
(03:25):
causes a lot of the cytopeniasas well as the cytoses.
Dr Gavin Nimon (03:30):
Right, and are there many things that can
affect those sort of pathways?
Is it more just aging andgenetic elements, or what are
the main factors that affectthem?
Dr Joanna Czerwinski (03:38):
So most of the times it's due to older age
and genetic damage.
So most of the conditions arediagnosed above the age of 65.
But in particularly the youngercohorts under the age of 50,
there are additional riskfactors that we look out for.
These can be things likeexposure to previous
chemotherapy and radiotherapies.
(03:59):
It can be radiation exposurejust in general, and it can also
include certain medicationsthat we don't really think about
as chemotherapeutics but fallunder the class of, like your
disease, modifying agents forrheumatoid arthritis and other
inflammatory conditions.
There is also a small groupthat it can be inherited
(04:19):
conditions passed along throughgenerations.
Dr Gavin Nimon (04:22):
What's your main ways of classifying these
conditions and how do theclassifications affect the
presentations?
Perhaps?
Dr Joanna Czerwinski (04:28):
So certainly I start off with acute
and chronic, because in theacute category you've got acute
myeloid leukemia and acutepromyelocytic leukemia.
Those are your only two acuteentities, realistically.
And then majority of the othermyeloid conditions falls under
the chronic banner.
And in the chronic banneryou've got the myelodysplastic
(04:50):
syndromes and the key word thereis dysplasia, meaning that the
cells don't look or act normally.
And then you have themyeloproliferative neoplasms
where the key word is theproliferative part, because most
of the time the cells are inoverdrive and there's far too
much production, and these arefurther subclassified as well.
(05:11):
So in the myeloproliferativeneoplasms you may have heard of
polycythemia vera, where youmake too many red cells.
Essential thrombocythemia,where you make too many
platelets.
Chronic myeloid leukemia, whereyou make too many of the
granular sites, particularly theneutrophils and precursors of
neutrophils, and myelofibrosis,which is in a way a burnt out
(05:33):
version of thesemyeloproliferative neoplasms,
where it initially starts withhigh numbers of cell counts
across the board, but then itburns out and it actually causes
cytopenias as the bone marrowscars over.
And we finally also have anoverlap syndrome, where you've
(05:54):
got a component that isdysplastic and a component that
is proliferative, and this iscalled myelodysplastic,
myeloproliferative overlapsyndrome.
It's a bit of a mouthful.
One of the problems that wehave with the dysplastic
syndromes is that you may nothave adequate cell counts so
they may have cytopenias andwith the remaining counts they
(06:15):
could be quite dysfunctional.
So they are at risk ofimmunodeficiencies,
immunocompromised states In themyeloproliferative neoplasms,
the polycythemia and essentialthrombocythemia conditions where
there's too many of the redcells and platelets respectively
, you end up having dysfunctionfrom either bleeding or clotting
(06:37):
perspective.
So usually it's not so muchthat they can't carry oxygen or
can't go and make a clotformation, but it's that they
try and overwhelm the system abit too well.
Dr Gavin Nimon (06:50):
So is that how most of them will present then
with bleeding and bruisings orDVTs and things?
Dr Joanna Czerwinski (06:56):
Most of them do present either through
incidental blood tests and youcan see an elevated platelet
count or an elevated hemoglobin.
But you can also see them interms of having VTE events, and
some of the VTE events can be instrange locations like
splanchnic vein.
They don't necessarily have tobe your traditional DVT or PE.
Dr Gavin Nimon (07:18):
We talked about lymphoid malignancies that had
some splenic conditions andother lumps and lymph node
conditions occurring.
Do you get any of thatoccurring in myeloid conditions
or is it all purely in the bonemarrow?
Dr Joanna Czerwinski (07:29):
So when the bone marrow is dysfunctional
and either doesn't have thecapacity 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 inthe myeloproliferative
conditions, you end up gettingextra medullary creation of
these cells, and this ispredominantly in the spleen.
(07:50):
So you can certainly getsplenomegaly in these cases, and
in the vast majority of themyeloproliferative cases it's in
myelofibrosis, Because in thatcondition your bone marrow ends
up being like one big scartissue where there's no capacity
for cell generation.
Dr Gavin Nimon (08:07):
I understand.
Also you can sometimes presentwith shortness of breath.
Now, is that from PEs or isthat from the actual cells
developing and occurring in thelungs?
Dr Joanna Czerwinski (08:16):
So it's in three parts, depending on the
condition.
So if they're anemic then theshortness of breath can be
attributed to anemia.
If they have something like aVTE, a PEE event, then they
certainly can have shortness ofbreath from that standpoint.
But the chronic myeloidleukemias and conditions where
the granulocytes can be quiteelevated you get this sometimes
(08:40):
in the acute myeloid leukemiasas well, where the total white
cell count is over 100 and whatcan happen in the lungs is that
you have a whole host ofneutrophils around the lung
tissues and their granularproducts.
So things like histamine andother cytokines they can release
(09:04):
in the lung area and it canpresent like an acute pulmonary
edema situation.
Dr Gavin Nimon (09:10):
Or it could also probably look a little bit like
asthma, could it in thatscenario?
Dr Joanna Czerwinski (09:13):
Yeah, it can.
And when we go into acutepromyelocytic leukemia, I'll
also talk about differentiationsyndrome, which can present like
an acute pulmonary edema aswell.
Dr Gavin Nimon (09:25):
I understand also you can get acute pulmonary
edema as well.
I understand also you can getsome skin itchiness as well.
Is that from the same sort ofprocess as you get occurring in
the lungs, or is it a differentsort of pathway?
Dr Joanna Czerwinski (09:32):
It's a similar pathway.
It's due to cytokine releaseand sometimes it can be due to
the thickness of the blood aswell.
So you often get, in particularin polycythemia vera, you can
get itchiness, you can get aredness discoloration of the
(09:53):
face.
Dr Gavin Nimon (09:53):
People look often quite flushed and they can
get quite sweaty as well.
Okay, so obviously the namepolycythemia vera makes you
think of redness.
Is that not just purely becauseof the actual cells affected,
but it's actually the appearanceof the person is it?
Dr Joanna Czerwinski (10:01):
Yes, it is Quite plethoric.
Dr Gavin Nimon (10:04):
So the vast majority of cases.
You see, though I think I saidpreviously when we're talking
about lymphoid malignancies.
They were incidental on bloodtests.
Is that still?
Dr Joanna Czerwinski (10:14):
the same case with myeloid conditions as
well.
So in the myelodysplasticsyndromes most of these occur
above the age of 65, 70, andit's usually on routine blood
tests that are done for otherreasons and you might only get
hints of this conditiondeveloping like they may have an
anemia of 120 for a male, whichis still anemic but is very
(10:36):
mild, and the only real symptomthat they may have is fatigue
and in some ways it can be hardto say you know a 75-year-old
that is otherwise fit that thiscondition is causing a lot of
their fatigue.
In the myeloproliferativeneoplasms there's some of my
patients where it's identifiedbecause they are again fatigued
(10:58):
for different reasons or theyhave developed a VTE event.
But we do see some of them comein with hemoglobins of 170, 180
, and you can't determinewhether that figure on its own
is the polycythemia vera thatcomes from the bone marrow or
whether it's secondary todiuretics, dehydration, chronic
(11:21):
airways diseases, sleep apnea.
Dr Gavin Nimon (11:23):
Okay, Of the particular different
classifications.
Obviously you talked aboutacute versus the chronic
episodes.
How does the acute presentationvary to a chronic presentation?
Dr Joanna Czerwinski (11:34):
The way that it presents is often florid
in emergency department and itusually only has a prodromal
illness of maybe one to twomonths at most.
So one of my cases that I'd hadhad been having back-to-back
viral infections or sinusinfections for a period of seven
weeks before he presented tohis GP and at that point he had
(11:58):
a white cell count of over 100.
So he was called in from SAPathology.
He was called in to present toemergency department and get
quickly worked up and he endedup having an acute myeloid
leukemia and the clue was thathe was getting recurrent
infections and not getting overthem.
Dr Gavin Nimon (12:17):
Right and a chronic one is more just, purely
a slow, insidious sort ofpresentation which is picked up
more on blood tests.
Dr Joanna Czerwinski (12:24):
Yeah, so most often it's anemia that's
been there for say 12, 18 monthsfor the myelodysplastic ones or
the myelofibrosis cases andconversely, on the other,
myeloproliferative neoplasmslike the polycythemia vera and
essential thrombocythemia.
Again it will be mildly abovethe mark but chronic, and the GP
(12:46):
has done a few different testsand can still not figure out why
this is.
Platelets of 500 to 600,hemoglobin of 170 to 180.
In those sort of mildcategories where you could
attribute it to they were a bitdehydrated or they've recently
had an infection you couldattribute it to they were a bit
dehydrated or they've recentlyhad an infection.
Dr Gavin Nimon (13:07):
So we've got these patients presenting with
some vague symptoms and they'repicked up on an abnormal blood
test.
Once the abnormal blood test isstandard, I presume complete
blood examination is performed.
What other investigations arerequired?
Are they the same as lymphoidtype conditions or are there
anything specific you'd do?
Let's just go through them allagain, just to remind me as well
.
Dr Joanna Czerwinski (13:25):
Yeah, absolutely so.
A complete blood examinationwith a blood film is a key,
particularly for themyelodysplastic syndromes and
the acute leukemias, becausethat's going to be pretty
diagnostic quite early on ifthey have these conditions, and
particularly the acute myeloidleukemia.
If you have a blood test atnine in the morning, it gets
(13:45):
sent through to SA Pathology.
You've got someone looking atit a few hours later and
bringing a patient into hospitallater that afternoon.
So it's quite a rapidturnaround for the acute
leukemia.
For the myelodysplasticsyndrome, there might be the
appearance of dysplasticneutrophils, for instance, and
that will be the first clue tothe diagnosis.
So blood film is definitelyessential For both the
(14:09):
myelodysplastic syndromes andthe acute leukemias.
I do flow cytometry becausethat helps to determine what the
blasts are.
Are they myeloid origin or arethey lymphoid origin?
Now, if we're going down theacute leukemia pathway, that is
usually managed in hospital andinvestigated in hospital.
(14:29):
But the things that we want toknow is what is their kidneys
doing, what is their liver doingand what is their cardiac
health like?
Because those three thingsdetermine their ability to
tolerate intensive chemotherapy.
For the myelodysplasticsyndromes it is helpful to have
creatinine and is helpful tohave liver function tests
(14:51):
predominantly because the maintreatments involve the kidney in
the filtration system.
So we need to have adequaterenal function to be able to
deliver treatments.
For the myeloproliferativeneoplasms, the renal function
and the liver function are lessrequired in terms of being able
to deliver treatments, but it isstill a good thing to help with
(15:13):
your differentials as to whatmay be causing, for instance,
your polycythemia vera.
If you've got an appearance ofdehydrated kidneys, then it
might be due to diuretic effect,as an example.
So the other tests that havebecome more recently available
that a hematologist could orderincludes the karyotyping or the
cytogenetics, and that's usuallydone on a bone marrow biopsy
(15:37):
specimen.
And they may also do a geneticpanel looking at molecular
mutations and again, that'spredominantly done on the bone
marrow.
Having said that, in some of myolder frail patients where I
don't think I'll be able toadequately give them treatment,
I can do the same genetic panelfrom their peripheral blood as a
(15:57):
bit of a prognostic indicatoras to how long I've got with the
patient and what else I can doto improve their quality of life
.
So certainly, the acuteleukemics, we all do bone
marrows.
On the myelodysplastic syndromeyou need to have a bone marrow
to access treatment.
If you're going down atreatment pathway and for most
(16:18):
of the myeloproliferativeneoplasms it's good to have bone
marrow, but not essential.
The only essential ones thatyou need is myelofibrosis,
because, again, treatment isreliant on that diagnosis being
confirmed, and the chronicmyeloid leukemia because it is a
way that you can monitoreffectiveness of treatment over
time.
(16:38):
But the majority, like thepolycythemia vera and the
essential thrombocythemia, it'sgood to have at diagnosis but
not essential to begin treatment.
Dr Gavin Nimon (16:48):
Excellent.
Are there other tests you mightdo as well, like apart from the
bone marrow or the bloodpicture?
Are there things like CTs orultrasounds that are also
required?
Dr Joanna Czerwinski (16:57):
So a good clinical examination for
splenomegaly is important forthe myeloproliferative neoplasms
and in clinical trials theywill always use splenic size to
determine how people areresponding, particularly for
myelofibrosis.
So a lot of people have a CTscan or an ultrasound at
baseline and then seriallyperformed to track response.
(17:19):
But if you can feel the spleenat the beginning and you can
measure, you know, for myfingers something starts out as
four finger breaths and goesdown to two finger breaths.
I know that they're respondingto treatment and I don't need
radiology to tell me that.
So it's not required to have aCT scan.
If they're going to haveintensive induction chemotherapy
(17:41):
for the acute leukemia we oftenget a CT sinuses because
they're at a lot of risk ofsinus infection and particularly
invasive fungal.
So we may sometimes in hospitalalso do a chest CT as part of
that.
Dr Gavin Nimon (17:56):
Right.
So that's really the fullworkup.
Then you can actually do fairlystraightforward investigations.
Then with the bone marrowbiopsy and a few other
investigations you can get thebaseline of what you really need
.
Dr Joanna Czerwinski (18:08):
Absolutely .
Dr Gavin Nimon (18:09):
How do you progress from there then?
What's the next step, Onceyou've got your biopsies and
you've got your blood picture?
Dr Joanna Czerwinski (18:20):
you've done your examination, what's
the next step?
So I guess if we're lookingdown the pathway of treatment, I
need to get the infectiousserologies ticked off, like your
hepatitis B, c and HIV, and forthe acute leukemias it's
helpful to have a uric acid fortumericis response, particularly
because the myeloid cells aregenerally bigger than lymphoid
and when these guys break apartand burst they do release toxic
(18:45):
products similar to the lymphoidcells.
So we still need to think abouttumor lysis syndrome in the
acute leukemia status.
With the chronic conditions,again, if I'm embarking on
treatment I want to know theirinfectious serology.
And then it's determining theirage and fitness and putting in
the different characteristicsinto like a prognostic scoring
(19:08):
system to determine whattreatment is best.
And this can be different forwhether they're young or old,
whether they have transfusiondependency or not and whether
they've had a VTE event or notwhen we're talking about the
chronic one.
Dr Gavin Nimon (19:23):
I might just stop you there for two seconds
and just ask you, because you'vejust raised some great thoughts
that I didn't know about.
So tumor lysis syndrome is that?
I presume that you can get goutfrom that because of the
release of uric acid.
What else does it involve?
Dr Joanna Czerwinski (19:37):
So tumor lysis syndrome.
I like to think of the acronymof CUP C-U-P-P, where your
calcium goes down by 25% frombaseline, your uric acid goes up
by 25%, your potassium goes upby 25% and your phosphate goes
up by 25%.
So these are the early markersof tumericis and it's what we
(20:02):
generally monitor twice to threetimes a day in an inpatient
setting.
When it's quite deteriorated itwill involve the kidneys and
you will see renal failure andyou will also see complications
such as acute pulmonary edemawhen the tumor lysis syndrome
further progresses.
So having those blood teststwice to three times a day
(20:24):
during the early inpatient stayduring their initial course of
treatment, that's where you'regoing to be able to pick it up
early and give them treatmentsto reduce their uric acid and
reduce those toxins.
So most patients get commencedon allopurinol and it's 300
milligrams a day and theycontinue it for the first seven
days of intensive inductiontreatment.
Dr Gavin Nimon (20:45):
Why is it important to know about the
infection status, the hep B, Cand HIV.
Why is that important?
Dr Joanna Czerwinski (20:50):
Because they become so heavily
immunocompromised with theirtreatments.
You want to detect whetherthey've got a chronic hepatitis
that you can treatsimultaneously or just prior to
initiating your inductiontreatment, and the prophylaxis
may also change.
So, for instance, if you have aHIV patient, you want to be
putting them on antiretroviralsand you want to make sure that
(21:13):
they don't interact with yourtreatment plans.
Dr Gavin Nimon (21:17):
So, jo, moving back on to talking about the
treatment plan, once you've doneyour standard workup looking
for infections and also checkingfor tuberculosis syndrome and
being prepared for it, what'sthe next steps?
How do you progress withtreatment following that?
Dr Joanna Czerwinski (21:31):
If we focus initially on the acute
leukemias, if they have a stockstandard acute myeloid leukemia
the first things that we want todo is bring down their white
cell count.
If it's elevated down to lessthan 25 so that we can start
induction chemotherapy, and thisis to try and reduce that risk
of tumerosis as well as to tryand reduce the risk of any acute
(21:55):
pulmonary edema or any othercomplications from things like
differentiation syndrome or,again, the tumerosis effect.
So what treatment is determinedis based on patient age and
fitness.
So if they're an under 70 yearold, we're usually offering
intensive induction therapy,which is what we colloquially
(22:17):
call 7 plus 3, which involvesseven days of citarabine and
three days of dawnerubicin orother anthracycline chemotherapy
.
So the way that this isdelivered is simultaneous seven
and three, so it's a total ofseven days duration of
chemotherapy.
But because this is such anintensive chemotherapy and aims
(22:39):
to clear out everything from thebone marrow and start from
scratch, it does take about twoto three weeks for recovery from
this kind of intensity of chemo, and so most patients will be
admitted for the entire monthduring their induction therapy
and they will have to workthrough any complications, most
commonly infections, after theseventh to tenth day and upon
(23:03):
recovery of their blood countsat day 25 plus, they're usually
scheduled for another bonemarrow to see how well that job
was done in clearing out theirleukemia.
And if they have achieved aremission so less than 5% blasts
in their bone marrow then theygo on to consolidation therapy
and then the following stepsafter that is dependent on what
(23:27):
risk category of leukemia theyhave.
So if they have a high riskleukemia where they've got
multiple mutations or very badmutations, these patients will
generally try and get onto theallogeneic stem cell transplant
pathway.
And most of the time we don'tcap it by age.
But generally speaking thereare not many 75-year-olds that
(23:52):
would be able to tolerate thatkind of treatment.
Broadly speaking, somewherebetween 70 and 75, with their
fitness level and theircomorbidity index.
That will determine who getsallowed to go to an allogeneic
transplant.
And that process involvesusually high doses of
chemotherapy to completely wipeout the bone marrow.
(24:13):
And then you have a replacementbone 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 (24:27):
With transplants in the myeloid conditions, do
you have to go on long-termimmunosuppression for the use of
them, like you do with kidneytransplants?
Dr Joanna Czerwinski (24:35):
So I like to think of allogeneic
transplants as the onlycircumstance where you are
usually not on long-termimmunosuppression.
You are certainly onimmunosuppression for the first
100 days, and it's usuallythings like cyclosporine,
tacrolimus, the usualanti-rejection medications, and
then after day 100, when thatrisk of acute graft versus host
(24:58):
disease has subsided.
That's when, if things aregoing well, they generally start
to taper it down over thesubsequent three months, so
usually by six months.
If it's gone all well, patientsare usually able to come off of
their anti-rejection meds andtheir new bone marrow and their
new blood type is completelyingrained into their own bone
(25:19):
marrow space.
Dr Gavin Nimon (25:20):
Does that mean that's really interesting?
Does that mean like you mightstart off as an A negative and
become back as a B positive?
Dr Joanna Czerwinski (25:26):
Absolutely .
That's what exactly that means.
That's crazy.
There's obviously a lot ofhigh-tech involvement with
regards to that because, if youcan imagine, we talk about
transfusion reactions beingincompatible blood and we're
talking about incompatible bonemarrow sources of blood.
Dr Gavin Nimon (25:46):
Wow, that's amazing.
Okay, all right.
Well, it's one of the mostinteresting 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 patientsover 70 or 75?
In the acute stage, they'reunfortunately not going to
(26:06):
tolerate the treatment very well.
Dr Joanna Czerwinski (26:08):
So a few years ago there became available
this protocol calledazacitidine and venetoclax.
Now azacitidine I'll speakabout again later because it's
involved in myelodysplasticsyndromes, but it's a
hypermethylating chemotherapyagent that is given as a
subcutaneous injection for sevendays every cycle, and each
(26:31):
cycle is usually 28 days, andthis is paired with a BCL-2
inhibitor, so an anti-apoptoticmarker, and that is a tablet
therapy that is takencontinuously.
And even I think my oldestpatient is in their mid-80s and
is tolerating that treatmentprotocol.
So again you would go throughthis induction treatment where
(26:53):
you're very quickly ramping upto the maximum dose of
venetoclax and you're alsosimultaneously giving the
azacitidine and it's a standardtreatment course for everyone
for cycle one.
At the end of cycle one you do arepeat bone marrow and again
you're seeing how much of cycleone.
You do a repeat bone marrow andagain you're seeing how much of
the leukemia you've cleared out.
Now in most cases the leukemiahas been cleared in that first
(27:16):
cycle.
Some additional people need asecond cycle of similar
intensity and then, once youhave cleared out the leukemia,
then you can adjust the dosesfor better tolerability, because
most of the time it is anoutpatient protocol, it is not
needing to remain in because itis that gentler level.
I've used this protocol alsofor people that are Jehovah's
(27:40):
Witnesses and are not acceptingof blood transfusions, because
the former the 7 plus 3, renderseveryone in need of transfusion
, whereas this provides anoption for if transfusions are
not in that person's religionand also is much more tolerable
for the older or frailer person.
Dr Gavin Nimon (27:58):
So this is more like a long-term suppressive
type of treatment as opposed toa trying or a curative type
treatment.
Dr Joanna Czerwinski (28:04):
Absolutely the longest person that I think
has been on that combinationhas been more than 15, 18 months
.
So it is something thattreatment protocol for 12 months
and they've cleared the bonemarrow of the leukemia and
(28:27):
they're in a complete molecularremission where you can't detect
their genetics from theirpresentation.
Whether those patients canactually safely come off of
treatment and have a drugholiday.
Dr Gavin Nimon (28:38):
We've got obviously using suppressive
agents or chemotherapy agents.
Are there any other types ofagents you might use?
Dr Joanna Czerwinski (28:44):
Something that we'll again be talking
about, mostly with themyeloproliferative neoplasms.
But we do use hydroxyurea orhydroxycarbamide as a tablet
treatment to cytoreduce or tobring down all of their cell
counts.
So it is a very old-fashioned,very indiscriminatory
chemotherapy agent and it'stablets, and it will bring down
(29:08):
not only the white cells thatyou're trying to bring down, but
it will also render them anemicand thrombocytopenic.
So you can only realisticallydo that for a few days, but
that's all you're trying toachieve is a much more tolerated
white cell count, so that thenyou can initiate the effective
treatment.
Dr Gavin Nimon (29:25):
And this is purely for the acute myeloid
leukemia, like promyelocyticleukemias.
So that's purely the white celltype leukemias Do you get.
I'm a little bit confused here.
For a second, can you get acuteleukemias involving red cells
or platelets as well, or is itpurely white cells?
I'm not making it too hard formyself here.
Dr Joanna Czerwinski (29:46):
It is only with the granular sites, so it
is predominantly the neutrophilsgone bad essentially.
So we are dealing with themyeloid precursors, but the
white cell versions there.
Technically is an acuteproerythroid leukemia very rare.
You only hear case studiesabout it.
(30:07):
But they are nucleolated redcells that you see in the bone
marrow and it has undergonemultiple reclassifications so
it's now more thought about asan acute myeloid leukemia with a
predominance of those red cellprecursors.
And there is an acutemegakaryoblastic leukemia and
(30:28):
again it's very rare.
It's very bad news if it occursin an adult and the prognosis
is better if it's in a childwith Down syndrome, where
there's an increased number ofcases in that particular cohort
of children with Down syndrome.
Dr Gavin Nimon (30:45):
Okay, so the red cell condition, the platelet
conditions, are really more onthe myelodysplastic or the
chronic conditions that we'retalking about then.
Dr Joanna Czerwinski (30:52):
Absolutely .
Dr Gavin Nimon (30:53):
Is there anything else that you'd want to
say about the acute conditionsbefore moving on to the chronic
conditions, then?
Dr Joanna Czerwinski (30:57):
I guess the acute promyelocytic leukemia
does not get treated the sameway as the acute myeloid does so
with the acute promyelocyticleukemia does not get treated
the same way as the acutemyeloid does so with the acute
promyelocytic leukemia.
It's treated with a combinationof all transretinoic acid or
ATRA, and combined with arsenic.
And it is because of theparticular translocation of the
(31:17):
genetic proteins in thatparticular leukemia and it was
discovered more than 10 yearsago that this combination of the
ATRA and the arsenic canactually break apart that fusion
protein and cause those blastcells or those promyelocytic
cells, the leukemia cells, todifferentiate into proper
(31:39):
neutrophils at the end stages.
And it is a highly curativecondition, highly curative
treatment and most patients gothrough it and the survival is
something like 95% long termwithout relapse.
Dr Gavin Nimon (31:55):
Wow.
Dr Joanna Czerwinski (31:56):
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 neutrophilsoccurs very instantaneously and
degranulates all their cytokinesand causes that acute pulmonary
edema syndrome.
(32:16):
The other thing that can happen, of course, is DIC, which is
disseminated intravascularcoagulopathy.
So whenever we see an acuteleukemia present into emergency
department we're always askingfor the extended coagulation
parameters to include thefibrinogen and the D-dimer and
you would see DIC if thefibrinogen is quite low, so less
(32:40):
than 1.5, and the D-dimer isabove 30,.
We're much more different thanyour VTEs where your D-dimer is
1.
Dr Gavin Nimon (32:48):
Right, yes, how many of these sort of cases
would you treat each year?
Dr Joanna Czerwinski (32:52):
So the acute promyelocytic leukemia is
less common, so we probably geta handful each.
Thinking back over the last fewmonths we probably had two or
three in the last three-ishmonths Whereas the acute myeloid
leukemia in adults is much morecommon than lymphoblastic
leukemia, and particularly nowthat we've got an older
(33:12):
population, we're picking thesethings up.
We now have treatmentsavailable for the older patient.
We're seeing maybe one everyweek or two.
Dr Gavin Nimon (33:22):
We talked about the causes.
We talked about justdegeneration or age-related
changes to the cells, but alsotalked about radiation exposure
and medications.
Is there a greater percentageof one over the other for causes
?
Dr Joanna Czerwinski (33:33):
So certainly most of them is due to
aging and bad luck.
You can get acute myeloidleukemia even as a teenager and
I've had very few cases ofpediatrics that we've seen
through the laboratory, butcertainly we have had
18-year-olds, we've had20-year-olds with acute myeloid
(33:53):
leukemia.
The ones where they've occurredpost-chemotherapy or other
treatments generally, areassociated with more high-risk
features because they've alreadyhad their DNA damaged from the
other treatment and they're nowcoming in with high-risk
features.
So those patients are very,very likely to go to an
allogeneic transplant unlessthey're unfit for one.
Dr Gavin Nimon (34:17):
Because that'd be like a field change.
I presume the whole, all thecells are being damaged along
the way.
Dr Joanna Czerwinski (34:22):
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 fromprostate cancer, but I have seen
a few after breast cancertreatments with chemotherapy, as
an example.
Dr Gavin Nimon (34:40):
If we move on to the chronic type conditions,
then you've divided those upinto the dysplastic syndromes,
often as being pre-malignantconditions.
Is there a particular type ofclassification of those
particular syndromes?
Dr Joanna Czerwinski (34:51):
Yeah, so it used to be that the
myelodysplastic syndromes wouldbe divided up into appearances
and the bone marrow technicalcomments of you know is it a
high blast count?
Is it a low blast count?
How many of the red cell, whitecell and platelet lineages are
affected?
So is it a multi-lineagedysplasia or a single lineage
(35:13):
dysplasia?
And there are certain mutationsthat it used to be classified
by as well.
So a deletion 5q would be inthe old classification systems.
These days it's excess blastsor not, multi-lineage or single
lineage, and sometimes therewill be key other features as
well.
So they might be defined bytheir molecular abnormalities or
(35:35):
their genetic abnormalities aswell.
But by and large most of themyelodysplastic syndromes that
come in to see me are what Iwould deem as low risk.
They're very mild.
They're, incidentally, pickedup over serial blood tests.
And you go and do a bone marrowand you find maybe they have
(35:55):
single lineage myelodysplasia.
Very low blast counts, lowblast counts.
And when you pop in those kindof numbers into the prognostic
scoring system we'll tell youthat their low risk and their
average overall survival is 10years, meaning that in a
population where you'repredominantly seeing
70-year-olds their averagesurvival is going to be another
(36:16):
10 years For the moreintermediate to high risk.
Those patients usually havestarted having blasts in their
blood tests, so you canimmediately tell that you're
dealing with a more aggressivecase and they're often needing
blood transfusions much earlier.
So those are the patients thatI would try and encourage them
(36:38):
to get a bone marrow sooner,because that will affect how I'm
going to treat them and when Ithink about the four different
types of treatment for yourmyelodysplastic syndrome.
The earliest is the watch andwait, where you're monitoring
their bloods every two or threemonths and you're looking for
changes over time.
And when you do see thosechanges, that's when you would
(36:59):
do a bone marrow to see what hasmolecularly changed or what's
changed under their bone marrow.
The next is supportivetreatments.
So these are things like bloodtransfusions, antibiotics,
vaccinations and in some casesyou can even get things like E2
bring up the hemoglobin.
Obviously that's not on the PBS.
(37:19):
The next third treatment isstandard chemotherapy and that
is indicated for yourintermediate to high-risk
players and it's to try andprevent the myelodysplastic
syndrome from progressing intoacute myeloid leukemia, because
there is a percentage chance andit's in those same prognostic
(37:39):
scores that I was talking abouta few minutes ago.
There is a chance that it willconvert over to acute leukemia
and you want to capture thembefore they make that transition
so that you can offer themchemotherapy.
And the chemotherapy is againthat same azacitidine that I
spoke about earlier incombination with the venetoclax.
(38:00):
But you are using justazacitidine by itself for the
myelodysplastic syndromes.
And then the fourth and finaltreatment is usually reserved
for, again, those really youngplayers.
But if you've developedmyelodysplastic syndrome and
you're under 50, you probablyhave genetics that are poor risk
(38:21):
and you probably want to bethinking about a transplant
early in the piece.
Dr Gavin Nimon (38:26):
So obviously the supportive treatments.
We're talking about using bloodtransfusions.
That's why it's so important tobe donating blood and giving
products for people who areundergoing this sort of
treatment.
And I presume they divide thosecells up into whether red cells
, platelets or neutrophils.
Is that correct when they givetransfusions?
In that scenario?
And if they're in a singlelineage, they just need one or
the other.
Dr Joanna Czerwinski (38:46):
Kind of mostly correct.
So when someone goes and donatesblood they generally donate
whole blood and that is split upinto its components of red
cells, platelets and plasma andthe plasma contains all the
different proteins.
But generally we don't transfusegranulocytes because that would
run the risk and it's a veryhefty risk of graft-versus-host
(39:10):
disease where the donor'sgranulocytes are attacking the
host.
There are very rarecircumstances where that's done
and it's usually in a plasticanemia, which is a non-malignant
condition.
But you're certainly right thatif a myelodysplastic patient
predominantly plastic anemia,which is a non-malignant
condition, but you're certainlyright that if a myelodysplastic
patient predominantly has anemia, they're predominantly going to
be transfused just red cellsand in the chronic transfused
(39:33):
patient cohort they might bebooked in for an outpatient
transfusion every two or threeweeks and it might be two units
at a time.
So when patients are beingtransfused for these chronic
myelodysplastic syndromeconditions we're also thinking
about their iron overloadbecause that comes with those
transfusions and there are ironchelators on the PBS which are
(39:58):
available to those patients.
So there is a requirement for acertain amount of transfusion
every two months and a certainlevel of anemia and a certain
level of ferritin before you cancommence one of these
treatments, and the treatment isonly advantageous if the
problem is more than two years,because it takes a very long
(40:19):
time to chelate the blood fromthat iron.
Dr Gavin Nimon (40:22):
I presume so you're trying to prevent
secondary hemochromatosis.
Then in that scenario, In thatscenario.
Dr Joanna Czerwinski (40:27):
Yes, you're trying to prevent other
organ damage from their ironload.
Dr Gavin Nimon (40:31):
Right.
Okay, there are other differenttypes of treatments.
I remember hearing about doingsplenectomies for ITP and things
like that.
Is that done in this sort ofconditions as well?
Dr Joanna Czerwinski (40:40):
It's generally reserved for the
myelofibrosis cases where thespleen can get quite big, and
some palliative measures caninclude splenic radiation as a
treatment option.
But these are usually whenyou've tried every other therapy
and the spleen is still hugeand still causing a lot of drama
.
Dr Gavin Nimon (40:59):
So okay.
So these are the main types oftreatments you use for the
chronic myelodysplasticconditions, and that's the sort
of intermediate sort of chronicconditions we're talking about.
Then you've got these chronicmyeloproliferative disorders,
which is really the next stage.
Dr Joanna Czerwinski (41:13):
Yeah.
So I think about themyeloproliferative neoplasms as
a condition where the gas pedalis fully firm to the floor and
we're overproducing too manycells.
So if we take polycythemia asthe best example, most of those
cases again we can see,incidentally, on routine blood
(41:33):
tests.
We can see it in thecircumstances of VTE and we can
see them in circumstances ofthey come to their GP
complaining of fatigue anditchiness and they're red in the
face, they're quite sweaty andin these conditions, whenever a
polycythemic patient comes to me, I try and establish a few
things quite quickly.
(41:54):
I try and establish thechronicity of how long this has
been over.
I try and see do they have anyrespiratory or cardiac issues
that might be causing them toneed more red cells and need
more oxygen, because that's thepolycythemic drive?
And I try and establish arethey on any diuretics or having
(42:14):
multiple coffees a day with notenough water intake?
And if I can't find anythingobvious then I'm sticking them
on aspirin, unless they've gotanticoagulants for other reasons
.
And the reason behind it isthat aspirin prevents a lot of
the complications ofpolycythemia vera when it comes
to thromboses, because thethromboses are mostly VTE, but
(42:37):
they can have arterial eventslike MI and stroke as well.
So I will put them on aspirinuntil I've seen their genetic
result.
And polycythemia is associatedwith two mutations both in the
JAK2 gene, and 95% of thepolycythemics will have one or
the other mutation.
And that mutation study takesabout three weeks to get results
(43:00):
.
So if I'm on the phone with aGP and they're telling me about
a polycythemic case, I will saystick on aspirin, send them
through to us, we'll do thegenetic testing and then we'll
talk to the patient about whatwe found.
So then again, it's a bitdetermined by age as to what
kind of treatment and whetherthey're of childbearing age in
(43:21):
particular.
So if I've got a young patientunder the age of 50 and they're
interested in having more family, then I would do venesections
and my aim is to get theirhematocrit down to normal, so
the hemoglobin will come down.
If I'm focusing on getting thathematocrit to the correct
values In females it's less than45% and in males I'm targeting
(43:43):
48% those venous sections mighthave to be quite frequent
initially, so maybe weekly orfortnightly.
But as you're getting furthercontrol you can spread those
venous sections further andfurther apart.
One of the ways that I can tellif a patient has polycythemia,
even before I've begun venoussections is what their iron
levels are doing, becausepolycythemia even before I've
begun venesections is what theiriron levels are doing.
(44:04):
Because polycythemia, the pedalon the gas will only be limited
by how much iron fuel you'regiving those red cells.
So by venesecting them it's notactually removing the red cells
, that's part of the process,but you're actually trying to
limit how much iron those redcells have in reserve to further
procreate.
(44:25):
So I would often try and getthem to as low a ferritin as
they can tolerate.
Sometimes that means a ferritinof 20.
So technically they're irondeficient by that point.
So long as they can manage withthe symptoms of that mild iron
deficiency by offsetting theirpolycythemia vera, then that
(44:45):
determines their venesectionfrequency.
So it's a bit of a balance.
The other type of treatment thatcan be available for young
persons is pegylated interferon,which is a weekly subcutaneous
injection.
But we don't like to do that forcurrently pregnant female.
We like to do that as a lead-inprior to pregnancy planning and
(45:06):
they may need to be on it for ayear or two to get their numbers
under adequate control and thenwe can have that luxury of
allowing them the nine to 12months of trying to fall
pregnant and then being pregnant.
The treatment for the olderpatient involves hydrea, which
we mentioned before as acytoreducing agent.
Now, the main risks of hydreais that it gives you a risk of
(45:31):
skin cancers.
So I usually have all of mypatients checked over quite
thoroughly before initiatingthat treatment and then regular,
at least annual, checksthereafter, and it causes wounds
to heal quite poorly.
Since a diabetic withpolycythemia and their diabetes
is out of control, I'm notlikely to initiate that
treatment straight away becauseI might be doing more harm than
(45:53):
good.
Diabetic ulcers are never goingto heal properly.
So those are broadly the threetreatments that we've got
available.
So the venous sections, theinterferon, the hydroxyurea and
then the aspirin or theanticoagulation as a
preventative of thromboembolicevents.
Dr Gavin Nimon (46:10):
All right, so that's polycythemia.
How do the other conditionsvary compared to the
polycythemia?
Dr Joanna Czerwinski (46:15):
So essential thrombocythemia is a
bit harder to treat becausevenous sections don't work as
well for them, so it's usuallyjust isolated platelet count
that's elevated.
So in the very extreme ET caseswhere the platelets are greater
than 1000, there is plateletphoresis, which is done in
hospital where when people go todonate blood they can sometimes
(46:38):
go and donate just platelets orjust plasma and they get placed
onto this machine which lookslike a big dialysis or
centrifuge machine where theyhave blood pulled into a machine
.
It's spun around so they'reseparated by different weights
of cells and then you can removethe platelet level of the
(46:59):
different weights beingseparated.
And that's the same processthat happens for platelet
phoresis, where you're justremoving the platelet layer from
that centrifuge and that's totry and rapidly bring down
platelet levels to preventbleeding and bruising and
clotting complications.
But you can't obviously go inand have that treatment
(47:19):
indefinitely and so mostpatients with ET get put on
hydroxyurea.
Dr Gavin Nimon (47:25):
Okay, and then moving on to the myelofibrosis
stuff, that's just where.
It's just worn out.
Dr Joanna Czerwinski (47:30):
Yeah.
Dr Gavin Nimon (47:30):
So is there any particular treatment for that?
I presume you're just gettingan allogeneic transplant for
those sort of conditions, areyou, or how is that one treated?
Dr Joanna Czerwinski (47:36):
So for the young patients certainly
allogeneic transplant is anoption for really severe
myelofibrosis where they've gotsplenomegaly or symptoms of
fatigue, tiredness, shortness ofbreath, itch.
Those patients I encourage themto have a bone marrow to
confirm the diagnosis becausethen they can access ruxolitinib
(47:58):
, which is a tablet therapy onthe PBS.
It's a form of a JAK inhibitorand it has improved quality of
life scores in the trials thatwere done with it.
So it improves spleen size andas a result it improves the
cytopenias.
It also improves those symptomsof the itch, postprandial
fullness, the fatigue.
Dr Gavin Nimon (48:20):
Okay, that brings us down to the last type
of condition, themyelodysplastic slash
myeloprolutative overlapsyndromes.
Is it really a combination ofwhat we've already talked about,
or are these separate all againas well?
Dr Joanna Czerwinski (48:31):
They're a combination of what we talked
about.
Most patients I treat verysimilar to the myelodysplastic
syndrome.
You've got the watch and waitapproach, the supportive care
approach.
The active treatment approachcan be azacitidine if they're
looking more like amyelodysplastic patient, or it
could be hydrea if it's aproliferative.
(48:53):
Look to it and then allogeneictransplant is an option for
those younger patients, butgenerally the
myelodysplasticastic,myeloproliferative overlap
syndromes are above the age of70.
Dr Gavin Nimon (49:05):
Well, that's a fair bit to go through.
Is there anything you'd like tosay to wrap up with that whole
sort of process?
Is there anything that comes tomind?
There's a lot we've gonethrough already so far tonight.
Dr Joanna Czerwinski (49:14):
Well, I guess, out of all the cases that
we've discussed today, I guessthe thing that I would inform
GPs is, if you've got a mildanemia, a mild thrombocytopenia,
a mild elevated hemoglobin,elevated platelet count, is to
monitor that over time, becauseif it's at the very mild stages,
(49:35):
most of the cases can bemonitored.
But if you've got a mildproliferative neoplasm, you want
to know is it because of theirbone marrow or is it a secondary
event?
And in most cases, thankfullyin this day and age, most of the
treatments are oral, andparticularly when it comes to
the chronic conditions.
Dr Gavin Nimon (49:55):
Where do you think the future holds for
hematologists in these two areas?
What's the next steps?
What do you want to see downthe track?
Dr Joanna Czerwinski (50:02):
Well, I guess a lot of the particularly
the chronic conditions in thisspace are diagnosed at much
older ages and we'repredominantly doing treatment to
prolong survival and improvequality of life, but there's
nothing that realisticallyprolongs it by years and years
and that's the hardest thing totalk to patients about.
(50:23):
But if there are treatmentsthat are in clinical trials to
try and extend thatsurvivability even further,
because I'm seeing patients thathave just hit retirement go to
their GP for the first time andthen they're landed with this
sort of a diagnosis because theprevious 10 years they were busy
working, doing other things,not necessarily seeing their GP
(50:45):
at that point.
Dr Gavin Nimon (50:47):
It must be very hard in that scenario.
Thank you very much, Jo, forcoming on Aussie Med Ed and
explaining these conditions forus.
I really appreciate your time.
Dr Joanna Czerwinski (50:54):
You're welcome.
Dr Gavin Nimon (50:55):
It's really interesting to learn about it
and I've learned some of themost amazing facts tonight.
So thank you very much.
Dr Joanna Czerwinski (51:00):
You're very welcome.
Thanks for having me again, meagain, thank you, thanks, joe.
Dr Gavin Nimon (51:03):
Thanks again for listening to the podcast and
please subscribe to the podcastfor the next episode.
Until then, please stay safe.
Popular Podcasts
Are You A Charlotte?
In 1997, actress Kristin Davis’ life was forever changed when she took on the role of Charlotte York in Sex and the City. As we watched Carrie, Samantha, Miranda and Charlotte navigate relationships in NYC, the show helped push once unacceptable conversation topics out of the shadows and altered the narrative around women and sex. We all saw ourselves in them as they searched for fulfillment in life, sex and friendships. Now, Kristin Davis wants to connect with you, the fans, and share untold stories and all the behind the scenes. Together, with Kristin and special guests, what will begin with Sex and the City will evolve into talks about themes that are still so relevant today. "Are you a Charlotte?" is much more than just rewatching this beloved show, it brings the past and the present together as we talk with heart, humor and of course some optimism.
On Purpose with Jay Shetty
I’m Jay Shetty host of On Purpose the worlds #1 Mental Health podcast and I’m so grateful you found us. I started this podcast 5 years ago to invite you into conversations and workshops that are designed to help make you happier, healthier and more healed. I believe that when you (yes you) feel seen, heard and understood you’re able to deal with relationship struggles, work challenges and life’s ups and downs with more ease and grace. I interview experts, celebrities, thought leaders and athletes so that we can grow our mindset, build better habits and uncover a side of them we’ve never seen before. New episodes every Monday and Friday. Your support means the world to me and I don’t take it for granted — click the follow button and leave a review to help us spread the love with On Purpose. I can’t wait for you to listen to your first or 500th episode!
Dateline NBC
Current and classic episodes, featuring compelling true-crime mysteries, powerful documentaries and in-depth investigations. Follow now to get the latest episodes of Dateline NBC completely free, or subscribe to Dateline Premium for ad-free listening and exclusive bonus content: DatelinePremium.com