Greetings and welcome to EHA Unplugged, the official podcast
channel of the European Hematology Association EHA.
OK, good afternoon. I would like to welcome
Professor Rusbecker from the University Clinic of Leipzig in
Germany. Well, Platt Speaker has been
working with MD's as long as I can remember and has been
running a lot of clinical trials, but also translation
research. And I think you have at least I
remember a lot of trials also in low risk MD's.
And I think that's the main topic of of today is low risk
low and, and how can we use these prognostic indexes.
So what do you think about using prognostic indexes and low risk
MD's? Can you sort of elaborate a bit
on that? Yeah, thank you.
Just also I would also for this complex question, I would like
to challenge you in in reverse about the terminology low risk.
I mean, you know, you, you, we both know that this terminology
is still coming from the old days when MD asked at least at
some point was not considered to be a cancer, maybe mild anemia,
thrombocytopenia, whatever. And it was not clear what the
cell of origin and also the mutation, the landscape I think
at this stage was not not known. So I think from from the old
days, the MD's subtypes were differentiated into low risk or
lower risk and higher is based on the natural course of the
disease. And you mentioned the scoring
systems which at the very beginning like IPSS were a
reflection of patients who actually received only
transfusions or antibiotics, sometimes growth factors.
So the natural course of the disease was served and therefore
patients were differentiated into lower risk and higher risk.
Meanwhile, the recent update of The Who classification reflected
or is now reflecting much better that MD's is not renal anemia.
It's now called myoplastic neoplasm.
Still the terminology MD's remains, but I think it's
important to say that it's it's a cancer sometimes very
aggressive with immediate survival in higher risk patients
of less than six months based on also recent molecular work up.
So now I will try to answer your question what what is low, what
is low risk and how to differentiate.
I think we have the IPSSR which I think we both now use for a
couple of years. And also the IPSR has come also
has been introduced into clinical trials and also
approval of agents like lispatacept where the clinical
trial was actually based on IPSSR.
On the other side, the majority of the drugs we still have in in
MD's like azazidine E PO, both are improved on the IMPSS.
So the old classification and I will give you I think a very
good example why the IPS is valid and is, is, is is very
good for for prognostication. But we're also the molecular
work up I think is important with regards to maybe also
treatment decisions. So for instance a patient with
ring sylloblastic phenotype with neutropenia O .7 with mild
thrombocytopenia but being heavily transfusion dependent
and an SFTB 1 mutation can still can or basically will be in the
box of so-called IPSSR intermediate being eligible for
loose patacet for instance as a second line therapy.
On the other side, the same patient maybe also with ring
cytoplastic phenotype just by morphology, but with other
splices of mutations and maybe also with AP53 mutation, which
sometimes occurs also ring cytoplastic phenotype.
Patients outside as if we want may still be just from
morphology, blood counts and blast counts in the same box
intermediate, but the prognosis is much worse in patients.
So this is a long answer to a short question, but I think you
touched base with a very complex and puzzling thing, which I
think now also when talking to fellows and also to to
hematologist, I think they are sometimes puzzled which score to
use. So I think the bottom line
message is IPSSR is still a valid score and very low, low
and parts of intermediate I would say are the lower risk
where prognosis even with supportive care can be
considered as in years and therefore it's they are lower
risk. But IPSSM, and I guess you come
to that in a second, has challenged this a bit.
Absolutely, Yeah, Yeah, I think this was very foreign nice
explanation on how this can actually really change the way
we see some of these low risk diseases.
So, so do you think we can use this also when we when we want
to select which patients to transplant early, I mean to
transplant in the lower states? Have you any?
I think we can, but transplant is not like mild surgery.
As you know, the intention is to replace the bone marrow and and
to to reset the immune system. But still there is an
unpredictable risk of mortality which is in the range of five to
10% in the in the during the first year, irrespective whether
you do everything right, you select the right donor, it's
it's unpredictable and therefore you again touch base in a very
important thing. We have very good scores.
We can select patients being lower risk by traditional tools,
but now being higher risk by implementing also the genetics.
But we only have a couple of agents.
Basically we have one agent as a Sidon and we have an approach
called allogeneic stencil transplantation and that's it.
So we don't have anything or only limited armamentarium of
weapons, if I may use this word here in this, in this context to
change the course of the disease.
And I think that's the dilemma we have now.
I think we should not stop to score patients, but I think we
should rather work on agents which may patients with let's
say lower, higher risk may benefit and which may alter the
disease course. So also talking about these new
classifications, you know, how, how, how good are they?
If you go to the very early stage MD's, you know, the sea
cost and I mean, can we use them there or because I think, you
know, that creates a new type of this thesis that we see in our
departments and we all discussing what to do with them.
Should we follow them? Should we, what should we do?
And what's your opinion on that? What you do?
What would you do and do you do in life?
Yeah. So the, let's say IPSSR and also
the IPSSM are not traditionally developed for CKAS patients.
There are numerous papers of course on CKAS where the bottom
line message basically is the number of mutations, the type of
mutations and the allelic burn and the level of cytopenia.
So very, very clear. I think a prognostic variables
predict the disease progression and I think, but still it's,
it's there's a great variability and many of these patients are
older. So the question is what is the,
what is the workflow? What is the follow up?
I think this is still under investigation.
The way we do it at least in life sick is that we look for
all these variables. So type of mutations for
instance TET DMT 3A is rather neutral from a prognosis of
mild, whereas ASAX one or additional mutations like 234
predict a much higher risk to undergo or to develop MD's.
So these patients let's say with a higher risk, we follow up
every three to six months or the other ones we see maximum once a
year. Yeah, I think I would say the
same. You know, that's about what we
do. That's good.
To hear of. Course, I think what about now
to go a little bit back to what you talked about before, because
now that we have this new classification, what do you do
with all the results from before?
I mean, from the clinical trials that we have?
Are we going to go back and try to to to sequence the material
if we have it and and maybe re evaluate for example, the
indications for those peticept or you know what's, or do you
already have those data? No, I mean we, we don't or at
least I myself don't doesn't have it.
But what we what we know from already published data.
For instance, Matteo de la Porter just published a paper
where we were Co authoring and we also provided some some some
data or some data set of patients is that the IPSSM has a
new scoring system is prognostic irrespective of what you do.
So let's say if you transplant, of course the, the patients with
a, with a, with a high or very high do much better than if you
gave Azacitin or if you basically observe the natural
cause of the disease. But the demarcation between
these groups remains the same. So let's say that the there's a
little upgrade with the survival curves, maybe also based on
selection of age and common abilities and so on.
But the IPSSM at least in the majority of analysis published
or now presented at the ASH meeting where there were a
couple of IPSSM based on analysis with retrospective,
they all look the same. So the IPSSM remains valid
irrespective of what you do. And I think this is also
something where we could learn from and the, the concept, I
think the next concept should be that we are as precise as
targeted as possible and maybe improve the prognosis of
molecular defined or molecular driven subgroups of patients
like IDHP tailed patients for instance, or yeah, 50P mutated
patients. I think this, this should be the
next, the next step because what we, the kind of therapy we
currently apply is very broad and very unselected.
So therefore I think the IPSSM is still valid across all these
different unselected therapies. Yeah, and and how difficult is
it to use the IPSSM? I mean, what does it take?
Well, it takes a minute at least I would say.
And of course #1 it, it takes, it takes an NGS based panel
where I think we do it in our academic center because we are
very curious and you know, we would like to learn but and so
on. But would I recommend it on a
broad scale for every patient? I wouldn't say so.
I mean, it's also a question of resources, of course.
But the question is if you have the 81 year old woman with a
Dell 5 QMDS being reptiles as fusion dependent, I think I
would go for P53 mutation analysis.
But apart from this, maybe to go to look for flat 3 KMT 2A and
all these things could be of course of interest, maybe you
find very small clones. But the question is what does it
change or does it change anything?
So I think at this stage I would recommend it for every patient
being eligible for allergenic stem cell transplantation.
So every patient less the below the age of 70, all the patients
above where you have a clear MDMS diagnosis based on genetics
side genetics, morphology, Histology.
So if if everything is clear and you have a treatment option
which is valid, which should work let's say ESA or let's say
lispatiscept in lower risk patients.
So there is even if you know that the disease may be more
aggressive or less aggressive, it doesn't change your treatment
paradigm. This is, I think, the the issue
and it may rather irritate or bewilder the patient who then
thinks, well, I belong to the to the bad guys, although my blood
counts are still very good. So I'm concerned now and and
actually they will maybe suffer from a worse quality of life
irrespective of a treatment of a treatment response which may
occur irrespective of IPSSM. So this is I think needs to be
balanced and also some patients want to know their prognosis,
their putative prognosis, some may not.
So I think before you tick Mark, you know on the on the lab
report that you wanted 50 genes analysis, which is can be done
as you know Kirsten within 2 seconds.
And then you, you know, a lot of workload is generated before you
do that. Think about it.
I. Think that's a very good advice.
And I think that's, that's where people have actually also come
into trouble sometimes. I think particularly with also
patients that do not want to know everything.
And I think you need to, to be very clear about that before you
you start also because some of the panel nowadays also have all
the, the hereditary, the genes that are involved in hereditary
myeloid cancer. So.
So how do you handle that? Yeah #1 I mean, it's, we know
now that for instance, DX 41 is not restricted to younger
patients, you know, so this is something which can occur at the
age of 7080. Even MD's, these patients seem
to have a more, let's say B9A course of the disease.
So how do we handle that? I mean, number one, in my
country, if you go for inherited mutations, if you really do do
this work up like the one I just mentioned or, or geta 2 or
others, you need to get a consent.
Oh yeah. I mean this is the same.
Way do Don't you have it in the regular pens as well?
We sometimes, yes, we some no, we, you are right.
We just amended it. So I have to admit it's there,
but still it requires consent. And again, this is something
which also has consequences for the family, for everybody.
And again, the, I mean, if the patient got MD's at the age of
82 and before was basically was healthy, everything was fine.
So you can get MD's at the age of 82.
There's nothing weird about it and it's nothing which may cause
a genetic work up of the entire family.
So we counsel the patient, we counsel also with our genetic
specialist, and then we draw conclusions.
I I think I would do it genetic work up with inherited genes in
every younger patients but below the age of 50, especially also
those with -7 for instance abnormalities where this is a
sign also of maybe inherited mutation, mutations like GATHA 2
or also the Funcone. So I think a brief history is
important. Cancer in the family?
Also cutaneous malformation Source or something like this?
And also of course, if you want to transplant then.
It's yes, yes, also the donor. And if it's a sibling donor,
this would also require work up. There are a lot of revenues now
on this topic and I think it's a very, very fascinating arena.
We we jumped in because there are many, many genetic traits
and predisposition, predisposition for patients
maybe more than we thought. But again, I come back to what I
said before Kirsten, I think you agreed on that.
Think about the consequences for a family trade and for all the
people before you tick mark this analysis and to know that you
may develop MD's in the next 20 to 25 years with the likelihood
of 50%. Let's say it this way.
Does it really help you and what what are do we have any
interceptive medicine at this stage?
I don't think we have and maybe you need an antidepressant pill
then as an interceptive medicine because you get so depressed
that you will maybe get MDFS in 20 years and you forget to live
and. That's the worst thing that can
happen, yeah. That's the worst thing which can
happen. And therefore I think it
requires into this interdisciplinary work up,
interdisciplinary collaboration with people who understand the
consequences not only I think from a life prognosis
perspective, but also from an emotional perspective and
psychological perspective. And that's what we what we
basically do here or what we tried to do.
But I think it is a very wide open box at the moment.
And if you enter it, I think you may basically sequence almost
every patient at the end of the day and also the family.
And I'm not talking about resources here.
This is not my subject because I'm a doctor and I wanted would
like to help patients but it's about consequences.
Yeah, yeah, yeah. This should have some
consequences actually when you do these advanced things and
when you challenge patients in that way.
Also. I think this is also a little
bit of an issue with if we go to the other end of the scene, sort
of the you know, if you have mutations than Ted 2 and you're
obviously not particularly sick. I mean if you have a secrets
with Ted 2 so so so is this you know, is this another group
where you should be a little bit careful?
I mean, because the thing you know you we also know that can
predispose to other things. And how do you inform these
patients if you find, you know, a mild anemia with the tip 2?
Mutation, I mean the immediate consequence for this is
basically surveillance and observation, especially majority
of these patients, it's just finding by chance.
So just we'll put the work up at the GP and then yeah, if if they
have a tech mutation, well, I mean this is definitely a clonal
disease. This is this that the patient
needs to know that this is not like reactive anemia, it's a
clonal disease. But what I basically do is that
I tell them that it's rather unpredictable when the disease
may further. Further evolve of course with
the tattoo mutation, the single mutation only maybe mild anemia.
The risk to to undergo this disease evolution within the
next 12 months into an MD's is rather unlikely.
But you never know of course in a given patient.
So I think the the immediate consequence is good.
A good relationship with the patient is to comfort the
patient and is also to implement a strategy of surveillance with
rather blood count assessment, which brings the patient into a
position of comfort where he or she feels embedded into a
strategy where all the the risk are mitigated or basically are
predictable and the patient feels safe and well with the
strategy. I think this is the immediate,
immediate the consequence of such findings rather than an
interceptive approach or early EPO into production or these
kind of things. I think it's rather the psycho
oncology around this. I mean, if you measure things,
if you detect things, you need to live with the consequences.
And I mean this not for the patient, I mean this rather for
the doctor. Yeah, that's true.
It's also true. So I think one thing we didn't
touch up on is the the P53 mutations, what I mean and the
IPSSM and and and how we can use this in a good way I mean.
I think the IPSSM, one of the novelties of IPSSM was the
implementation of P53 not as a stand alone mutation, but given
the risk of B allelic alterations or inactivations
either by mutation or by deletion.
Those are those one, those are the ones being associated with a
very bad prognosis. Whereas a patient with a stand
alone single Axon mutation is is still not a very good prognosis,
but it's much better than the patients with this B allelic
alteration. I think would you use that when
you choose who to transfer? Yes.
And I, I must tell you I would rather, I mean the B allelic are
really the worst and whatever you do it it doesn't work.
So I would, I mean maybe you have expected the answer that I
say I would transfer the B allelic but I would rather say I
would transfer the non B. Allelic.
No, that's what I would do that. Too Exactly.
Yeah, that's what I think. That's what our transplanted
says too. I mean it's.
Not yes, yes. I mean, we, we, we, we currently
have a patient here with B allelic PP3 complex care type
who had EB2 and developed AML very early.
Thereafter got an induction chemotherapy, did not respond,
got azocydin slash, decided when we switched because of P53.
Then later when it took like 3 cycles, did not respond.
Is still in a good condition, but it's basically full of MD's
slash AML, the cells in the bone marrow.
So we decide not to transplant because you would not get this
patient into long term remission.
So this is I think we need other tools, we need maybe car T's, we
need immune therapy for these patients.
There are also other agent as you know in development.
But I would as you said before in the with the B allelic, I
think the only chance of cure potentially cure is that you
induce certain level of remission before transplant and
then you go maybe you go for MRD driven approaches after or
maintenance or whatever. A patient who has biletic
disease and is uncontrolled still with excessive blast but
before transplant, I would not under, I would not go for
transplant. And then there are those very
rare cases with less than 5% blast and maybe pancytopenia.
So these are patients at this stage of developing higher risk
MD's within the next three to six months.
Those ones I think you may transplant upfront and don't go
for any prior therapy, but again, still long term Disease
Control can be achieved in less than 20% of patients.
Yeah. So this is really still a tough
case, I guess. Good.
I think we were came around a lot of issues here whereas is
there anything else you want to add or out prognosis and
prognostication? I think what I would I'd like to
add is that don't only look at the genes, also look at the
patients. Yeah, that's so important.
Yeah. Maybe we actually need a new
prognostication where you actually include also
comorbidities and, you know, age of the patients and sort of in a
way in the future. I don't know.
What do you think about immunology?
Actually, yes, immunology ever be part of?
This is very important. There is an initiative led by
Sharam called St. Now to bring up a work group
maybe into this, into this. I think we what would be #1 what
we need is proper and homogenized assessment of
immunologic factors in NDS at, at diagnosis.
And also we need to understand be correlated.
Now drag activity with mutations or blast counts or transfusion
or EPO level, but we never correlate them with any
immunological marker. So.
If this work has to be done, and then yes, I fully agree that at
the long run there's a high chance that this may be
integrated. Yeah, that would be very
interesting. And you know, the only thing
that cures and yes, is immunology, some sort of
immunology and transportation, right, Although we don't know
exactly what it is. So yeah, well, I think we came
around a lot of issues here. So thank you so much for your
time. I know how busy you are, so it
was really nice. Thank you.
Thanks for having me.