Latest / EHA Unplugged / Is low-risk MDS really low risk? (with Prof Uwe Platzbecker)

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Is low-risk MDS really low risk? (with Prof Uwe Platzbecker) · EHA Unplugged

• 0:07
  Greetings and welcome to EHA Unplugged, the official podcast
• 0:11
  channel of the European Hematology Association EHA.
• 0:15
  OK, good afternoon. I would like to welcome
• 0:19
  Professor Rusbecker from the University Clinic of Leipzig in
• 0:22
  Germany. Well, Platt Speaker has been
• 0:25
  working with MD's as long as I can remember and has been
• 0:29
  running a lot of clinical trials, but also translation
• 0:32
  research. And I think you have at least I
• 0:35
  remember a lot of trials also in low risk MD's.
• 0:38
  And I think that's the main topic of of today is low risk
• 0:42
  low and, and how can we use these prognostic indexes.
• 0:48
  So what do you think about using prognostic indexes and low risk
• 0:51
  MD's? Can you sort of elaborate a bit
• 0:54
  on that? Yeah, thank you.
• 0:56
  Just also I would also for this complex question, I would like
• 1:00
  to challenge you in in reverse about the terminology low risk.
• 1:08
  I mean, you know, you, you, we both know that this terminology
• 1:11
  is still coming from the old days when MD asked at least at
• 1:16
  some point was not considered to be a cancer, maybe mild anemia,
• 1:21
  thrombocytopenia, whatever. And it was not clear what the
• 1:25
  cell of origin and also the mutation, the landscape I think
• 1:28
  at this stage was not not known. So I think from from the old
• 1:32
  days, the MD's subtypes were differentiated into low risk or
• 1:38
  lower risk and higher is based on the natural course of the
• 1:41
  disease. And you mentioned the scoring
• 1:44
  systems which at the very beginning like IPSS were a
• 1:49
  reflection of patients who actually received only
• 1:53
  transfusions or antibiotics, sometimes growth factors.
• 1:57
  So the natural course of the disease was served and therefore
• 2:01
  patients were differentiated into lower risk and higher risk.
• 2:04
  Meanwhile, the recent update of The Who classification reflected
• 2:10
  or is now reflecting much better that MD's is not renal anemia.
• 2:15
  It's now called myoplastic neoplasm.
• 2:18
  Still the terminology MD's remains, but I think it's
• 2:22
  important to say that it's it's a cancer sometimes very
• 2:25
  aggressive with immediate survival in higher risk patients
• 2:28
  of less than six months based on also recent molecular work up.
• 2:31
  So now I will try to answer your question what what is low, what
• 2:37
  is low risk and how to differentiate.
• 2:41
  I think we have the IPSSR which I think we both now use for a
• 2:47
  couple of years. And also the IPSR has come also
• 2:51
  has been introduced into clinical trials and also
• 2:53
  approval of agents like lispatacept where the clinical
• 2:58
  trial was actually based on IPSSR.
• 3:01
  On the other side, the majority of the drugs we still have in in
• 3:05
  MD's like azazidine E PO, both are improved on the IMPSS.
• 3:10
  So the old classification and I will give you I think a very
• 3:15
  good example why the IPS is valid and is, is, is is very
• 3:19
  good for for prognostication. But we're also the molecular
• 3:26
  work up I think is important with regards to maybe also
• 3:30
  treatment decisions. So for instance a patient with
• 3:33
  ring sylloblastic phenotype with neutropenia O .7 with mild
• 3:40
  thrombocytopenia but being heavily transfusion dependent
• 3:44
  and an SFTB 1 mutation can still can or basically will be in the
• 3:50
  box of so-called IPSSR intermediate being eligible for
• 3:55
  loose patacet for instance as a second line therapy.
• 3:58
  On the other side, the same patient maybe also with ring
• 4:01
  cytoplastic phenotype just by morphology, but with other
• 4:05
  splices of mutations and maybe also with AP53 mutation, which
• 4:09
  sometimes occurs also ring cytoplastic phenotype.
• 4:12
  Patients outside as if we want may still be just from
• 4:18
  morphology, blood counts and blast counts in the same box
• 4:23
  intermediate, but the prognosis is much worse in patients.
• 4:27
  So this is a long answer to a short question, but I think you
• 4:31
  touched base with a very complex and puzzling thing, which I
• 4:37
  think now also when talking to fellows and also to to
• 4:42
  hematologist, I think they are sometimes puzzled which score to
• 4:46
  use. So I think the bottom line
• 4:48
  message is IPSSR is still a valid score and very low, low
• 4:54
  and parts of intermediate I would say are the lower risk
• 4:58
  where prognosis even with supportive care can be
• 5:02
  considered as in years and therefore it's they are lower
• 5:05
  risk. But IPSSM, and I guess you come
• 5:09
  to that in a second, has challenged this a bit.
• 5:13
  Absolutely, Yeah, Yeah, I think this was very foreign nice
• 5:17
  explanation on how this can actually really change the way
• 5:20
  we see some of these low risk diseases.
• 5:22
  So, so do you think we can use this also when we when we want
• 5:26
  to select which patients to transplant early, I mean to
• 5:29
  transplant in the lower states? Have you any?
• 5:34
  I think we can, but transplant is not like mild surgery.
• 5:43
  As you know, the intention is to replace the bone marrow and and
• 5:46
  to to reset the immune system. But still there is an
• 5:50
  unpredictable risk of mortality which is in the range of five to
• 5:54
  10% in the in the during the first year, irrespective whether
• 5:58
  you do everything right, you select the right donor, it's
• 6:02
  it's unpredictable and therefore you again touch base in a very
• 6:07
  important thing. We have very good scores.
• 6:10
  We can select patients being lower risk by traditional tools,
• 6:15
  but now being higher risk by implementing also the genetics.
• 6:20
  But we only have a couple of agents.
• 6:24
  Basically we have one agent as a Sidon and we have an approach
• 6:28
  called allogeneic stencil transplantation and that's it.
• 6:30
  So we don't have anything or only limited armamentarium of
• 6:37
  weapons, if I may use this word here in this, in this context to
• 6:43
  change the course of the disease.
• 6:45
  And I think that's the dilemma we have now.
• 6:48
  I think we should not stop to score patients, but I think we
• 6:53
  should rather work on agents which may patients with let's
• 6:58
  say lower, higher risk may benefit and which may alter the
• 7:01
  disease course. So also talking about these new
• 7:04
  classifications, you know, how, how, how good are they?
• 7:08
  If you go to the very early stage MD's, you know, the sea
• 7:12
  cost and I mean, can we use them there or because I think, you
• 7:16
  know, that creates a new type of this thesis that we see in our
• 7:19
  departments and we all discussing what to do with them.
• 7:23
  Should we follow them? Should we, what should we do?
• 7:25
  And what's your opinion on that? What you do?
• 7:27
  What would you do and do you do in life?
• 7:30
  Yeah. So the, let's say IPSSR and also
• 7:34
  the IPSSM are not traditionally developed for CKAS patients.
• 7:39
  There are numerous papers of course on CKAS where the bottom
• 7:45
  line message basically is the number of mutations, the type of
• 7:49
  mutations and the allelic burn and the level of cytopenia.
• 7:53
  So very, very clear. I think a prognostic variables
• 7:58
  predict the disease progression and I think, but still it's,
• 8:03
  it's there's a great variability and many of these patients are
• 8:06
  older. So the question is what is the,
• 8:09
  what is the workflow? What is the follow up?
• 8:11
  I think this is still under investigation.
• 8:14
  The way we do it at least in life sick is that we look for
• 8:19
  all these variables. So type of mutations for
• 8:22
  instance TET DMT 3A is rather neutral from a prognosis of
• 8:26
  mild, whereas ASAX one or additional mutations like 234
• 8:33
  predict a much higher risk to undergo or to develop MD's.
• 8:39
  So these patients let's say with a higher risk, we follow up
• 8:42
  every three to six months or the other ones we see maximum once a
• 8:47
  year. Yeah, I think I would say the
• 8:50
  same. You know, that's about what we
• 8:52
  do. That's good.
• 8:53
  To hear of. Course, I think what about now
• 8:57
  to go a little bit back to what you talked about before, because
• 9:00
  now that we have this new classification, what do you do
• 9:02
  with all the results from before?
• 9:04
  I mean, from the clinical trials that we have?
• 9:07
  Are we going to go back and try to to to sequence the material
• 9:11
  if we have it and and maybe re evaluate for example, the
• 9:14
  indications for those peticept or you know what's, or do you
• 9:17
  already have those data? No, I mean we, we don't or at
• 9:23
  least I myself don't doesn't have it.
• 9:27
  But what we what we know from already published data.
• 9:31
  For instance, Matteo de la Porter just published a paper
• 9:35
  where we were Co authoring and we also provided some some some
• 9:41
  data or some data set of patients is that the IPSSM has a
• 9:47
  new scoring system is prognostic irrespective of what you do.
• 9:55
  So let's say if you transplant, of course the, the patients with
• 9:59
  a, with a, with a high or very high do much better than if you
• 10:05
  gave Azacitin or if you basically observe the natural
• 10:09
  cause of the disease. But the demarcation between
• 10:12
  these groups remains the same. So let's say that the there's a
• 10:17
  little upgrade with the survival curves, maybe also based on
• 10:20
  selection of age and common abilities and so on.
• 10:23
  But the IPSSM at least in the majority of analysis published
• 10:28
  or now presented at the ASH meeting where there were a
• 10:31
  couple of IPSSM based on analysis with retrospective,
• 10:36
  they all look the same. So the IPSSM remains valid
• 10:41
  irrespective of what you do. And I think this is also
• 10:44
  something where we could learn from and the, the concept, I
• 10:50
  think the next concept should be that we are as precise as
• 10:54
  targeted as possible and maybe improve the prognosis of
• 10:59
  molecular defined or molecular driven subgroups of patients
• 11:03
  like IDHP tailed patients for instance, or yeah, 50P mutated
• 11:06
  patients. I think this, this should be the
• 11:09
  next, the next step because what we, the kind of therapy we
• 11:14
  currently apply is very broad and very unselected.
• 11:17
  So therefore I think the IPSSM is still valid across all these
• 11:25
  different unselected therapies. Yeah, and and how difficult is
• 11:30
  it to use the IPSSM? I mean, what does it take?
• 11:35
  Well, it takes a minute at least I would say.
• 11:39
  And of course #1 it, it takes, it takes an NGS based panel
• 11:46
  where I think we do it in our academic center because we are
• 11:51
  very curious and you know, we would like to learn but and so
• 11:54
  on. But would I recommend it on a
• 11:56
  broad scale for every patient? I wouldn't say so.
• 11:59
  I mean, it's also a question of resources, of course.
• 12:02
  But the question is if you have the 81 year old woman with a
• 12:08
  Dell 5 QMDS being reptiles as fusion dependent, I think I
• 12:13
  would go for P53 mutation analysis.
• 12:15
  But apart from this, maybe to go to look for flat 3 KMT 2A and
• 12:21
  all these things could be of course of interest, maybe you
• 12:25
  find very small clones. But the question is what does it
• 12:28
  change or does it change anything?
• 12:31
  So I think at this stage I would recommend it for every patient
• 12:35
  being eligible for allergenic stem cell transplantation.
• 12:38
  So every patient less the below the age of 70, all the patients
• 12:44
  above where you have a clear MDMS diagnosis based on genetics
• 12:49
  side genetics, morphology, Histology.
• 12:52
  So if if everything is clear and you have a treatment option
• 12:56
  which is valid, which should work let's say ESA or let's say
• 13:01
  lispatiscept in lower risk patients.
• 13:05
  So there is even if you know that the disease may be more
• 13:09
  aggressive or less aggressive, it doesn't change your treatment
• 13:12
  paradigm. This is, I think, the the issue
• 13:15
  and it may rather irritate or bewilder the patient who then
• 13:20
  thinks, well, I belong to the to the bad guys, although my blood
• 13:24
  counts are still very good. So I'm concerned now and and
• 13:29
  actually they will maybe suffer from a worse quality of life
• 13:36
  irrespective of a treatment of a treatment response which may
• 13:39
  occur irrespective of IPSSM. So this is I think needs to be
• 13:44
  balanced and also some patients want to know their prognosis,
• 13:49
  their putative prognosis, some may not.
• 13:51
  So I think before you tick Mark, you know on the on the lab
• 13:56
  report that you wanted 50 genes analysis, which is can be done
• 14:00
  as you know Kirsten within 2 seconds.
• 14:05
  And then you, you know, a lot of workload is generated before you
• 14:08
  do that. Think about it.
• 14:10
  I. Think that's a very good advice.
• 14:12
  And I think that's, that's where people have actually also come
• 14:15
  into trouble sometimes. I think particularly with also
• 14:20
  patients that do not want to know everything.
• 14:21
  And I think you need to, to be very clear about that before you
• 14:25
  you start also because some of the panel nowadays also have all
• 14:28
  the, the hereditary, the genes that are involved in hereditary
• 14:32
  myeloid cancer. So.
• 14:34
  So how do you handle that? Yeah #1 I mean, it's, we know
• 14:42
  now that for instance, DX 41 is not restricted to younger
• 14:48
  patients, you know, so this is something which can occur at the
• 14:53
  age of 7080. Even MD's, these patients seem
• 14:56
  to have a more, let's say B9A course of the disease.
• 15:02
  So how do we handle that? I mean, number one, in my
• 15:05
  country, if you go for inherited mutations, if you really do do
• 15:11
  this work up like the one I just mentioned or, or geta 2 or
• 15:18
  others, you need to get a consent.
• 15:20
  Oh yeah. I mean this is the same.
• 15:22
  Way do Don't you have it in the regular pens as well?
• 15:26
  We sometimes, yes, we some no, we, you are right.
• 15:29
  We just amended it. So I have to admit it's there,
• 15:32
  but still it requires consent. And again, this is something
• 15:40
  which also has consequences for the family, for everybody.
• 15:44
  And again, the, I mean, if the patient got MD's at the age of
• 15:49
  82 and before was basically was healthy, everything was fine.
• 15:54
  So you can get MD's at the age of 82.
• 15:57
  There's nothing weird about it and it's nothing which may cause
• 16:01
  a genetic work up of the entire family.
• 16:04
  So we counsel the patient, we counsel also with our genetic
• 16:07
  specialist, and then we draw conclusions.
• 16:10
  I I think I would do it genetic work up with inherited genes in
• 16:17
  every younger patients but below the age of 50, especially also
• 16:21
  those with -7 for instance abnormalities where this is a
• 16:27
  sign also of maybe inherited mutation, mutations like GATHA 2
• 16:33
  or also the Funcone. So I think a brief history is
• 16:39
  important. Cancer in the family?
• 16:42
  Also cutaneous malformation Source or something like this?
• 16:45
  And also of course, if you want to transplant then.
• 16:48
  It's yes, yes, also the donor. And if it's a sibling donor,
• 16:52
  this would also require work up. There are a lot of revenues now
• 16:55
  on this topic and I think it's a very, very fascinating arena.
• 17:00
  We we jumped in because there are many, many genetic traits
• 17:05
  and predisposition, predisposition for patients
• 17:08
  maybe more than we thought. But again, I come back to what I
• 17:12
  said before Kirsten, I think you agreed on that.
• 17:14
  Think about the consequences for a family trade and for all the
• 17:19
  people before you tick mark this analysis and to know that you
• 17:27
  may develop MD's in the next 20 to 25 years with the likelihood
• 17:32
  of 50%. Let's say it this way.
• 17:34
  Does it really help you and what what are do we have any
• 17:38
  interceptive medicine at this stage?
• 17:43
  I don't think we have and maybe you need an antidepressant pill
• 17:47
  then as an interceptive medicine because you get so depressed
• 17:52
  that you will maybe get MDFS in 20 years and you forget to live
• 17:56
  and. That's the worst thing that can
• 17:58
  happen, yeah. That's the worst thing which can
• 18:00
  happen. And therefore I think it
• 18:03
  requires into this interdisciplinary work up,
• 18:07
  interdisciplinary collaboration with people who understand the
• 18:10
  consequences not only I think from a life prognosis
• 18:16
  perspective, but also from an emotional perspective and
• 18:19
  psychological perspective. And that's what we what we
• 18:24
  basically do here or what we tried to do.
• 18:27
  But I think it is a very wide open box at the moment.
• 18:32
  And if you enter it, I think you may basically sequence almost
• 18:37
  every patient at the end of the day and also the family.
• 18:40
  And I'm not talking about resources here.
• 18:42
  This is not my subject because I'm a doctor and I wanted would
• 18:46
  like to help patients but it's about consequences.
• 18:51
  Yeah, yeah, yeah. This should have some
• 18:53
  consequences actually when you do these advanced things and
• 18:57
  when you challenge patients in that way.
• 18:59
  Also. I think this is also a little
• 19:01
  bit of an issue with if we go to the other end of the scene, sort
• 19:04
  of the you know, if you have mutations than Ted 2 and you're
• 19:09
  obviously not particularly sick. I mean if you have a secrets
• 19:13
  with Ted 2 so so so is this you know, is this another group
• 19:18
  where you should be a little bit careful?
• 19:19
  I mean, because the thing you know you we also know that can
• 19:22
  predispose to other things. And how do you inform these
• 19:25
  patients if you find, you know, a mild anemia with the tip 2?
• 19:28
  Mutation, I mean the immediate consequence for this is
• 19:35
  basically surveillance and observation, especially majority
• 19:39
  of these patients, it's just finding by chance.
• 19:42
  So just we'll put the work up at the GP and then yeah, if if they
• 19:46
  have a tech mutation, well, I mean this is definitely a clonal
• 19:50
  disease. This is this that the patient
• 19:52
  needs to know that this is not like reactive anemia, it's a
• 19:57
  clonal disease. But what I basically do is that
• 20:00
  I tell them that it's rather unpredictable when the disease
• 20:05
  may further. Further evolve of course with
• 20:08
  the tattoo mutation, the single mutation only maybe mild anemia.
• 20:12
  The risk to to undergo this disease evolution within the
• 20:17
  next 12 months into an MD's is rather unlikely.
• 20:20
  But you never know of course in a given patient.
• 20:24
  So I think the the immediate consequence is good.
• 20:29
  A good relationship with the patient is to comfort the
• 20:33
  patient and is also to implement a strategy of surveillance with
• 20:39
  rather blood count assessment, which brings the patient into a
• 20:45
  position of comfort where he or she feels embedded into a
• 20:51
  strategy where all the the risk are mitigated or basically are
• 20:58
  predictable and the patient feels safe and well with the
• 21:04
  strategy. I think this is the immediate,
• 21:06
  immediate the consequence of such findings rather than an
• 21:10
  interceptive approach or early EPO into production or these
• 21:14
  kind of things. I think it's rather the psycho
• 21:18
  oncology around this. I mean, if you measure things,
• 21:23
  if you detect things, you need to live with the consequences.
• 21:27
  And I mean this not for the patient, I mean this rather for
• 21:29
  the doctor. Yeah, that's true.
• 21:31
  It's also true. So I think one thing we didn't
• 21:34
  touch up on is the the P53 mutations, what I mean and the
• 21:40
  IPSSM and and and how we can use this in a good way I mean.
• 21:46
  I think the IPSSM, one of the novelties of IPSSM was the
• 21:51
  implementation of P53 not as a stand alone mutation, but given
• 21:57
  the risk of B allelic alterations or inactivations
• 22:03
  either by mutation or by deletion.
• 22:06
  Those are those one, those are the ones being associated with a
• 22:10
  very bad prognosis. Whereas a patient with a stand
• 22:15
  alone single Axon mutation is is still not a very good prognosis,
• 22:21
  but it's much better than the patients with this B allelic
• 22:26
  alteration. I think would you use that when
• 22:28
  you choose who to transfer? Yes.
• 22:31
  And I, I must tell you I would rather, I mean the B allelic are
• 22:37
  really the worst and whatever you do it it doesn't work.
• 22:42
  So I would, I mean maybe you have expected the answer that I
• 22:47
  say I would transfer the B allelic but I would rather say I
• 22:50
  would transfer the non B. Allelic.
• 22:52
  No, that's what I would do that. Too Exactly.
• 22:55
  Yeah, that's what I think. That's what our transplanted
• 22:57
  says too. I mean it's.
• 22:58
  Not yes, yes. I mean, we, we, we, we currently
• 23:01
  have a patient here with B allelic PP3 complex care type
• 23:05
  who had EB2 and developed AML very early.
• 23:10
  Thereafter got an induction chemotherapy, did not respond,
• 23:14
  got azocydin slash, decided when we switched because of P53.
• 23:18
  Then later when it took like 3 cycles, did not respond.
• 23:22
  Is still in a good condition, but it's basically full of MD's
• 23:26
  slash AML, the cells in the bone marrow.
• 23:29
  So we decide not to transplant because you would not get this
• 23:33
  patient into long term remission.
• 23:34
  So this is I think we need other tools, we need maybe car T's, we
• 23:38
  need immune therapy for these patients.
• 23:41
  There are also other agent as you know in development.
• 23:44
  But I would as you said before in the with the B allelic, I
• 23:49
  think the only chance of cure potentially cure is that you
• 23:54
  induce certain level of remission before transplant and
• 23:58
  then you go maybe you go for MRD driven approaches after or
• 24:01
  maintenance or whatever. A patient who has biletic
• 24:05
  disease and is uncontrolled still with excessive blast but
• 24:10
  before transplant, I would not under, I would not go for
• 24:14
  transplant. And then there are those very
• 24:16
  rare cases with less than 5% blast and maybe pancytopenia.
• 24:21
  So these are patients at this stage of developing higher risk
• 24:25
  MD's within the next three to six months.
• 24:27
  Those ones I think you may transplant upfront and don't go
• 24:33
  for any prior therapy, but again, still long term Disease
• 24:37
  Control can be achieved in less than 20% of patients.
• 24:41
  Yeah. So this is really still a tough
• 24:44
  case, I guess. Good.
• 24:46
  I think we were came around a lot of issues here whereas is
• 24:51
  there anything else you want to add or out prognosis and
• 24:55
  prognostication? I think what I would I'd like to
• 24:59
  add is that don't only look at the genes, also look at the
• 25:02
  patients. Yeah, that's so important.
• 25:06
  Yeah. Maybe we actually need a new
• 25:07
  prognostication where you actually include also
• 25:10
  comorbidities and, you know, age of the patients and sort of in a
• 25:14
  way in the future. I don't know.
• 25:16
  What do you think about immunology?
• 25:18
  Actually, yes, immunology ever be part of?
• 25:22
  This is very important. There is an initiative led by
• 25:25
  Sharam called St. Now to bring up a work group
• 25:29
  maybe into this, into this. I think we what would be #1 what
• 25:33
  we need is proper and homogenized assessment of
• 25:37
  immunologic factors in NDS at, at diagnosis.
• 25:41
  And also we need to understand be correlated.
• 25:44
  Now drag activity with mutations or blast counts or transfusion
• 25:50
  or EPO level, but we never correlate them with any
• 25:54
  immunological marker. So.
• 25:56
  If this work has to be done, and then yes, I fully agree that at
• 26:00
  the long run there's a high chance that this may be
• 26:05
  integrated. Yeah, that would be very
• 26:08
  interesting. And you know, the only thing
• 26:11
  that cures and yes, is immunology, some sort of
• 26:13
  immunology and transportation, right, Although we don't know
• 26:16
  exactly what it is. So yeah, well, I think we came
• 26:19
  around a lot of issues here. So thank you so much for your
• 26:22
  time. I know how busy you are, so it
• 26:24
  was really nice. Thank you.
• 26:27
  Thanks for having me.