Latest / EHA Unplugged / From MDS to AML: Genetics of Progression (featuring Prof Lars Bullinger)

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From MDS to AML: Genetics of Progression (featuring Prof Lars Bullinger) · EHA Unplugged

• 0:07
  Greetings and welcome to EHA Unplugged, the official podcast
• 0:11
  channel of the European Hematology Association EHA.
• 0:15
  So I would like to welcome Professor Las Bulinga from
• 0:18
  Shiaji University of Medicine in Berlin.
• 0:21
  And he's going to talk to us about how we can actually look
• 0:27
  at the progression from MD's to AML with respect to genetics.
• 0:32
  So please last. Yeah, hi Kirsten, thanks a lot
• 0:35
  for the invitation to be with you today.
• 0:38
  And I'm yeah, happy to to give you, let's say my view of
• 0:42
  things. I mean as as many all, I think
• 0:45
  almost all of you are there. Recently there have been some
• 0:48
  changes. We now have the new WHO
• 0:50
  classification. Now we have a new category or
• 0:55
  order, let's say the cloning hematopoiesis of indeterminate
• 0:59
  potential made it into The Who it's called myeloid precursor
• 1:03
  lesions that cohort. And then we also already
• 1:07
  distinguish the CLO or we take into account the clonal
• 1:11
  evolution when Chip that develops towards MD's.
• 1:15
  We have have also the category of C CAS clonal cytopenia of
• 1:21
  undetermined significance. And then if if you look at at
• 1:25
  myelodysplasia, it's now called myelodysplastic neoplasms, even
• 1:29
  though we still stick to the same abbreviation MD's
• 1:35
  myelodysplastic syndromes in the past.
• 1:37
  But here the the novelty is now that we have more genetically
• 1:42
  defined subgroups. And in my opinion also the
• 1:45
  classification became a little bit more easy, straightforward,
• 1:49
  yeah. And then with regard to AML,
• 1:53
  there's also more genetically defined cohorts.
• 1:57
  And the other problem or, or what makes our lives a little
• 2:00
  harder is that we now have The Who and the international
• 2:03
  consensus classification. Perhaps we can also talk about
• 2:06
  that. I think maybe we should, yeah,
• 2:08
  talk about that later because I think, I really think that that
• 2:11
  is a challenge for many clinicians at the moment, right.
• 2:14
  So, yeah. But also the the the new
• 2:17
  category in the minor precursor lesions, I mean, how do you how
• 2:20
  do you place that in your own institution?
• 2:24
  Do you see these patients or is it?
• 2:26
  Yeah. Yeah.
• 2:26
  So I mean, of course as more and more sequencing is done, right,
• 2:31
  I mean they are then also detected by chance very often
• 2:35
  they also detected if for example patients are screened
• 2:38
  for other cancers. The question is what what do we
• 2:43
  do with that? Whom should be what?
• 2:46
  Yeah, consider for watching rating.
• 2:48
  And then of course also it will become more and more an issue if
• 2:52
  if you think of autologous or allergenic transplantation, sure
• 2:59
  what what to do with those lesions there as well?
• 3:02
  Yeah, exactly. Yeah, yeah.
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  There's a lot of new things to to learn there still, I think.
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  Yeah. So I mean I think what is what
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  is known so far is that the the older we get, we acquire like
• 3:12
  every 1010 years one to two new mutations in our hematomatic
• 3:17
  stem cell compartment. And I think then if one of them
• 3:20
  takes or provides that proliferative advantage and we
• 3:24
  accumulate them, another thing I think we we have to learn more
• 3:28
  about and to consider is then of course also, for example, you
• 3:32
  have cloning that agrees with the T53 mutant sub clone and you
• 3:35
  are diagnosed with breast cancer, for example.
• 3:38
  Do we have to also take more? Yeah.
• 3:43
  Sophisticated. Care of these patients.
• 3:45
  Exactly. Yeah, maybe we need to choose
• 3:47
  another different kind of treatment, right?
• 3:49
  Sometimes, yeah. So I think there's a lot of
• 3:51
  things to learn there. And also sometimes it's an
• 3:53
  advantage to have cloning degrees, as I understand it,
• 3:56
  right? So yeah, this I think, was shown
• 3:58
  in your institution also. So yeah, in transplantation,
• 4:02
  right, in donors. So yes, yes, so nice work
• 4:05
  published by federally comes group.
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  But the interesting thing here the there was some slight
• 4:11
  increase in, in let's say transplant related leukemia or
• 4:18
  leukemia from the donor donor derived leukemia.
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  It was slightly elevated. But on the other hand that the
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  risk of, of relapse was lower because the of this more
• 4:29
  inflammatory phenotype. And I think this favors TVHD and
• 4:32
  therefore the, the the the the leukemic clone might be
• 4:36
  controlled better. So yeah, exactly.
• 4:39
  Yeah. Double edged sword or advantages
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  and disadvantages. But the the question is what do
• 4:44
  we do then we see cus right? What?
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  Yeah. I think that's a, that's a very
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  interesting group of patients because those we do get referred
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  all the time, right, because they have cytopenia.
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  So, So what what? How would you handle that in
• 4:56
  your institution? So usually we, we, we monitor
• 5:00
  them closely, watch and wait. And yeah, but also depending, of
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  course, also how, how, I mean you always have to take into
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  account the how the the patient feels about the disease.
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  I mean, for many of them there, there is something wrong, right.
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  And they have a problem with waiting and just watching it,
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  whereas others, yeah, don't want us treatment anyway.
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  Yeah, it's a difficult. So and also I think you know,
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  it's sometimes a problem we really don't have anything to
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  offer them. So, so do you think this is a
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  new area for clinical trials maybe if we can?
• 5:36
  Definitely, Yeah, I think we we have to collect more data and
• 5:41
  and do prospective trials completely agree.
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  And of course also monitor the disease perhaps more broadly
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  with novel innovative technologies to, to to capture
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  the the clonal evolution and perhaps we can identify new
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  markers that let us distinct the the ones that are really at risk
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  for moving forward versus the ones that are stable.
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  Yeah, because one thing I also think though, when when we talk
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  about clone heap which freezes at least for most, most cases,
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  we don't think about the, the, the additional structural
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  variations so far or the the consumer operation.
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  So I guess, I guess maybe maybe when we have the whole puzzle,
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  maybe maybe we can identify some some.
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  If you, if you think how fast these technological developments
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  are moving forward, I mean, now with novel or 4th generation
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  sequencing technologies, I mean, there is benchtop sequencers
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  that, that even allow you to do a genome overnight to, to
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  capture the structural variations such as specific
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  Biosciences on nanopore. And, and also those technologies
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  get better and better with regard to the signal nuclear
• 6:54
  type variations so that we also can comprehensively capture them
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  and do not only have to rely on on panels anymore.
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  Because here we also see the how, how things are moving
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  forward. I mean, if, if you think of the
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  ESMO guidelines, there were, there were already many
• 7:09
  mutations described. But on the other hand, if you
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  look at current reviews, of course, there's many more the S
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  related mutations that have been reported so far.
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  They, they tend to cluster of course into the gene categories
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  that are linked to clonal hematopoiesis, the epigenetic
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  regulators, the spices on genes cohesing complex.
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  But then of course we also have these mutations and
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  transcription factors that predispose to to MD's, which you
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  already can have as a child, right?
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  Yeah, exactly that that category is also growing quite
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  significantly these years because of the the whole genome
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  sequencing and and studies and and I think one important or
• 7:53
  interesting thing there is that you see it also, I mean that you
• 7:56
  discover it in in in elderly patients this.
• 8:00
  Was the most amazing thing for me.
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  For example, if you think of DDX 41 right, I mean that that can
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  take 5060 years until you then or to acquire that additional
• 8:12
  hits to then transform you into an MD's or an AML.
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  And, and I think it's interesting what it will do to
• 8:20
  families that we find these things, you know, at the latest,
• 8:24
  you know, it's. That's true.
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  I mean, yeah, that that's definitely a good, good thing to
• 8:30
  point. I mean, if if you think how
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  short really we are of geneticists who can do the
• 8:37
  counselling. And I think this is an area
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  where I think hematologists, oncologists really should also
• 8:44
  should be trained on. Yeah, I think that's a very good
• 8:46
  idea to. Do that ourselves in the future.
• 8:48
  Yeah, yeah. Yeah, that's a great.
• 8:51
  Yeah, We'll make a course. Yeah, definitely.
• 8:55
  Especially as if you now look at The Who classification and those
• 9:00
  those mutations really also make it into the the classification
• 9:04
  right there. We now have the new category
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  with S, S, B1SF3B1 mutations and low blasts and also the
• 9:13
  important category in my opinion with with bilelic P53IN
• 9:16
  activation. Yeah.
• 9:19
  But I think the nice thing about this, I mean the scheme you have
• 9:22
  here is that it actually, you know, it, it makes it more
• 9:25
  clinically relevant and, and a little bit more simple than we
• 9:28
  were used to when we had MD's classifications.
• 9:30
  And I think it's really nice that that there is now this
• 9:34
  consideration of what is clinically relevant because
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  otherwise for clinicians, this has been a nightmare sometimes
• 9:40
  for the MD's. I fully agree.
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  And before I became a hematologist this, I mean there
• 9:45
  was always hard to understand MD's right student.
• 9:51
  Yeah, yeah, definitely. Also I think the the categories
• 9:55
  are more straightforward. Of course there is still this
• 9:57
  discussion and this is yeah, perhaps what we will talk about
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  at the end. So when, when is it still an
• 10:02
  MD's and when is it progressing really into an AML and when
• 10:07
  should the treatment? Yeah, yeah.
• 10:12
  I think, you know, classifications are nice, but
• 10:14
  but, but but of course, patients are different, right?
• 10:16
  So I think yes. And on the other hand, I mean,
• 10:19
  it's, I mean, this is how the biology is.
• 10:21
  It's, it's really a continuum, right?
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  And while not some some, some diseases might still already
• 10:28
  behave like an AML with 11% blasts, others with 18, perhaps
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  some much more stable and you're still on the slope and.
• 10:37
  Actually GDX 41 you can have 30% blast and still behave like an
• 10:41
  yes. Yes, yes, yes.
• 10:43
  So I think it's definitely yeah that the blast count can can
• 10:48
  guide you or help you, but it's not I think definitely answering
• 10:53
  the question or won't give you a definite answer.
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  So I think we have to better understand the biology and the
• 10:59
  molecular operations and what very often you see if you look
• 11:04
  at the disease that can perhaps you already see mutations that
• 11:09
  are clearly linked to leukemia such as NPM 1 mutations.
• 11:12
  And my understanding is that you still have the, the bulk is the
• 11:16
  MD's clone, but one of them already transformed and then you
• 11:20
  have already an AML sub clone into within your MD's.
• 11:24
  But then for me, that definitely would be an indication to treat
• 11:29
  the patient such as, Yeah, the MPM one is one example that very
• 11:34
  frequently, yeah, also can arise on let's say clodal
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  hematopoiesis or MD's very often driven by these epigenetic
• 11:44
  drivers. I think this is a very important
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  list you have here actually, because I don't consider except
• 11:50
  for DNMT 3 AI don't consider any of these genes associated with
• 11:54
  the MPs. It's for me.
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  This is really AML. Those are the drivers in AML.
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  So this is really important to keep in mind.
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  Yeah. So with if we now talk about
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  AML, this is where I'm then again much more comfortable as
• 12:10
  you know coming more from the other side.
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  I mean there we also had some some changes.
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  But what I like here also in the new WHO classification and the
• 12:19
  same is true for the ICC that on one hand we we increase the new
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  knowledge we have from these sequencing studies from the
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  better understanding of the molecular biology of the
• 12:31
  disease. So there is also more
• 12:33
  genetically defined AML subgroups and the most important
• 12:38
  thing for me here is this new cohort of myelodysplasia related
• 12:43
  AML where they now, I mean we had that before it was called
• 12:47
  MRC myelodysplasia related cytogenetic abnormalities.
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  But the novel thing here is that now also the molecular genetic
• 12:56
  mutations made it into the classification that also makes
• 12:59
  that cohort, yeah, much more objective to to be determined.
• 13:05
  And actually that cohort, don't you think that they all come
• 13:08
  from MD's or? Oh yes, definitely.
• 13:11
  I think they all come from MD's. Also the ones where no MD's was
• 13:17
  reported in the past because I mean if if the patients are
• 13:21
  having this indolent disease for several, I mean they I mean how
• 13:26
  many patients don't I mean you same thing for CML right?
• 13:30
  Yeah, it depends on when you when you meet them.
• 13:32
  Yeah, after four or five years where you would think, OK,
• 13:34
  didn't they? That gave me another question,
• 13:38
  because then do you think that you think we'll be able in the
• 13:41
  future actually to prevent maybe more because now we know with,
• 13:46
  with these audio sequencing techniques that, that we, that
• 13:49
  we actually can introduce preventive medicine, you know,
• 13:51
  prevent the MLL? That's that's also a very good
• 13:53
  question. I mean, I think there if if we
• 13:56
  move forward or if you think of the new opportunities which we
• 13:59
  also have, let's say if you perhaps could, could design
• 14:04
  strategies, ways to eliminate that clone who has the
• 14:11
  proliferative advantage and only that close, right.
• 14:14
  If you think of for example, genetically engineered TCRS that
• 14:21
  that are targeting only for example mutant D and MT3A, but
• 14:27
  not the mild type. And yeah, yeah, I think.
• 14:30
  And maybe target the MPN clone, you know, And then maybe it
• 14:33
  doesn't matter so much if you have a background of the tip 2
• 14:36
  mutation, but. I mean, there for example, yeah,
• 14:39
  I think this was word published by Scott Armstrong in his mouse
• 14:42
  model. I mean, if he if he starts the
• 14:44
  many inhibitor early, he could eliminate that clone.
• 14:50
  But yeah, pharmacologically, I think it nevertheless will be
• 14:54
  difficult, but I think all these immunological treatment
• 14:56
  approaches that are now appearing also with the new
• 15:00
  genetic engineering possibilities might allow us to
• 15:03
  to do. That, that's very interesting.
• 15:05
  I think maybe we'll be able to vaccinate or something like
• 15:09
  that. Vaccination is another good
• 15:10
  opportunity. Yeah, definitely.
• 15:12
  But I think we need the immune system and learn more how it
• 15:17
  functions to get, yeah, take care of it.
• 15:19
  But then of course, if you think of clothing, is this also a
• 15:22
  stage earlier? It also could could make them
• 15:25
  the cardiologist unemployed one day, right?
• 15:27
  Yeah, yeah, that would be. Fantastic cardiovascular risk.
• 15:31
  So it will have many, many benefits.
• 15:34
  Yeah, yeah. And I think then the only
• 15:37
  difference here or the problem we are now facing for AML is
• 15:40
  that we now have two classifications, right.
• 15:42
  We also have the international consensus classification with
• 15:46
  regards it's this hierarchical model.
• 15:48
  So when you first look at the AML defining genetic
• 15:52
  abnormalities, I think that the overlap is is almost 100% and
• 15:56
  you have the P53 mutant ones and then the the ones who have the
• 16:01
  molecular genetic and cytogenetic aberrations that are
• 16:05
  linked to MD's. But here now you have always
• 16:08
  this additional subcategory MDS AM L with myelodysplasia related
• 16:13
  chain mutates if they have 10 to 19%.
• 16:16
  So that gives you the freedom to treat them either as MTS or AML.
• 16:22
  Yeah, it's making our life a little harder or more not
• 16:27
  harder, perhaps more complicated.
• 16:29
  You can see it both ways. You have more opportunities, but
• 16:32
  once in a while it's difficult to decide.
• 16:36
  But I think, I think for from, from my perspective that there
• 16:39
  could be an issue with MD's patients being older and having
• 16:44
  more comorbidity and so and they might fit into that box.
• 16:47
  But I think it's so important that you that you look at, I
• 16:50
  mean, they might have the right mutation, but they can't, they
• 16:53
  can't tolerate the treatment, right?
• 16:54
  The AML treatment is probably often more aggressive, right?
• 16:58
  And I think that's where, that's where I think the big issue is.
• 17:00
  And I think maybe do you think in the future we could make a
• 17:03
  new classification where we actually, you know, like
• 17:06
  artificial and children. So I don't know where we
• 17:08
  actually also include the patients, you know, physical
• 17:11
  state. Yeah, I think for the younger
• 17:13
  ones, I mean, in the past many study groups already treated
• 17:16
  these MD's ribe to patients aggressively, right.
• 17:21
  I mean, yeah, they are. I think also we need more
• 17:23
  retrospective studies to to look at the outcome of those
• 17:26
  patients. On the other hand, the CSU
• 17:28
  completely right for the older ones, I mean you still can have
• 17:31
  patients with higher last numbers whether the the disease
• 17:35
  still behaves not aggressively, right.
• 17:39
  I think their the understanding of what additional drivers are
• 17:43
  there. I think also the the gene, gene
• 17:45
  interactions might might tell you a little more who will be
• 17:50
  rather AML like or or MD's like. And yeah, I think there we
• 17:55
  still. Even though they are, I mean,
• 17:56
  like, I mean, you know. To learn more, That's true.
• 18:01
  But of course they're, I mean we now have with with venetoclax a
• 18:05
  good combination partner for for hypo methylating agents and that
• 18:10
  of course also might be relevant in MD's.
• 18:12
  And then if you also think of them more molecular targeted
• 18:15
  therapies like targeting IDH and their perhaps is all.
• 18:19
  I hope there's more to come. Yeah.
• 18:23
  But then then I think it's very important that MD's and AML
• 18:26
  doctors collaborate more because no, definitely I think in many
• 18:29
  institutions it has been different doctors treating one
• 18:32
  thing and the other. I think you know really need to
• 18:34
  have like a discussion about this this.
• 18:39
  Yeah, especially as those diseases are so tightly linked.
• 18:42
  It definitely should collaborate and work together.
• 18:45
  I fully agree. One thing I think, so these new
• 18:49
  classifications, are they more helpful than for us in deciding
• 18:52
  who we're going to transplant, do you think or because I think
• 18:54
  that's always for MD's obviously that's so important because it's
• 18:58
  the only cure, yes, so. Yeah, I think they they can
• 19:02
  guide treatment decisions, but they're also of course the
• 19:08
  question and always will be first try to get rid of the
• 19:12
  clone or you move directly into transplant, right, I mean.
• 19:16
  That's. That's, that's a whole.
• 19:18
  I mean, that's. A whole.
• 19:20
  If you think of ASH, the the study that was presented also by
• 19:23
  the colleagues from Tristan also even for AML that is now open
• 19:28
  for discussion. I think we have to.
• 19:30
  Perhaps it can help to define the ones that that are chemo
• 19:33
  resistant from the ones that are chemo sensitive.
• 19:36
  The chemosensitive ones, if you think that they are a MLMDS like
• 19:41
  I would also if they are termed MD's, rather try to get rid of
• 19:46
  the clone and then go into transplant.
• 19:48
  For the other ones, I think we need new strategies, especially
• 19:51
  if you think for example of the P53 new ones.
• 19:53
  Oh, yeah, yeah, yeah, I think that will, that will always be
• 19:56
  our headache, right? Yeah, to do with that.
• 19:59
  For yeah, for some more years, but then hopefully with a new
• 20:02
  one. Hopefully we will find out,
• 20:03
  yeah. Immunological approaches.
• 20:05
  New antibody based treatment targets like yeah, CD 47,
• 20:10
  perhaps that can help a little bit.
• 20:12
  The immune system is what we have to rely on there, I think.
• 20:16
  Good. It was very nice to talk to you.
• 20:19
  Thank you very much for your time.