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Management of High-risk MDS: Seeking Clarity for Classification and Treatment · EHA Unplugged

• 0:07
  This week's episode of EHA Unplugged highlights a
• 0:10
  discussion on the management of high risk MD's.
• 0:13
  For more information on the treatment and management of
• 0:15
  MD's, check out the newly published MD's treatment
• 0:18
  algorithm on the EHA campus. The MD's algorithm and
• 0:22
  associated vodcasts were planned, conceptualized by EHA,
• 0:26
  and funded with an unrestricted grant from Novartis.
• 0:29
  Welcome to Malaria and Katharina.
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  And today we're going to talk about high risk NDS and how we
• 0:39
  actually treat high risk NDS and how we define high risk NDS.
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  And I'd just like to ask you to introduce yourself.
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  OK. My name is Valeria Santini.
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  I work at the University of Florence.
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  I'm the chair of the MD's unit and I work in the hematology
• 0:56
  department. My name is Katarina Goetze.
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  I'm at the Technical University of Munich and head of leukemia
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  service there. So we've been looking forward to
• 1:04
  this. So there's a lot of new things
• 1:06
  going on with respect to how we actually diagnose high risk MD's
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  and what we call our high risk MD's nowadays.
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  So would you please comment on what your thoughts are about
• 1:17
  this? You know, there have been very
• 1:20
  recently 2 publications in June 2022 that are setting the point
• 1:26
  for a new classification of MD's.
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  Unfortunately, they're a little bit some differences among the
• 1:32
  two classification 1 is The Who classification and the other one
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  is the ICC. While there are these
• 1:40
  discrepancy, we think that both of the classification just
• 1:45
  target some critical points in the classification of MD's.
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  That is the fact that in in fact MD's and AML are two different
• 1:56
  disease. But especially talking about
• 1:59
  high risk MDSDWHO 2022 indicates still the difference in in
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  increased blast one with blast from 5 to 9% in the bone marrow
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  and in increased blast 2 from 10 to 19.
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  Whereas in the ICC, the high risk, let's say MD's considered
• 2:26
  as the ones with blast in the bone marrow are all put
• 2:29
  together. So if you have more than 5%
• 2:32
  blast, this is considered an MD's.
• 2:35
  And then if you have higher than 10%, you are already, you know
• 2:42
  you are already an MD's CML. And this is can be confusing for
• 2:47
  many reasons for patients mainly because they get to they can get
• 2:52
  two different diagnosis and also for reimbursement because some
• 2:57
  drugs are directed to MD's and some other to AML and registered
• 3:02
  and approved for that. So this is something we should
• 3:06
  really correct some way. And the other problem could be
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  also the fact that there are some MD's and we will discuss it
• 3:15
  largely that are characterised by mutation in TP53 and while in
• 3:21
  one classification the difference between BL bialilic
• 3:26
  and monolilic TP 53 is stressed and in the other is only linked
• 3:31
  to the blast percentage yes or no.
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  So I and which? One is.
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  Which one please of these two? So in The Who there is a
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  difference in bialilic and monolilic and I think that this
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  is something that it makes a difference.
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  But we all agree and all the the two classifications to indicate
• 3:54
  the same, that TP 53 MD's are really a different kind of
• 4:00
  disease and they are indeed a category a part of MD's.
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  Now, so, so you, you, you, you say that there are some some
• 4:09
  problems with respect to reimbursement and understanding
• 4:12
  from the patients and so are there any good things about
• 4:15
  mixing these things together, you know AML and MD's?
• 4:18
  I think that grouping the classes according to their
• 4:24
  genetic subtypes actually does make sense because we know that
• 4:28
  TP 53 multi hit MD's and TP53 multi hit AML have the same
• 4:36
  survival curve. So they're actually completely
• 4:39
  the same. There's no difference in the
• 4:41
  overall survival curves in the Kaplan Meyer.
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  So I think that putting those two together and treating them
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  the same way absolutely makes sense.
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  And for the ICC, having MD's slash AML opens the trials for
• 4:57
  patients with MD's into the AML trials, which I think is one of
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  the reasons that that was grouped together.
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  Yeah. There are pros and cons and I
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  think that we should come to emerging of the two of the two
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  classification because we can actually point out very good
• 5:15
  indication and characterization of MD's in both the
• 5:19
  classifications. There is a little bit.
• 5:21
  Confusing, I agree. I also and when you, when you,
• 5:24
  when you teach also MD's nowadays it's very complicated
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  because you all the time you have to say this is two
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  different things, right. So actually I think it is
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  confusing for everybody, but what do we do for now?
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  What about now? I think we have already in some
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  of these sessions talked a bit about P53, because this is a
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  major issue, right? But what about all the other
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  mutations? Would they help us in sort of
• 5:47
  the classification? I do think it's an important,
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  it's becoming increasingly important to classify MD's and
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  genetic subtypes. And we know that for instance
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  for SF3B1 we have a predictor for response to Los patriceps.
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  So that absolutely makes sense. But we also know that low risk
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  MD's was SF3B1 as soon as there's a second or third
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  mutation in del 5Q and then maybe something else Bronx or a
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  SXO 1, the prognosis is a lot worse all of a sudden.
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  So these are this is information that we need to have on their
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  SF3B1 mutated patients. Do they have additional
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  mutations And for IDH mutations, which are about 7% of all MDD s
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  s, we hope that we will be able to target those with IDH
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  inhibitors together with HMA. And there's preliminary phase
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  one data on this and the phase two data from from MD Anderson
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  that's looking quite good. So also for refractory and
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  relapsed MD's after HMA, it might be good to target them
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  with IDH inhibitors. So yes, I think it's important
• 6:53
  to have these classes because they do to form therapy.
• 6:57
  Yeah. This is particularly true for
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  lower risk MDS. But as Katarina mentioned, IDH 1
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  and IDH 2 may be very important for higher risk MDS as well.
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  And we already know that the number of mutations is critical
• 7:13
  for outcome. So not only the type of
• 7:16
  mutation, but also the number of mutational events in in an MD's
• 7:22
  and for higher MD's. Of course, the combination of TP
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  53 and and the complex stereotype can be really
• 7:30
  determinant for for prognosis. So and now we have a new
• 7:37
  classification that is upgrading mainly what was considered with
• 7:43
  IPSSR as lower or intermediate risk to higher risk just on the
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  basis of the type and number of mutation.
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  So DNA mutation are becoming increasingly important.
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  And do you think we can reach a point where we actually don't
• 7:56
  need to count the bone marrow blasts anymore?
• 7:59
  Yeah. That's a difficult question,
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  question. I I actually do think that
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  blasts are important in the census when you're thinking of
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  treating a patient with HMA and perhaps they have no blasts at
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  all, but they have an IPSSM that's higher because of their
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  mutations. I would have the difficulty
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  giving a patient HMA with no blasts at all because I wasn't
• 8:23
  sure. I wouldn't be sure of the
• 8:25
  benefit that the patient is getting it as the patient's age
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  and maybe there are 85. I'm not sure that they would
• 8:32
  actually derive a benefit from the HMA at that point.
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  And maybe just, you know, do best supportive care and leave
• 8:40
  them alone. That's also always an option,
• 8:42
  yeah. Absolutely.
• 8:43
  Absolutely. Yeah.
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  Yeah. And in Europe we are not using
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  HMA in lower risk MD's. We use them only in higher risk
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  MD's. So even if you have a known
• 8:54
  blasting marrow and mutation, as Katarina said, there is some
• 8:58
  reluctancy in using HMAS because of myeloscopers.
• 9:03
  Exactly. And and, and also do you see
• 9:06
  good results in that situation? Do you know about that?
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  I mean, they do it in the States, right, But.
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  Well, you can alleviate the anemia quite well, but if you
• 9:15
  have neutropenia, I don't really see any effect.
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  So I think for anemia after maybe failure of EPO, failure of
• 9:25
  Los patricept and all these things that could be useful, but
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  if there's no blasts in the bone marrow, I'd be very hesitant.
• 9:33
  Yeah, yeah, you can be alleviated.
• 9:37
  But again, it's it's something we should use with real care and
• 9:42
  and attention. Yeah.
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  It, it's kind of the issue that this is all we have for high
• 9:48
  risk MD's in spite of allogeneic transplant, which of course we
• 9:53
  can offer to some of the younger patients.
• 9:55
  And then we have HMA. So it's kind of like, oh, we
• 9:58
  give HMA to everyone because it's, it's the only thing that
• 10:01
  we have for high risk MD's. But I think we need to be a
• 10:03
  little more discerning and and, and really choose a patient's
• 10:06
  well that will benefit. Yeah, yeah.
• 10:09
  Regarding. So do you have like a limit for
• 10:11
  when you're using HMA's or you know is it individual from these
• 10:16
  patients? Really depends on the conditions
• 10:19
  of health conditions of the patient.
• 10:21
  I treated patients who were 90 and above but had a very fit
• 10:25
  condition and others who were 80 but were not really eligible,
• 10:30
  not even for HMAS. The only it's physiological
• 10:34
  aids. Really you have to evaluate your
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  patient with comorbidities, general also geriatric
• 10:40
  assessment somehow to see whether compliance and.
• 10:45
  And. Also care givers and everything.
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  So in this maybe oral HMA could help us because then the
• 10:55
  management of elderly patients who could be easier.
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  Nevertheless, even if oral these are myelotoxic,
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  myelosuppressive, let's say drugs.
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  So even when we have the oral formulation, it would be
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  extremely well, extremely delicate to to manage an elderly
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  MD's, Higher East MD's. Patient and we don't have this
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  in most countries. We don't have the same set up
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  that I know that you have in Denmark where you can do the
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  outpatient nursing going around to the homes and giving HMA and
• 11:28
  we don't have that set up in Germany.
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  So the patient has to come in all the time and get their blood
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  values checked and so that can be quite.
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  That's kind of so I think, yeah, I think, you know, a lot of
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  patients actually like being treated at home.
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  I think that's that's, that's one thing we've been doing a lot
• 11:47
  here. Yeah, it's true.
• 11:48
  Yeah, they are relieved. Yeah.
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  Yeah. Makes a lot of difference
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  actually for the quality of. Life.
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  And are we good enough to measure quality of life in this
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  patient category? Because I think this is
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  probably. Very pertinent question, I think
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  and I, I don't think we've had the right kind of quality of
• 12:10
  life scoring yet in MD's to be honest.
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  There's the qualms. It's pretty good, but it, you
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  know, hasn't shown that big of effect in a lot of the trials
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  so. Yeah.
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  And then higher risk MD's patients have of course
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  different issues than lower risk in terms of quality of life,
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  even if independency from hospital care can be a very good
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  point for both of the MD's patients.
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  This is why in Florence we are now evaluating the possibilities
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  to switch from sub Q as A cited into oral as a cited in, in the
• 12:48
  patients with higher risk MD's who responded well to the sub Q.
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  So the ones who are in PR or CR, they can go on with the with the
• 12:59
  oral formulation. Of course we have to.
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  Again, as I mentioned before, we have to control them and and see
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  how it goes because we cannot just leave them alone at home
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  and and. And what about gastrointestinal
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  problems? I mean, there used to be quite a
• 13:15
  lot. Is that still the case or is it
• 13:17
  formulation become better? I think for oral, I think for
• 13:20
  oral it's much more, much bigger problem than.
• 13:23
  For this, yeah, yes. Exactly, Yeah.
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  This can be a obstacle to the use.
• 13:29
  Of tracks. Still.
• 13:33
  Anything maybe so, I mean, nowadays you know, venetoclax is
• 13:38
  very hyped in AML, right? And you know, we now have the
• 13:40
  MDS is less AML subtype. So in my country a lot of people
• 13:45
  think now that they should also that also the MD's patients
• 13:48
  should have venetoclax. What's your opinion on this?
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  You go for it. I think that's a very difficult
• 13:53
  question in the sense that we all put a lot of hope into the
• 13:57
  venetoclax HMA combination for MD's patients.
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  I think probably if they have a high blast count and they're
• 14:04
  going towards AML, it will probably be the right therapy.
• 14:08
  As we talked before about high risk MD's without blasts, that's
• 14:13
  probably going to be too myelotoxic for these patients.
• 14:16
  I think and we'll be very curious to see the results of
• 14:20
  the Phase 3 Verona trial because I think that the myelotoxicity
• 14:24
  may balance out the remission rates.
• 14:28
  You know, so in the end, you might not see an effect in the
• 14:30
  overall survival because of the toxicity.
• 14:33
  And, and these older patients are very, very frail in their
• 14:37
  balance and they need a lot of support for sepsis.
• 14:42
  And you have to really teach them well about what to look
• 14:47
  for. And if they're not feeling well,
• 14:49
  that they have to come in right away.
• 14:50
  And that can be, that can be a difficult issue.
• 14:53
  So I'm, I'm a big fan of Venetoclap HMA for AML patients,
• 14:57
  even for younger patients, it's doing really well.
• 14:59
  I think it might, might be a game changer even for 7 + 3.
• 15:04
  But for MD's I'm not so sure. Yeah, you know, especially
• 15:09
  regarding the schedule of venetoclax and and our society
• 15:13
  in order or other HMAS, it's difficult to keep the entire
• 15:18
  schedule for all the cycles. So very often for patients with
• 15:22
  MD's we have to stop giving venetoclax for well, I don't
• 15:27
  speak about 21 days that is extremely difficult, but even 14
• 15:32
  sometimes is a challenge. So the, the bone marrow of MD's
• 15:36
  it's that's somehow biologically different from AML and we have
• 15:41
  to take this into account beyond and beside the fact that these
• 15:46
  patients are elderly and as it was mentioned.
• 15:50
  So it's, it's going to be an interesting tool.
• 15:54
  We have to allow to to to select the patients that can and.
• 15:59
  Yeah. And we might need to do MRG
• 16:01
  monitoring to see if we could add some stop the venetoclax and
• 16:05
  just continue with HMA maintenance, maybe in an oral
• 16:08
  setting if they're MRD negative and have benefited.
• 16:13
  From. From induction kind of type of
• 16:15
  venetoclax HMA. But do you think that HMA will
• 16:20
  be always be sort of the backbone in high risk NDS or are
• 16:25
  we moving away from this or how do you see it?
• 16:28
  It could be by now as you know, there have been several efforts
• 16:33
  to have a combination always with either decytabine last or
• 16:37
  azocytidine and it has always been considered a session
• 16:41
  essential. Unfortunately, none of these new
• 16:45
  combination trials with Pingo and any start or with also with
• 16:50
  the APR the apron network very difficult to say Yeah, 53
• 16:58
  reactive in phase three. They never shown an an efficacy
• 17:03
  higher than as a sighted in alone.
• 17:05
  So we are stuck to what we were 15 and 20 years ago with as a
• 17:09
  sighted in. But especially with the new
• 17:12
  immunomodulatory and agents, it could be that we will get rid of
• 17:18
  the hyper methylating agents and and use only the the novel
• 17:25
  agents let's say. Yeah.
• 17:27
  There are several. You're thinking of in
• 17:30
  particularly magrudumab or what are you thinking?
• 17:33
  What do you when you say? Yeah, Magrudumab until now has
• 17:36
  been the most effective one. Always in combination this anti
• 17:42
  CD 47 antibody has given very good results even in TP 53
• 17:48
  positive dictated MD's more than 7075% response, which is a very
• 17:56
  good overall I mean in all patients which is a very good
• 18:00
  result. So we.
• 18:01
  Have long time does that last then do we know that?
• 18:05
  Is that lasting or? Yeah, the duration of responses
• 18:08
  seems to be quite good and stable.
• 18:11
  I think it's near one year, but we still have to wait again for
• 18:17
  the phase three. Notes.
• 18:19
  And it's not an easy drug to to apply, right?
• 18:23
  I mean, for the way we have to give it and watch out for anemia
• 18:27
  and all these things, it's not going.
• 18:29
  To So what are the main side effects with that going?
• 18:31
  To make patient care that much easier, right?
• 18:33
  Yeah. The the most important and
• 18:36
  relevant management problem with magrolimab is the on target
• 18:40
  hemolytic anemia. So the patient may have a very
• 18:45
  sudden and deep loss of hemoglobin, decrease in
• 18:49
  hemoglobin even 3G. So you have to be ready to.
• 18:54
  Not just at the beginning of treatment or something.
• 18:56
  It could come anytime or. It is at the beginning of
• 18:59
  treatment but can be very, very rapid.
• 19:01
  So again we have to set up a strategy because we know that it
• 19:06
  may happen. So all the centers should be
• 19:10
  aware and prepared to have a very strict the control of
• 19:16
  hemoglobin levels even immediately after treatment do
• 19:22
  let's say an escalating nose and a priming with the magrolimab
• 19:26
  and also try to set up a very good collaboration with the
• 19:31
  blood Centers for the immediate transfusions.
• 19:35
  Yeah, one thing I forgot to ask you about.
• 19:38
  I'm still going back to the supplies.
• 19:40
  When So when can we expect the results from the Verona trial,
• 19:44
  you know that? Cut off has been, I mean they're
• 19:46
  doing that, the data cut off has been done and and they're
• 19:49
  cleaning their data. I don't know if we'll be able to
• 19:52
  see it for Ash, maybe at the end of the year.
• 19:55
  Hopefully, we hope. So otherwise as ESA next year,
• 19:58
  right? Yeah, that'd be interesting.
• 20:03
  Sure. Yeah, yeah.
• 20:06
  And of course, then it will take a couple of years before it gets
• 20:08
  approved in Europe, right? So even if it gets approved
• 20:12
  right So but. We could still use it.
• 20:14
  I mean, that's what we did with HMAS.
• 20:16
  We were using them long before they got approved in Europe.
• 20:20
  Yeah, yeah, yeah. But you get reimbursed, don't
• 20:22
  you? Or how does it work in your
• 20:24
  country? Because I mean, here we have a
• 20:25
  social system for reimbursement. So you know, it has to be
• 20:29
  everything has to be approved for everyone.
• 20:30
  It's not like. If it's not approved, we have to
• 20:33
  ask the insurance company. Yeah, yeah, easily.
• 20:36
  You can apply for a compassionate use or.
• 20:41
  Or yeah, we can do that too. Yeah.
• 20:42
  Or a personalized use. Of course, it's a lot of
• 20:45
  paperwork and and the Attic committee have to check very
• 20:50
  carefully, because we have the same system in Italy as in
• 20:52
  Denmark. Every public and everything has
• 20:55
  to be approved, of course. Yeah.
• 20:58
  So which is good for patients in in some sense and for other
• 21:02
  sense it can be a little bit slower for the approvals, Yeah,
• 21:08
  for getting the drugs anyway. OK.
• 21:12
  So I was asking a little bit about transplantation.
• 21:15
  So which patients would you select for transplantation?
• 21:18
  Would you treat them up front with the Neto clocks or how do
• 21:20
  you condition them? Since it's the only curative
• 21:23
  option for MD's, we do try to offer it to patients that are
• 21:27
  eligible. I think the I new IPSSM, the
• 21:31
  molecular IPSS has been pretty helpful in choosing patients for
• 21:35
  allergenic transplant, at least at our center.
• 21:37
  I think so, because I've actually noticed that some of my
• 21:42
  low or intermediate risk patients become very high risk
• 21:45
  in the IPSSM if they don't, if they have low blast counts or no
• 21:50
  blast counts. So I've been using that for
• 21:53
  transplant decisions. It used to be that we use the
• 21:57
  IPSSR and if they had four risk molecular mutations, then we
• 22:01
  would upgrade them. Yeah.
• 22:03
  And now we have a better tool, so especially.
• 22:07
  Same experience actually. Yeah, yeah, I.
• 22:09
  Think the IPSSM has been very helpful for the transplant
• 22:12
  eligible patients. And can you institution find all
• 22:16
  the variants? You know, we had some problem
• 22:18
  in, you know, always getting the the PLA limited, you know, can
• 22:24
  you get how, how does that work for you?
• 22:27
  No. That's the same problem, you
• 22:28
  know the availability of all the entire set of mutation that is
• 22:33
  indicated in IPS small. It's difficult to get in all
• 22:37
  centers. Yeah, it's a flexible system.
• 22:40
  So we may adapt even if we have missing data.
• 22:45
  Yes, this is becoming a huge problem also for availability of
• 22:49
  NGS in general. So we again, that's another
• 22:53
  objective and goal we have to have to render the treatment and
• 22:58
  management of MD's equitable and possible for for all the
• 23:05
  standards and all the countries. It's a very powerful tool,
• 23:09
  IPSSMI mean, but it has to be adapted to the to the single
• 23:14
  possibilities of again, countries and centres.
• 23:17
  It's very well. I would fully agree on that.
• 23:21
  And kind of. Struggling.
• 23:22
  I was wondering if you figure out how to do?
• 23:25
  It no, it is, it is a challenge of course, everyday challenge,
• 23:29
  but we, we can implement it, but not all the centres can do it.
• 23:34
  No, exactly. And we need to have certified
• 23:37
  centres in all countries, possibly centralized initially.
• 23:42
  We have since a long time the possibility to be reimbursed for
• 23:47
  all the NGS studies. But in some other countries,
• 23:51
  even countries, it's not possible.
• 23:54
  So it's, it's something that we should face.
• 23:57
  Yeah. With, with E ha or with.
• 24:00
  That's a good point, yeah. Yeah.
• 24:02
  You know, we have the new topic in focus is persistent medicine.
• 24:06
  So I think maybe maybe there's actually an issue here we could
• 24:09
  something we could work on. Yeah, it's a very important
• 24:12
  issue because we have to homogenize the possibility to
• 24:16
  competed in old countries. Yeah, so.
• 24:19
  We'll agree on that. So maybe we should work on that.
• 24:23
  But. Happy.
• 24:24
  Yeah. So, so then then I was asking
• 24:26
  about your conditioning. I mean, how do you or how do you
• 24:29
  treat your patients before you transplant?
• 24:31
  What? What do you if?
• 24:33
  If at all possible, I would not pretreat them so if I have.
• 24:38
  What? What kind of blast counts do you
• 24:39
  accept before transplantation? 10% usually.
• 24:43
  Up to 10%, yeah. And if I if I can do a rapid
• 24:46
  donor search and maybe have a a haploidentical child to to
• 24:52
  transplant or or sibling, even then we try to do a rapid
• 24:57
  upfront transplantation instead of pre treating because there is
• 25:01
  this concern. If you pre treat with HMA, you
• 25:04
  either induce mild suppression, then you get maybe in fungus or
• 25:09
  some kind of infection in your lung which would which would
• 25:12
  preclude doing the transplant. And also there is a data saying
• 25:16
  that you actually create resistant leukemic stem cells
• 25:20
  that can, you know, persist and then make a problem and at
• 25:24
  relapse. So you might not be doing a
• 25:26
  patient a favor. Because you sort of select for
• 25:29
  them or yeah. So we try to do upfront wherever
• 25:33
  possible, but if we can't, we we do have do give the patient HMA
• 25:41
  or transplant and if they have more than 10% less, you could
• 25:45
  also think about doing the CPX 3 351 instead.
• 25:50
  Yeah. And we have absolutely the same
• 25:55
  strategy. That's good to know.
• 25:57
  Absolutely. So you're doing well.
• 25:58
  With the haplo, because I think we're not really using that a
• 26:01
  lot, so. We use it a lot.
• 26:03
  The results are very. Good.
• 26:05
  A lot of Applo. Yeah.
• 26:07
  Oh, interesting. We need to.
• 26:09
  Yeah. Good.
• 26:14
  So what what thing you haven't talked about is about what do we
• 26:18
  do when when high risk NDS relapses?
• 26:21
  That's a that's a great challenge.
• 26:24
  If they do relapse like AML, so they progress more than
• 26:29
  relapsing, then we may try some more aggressive if feasible and
• 26:34
  if the patient is not frail. Of course.
• 26:38
  There have been numerous publication indicating and and
• 26:42
  data that chemo after HMA it doesn't work.
• 26:48
  There have been several attempt to use novel drugs that
• 26:52
  unfortunately didn't show any advantage.
• 26:55
  I can just remind remember regulatory deep and then exactly
• 27:05
  the bites and then we we got other attempt that unfortunately
• 27:10
  didn't increase the response or the overall survival I would
• 27:15
  say. And would you think Vanessa
• 27:16
  class would help in this situation?
• 27:18
  It has been shown that has an activity in 40% of the patients
• 27:23
  who received HMA and relapsed and then added to HMA could
• 27:29
  could induce 40% response still and an overall survival more
• 27:34
  than acceptable giving that it was 12 months instead of 6. 5 or
• 27:39
  whatever, yeah. Yeah, that we are used to.
• 27:43
  So this could be a good option. A single drug doesn't work
• 27:47
  doesn't seem to work so well, but as an add on it could be
• 27:52
  really helpful. And IDH for those.
• 27:56
  IDH inhibitors for those patients that have IDH one or
• 27:59
  two. How many are those?
• 28:01
  How frequent is this? Not many.
• 28:04
  Not very many. No, but some patients may
• 28:07
  acquire it and and they can also acquire Flt 3, Flt 3.
• 28:14
  Yeah. Oh yeah.
• 28:15
  And then you can use, yeah. And you can do giltarinib or you
• 28:18
  can do one of the specific inhibitors.
• 28:23
  I have patients even older, very old patients, so who progressed
• 28:28
  to AML. They were treated after relapse,
• 28:32
  after HMA with goddacitabine, obtain a sort of response.
• 28:36
  And then they had acquired IDH 2 and now there have been
• 28:41
  maintained for a very long time with an acid.
• 28:44
  So this is we should show it in a more consistent way and show
• 28:50
  that it's possible just sporadic.
• 28:52
  No. Sporadic cases are interesting,
• 28:54
  but not. Really.
• 28:55
  That you can't? Yeah, of course.
• 28:57
  Not making the the path for a new for new use.
• 29:01
  But that might be at least one option for something that might
• 29:04
  work, right? I mean, we need some hopes
• 29:06
  there. I think it's in we.
• 29:09
  Try to put our patients on on clinical trials in this
• 29:12
  situation if we have one on offer.
• 29:15
  We have the IREC 4 inhibitor trial, which has it's a Phase 1
• 29:19
  and it has a good signal for slip 3 and splicing mutations.
• 29:24
  So it could maybe be an option after HMA failure might become
• 29:29
  an interesting drug. Hopefully it has a little bit of
• 29:34
  a problem with reptomyolysis, so you have to be careful with
• 29:38
  that. But I think it's manageable.
• 29:41
  And for patients that relapse after allergenic transplant, we
• 29:44
  try to do donor lymphocyte infusion plus HMA.
• 29:47
  So DLI plus HMA which work can work quite well actually.
• 29:51
  Yeah. I think this is.
• 29:53
  We all do, don't we? Yeah.
• 29:55
  Yes, hopefully. Yes, yeah, there are some new
• 29:59
  drugs coming with a new mechanism of action very, very
• 30:03
  preliminary data. So I think that it is difficult
• 30:08
  to set up a study in re in refractory or relapsed HMA high
• 30:13
  risk MDS patients because of course it's a very treacherous
• 30:18
  field and, and, and it's a great, it's a, it's a ground
• 30:23
  that has to be, let's say attack with the with the care because
• 30:30
  it is difficult to obtain a real response.
• 30:33
  So also the companies are not so interested actually in doing.
• 30:37
  They might fail. Are they likely to fail?
• 30:40
  It could kill the drug even if it's a good.
• 30:42
  Drug yeah, yeah, so that's that of course is a big.
• 30:47
  Risk to. Take so I think, what do you
• 30:51
  think? I think we have been really well
• 30:54
  around the whole topic. I think it's something else we
• 30:57
  should talk about that we haven't talked about.
• 30:59
  Now there are other drugs that are immunomodulatory, the
• 31:03
  sabatolimab, the the in 3D drug that is targeting both the T
• 31:08
  exhausted, the T exhausted cells and some other immune
• 31:14
  macrophages as well as possibly the leukemic cells that that we
• 31:20
  have seen until now are indicating more prolongation of
• 31:25
  response than an increase on the rate of response.
• 31:28
  But again this is just phase two.
• 31:31
  We have to wait for the phase three trial and see how it goes.
• 31:34
  But there is much more attention to immune modulation now, and.
• 31:39
  Even in high risk, because I know this is very hard and low
• 31:42
  risk, right? But but you also see a lot of
• 31:46
  things going on in high risk now, right?
• 31:48
  Oh, yeah, yeah. It's very interesting.
• 31:53
  Hopefully, yeah. But at least we know what
• 31:56
  actually, you know, transplantation is immune
• 31:58
  therapy, right? So this is where we have seen
• 32:01
  the response. Yeah, it's, it's, it's a little
• 32:04
  bit discouraging that we haven't in the myeloid field seen the
• 32:08
  same successes with with immune therapy as we have Goma fields.
• 32:14
  So we're really. Like so.
• 32:16
  I'm not. Sure.
• 32:17
  Do you know of any results with the bispecifics and how well
• 32:20
  does that work And and what about what about car T?
• 32:23
  And you know the patients always ask because they read about
• 32:26
  this. So yeah, we are.
• 32:27
  A little bit backwards respect to the lymphoid disease.
• 32:31
  Oh yeah, they have a great time. Yeah.
• 32:33
  But I because the diseases we're dealing with are hematopoietic
• 32:38
  stem cell diseases in the very high hierarchy of the
• 32:41
  hematopoiesis, it's just much, much harder to find an adequate
• 32:45
  target than it is for for lymphoid diseases.
• 32:48
  And actually what we experienced, you know, with was
• 32:51
  it after, after HMA, you'll actually get selection also of
• 32:54
  clones that also have mutations in the T cells.
• 32:57
  So, so maybe, I mean maybe it can this can also affect, you
• 33:03
  know, how immune therapy would work I.
• 33:05
  Guess, absolutely, yeah. And the way to go is any way to
• 33:09
  find new mutation, acquired mutation and possibly target
• 33:13
  them because it could be that you need a sequential therapy,
• 33:18
  that you need combined therapy with different inhibitors.
• 33:22
  This is what we have to find out.
• 33:24
  And the way again is to evaluate the molecular set of these
• 33:29
  patients. Yeah.
• 33:31
  So, so you think we need also to do sort of MRD studies or or how
• 33:36
  do we or or at least repeated molecular studies?
• 33:40
  And it means that this is something very relevant to
• 33:44
  patients doing their disease history.
• 33:46
  Yeah. Yeah.
• 33:48
  So actually we need to work on precision MD's a little bit.
• 33:51
  Absolutely, yeah. We agree with that.
• 33:54
  Pressure. Very good.
• 33:57
  So I think I would like to thank you very much for your time.
• 34:00
  It was fantastic. And you could find time in the
• 34:04
  middle of your busy meeting there.
• 34:05
  So it's really good. It's a beautiful place.
• 34:09
  Yeah, yeah. It's nice to actually very nice
• 34:12
  to do it together. I think we should do more of
• 34:14
  that. Yeah, absolutely.
• 34:16
  More fun. Yeah, Yeah.
• 34:19
  Thank you very much. Thank you.
• 34:21
  Thank you.