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Managing Young Fit AML patients with Prof Konstanze Döhner · EHA Unplugged

• 0:03
  Greetings and welcome to EHA Unplug, the official podcast
• 0:06
  channel of the European Hematology Association EHA.
• 0:10
  Hello, I am Isabella Livera, a medical writer for EHA.
• 0:15
  Today, we're thrilled to have Professor Constance Donor
• 0:20
  joining us to discuss how to manage acute myeloid leukemia
• 0:24
  AML in young and fit patients. Welcome, Professor Donner.
• 0:30
  Thank you for being with us today.
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  So first of all, I would like to thank EHA for the kind
• 0:36
  invitation to discuss with you today how to manage AML patients
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  fit for intensive chemotherapy. I'm very happy to be here.
• 0:46
  What are the essential steps in the diagnostic work up for young
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  fit AML patients? So the essential steps for the
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  diagnostic work up in young fit AML patients starts with
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  morphology. So by performing a bone marrow
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  and the blood smear followed by multicolour flow cytometry to
• 1:09
  determine the correct lineage assignment.
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  And also flow is more and more used now to determine the
• 1:17
  leukemia associated immunophenotype for MRD
• 1:24
  monitoring in these AML patients.
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  And then we still have cytogenetic analysis.
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  This is still the gold standard for the diagnostic workup in an
• 1:33
  in AML followed by molecular profiling.
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  That means analyzing molecular markers, analyzing gene
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  mutations to determine the genetic risk profile of the
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  patients according to the European Leukemia NET
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  recommendations. Can you tell us how has the 2022
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  ALN risk stratification system changed our approach to young
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  feet AML? Patients.
• 2:01
  So the updated European leukemia net recommendation that have
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  been published in 2022 in blood, they are not only an update, but
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  they further refine AML genetic risk stratification and there
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  are two major changes that we can see in this updated ELN
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  recommendations. So first of all, all patients
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  harbouring a flit 3 ITD mutation are now categorized into the
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  intermediate risk group and there are several reasons for
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  that. So one reason is that it was
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  really difficult to harmonize the essays and by determining
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  the flit 3 mutant to wild child Lily Gratio, there was a broad
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  variation. Second is that MRD monitoring
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  plays an increasing role, in particular in patients
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  harbouring an MPM one Co mutation.
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  And 3rd, we are now having very successful FLITS 3 inhibitors
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  for the treatment of AML patients with Flits 3 ITD
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  mutations. Another very important change in
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  the updated ELN recommendation is the introduction of a new
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  category of a new gene signature that is defined by AML with
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  myelodysplasia related gene mutations.
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  And these patients are now categorized into the high risk
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  group. And that means that a
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  considerable proportion of patients with firmer
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  intermediate risk are now categorized into high risk
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  group. And that means for us that these
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  patients are now assigned to receive allogeneic stem cell
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  transplantation. Can you tell us what is the
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  current standard for induction therapy in young feet AML
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  patients? So the current standard
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  therapies is the standard therapy for many, many years is
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  the so-called 3 + 7 schedule. And this consists of treatment
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  with an antracycline for three days and cytarabine for seven
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  days. I think this is still a very
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  important backbone of intensive treatment in fit AML patients.
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  There have been some modifications of these intensive
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  chemotherapy because of the development of novel drugs.
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  For example, we are now combining these intensive
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  chemotherapy, the 3 + 7 with the available FLIT 3 inhibitors in
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  FLIT 3 mutated patients. And we also have chemtuzumab,
• 4:44
  ozogamycin and antibody drug conjugate that is in particular
• 4:51
  effective in the CD 33 positive AML patients.
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  That means in patients with core binding factor leukemias, but
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  also in patients with MPM 1 mutations and other patients of
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  the intermediate risk group. And finally, we have CPX 351
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  which is a liposomal formulation of an andracycline of
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  downorubicin and cyterebin and that has been approved for the
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  treatment of AML with myelodysplasia related changes
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  and therapy related AML. How do you integrate targeted
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  therapies such as Flt 3 inhibitors into intensive
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  chemotherapy regimens? It is our current standard to
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  combine intensive chemotherapy with the available FLIT 3
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  inhibitors in patients with FLIT 3 mutations and this is mainly
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  based on the so-called RATIFY study that has been performed
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  more than 10 years ago. At the ASH meeting this year,
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  there is a 10 year follow up of this RATIFY study showing very
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  interesting data. And in the ratified trial, the
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  FLIT 3 inhibitor, mydostorin, the first generation FLIT 3
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  inhibitor was evaluated in combination with intensive
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  chemotherapy in FLIT 3 mutated patients.
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  And this opens the ERA to precision medicine in AML.
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  And based on the very positive results of this ratified trial,
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  mydostorin was approved by FDA and EMA in 2017 for the
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  treatment of FLIT 3 mutated AML patients in combination with
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  intensive chemotherapy. We also have second generation
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  FLIT 3 inhibitors and recently last year quisartinib was
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  approved for the treatment of AML patients with the FLIT 3 ITD
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  mutation in combination with intensive chemotherapy.
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  And we also have other very interesting novel drugs in the
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  vehicle development, like for example, the combination of
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  intensive chemotherapy with IDH inhibitors in patients with IDH
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  one or IDH 2 mutated AML. We now have the Menin inhibitors
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  in clinical trials investigating the effect of the addition of
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  this Menin inhibitors with intensive chemotherapy.
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  And we also have trials evaluating the combination of
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  intensive chemotherapy with the PCL 2 inhibitor when it took
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  lacks. However, these trials are still
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  ongoing and we have to await for the results.
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  And when do you recommend allogeneic stem cell
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  transplantation for young AML patients?
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  The recommendation to perform an allogeneic stem cell
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  transplantation is depending on the risk benefit ratio and that
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  is based on the cytogenetic on the molecular risk of the
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  individual patient. For sure, this is also depending
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  on the patient, on the patient's wish, on the donor availability,
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  the type of donor and on many other factors like
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  comorbidities. But in principle, I think one
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  has to recommend allergenic stem cell transplantation in patients
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  having a higher probability to relapse.
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  And for us a higher probability means a risk of more than 35 to
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  40% of relapse. And in these cases, we do
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  recommend allergenic stem cell transplantation.
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  And in directise that means that all patients having an adverse
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  risk and genetically adverse risk, we are recommending
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  allergenic stem cell transplantation.
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  And also for intermediate risk patients, we are now
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  recommending allergenic stem cell transplantation in first
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  complete remission. How does MRD measurable residual
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  disease monitoring influence treatment decisions in young AML
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  patients? So this is a very important and
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  rapidly developing field. The MRD status is very important
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  for treatment decision making in particular for the type of post
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  remission therapy and that means if a patient should receive
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  allogeneic stem cell transplantation or not.
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  So in recent years we have seen a large number of studies
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  clearly showing that the MRD status at defined time points
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  during the treatment and after the treatment that means during
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  the follow up period is of prognostic relevance.
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  And you can also use MRD, the MRD status to identify an early
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  molecular relapse at any time point, in particular also after
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  allogeneic stem cell transplantation.
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  And based on the MRD status, you can start pre emptive therapy.
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  So with regard to the molecular markers that are currently used
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  for MRD monitoring, we have very, very solid data for using
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  the MPM 1 mutation and also gene fusions resulting from the core
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  binding factor leukemias as molecular markers for MRD
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  monitoring. And very recently, we also now
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  have very solid data on MRD monitoring in FLIT 3 ITD mutated
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  AML. And with regard to multicolor
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  flow cytometry using this technique for MRD monitoring, we
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  also have very solid data that the MRD status based on flow
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  after one better after two cycles is of prognostic
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  relevance. However, I think it's important
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  to mention that flow based MRD monitoring is technically
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  demanding and is restricted to really very experienced
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  laboratories. What are your thoughts on the
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  potential of Carty cell therapy in AML, particularly regarding
• 11:16
  recent developments targeting CD123 and CLL One?
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  So in contrast to the lymphoid neoblasm, the development of T
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  cell therapy or immunotherapy and AML is a major challenge.
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  It still remains a major challenge and this is depending
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  on several factors just to mention to find an appropriate
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  target and the fact that there is a lack of immunocompetent
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  cells in this really active leukemias.
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  So gamtosumab, ozogamycin, this is an antibody drug conjugate
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  against CD33 is the only immunotherapeutic target that
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  has been approved for the treatment of AML.
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  And with regard to the development of CAR T cell
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  therapies, there are currently some studies under investigation
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  using several targets such as the CD 123, the CD 33, the CLL
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  one or the FLIT 3. But the first results from this
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  study are really more than disappointing.
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  And I don't believe that any of these CAR T cell therapies will
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  become approved for the treatment of AML in the next two
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  to three years. Thank you very much, Professor
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  Donner, for this insightful conversation and for sharing
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  your valuable expertise with us. Thank you to all of you for
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  listening and stay tuned for our next episodes.
• 12:53
  Thank you.