Latest / EHA Unplugged / AML Management in the Old and Unfit (with Prof Hartmut Döhner)

Transcript

AML Management in the Old and Unfit (with Prof Hartmut 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 Rivera, a medical writer for EHA.
• 0:16
  Today, we are honored to have Professor Heartwood, Donor, who
• 0:20
  is joining us to discuss the management of acute myeloid
• 0:25
  leukemia AML in older unfit patients.
• 0:30
  Welcome Professor Donner. Professor Donner is an
• 0:33
  internationally recognized expert in AML.
• 0:37
  He leads the Department of Internal Medicine at the
• 0:40
  University Hospital on in Germany.
• 0:44
  His groundbreaking work has significantly advanced our
• 0:49
  understanding of genetic alterations in AML and has led
• 0:55
  to the development of personalized treatment
• 0:58
  strategies. In this episode, we will explore
• 1:03
  the complex landscape of AML management in older or unfit
• 1:08
  patients, a vulnerable population that represents a
• 1:13
  significant proportion of AML cases.
• 1:17
  Thank you for being with us today.
• 1:22
  To start off, can you explain please what are the key factors
• 1:28
  in assessing fitness for intensive chemotherapy in older
• 1:33
  AML patients? Well, thank you.
• 1:38
  First of all, thank you for your kind introduction.
• 1:42
  There are several factors that we need to take into account.
• 1:47
  First of all, of course it's patient age.
• 1:50
  Although patient age should not be the decisive determinant to
• 1:55
  to guide therapy, it's of course the patient performance status
• 2:00
  usually according to ECOC, it's one important factor,
• 2:06
  comorbidities very important, for example, renal
• 2:11
  insufficiency, pulmonary insufficiency, cardiac failures.
• 2:15
  These are all factors influencing therapy and in in
• 2:20
  particular adverse events following therapy and
• 2:25
  importantly cytogenetics and molecular features of the
• 2:31
  leukemic cells that are also very important in guiding
• 2:34
  therapy in these older unfit patients.
• 2:37
  And last not least, I would say it's of course also the patient.
• 2:41
  What does the patient want and his family.
• 2:45
  I think that's something very important that we always need to
• 2:48
  take into account. So you mentioned it briefly, but
• 2:54
  how do molecular genetic profiles influence treatment
• 2:59
  decisions in unfit AML patients? Well, regardless of fitness and
• 3:08
  age, genetics is important to establish the correct diagnosis
• 3:15
  according to know the new disease classifications.
• 3:20
  According to the international consensus classification and The
• 3:24
  Who classification with regard to molecular treatment are
• 3:31
  currently genetics in these old unfit patients is perhaps a bit
• 3:37
  less important compared to younger fit patients.
• 3:41
  So with our current standard treatment, the combination of
• 3:47
  the BCL 2 inhibitor venetoclaxin and hypermesylating agent either
• 3:52
  azocytidine and bicytabine, we have a treatment that is given
• 3:59
  mutation agnostic. So it's not really focusing on a
• 4:04
  specific molecular subset of the disease.
• 4:08
  One important exception to to this is IDH 1 mutated AML
• 4:15
  because now we have a very efficacious combination
• 4:19
  treatment with ibacitinib and a society Dean in this patient
• 4:24
  group. With regard to our
• 4:27
  prognostication, several studies have now shown that the both the
• 4:34
  2017 and 2022 ELN risk classifications do not provide
• 4:41
  clinically meaningful outcome prediction for these patients.
• 4:46
  And therefore recently we have developed the 2024 risk
• 4:54
  stratification specifically for patients receiving less
• 4:59
  intensive therapies. These all the risk
• 5:04
  classifications have actually been developed exclusively on on
• 5:09
  data from intensively treated patients.
• 5:11
  That's why it was not so surprising that these risk
• 5:15
  classifications did not really work for these older unfit
• 5:18
  patients. And this new 2024 genetic risk
• 5:22
  classification is a pure molecular genetic signature
• 5:28
  actually are consisting only of a few genes, the signaling genes
• 5:33
  flits 3 N Ras, K Ras and the tumor suppressor gene TP 53.
• 5:41
  It's a signature that was mainly built upon data that we
• 5:46
  generated within the pivotal BILIA, a trial that evaluated
• 5:51
  the combination of venetoclaxine a society.
• 5:54
  Can you discuss a bit further the role of venetoclax
• 5:58
  combinations in treating unfit AML patients?
• 6:03
  The introduction of venetoclax in the treatment of of all the
• 6:07
  patients really has been a major breakthrough for these older
• 6:11
  patients. It was the pivotal via LA study.
• 6:16
  So this trial evaluated the combination of asocytidine plus
• 6:22
  venetoclax versus asocytidine plus placebo and the combination
• 6:28
  of a society in plasma neto clocks led to a significant
• 6:32
  improvement of overall survival 14.7 versus 9.6 months.
• 6:39
  So that was a significant improvement compared to the
• 6:44
  standard of care. An alternative is combining the
• 6:49
  BCL 2 inhibitor venetoclax with low dose cyterabin.
• 6:53
  This has been evaluated in the VIA LACC trial.
• 6:57
  And this is a combination in particular important for those
• 7:01
  countries where the Hmas, the hypermethylating agents are not
• 7:06
  improved or are not reimbursed. What are the current
• 7:10
  recommendations for less intensity chemotherapy regimens
• 7:14
  in older unfit AML patients? Yeah, as I already mentioned,
• 7:20
  current standard of care in I would say in most countries it's
• 7:25
  the combination of the BCL 2 inhibitor venetoclax with an
• 7:30
  hypermesylating agent and HMA, either azocytidine or
• 7:35
  bicytidine. An alternative is combining
• 7:39
  venetoclax with low dose cyterebine.
• 7:42
  For some all the patients this treatment might even be too
• 7:48
  intensive. And an alternative for even more
• 7:52
  unfit patients is to give HMA as a single agent treatment or just
• 7:59
  low dose cyterabine. And we need to consider that
• 8:04
  that there is a proportion of patients in real world practice
• 8:10
  who will not tolerate either of these treatments.
• 8:14
  So these patients will receive what we call best supportive
• 8:18
  care. So hydroxyurea in case of
• 8:21
  proliferation of the leukemia and transfusion support and
• 8:28
  another very important development of the last 2-3
• 8:33
  years is the introduction of the IDH 1 inhibitor.
• 8:37
  I will sit in it. This has become also a standard
• 8:40
  of care for those patients. So these are currently the
• 8:46
  approved treatment options we have for all the unfit patients.
• 8:52
  How does the monitoring of measurable residual disease MRD
• 8:57
  impact prognosis and treatment strategies in unfit AML
• 9:02
  patients? Well, so far MRD does not have a
• 9:11
  major role in monitoring treatment in in these older
• 9:16
  patients, mainly because we don't have a lot of data.
• 9:21
  But first studies using multi colour flow cytometry and
• 9:26
  quantitative PCR actually have shown that those patients who
• 9:30
  achieve MRD negativity have a better outcome, have a better
• 9:36
  overall survival compared to those who who remain MRD
• 9:40
  positive. But I think before entering
• 9:43
  clinical practice, we need many more data on on MRD.
• 9:50
  For example, we first need to define the right time points
• 9:55
  where MRD has to be tested in these patients in these less
• 10:00
  intensive therapies. There will be upcoming new ELN
• 10:04
  recommendations from the MRD Group and we hope that these new
• 10:09
  recommendations will be published sometime next year.
• 10:15
  And how have the prognosis and survival rates for older unfit
• 10:22
  ML patients changed in recent years with the introduction of
• 10:27
  new targeted therapies and less intensity chemotherapy regimens?
• 10:36
  Well, we have achieved significant improvement.
• 10:41
  It started with the introduction of the hypermesylating agents
• 10:46
  about 15 years ago. It was only a moderate
• 10:52
  improvement in overall survival by introducing the HMAS
• 10:58
  asocytidine and the side beam. And as I mentioned earlier, the
• 11:03
  major breakthrough came with the clinical development of the BCL
• 11:07
  2 inhibitor venetoclax. This really led to a significant
• 11:13
  improvement of overall survival and more recently, the
• 11:20
  development of the IDH 1 inhibitor ibucidinib with a
• 11:25
  societidine specifically for AML with IDH 1 mutations.
• 11:30
  This has become a very efficacious treatment and this
• 11:35
  was based on data from the pivotal AGILE study.
• 11:39
  And these data led to the approval of this combination
• 11:42
  both by FDA and the European Medicines Agency.
• 11:47
  What emerging targeted therapies show promise for improving
• 11:53
  outcomes in older, unfit ML patients further?
• 11:58
  Yeah, there, there are quite a few very interesting
• 12:00
  developments. First of all, the development of
• 12:04
  the oral Acer cytidines, notably the oral decytabine Aztecs 727,
• 12:12
  which has already been approved by EMA for the time being only
• 12:17
  as single agent. But we are expecting also the
• 12:21
  approval sometime for the combination of Aztecs 727 with
• 12:25
  with Veneto clocks. And the second a very important
• 12:29
  development is the introduction of the so-called triplet
• 12:33
  combinations. So combining the backbone of
• 12:36
  venaza plus additional targeted agents, for example Venaza plus
• 12:42
  Lipfit 3 inhibitor gilteretinib or the backbone of Iwostitinib,
• 12:48
  azocytidine plus venetoclox For IDH 1 mutated AML, there's
• 12:56
  another interesting development. This is the development of
• 13:00
  second generation BCL 2 inhibitors.
• 13:03
  So beyond Veneto clocks, now we have a second BCL 2 inhibitor in
• 13:08
  early clinic development for AML, this is Sundarotto clocks.
• 13:13
  And probably one of the most promising new class of agents
• 13:18
  are the so-called Menin inhibitors.
• 13:21
  These men in inhibitors are specifically developed for two
• 13:25
  molecular classes of AML and this is AML with mutated NPM 1
• 13:30
  and AML with KM22A rearrangements.
• 13:36
  So the first data we have from relapse refractory AML are very
• 13:41
  encouraging and these agents are now rapidly moving into
• 13:45
  frontline therapies in combination with standard of
• 13:48
  care regimen. So for example, Venaza plus
• 13:52
  Menin inhibitor for first line treatment of AML with either NPM
• 13:58
  1 mutation or came to 2A rearrangements.
• 14:01
  So these are some of the new developments which are in phase
• 14:07
  one or even now starting phase three clinical trials.
• 14:14
  And how do you approach treatment decision making for
• 14:20
  unfit patients with high risk molecular features?
• 14:26
  Yeah. This remains actually
• 14:29
  irrespective of age, an area of great unmet medical need, AML
• 14:36
  with high risk molecular genetic features.
• 14:39
  So one prime example of course is AML with mutated TP53.
• 14:46
  Whatever we do in terms of treatment for these patients,
• 14:50
  the median overall survival time ranges between 6:00 and and nine
• 14:55
  months, which which of course is very short and everything that
• 14:59
  has been tried in the past has failed.
• 15:04
  So even with the combination of venetoclax, A societidine, we
• 15:09
  can improve response rates, but these improved response rates do
• 15:14
  not translate into improved overall survival.
• 15:18
  So actually some of the the centres have become hesitant to
• 15:24
  offer these patients this combination because there's no
• 15:28
  improvement in overall survival. Some centres still do it because
• 15:34
  they think that some of these patients who achieve remission
• 15:40
  can eventually be assigned to allogeneic transplantation.
• 15:44
  So this might be an advantage of achieving remission by the
• 15:48
  combination of ANASA. Although by the treatment itself
• 15:51
  we do not prolong overall survival, there has been great
• 15:56
  hope in improving outcome of these patients by targeting the
• 16:03
  immune checkpoint CD47 using bogrolimab.
• 16:07
  Mogrolimab was the first in class CD47 inhibitor, but all
• 16:13
  three pivotal studies failed, did not improve survival and
• 16:20
  turned out to be too toxic. So this was a major
• 16:23
  disappointing only recently for these high risk AML actually.
• 16:31
  What about car T? Are they close to be developed
• 16:38
  Carty cells for AML? It's been really difficult, I
• 16:42
  know. Unfortunately not.
• 16:45
  And this is a major difference between lymphoid neoplasms and
• 16:48
  myeloid neoplasms. I mean we have seen great
• 16:51
  success with CAR T bispecific antibodies in lymphoid
• 16:57
  malignancies, but myeloid malignancies is lagging far
• 17:02
  behind. It's sometimes difficult to
• 17:07
  explain, but one factor is, is certainly identifying the right
• 17:12
  target whether it's CD33, CD 123, CLL one, Fleet three also
• 17:20
  immunocompetence. So we do not have probably
• 17:24
  enough immune competence cells at least in the setting of
• 17:28
  active leukemia. And if I look at the results of
• 17:34
  the ongoing CAR T cell studies or you know studies with
• 17:39
  bispecific antibodies, they're not really very encouraging.
• 17:45
  So I do not expect that within the next 3-4 years we have any
• 17:51
  of these compounds approved by competent authority.
• 17:57
  Thank you, Professor Donner, for this insightful conversation and
• 18:02
  for sharing your valuable expertise with us.
• 18:05
  Thank you to all of you for listening and staying tuned for
• 18:09
  our next episodes.