These guidelines today have much more clinical trial based
evidence than guidelines from 10 years ago, even if it is a rare
disease. And we have introduced in the
first line a more refined application of standard tools
that existed so far. Welcome to EHA Unplugged, the
official podcast channel from the European Hematology
Association EHA. I'm your host, Isabella Olivera.
Today we're talking about the recent ESMO EHA guidelines for
peripheral T and natural killer cell lymphomas.
This is a collaboration between ESMO and EHA.
To walk us through these wide lines, we have today 2
professors, Francesco Lamore from ESMO and Massimo Federico
from EHA. Professor Damore is a clinical
professor and chair of the Department of Hematology at Arus
University in Denmark. And Professor Massimo Federico
is a senior professor of medical oncology at the University of
Modena and Radio Media in Italy. They were both deeply involved
in shaping these guidelines, and they're here to help us
understand what's new in these guidelines, why these changes
matter, and how they can make a difference for patients.
Thank you for being with us today.
Thank you for your invitation. Thank you for invitation.
We're going to start by clarifying which informants are
in this guideline that uses the term PTCL to cover malignancies
that are derived from either T or NK cells.
There are many two types what is covered in this guideline.
These guidelines cover the different peripheral T cell
lymphomas that are classified as a nodal, extra nodal, and
leukemic disseminated. We did not cover the topics of
cutaneous peripheral T cell lymphoma.
We did not cover the pretymic either, that is the T cell
derived acute lymphoblastic leukemias and lymphoblastic
lymphomas. So it is the mature entities,
postymic with the exclusion, as Professor Federico just said, of
the cutaneous one among the mature entities.
And why was there a need for this new guidelines?
The last guidelines were that the community received in this
context were produced in 2015. A decade ago landscape of
peripheral T cell lymphomas, T&K cell lymphomas was significantly
more simple. But there has been an increase,
a dramatic increase in complexity due to steep growth
of knowledge in the in these entities, knowledge about their
biology, which also has led to the definition of new entities.
As we take for example, the breast implant associated
anaplastic glass cell informer was something absolutely absent
in the latest guidelines. In the latest guidelines we were
talking about intestinal T cell informers that were enteropathy
associated type 2 which we called it enteropathy associated
but there was no enteropathy around.
Today this has changed the name and has also completely
different biology and background from the well known and celiac
disease associated T cell informers.
These are two examples of brand new things, and there are many
more to to mention that make the complexity level of these
guidelines much more difficult to see and to understand if you
if you don't have specific guidelines looking at all the
entities. In addition to the clarification
of Professor Damore, I would like to also underline that we
did our best to offer practical deadlines for more than a dozen
of different subtypes just to help physicians to find
correctly the deadlines for the specific, for the single
patients. So it was really a huge effort
to not to offer detailed information on how to treat
nodal, different types of nodal extranodal, different types of
extranodal and so on. And this was one of the most
relevant reasons for the need of an update.
The first program I imagine is to diagnose this lymphomas
because there are so many subtypes and they are rare.
How to diagnose today? What are the recommendations in
this guideline? To begin with, as the answer of
this question to this question, we have one of the most
recognized T cell lymphoma pathologist as a member of our
author group, Professor de la Belle that has produced quite
detailed overviews and algorithms for the diagnosis
which is based on a three level tire diagnostic approach.
The first level is the morphology, the second level is
the immunohistochemistry as we are used.
But then there is 1/3 tire which is the molecular profiling at
genomic level which today has entered the diagnostic area no
longer as a research topic but more and more interacting with
the daily diagnostic decisions. So the genomic profile for
example in TFH particular helper T cell derived lymphomas will
allow you to make decisions in the in the first line and
relapse, relapse setting for example, for the use of hyper
methylating agents that are no no longer only for research, but
also introduced in the daily practice today.
So these are new things that they got the guidelines from
2015 did not have at all. And so I would also add that we
did our best that we tried also to clarify the complexity,
complexity of the initial diagnosis for the needs for
confirmation by an expert pathologist and also the need to
have a multidisciplinary approach in planning right to
treatment according to the subtypes and the extension of
the disease. But also we would like to help
physicians to treat their patients in the area of
residency of the patients. So it's a rare disease.
Now it is impossible to imagine that we can cover with the
referral center everywhere. So we we have to also to try to
combine the the needs for a correct diagnosis and the needs
for the treatment not so far from the area of residency of
the patients. And this is an effort of of the
group to clarify what is essential.
First level, second level, third level, the need for discussing
the diagnosis, the suspected diagnosis at the referral level
and then offered the opportunity to treat the patients as close
as possible to their residency. So it is not so easy, but so
we're trying to do this. But it's not something that the
guidelines can go and, and organize in the, in the text
because there is such a heterogeneity of realities out
there. And these are guidelines that
are, that are read across the world of global guidelines.
Although they're European in origin, they will be, they will
be read in the, in the Americas, in Asia, in global fashion.
So it's difficult to come and organize things that are
extremely heterogeneous. It is a rare disease, it is a
difficult disease even for experts.
And if you have to be treated firstly, diagnosed correctly and
then treated, it is important that, as the professor said,
Federico said, it is important that a person with experience is
looking at these things and a group, A-Team, a
multidisciplinary team, where it is possible to have it, is there
because that offers the patient the possibility of survival,
which is significantly higher than if you're treated standard
of care in some kind of discipline, viable environment.
So with respect, with the difference, huge difference that
there is not only in countries, but areas of the world, this
must be said about these diseases because they, they are,
they are very difficult. We we had recently a meeting in
Asia. In different countries it's
extremely different how diagnostic and interpretation is
depending on the region you're taught talking about.
So the first the big challenge is diagnosis, but then can you
summarize how these guidelines approach the treatment in first
line? Which are the main points you
want to highlight? Yes, the, the, the first line is
of course something that needs as much evidence as possible.
We are, we work in these guidelines with levels of
evidence and in, in the, in the recognized international
terminology. And as you can imagine in
diseases that are rare, there will never be the big trials
with hundreds or thousands of patients like you have in some
other some other sections of oncology like breast cancer,
colon cancer. This is a rare disease.
So there will be small trials. The evidence will be relatively
weak and we have to work with that.
But these guidelines today have much more clinical trial based
evidence than guidelines from 10 years ago, even if it is a rare
disease. And we have introduced in the
first line a more refined application of standard tools
that existed so far. The use, for example, of a
chopped backbone CHOP is an abbreviation for
cyclophosphamide, hydroxydonor, rubicine, vincristine and
Prednisolone, with or without the addition of a topocyte, with
or without the use of a stem cell cell transplant of some
kind, autologous or allogeneic. But these things were also
mentioned in decade ago. What is different is that it is
a refined mentioning based on recent clinical trials, based
also on world evidence from registries, population base and
also from experience with long term follow up.
So this refinement is something that we didn't have in the past.
We have looked at for example a toposite has been a long
discussion in the community. But the, the guidelines now say,
we know that a toposite has time after time shown an effect in
elk positive ALCL. It it has been shown in
prospective trials and it has been shown in several
retrospective analysis. So you can, you can say that the
use of a topazide in elk positive ALCL is not just at the
same level as the other entities.
Elk positive ALCL seem to have a predilection, seems to have a
specifically good response compared to the other entities.
So this is what I mean by refinement of what we told
people 10 years ago. In first line therapy, what we
clearly tried to do is to offer the opportunity to select the
right management, the right approach according to stage of
the disease and histologic subtype.
And when is better to use CHOP, CHOP, eat a chopper plus a
topocide. When adding novel agents like
brintuximabedotin in anaplastic large cell lymphoma setting.
And also the the more appropriate approach for
offering a stem cell transplant at the end of induction therapy
in those entities where it is clear that this could be of
benefit. Although we are still lacking
prospective randomized at the clinical trial.
So just for summarizing this aspect of first line therapy,
first the panel suggests to consider patients for enrollment
in clinical trial. Second, in terms of standard
care, those people that like to check for our deadlines have
three figures to summarizing the flow chart for patients with
nodal extranodal and low clinic disease.
So we hope for a lot of opportunities to try to find the
right place for selecting treatment for the patient.
So just to just to, just to mention on the on the transplant
have we have the trials that have been published one year ago
2024 showing for example the randomized trial run in France
and Germany, the AATT trial published in 2021 in blood and
then again now in 2024 with a long term follow up.
This information with a with a comparison between autologous
and allogeneic transplant in the front line setting was an
important information for the community because you you could
see and confirmed in both the final analysis of 21 and the
long term follow up of 24 that what you gain in terms of better
duration of response with a Nello transplant in.
In other words, less relapses, lymphoma related relapses you
lose on in term of transplant related mortality.
So there is a toxicity from the modality which has less relapses
at at the end of the day, they balance each other completely.
So there is no difference. So this information is important
for the community. And this is another example of
applying things at at the right time, the right thing at the
right time. The guideline ends up if you, if
you have a transplant eligible patient saying, well transplant
should be autologous in the upfront setting where you don't
where you still have the LO option in the relapse setting to
salvage your patient if the patient relapses.
So this isn't quite important message from from the guideline,
which is sustained not just by a gut feeling, but by a randomized
trial that has been published in the Journal of Clinical Oncology
just 12 months ago. Is there anything you would like
to highlight about the second line so the relapse?
Setting. Yes.
So we started the from the the knowledge that so far the
outcome of patients with refractory or relapsed
peripheral tisel lymphoma is usually dismal.
So there is a need for improvement and the deadlines
also offer the best evidence on the new agents that have to be
considered for patients with relapsed or refractory disease
together with the best use of Autolu stem cell transplant and
also other innovative approach. But probably professor for the
more already can just underline some specific benefit of new
agency in specific subtypes of relapse of the T cell lymphoma.
I want to just wrap up on around the approach of the stem cell
transplant that in the guidelines you will see
autologous transplant applied to frontline approach with some
notable exception exceptions For example, the hepatosplenic T
cell Informa and the monomorphic epitheliotropic intestinal T
cell Informa. The Michael, those two we
recommend allogeneic upfront otherwise most of the others
nodal and externodal will be would be the recommendation of
photologists. Whereas in the relapse setting
all chemosensitive patients that are transplant eligible are
recommended treated by allogeneic transplant.
This is a major pattern and for the leukemic entities that we
have in these guidelines, we didn't have them ten years ago.
If they are chemosensitive in the three aggressive entities,
then we recommend to treat them or consolidate them with
allogeneic transplant in the relapse setting.
One comment is also a new trend surging significantly in the
field of T cell informers of the importance of minimal residual
disease. We know minimal residual disease
from leukemia, we know it from mental cell Informa, We know it
even for a diffuse large B cell Informa.
It is a topic that is more and more usual in these discussions.
But for T cell entities, it has been a challenge also in this
field because the T cell receptor rearrangement clone
clonality has not been easy to demonstrate.
But today the tool of circulating T circulating tumor
DNA, CT DNA really taking speed and, and and and increasing in
publications. I just came home from from a
meeting a few days ago. There was a huge publication
that shows patients we call incomplete remission with
standard of care tools today, which is the PET CT scanning
metabolic complete remission. Almost half of them that are
called CRS by PET CT, they still have minimal as usual disease if
you if you look at it with MRD. So actually in shop only treated
PTCL in that publication at the end of the day, 29% of the
patients treated had MRD negative status at the end of
the treatment. So what I'm saying is we will
learn in time already, not in time, but it's already there.
It's already now we will learn that MRD will give us new way of
approaching the disease because what we have been calling CR
until now is maybe not CR. Is this already in the
guideline? The MRDN.
We just mentioned it, but CT DNA will be one of the two topics in
my opinion, that will dominate the update of the next
guideline. If you, if you ask me what,
what, what will happen for in the next guideline?
What do you expect to be the new hot topics in the next
guidelines? And of course, in guidelines,
you cannot have publications that are so recent that you
need, you need more confirmation, you need third
publication that shows the same. So it takes a little bit of
time. Guidelines will always be a
little bit the breaking news of of of the field, but I think the
next guideline will contain it so.
There's this concept of living guideline.
Yes, yeah, it is. It is necessary.
Otherwise, you know, they become like dinosaurs, they become like
some some stone in past, which is very interesting to see from
an archaeological point of view. But if you if you have to work
with that every day in your clinic, then you would like to
have something more living. And the NCCN has done that.
We try to do the same. Exactly 1 of the aims of this
group of people supported by ESMA is to update guidelines as
timely as possible. I don't know if we will be able
to do twice the year or three times per year or once in two
years. However, once we will have
relevant information coming from research being the clinical
trials or other biological news. Of course, Francesco and all the
group is in agreement with the discuss the opportunity to
create an update or to inform the community that there are
news compared to the already released deadlines.
This is very important it. Must be also easier by the
collaboration between ESMO and EHA to keep updating this
guidance to join the airports. It's good that societies,
European societies show they can work together and we, I mean, it
is the first time in T cell informers.
But if you look at myeloma, they're just being published the
ESMO AI myeloma guideline, common guideline.
So there are good examples and other that are continuously
produced. Get back to your question about
about refractory, relapsed refractory disease.
The guidelines also have caught some of the very, very new
publications about novel drugs that have been clinical trial
based. And just to anecdotally for this
podcast, I can tell you we got the results of the clinical
trial, the SPIRIT trials by the professor of Chai that published
that in Lensity Hematology in the summer of 2000 and it
appeared in Density Hematology. Actually I think it was one week
or two weeks before we had to send the manuscript out in
external review and and we sat in the group.
Well, we would like to have this publication mentioned.
So it was very last second. We caught that bus and put and
put that publication in our references.
And it is a treatment of external NKT lymphoma that is a
typical nasal type lymphoma present in Europe but more
frequent in Asia where the use of checkpoint inhibitor, which
is a novel drug in the context of NKT lymphoma.
But it has unique favorable effect combined with the usual
Aspergenase containing regiments.
So if you add upfront, actually this trial was upfront first
line, it came on top of results that we already had in small
phase two trials in the relapse setting.
But this upfront trial with overall response rate of almost
80% that that has been completely new in the field.
So I'm very happy and a little bit proud that we had this
publication included at the last minute in the in these in these
guidelines. So Professor Federico, what
would be your take away message for the audience?
The the most important recommendation in my view is one
of you suspect to have a patients with peripheral test
cell lymphoma. Please check for a correct
diagnosis. This is first, if you are not
all the facilities in your area, please connect with the centers
that can help you in confirming or not confirming the diagnosis.
This is the first step. Now correct diagnosis will
translate in the best opportunity to offer the right
treatment and the best options for cure.
So the second is if you have a patients with a confirmed
diagnosis of peripheral lymphoma, consider the
opportunity to enroll the patients in a clinical trial.
Third, if you have to offer just a standard care, please follow
the deadlines. We have recently released that,
in my opinion, they have one of the most relevant efforts to
help physicians to make the right decision for the patients.
And I asked the same question to you, Professor Amore, what would
be for you the take away message for everybody to go and read
this guideline? Because it's a very complex
subject, we cannot cover the whole thing in.
I would say to the to the reader of the guideline, the
recommendation how to read the guideline is Please.
If you mean it seriously, then read the guideline in its
entirety. Read the main manuscript, but
read also the supplementary of the guideline.
The supplementary is only supplementary because there is a
limit of words from the journals.
The things in the supplementary are important things,
particularly in T cell lymphomas where we have so many entities
and particularly the very rare entities that many physicians
feel a little bit shaky about because they maybe have not seen
such a patient ever. So my recommendation is please
read the entire guideline. In my opinion, you have not read
the guideline if you don't read both the main manuscript and the
supplementary as a recommendation for what to do to
your pace to your patient with preferred T cell informers.
As as it was said by Massimo, by Professor Federico, the the
importance of trying to put patient in a clinical trial is
just because what happens in a clinical trial is that you have
more precision about what's going on.
You gather information, you have a monitoring of your patients
and those that have looked at it.
There are some interesting, interesting studies done on plus
minus clinical trial within a certain disease.
And there is a difference in in survival, not because the
clinical trial was the best clinical trial in the world, but
the fact that the patient is monitored and is carefully
followed that makes it less likely to have complications
that come maybe suddenly without anybody expecting it and also a
better care of the patient. So there is an there is an
advantage to have a patient in a clinical trial.
But the problem is and any reader of the guidelines will of
course agree that if there is no clinical trial, which is the
most frequent situation you are in, then the recommendation to
to bring your patient in the clinical trial is not so easy.
And sometimes you can get a clinical trial, you have to send
your patient out of the country and that is also a little bit
heavy for the patient and the family.
But but that, that would be best.
And we have highlighted that in the guidelines and importantly
that disciplines talk together. So it is important to have a
tertiary center. I know there will be different
realities around the world, but this multidisciplinary approach
from pathology in one end to clinical, clinical intervention
in the other end, our treatment will never be better than the
diagnosis we are offered from the from the diagnostic side.
If the diagnosis is wrong, our treatment will be wrong or not
appropriate. So, and I have the impression in
this particular guideline, the first key aspect is really a
correct diagnosis because there are so many entities.
And from what I could see in the guideline also each entity is
treated in a different way, in a slightly different way in any
case. So it's key to go and look at
all the details and be precise. So you know you have a
heterogeneity here which is practically unseen.
I know there are variants in mental cell lymphoma, there are
variants in diffuse large B cell lymphomas, but but these are
biologically completely different diseases.
If you think about the lymphoma arising from a breast implant
and the lymphoma arising from a patient with celiac disease in
the in the small bowel, these two diseases are so far from
each other. OK, they derive from T cell from
T cells, but they are two complete different planets.
So is there anything else you would like to add for the
audience? My wish is to ask the audience
to use the deadlines and in case they need some more explanation,
contact us and we will do our best also to clarify.
And I would say to the audience, stay tuned for CTDNA and
combination of new drugs and combination of new drugs, HTAC
inhibitors and easy H2 inhibitors, both oral.
So that is just some teasers for the next guidelines.
OK, so there. Thanks a lot.
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