Why was there a need for new guidelines?
So we had the European guidelines written in in 2017,
but a lot has happened since then.
We have now number of novel agents that have become
available both initially at relapse.
I'm talking about BTK inhibitors that are now also entering first
line treatment and we also have a number of agents available at
Relapse, for instance, CAR T cell therapy, important BCL 2
inhibitors and also novel BTK inhibitors.
So there was definitely a need for for an update.
Welcome to EHA Unplugged, the official podcast channel from
the European Hematology Association.
EHAI am your host Isabel Olivera.
Today we're joined by Professor Matz Jerkeman, who is a
professor of oncology at London University in Sweden.
Professor Jerkeman has been instrumental on shaping the
recent EHA clinical guidelines on Mantel cell lymphoma MCL.
So we are delighted to have you with us today to discuss these
guidelines and what they mean for clinicians and MCL patients
across Europe and beyond. So thank you very much for being
with us today. Thank you for hosting me SO.
To start off, could you explain what are the main clinical
features of MCL? Yes, Mantel cell lymphoma is
something in between the and aggressive lymphomas.
It's a it's AB cell malignancy and it can sometimes be very
indolent and be managed by watch and wait approach actually like
other indolent lymphomas, perhaps around 20% or so or can
be managed like that. But it can also be a very
aggressive disease and that require very intensive therapy
and especially at at relapse it can be very aggressive and it
presents usually as lymphadenopathy but often also
with lymphocytosis and bone marrow involvement is almost
mandatory, occurs in about 90% of patients.
Also, gastrointestinal involvement is characteristic
for mantle cell lymphoma. How are patients stratified?
You were saying that you can have from indolent lymphoma to a
very aggressive form. So what are the main challenges
when you have a newly diagnosed MCL?
How do you? What are the risk factors to
take into account? Yes, additionally we have the
main looked at age because the the the previous standard
treatment for younger patients at least up to 65 years it's
been treatment involving high dose cyterabin as induction and
also consolidation with high dose chemotherapy and autologous
stem cell support treatment has been divided according to
tolerability for for autologous stem cell transplant.
So that that has been an important point.
But we have now learned that biological risk factors may be
more important and that includes histological subtype.
There are a proportion of patients present with blastoid
or pleomorphic Histology, which is a high risk factor.
Also, proliferation is important, EI 67, about 30% is a
biological risk factor. And perhaps the most important
one that has been recognized is the presence of TP53 mutations.
It means that the patient will have a very short remission with
standard chemo immunotherapy. So in first line, what, what is,
what was the standard of care before in first line and what is
it today? Yes.
So this for as I mentioned younger patients, the standard
of treatment was alternating and recycling based therapy like our
CHOP alternating with hydrocytairabin based regimen
that could be cytairabin only or the HAP and then consolidation
with Toluca stem cell transplant.
We also learned that maintenance with ritaximab prolongs overall
survival for this subgroup. So that was the standard for
younger patients. For elderly patients that are
not eligible for Toluca stem cell transplant, the standard
has been more lower intense chemotherapy like arbenomastin
has been the most frequently used.
Our CHOP has been used and also VR cap which is art chop with
bortisamib instead of being Christine that has been shown to
improve survival compared to to art chop.
But for elder patients, the most common has been Arban, I would
say. And what is it now?
What are the the recommendations in the new guidelines?
Yes, for younger patients a major step forward has been the
results of the huge European Triangle trial which has been
meant paradigm ship 5th in the treatment of of methyl cell
lymphoma. In this trial, the standard
treatment that I mentioned with hydrocydiabine and autologous
stem cell transplant was compared to two experimental
arms. In one arm, ibrutinib was added
to our shop in induction and also as maintenance for two
years. And in the third arm, the second
experimental arm ibrutinib was added but autologous stem cell
transplant was removed. So and the results show that the
addition of ibrutinib to induction and maintenance
improves overall survival. We all know that and there is no
difference if we use we give autologous stem cell transplant
or not. So the standard treatment now is
Archop plus ibrutinib alternating with D Hep or D hex
which is oxaliplatin instead of synthpatin and then maintenance
with ibrutinib and ritaximab. So no more a Tolga stem cell
transplant. So that, that is the most
important change. So that will definitely reduce
toxicity for patients and the efficacy is also much better.
So with an improvement in overall survival.
So that's the new standard treatment.
And this as we remove autologous stem cell transplant, we can
give this type of regimen to also patients that are above 65
years, perhaps around 70 years. So that that's the new treatment
for that population. And then the but the majority of
patients with mental cell lymphoma, they are elderly.
The median age is about 71 years in population based studies, a
large proportions will not tolerate this regimen.
And they for for that population are still an option, I would
say. And VCAP as mentioned, but there
has also been studied studies that add ABTK inhibitor to
arbenomastin to see if that improves outcome and it has been
shown to improve progression free survival definitely by
adding ibrutinib or acalabrutinib to arbenomastin.
So that can also be a standard option for for some patients,
but it also increases the toxicity of this regimen.
But that's another standard option.
And there are also now trials showing that only a BTK drib in
combination with the CDT, the CD 20 antibody like
ibrutinibritaximab is at least equal in efficacy to
urbanaumastin. So that may also be an option
for for elderly patients. And how do you choose among all
these options that are suggested in the guideline?
Yes, for younger patients, I think it's easy because we have
a very good regimen according to the Triangle trial.
But for elderly patients, it's it's, it's, it's difficult, I
think to choose the right treatment because an important
study regimen in at relapse is CAR T cell therapy.
And we know that benamastin impairs T cell activity, both
the number of T cells and the activity of T cells.
So in patients that have a high risk of relapse and may need
cortisol therapy, we'd we'd like to avoid benamastin.
Then we look at biological risk factors.
So patients without biological risk factors, I would prefer are
benamastin or are ibrutinib if that is available, if that is
possible to use or retax combined with another BTK
inhibitor. But for high risk patients it's
it's harder. We would like to avoid
bendamustin. So in that situation, I think
the CAP could be an option for elderly patients avoiding
Bendamustin. So as you mentioned now there is
an option of using BTKI in first line in all patients and frayed
patients. So now that BTK is are moving
into first line, what are the recommendations for second line?
Yes, it depends on on the situation also here because now
in the triangle regimen the the there is a specified duration of
limited duration of of maintenance with BTK inhibitors.
So patients who have received ibrutinib for two years
according to the triangle regimen and stop and then a year
after have a relapse, they can be restarted on a BTK inhibitor
again. So that is one situation perhaps
more commonly that the relapse occurs during the treatment with
the BTK inhibitor and then the disease is refractory to BTK
inhibitors and we we need something else.
And then we have a couple of options.
We have CAR T cell, Brexit cell is the one that is approved in
in Europe. So that is 1 standard option in
this situation and the one with perhaps the highest activity as
well. But we also have now available
in Europe pertobrutinib which is a non covalent BTK inhibitor
that has activity also in patients that are refractory to
to covalent BTK inhibitors. So that that is another option
and it can also be used as a bridge to to Cartesian treat.
But there are also other possibilities like chemo,
immunotherapy, our back for instance, that is retax map,
venomastin and cytourbin is an option and our Gemox can be an
option as well. And there are also other agents
that are under development like other BCL 2 inhibitors and buy
specific antibodies. So all of these novel therapies
are not the same price tag. How widely are they available,
especially obviously car T, but some over the others are also
very expensive. Are they used widely in Europe?
Yes, I think they are available in most European countries now.
Brexit sell but not in every country.
But in most countries they are available.
They are considered cost of cost effective and are reimbursed,
but not not everywhere. So this doesn't play a role or a
big role in choosing which will be the second line, not the
price tag. It will be really the clinical
situation. Yes, I think in most cases yes.
But the problem is that the cortisol therapy in mental cell
lymphoma is not curative as it is in diffuse large B cell
lymphoma. So we don't see a plateau in in
progression free survival as clearly at least as in as as in
diffuse large B cell lymphoma. So which other therapies can we
expect in the future? What is in the pipeline that you
were referring to? Yes there is.
For instance, Sondrotoplex that is another BCL 2 inhibitor that
is active in relapsed mantle cell lymphoma also after BTK eye
failure and also CD20CD3 bispecific antibodies like
glofetamab and epcoritamab are very active in in this
situation. We will also probably see other
CAR T cell products like Lisa cell is approved in in the US
for instance for relapsed mantle cell lymphoma and has a lower
frequency of of the CNS toxicity compared to to Rexocell.
It's also an attractive option. So how do you feel this new
guidelines fit in the daily clinical practice?
Well, now I think the the the guidelines are in line with the
current situation and what is also very positive, I think that
these can be updated more frequently than that.
We hope that these will be updated yearly at least, so we
don't have to rely on obsolete guidelines that cannot be used.
So I think we're in a much better situation now than we
were before. So is there anything else that
you would like to add for the audience that I haven't asked?
Radiotherapy is also very active treatment in mental cell
lymphoma. That's that's something we may
forgot. It's, it's easier for
oncologists to use radiotherapy perhaps than for hematologists.
Mentholine format is extremely sensitive to radiotherapy.
So that that's a good option also at relapse and also as a
bridge to to call T cell therapy.
Another possible treatment is is also allergenic stem cell
transplant and that was used more frequently before, less
frequently when we have access to Corti cell therapy.
Limitation is also age that many patients are elderly with mental
cell lymphoma. But there are still I think a
population that may benefit from allotransplant at least after
Corti cell therapy. It may be still the only
curative treatment for mental cell lymphoma, but I think
Mantasalam foam has not been considered curable.
But that is something that I think and hope will change that
this will be a curable disease. I think we will be able to see
that. With which agents?
So you say that car T therapy is not doing it so ACT it's an
option but less use now And what could be a curative option?
I think we cure patients already now with the more intensive
treatment and the triangle regimen I think will be curative
in a higher proportion of patients.
That's my hope at least because it's clearly improves overall
survival. And I think even even with this
previous standard of treatment, we have seen that after 20
years, 1/4 of the patients are without relapse and remission.
They may be cured with a with a new regimen that is more
effective. I I expect we see an even higher
proportion that will be have a long term remission.
Which is excellent use. So if you want the audience to
remember just one thing from the guidelines or this podcast, what
would it be? Well, the treatment for at least
for younger patients with metals and lisinophone has undergone a
significant change now during the the last couple of years
that will probably probably have a major impact on on the outcome
and possibly be a curative treatment for mental health.
So pay attention to these guidelines and use the new
treatments and the recommendations that you have
made. So thank you very much for
sharing your experience with us. Thank you so much.
Thank you to the audience for listening and if you enjoyed
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Stay tuned for more episodes of EHA Unplugged.