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Why was there a need for new 
guidelines? 

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So we had the European 
guidelines written in in 2017, 

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but a lot has happened since 
then. 

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We have now number of novel 
agents that have become 

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available both initially at 
relapse. 

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I'm talking about BTK inhibitors
that are now also entering first

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line treatment and we also have 
a number of agents available at 

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Relapse, for instance, CAR T 
cell therapy, important BCL 2 

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inhibitors and also novel BTK 
inhibitors. 

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So there was definitely a need 
for for an update. 

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Welcome to EHA Unplugged, the 
official podcast channel from 

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the European Hematology 
Association. 

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EHAI am your host Isabel 
Olivera. 

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Today we're joined by Professor 
Matz Jerkeman, who is a 

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professor of oncology at London 
University in Sweden. 

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Professor Jerkeman has been 
instrumental on shaping the 

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recent EHA clinical guidelines 
on Mantel cell lymphoma MCL. 

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So we are delighted to have you 
with us today to discuss these 

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guidelines and what they mean 
for clinicians and MCL patients 

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across Europe and beyond. 
So thank you very much for being

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with us today. 
Thank you for hosting me SO. 

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To start off, could you explain 
what are the main clinical 

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features of MCL? 
Yes, Mantel cell lymphoma is 

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something in between the and 
aggressive lymphomas. 

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It's a it's AB cell malignancy 
and it can sometimes be very 

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indolent and be managed by watch
and wait approach actually like 

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other indolent lymphomas, 
perhaps around 20% or so or can 

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be managed like that. 
But it can also be a very 

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aggressive disease and that 
require very intensive therapy 

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and especially at at relapse it 
can be very aggressive and it 

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presents usually as 
lymphadenopathy but often also 

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with lymphocytosis and bone 
marrow involvement is almost 

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mandatory, occurs in about 90% 
of patients. 

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Also, gastrointestinal 
involvement is characteristic 

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for mantle cell lymphoma. 
How are patients stratified? 

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You were saying that you can 
have from indolent lymphoma to a

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very aggressive form. 
So what are the main challenges 

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when you have a newly diagnosed 
MCL? 

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How do you? 
What are the risk factors to 

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take into account? 
Yes, additionally we have the 

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main looked at age because the 
the the previous standard 

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treatment for younger patients 
at least up to 65 years it's 

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been treatment involving high 
dose cyterabin as induction and 

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also consolidation with high 
dose chemotherapy and autologous

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stem cell support treatment has 
been divided according to 

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tolerability for for autologous 
stem cell transplant. 

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So that that has been an 
important point. 

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But we have now learned that 
biological risk factors may be 

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more important and that includes
histological subtype. 

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There are a proportion of 
patients present with blastoid 

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or pleomorphic Histology, which 
is a high risk factor. 

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Also, proliferation is 
important, EI 67, about 30% is a

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biological risk factor. 
And perhaps the most important 

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one that has been recognized is 
the presence of TP53 mutations. 

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It means that the patient will 
have a very short remission with

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standard chemo immunotherapy. 
So in first line, what, what is,

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what was the standard of care 
before in first line and what is

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it today? 
Yes. 

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So this for as I mentioned 
younger patients, the standard 

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of treatment was alternating and
recycling based therapy like our

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CHOP alternating with 
hydrocytairabin based regimen 

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that could be cytairabin only or
the HAP and then consolidation 

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with Toluca stem cell 
transplant. 

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We also learned that maintenance
with ritaximab prolongs overall 

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survival for this subgroup. 
So that was the standard for 

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younger patients. 
For elderly patients that are 

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not eligible for Toluca stem 
cell transplant, the standard 

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has been more lower intense 
chemotherapy like arbenomastin 

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has been the most frequently 
used. 

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Our CHOP has been used and also 
VR cap which is art chop with 

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bortisamib instead of being 
Christine that has been shown to

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improve survival compared to to 
art chop. 

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But for elder patients, the most
common has been Arban, I would 

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say. 
And what is it now? 

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What are the the recommendations
in the new guidelines? 

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Yes, for younger patients a 
major step forward has been the 

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results of the huge European 
Triangle trial which has been 

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meant paradigm ship 5th in the 
treatment of of methyl cell 

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lymphoma. 
In this trial, the standard 

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treatment that I mentioned with 
hydrocydiabine and autologous 

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stem cell transplant was 
compared to two experimental 

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arms. 
In one arm, ibrutinib was added 

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to our shop in induction and 
also as maintenance for two 

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years. 
And in the third arm, the second

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experimental arm ibrutinib was 
added but autologous stem cell 

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transplant was removed. 
So and the results show that the

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addition of ibrutinib to 
induction and maintenance 

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improves overall survival. 
We all know that and there is no

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difference if we use we give 
autologous stem cell transplant 

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or not. 
So the standard treatment now is

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Archop plus ibrutinib 
alternating with D Hep or D hex 

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which is oxaliplatin instead of 
synthpatin and then maintenance 

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with ibrutinib and ritaximab. 
So no more a Tolga stem cell 

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transplant. 
So that, that is the most 

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important change. 
So that will definitely reduce 

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toxicity for patients and the 
efficacy is also much better. 

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So with an improvement in 
overall survival. 

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So that's the new standard 
treatment. 

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And this as we remove autologous
stem cell transplant, we can 

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give this type of regimen to 
also patients that are above 65 

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years, perhaps around 70 years. 
So that that's the new treatment

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for that population. 
And then the but the majority of

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patients with mental cell 
lymphoma, they are elderly. 

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The median age is about 71 years
in population based studies, a 

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large proportions will not 
tolerate this regimen. 

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And they for for that population
are still an option, I would 

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say. 
And VCAP as mentioned, but there

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has also been studied studies 
that add ABTK inhibitor to 

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arbenomastin to see if that 
improves outcome and it has been

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shown to improve progression 
free survival definitely by 

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adding ibrutinib or 
acalabrutinib to arbenomastin. 

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So that can also be a standard 
option for for some patients, 

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but it also increases the 
toxicity of this regimen. 

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But that's another standard 
option. 

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And there are also now trials 
showing that only a BTK drib in 

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combination with the CDT, the CD
20 antibody like 

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ibrutinibritaximab is at least 
equal in efficacy to 

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urbanaumastin. 
So that may also be an option 

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for for elderly patients. 
And how do you choose among all 

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these options that are suggested
in the guideline? 

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Yes, for younger patients, I 
think it's easy because we have 

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a very good regimen according to
the Triangle trial. 

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But for elderly patients, it's 
it's, it's, it's difficult, I 

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think to choose the right 
treatment because an important 

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study regimen in at relapse is 
CAR T cell therapy. 

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And we know that benamastin 
impairs T cell activity, both 

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the number of T cells and the 
activity of T cells. 

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So in patients that have a high 
risk of relapse and may need 

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cortisol therapy, we'd we'd like
to avoid benamastin. 

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Then we look at biological risk 
factors. 

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So patients without biological 
risk factors, I would prefer are

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benamastin or are ibrutinib if 
that is available, if that is 

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possible to use or retax 
combined with another BTK 

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inhibitor. 
But for high risk patients it's 

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it's harder. 
We would like to avoid 

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bendamustin. 
So in that situation, I think 

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the CAP could be an option for 
elderly patients avoiding 

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Bendamustin. 
So as you mentioned now there is

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an option of using BTKI in first
line in all patients and frayed 

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patients. 
So now that BTK is are moving 

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into first line, what are the 
recommendations for second line?

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Yes, it depends on on the 
situation also here because now 

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in the triangle regimen the the 
there is a specified duration of

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limited duration of of 
maintenance with BTK inhibitors.

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So patients who have received 
ibrutinib for two years 

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according to the triangle 
regimen and stop and then a year

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after have a relapse, they can 
be restarted on a BTK inhibitor 

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again. 
So that is one situation perhaps

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more commonly that the relapse 
occurs during the treatment with

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the BTK inhibitor and then the 
disease is refractory to BTK 

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inhibitors and we we need 
something else. 

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And then we have a couple of 
options. 

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We have CAR T cell, Brexit cell 
is the one that is approved in 

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in Europe. 
So that is 1 standard option in 

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this situation and the one with 
perhaps the highest activity as 

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well. 
But we also have now available 

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in Europe pertobrutinib which is
a non covalent BTK inhibitor 

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that has activity also in 
patients that are refractory to 

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to covalent BTK inhibitors. 
So that that is another option 

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and it can also be used as a 
bridge to to Cartesian treat. 

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But there are also other 
possibilities like chemo, 

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immunotherapy, our back for 
instance, that is retax map, 

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venomastin and cytourbin is an 
option and our Gemox can be an 

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option as well. 
And there are also other agents 

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that are under development like 
other BCL 2 inhibitors and buy 

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specific antibodies. 
So all of these novel therapies 

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are not the same price tag. 
How widely are they available, 

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especially obviously car T, but 
some over the others are also 

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very expensive. 
Are they used widely in Europe? 

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Yes, I think they are available 
in most European countries now. 

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Brexit sell but not in every 
country. 

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But in most countries they are 
available. 

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They are considered cost of cost
effective and are reimbursed, 

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but not not everywhere. 
So this doesn't play a role or a

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big role in choosing which will 
be the second line, not the 

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price tag. 
It will be really the clinical 

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situation. 
Yes, I think in most cases yes. 

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But the problem is that the 
cortisol therapy in mental cell 

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lymphoma is not curative as it 
is in diffuse large B cell 

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lymphoma. 
So we don't see a plateau in in 

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progression free survival as 
clearly at least as in as as in 

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diffuse large B cell lymphoma. 
So which other therapies can we 

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expect in the future? 
What is in the pipeline that you

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were referring to? 
Yes there is. 

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For instance, Sondrotoplex that 
is another BCL 2 inhibitor that 

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is active in relapsed mantle 
cell lymphoma also after BTK eye

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failure and also CD20CD3 
bispecific antibodies like 

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glofetamab and epcoritamab are 
very active in in this 

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situation. 
We will also probably see other 

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CAR T cell products like Lisa 
cell is approved in in the US 

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for instance for relapsed mantle
cell lymphoma and has a lower 

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frequency of of the CNS toxicity
compared to to Rexocell. 

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It's also an attractive option. 
So how do you feel this new 

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guidelines fit in the daily 
clinical practice? 

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Well, now I think the the the 
guidelines are in line with the 

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current situation and what is 
also very positive, I think that

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these can be updated more 
frequently than that. 

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We hope that these will be 
updated yearly at least, so we 

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don't have to rely on obsolete 
guidelines that cannot be used. 

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So I think we're in a much 
better situation now than we 

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were before. 
So is there anything else that 

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you would like to add for the 
audience that I haven't asked? 

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Radiotherapy is also very active
treatment in mental cell 

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lymphoma. 
That's that's something we may 

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forgot. 
It's, it's easier for 

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oncologists to use radiotherapy 
perhaps than for hematologists. 

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Mentholine format is extremely 
sensitive to radiotherapy. 

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So that that's a good option 
also at relapse and also as a 

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bridge to to call T cell 
therapy. 

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Another possible treatment is is
also allergenic stem cell 

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transplant and that was used 
more frequently before, less 

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frequently when we have access 
to Corti cell therapy. 

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Limitation is also age that many
patients are elderly with mental

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cell lymphoma. 
But there are still I think a 

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population that may benefit from
allotransplant at least after 

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Corti cell therapy. 
It may be still the only 

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curative treatment for mental 
cell lymphoma, but I think 

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Mantasalam foam has not been 
considered curable. 

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But that is something that I 
think and hope will change that 

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this will be a curable disease. 
I think we will be able to see 

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that. 
With which agents? 

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So you say that car T therapy is
not doing it so ACT it's an 

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option but less use now And what
could be a curative option? 

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I think we cure patients already
now with the more intensive 

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treatment and the triangle 
regimen I think will be curative

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in a higher proportion of 
patients. 

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That's my hope at least because 
it's clearly improves overall 

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survival. 
And I think even even with this 

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previous standard of treatment, 
we have seen that after 20 

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00:14:32,520 --> 00:14:37,480
years, 1/4 of the patients are 
without relapse and remission. 

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They may be cured with a with a 
new regimen that is more 

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effective. 
I I expect we see an even higher

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proportion that will be have a 
long term remission. 

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Which is excellent use. 
So if you want the audience to 

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remember just one thing from the
guidelines or this podcast, what

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would it be? 
Well, the treatment for at least

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for younger patients with metals
and lisinophone has undergone a 

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significant change now during 
the the last couple of years 

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that will probably probably have
a major impact on on the outcome

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and possibly be a curative 
treatment for mental health. 

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So pay attention to these 
guidelines and use the new 

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treatments and the 
recommendations that you have 

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made. 
So thank you very much for 

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sharing your experience with us.
Thank you so much. 

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Thank you to the audience for 
listening and if you enjoyed 

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this episode, please like it and
subscribe to our channel. 

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Stay tuned for more episodes of 
EHA Unplugged.