1. Mats Jerkeman Department of Oncology Lund University Sweden
Mantle cell lymphoma
Mats Jerkeman
Department of Oncology
Lund University
Sweden
I feel very honored to be invited to this excellent meeting, so far away. Today, I will try to give my personal view on current treatment of mantle cell lymphoma, and how genetics may have impact on the choice of therapy.

2. History of MCL
1990
Association of centrocytic lymphoma and t(11;14)
Williams ME, Blood 1990
2019
Increasing incidence
New potent agents
Cure?
1997
’The worst lymphoma to have’
The Non-Hodgkin’s Lymphoma Classification Project, 1997
MCL is a relatively young disease. Less than 30 years ago, the association between t(11;14) and what was then called centrocytic lymphoma was reported, and this entity, named MCL entered the REAL Classification in By that time this was called ´The worts lymphoma to have’ by some one. I don’t think that is true anymore. Today, we see an increasing incidence in both North America and Europé, we have several new potent drugs, effective in MCL, and we may hope for a cure of this disease.

3. Back to 1990s Nordic Lymphoma Group Christian Geisler
NORDIC MCL
NORDIC MCL2 –
Escalated CHOP
BEAM consolidation
Autologous stem cell transplant
High dose cytarabine
Rituximab
MRD assessment
Treat molecular relapse
FAILURE
In the 90s, when MCL was considered the worst of all lymphomas, my dear colleague in Copenhagen, Denmark, Christian Geisler, proposed a phase 2 trial for MCL, including escalated CHOP (called MAXI-CHOP) and consolidation with autologous stem cell transplant. This trial was actually a failure – almost all patients relapsed early. Still, we did not give up, and added two more components – rituximab and high dose ara-c. We also added pre-emptive treatment with rituximab in patients with molecular relapse.

4. NORDIC MCL2 – an international standard?
Event-free survival
This turned out to be a very successful combination. By intention to treat, we see an event-free survival plateau at 63% at 5 years in protocol 2, vs 15% in protocol 1. We also imagined that there may be a plateau in EFS after 5 years, suggesting that this may be a curative treatment.
Is MCL a curable disease?
Geisler et al Blood 2008

5. 15‐year follow‐up of the Nordic MCL2 trial
Eskelund et al, British Journal of Haematology, 2016
Unfortunately, when we have followed these patients for more than 15 years, we see late relapses, and the plateau is gone. Still, I would like to point out that at 10 years, almost 50% are progression free.
At 10 years – no cure, but –
almost 50% free from progression!

6. RITUXIMAB MAINTENANCE every 2 months during 3 years
The Next Step – R maintenance?
LyMa trial – France
OBSERVATION W1 W4 W7
W10
R-DHAP
R-DHAP
R-DHAP
R-DHAP
R-DHAP
R-BEAM
If < VGPR
If > VGPR
RITUXIMAB MAINTENANCE
every 2 months during 3 years
R-CHOP
The next step in improving treatment for younger patients with MCL was taken by the French LySa group, designing a trial, the LyMa trial, where patients were randomized to observation or rituximab maintenance after autologous stem cell transplant.
R-DHAP: Rituximab 375mg/m2; aracytine 2g/m2 x2 IV 3 hours injection 12hours interval;
dexamethasone 40mg d1-4; Cisplatin 100mg/m2 d1 (or oxaliplatin or carboplatin)
R-BEAM: Rituximab 500mg/m2 d-8; BCNU 300mg/m2 d-7; Etoposide 400mg/m2/d d-6 to -3; aracytine 400mg/m2/d d-6 to d-3; melphalan 140mg/m2 d-2

7. LyMA – Overall survival
mFU: 50.2m ( ) OS
Obs (95%CI) vs Rituximab (95%CI)
24m: % ( ) % ( )
36m: % ( ) % ( )
48m: % ( ) % ( )
In this trial, they showed that rituximab maintenance for 3 years in able to prolong overall survival, establishing a new standard for these patients. MCL seems to be particularly sensitive to rituximab.
Le Gouill, NEJM 2017

8. Next step- add ibrutinib?
TRIANGLE
Within our European MCL Network, we are now investigating if the addition of ibrutinib to this backbone of R-CHOP, cytarabine and ASCT may further improve survival, and if ibrutinib may even replace the autologous stem cell transplant.

9. 870 pts, 230 sites 404 pts randomized
This is the largest trial ever conducted in MCL, with 870 pts at 230 sites, with three arms, a standard arm, with R-CHOP/DHAP-ASCT, a second arm where ibrutinib is added, and a third arm with ibrutinib, but without ASCT. About half of the patients have een randomized so far.
870 pts, 230 sites
404 pts randomized

10. on the brink of curability
Systemic MCL ≤70 years –
on the brink of curability
To be a bit dramatic, we may be close to a cure for MCL, but so far, only for patients eligible for ASCT, up to about 70 years.

11. Treatment of elderly MCL patients >70 years
Much more common
Much more difficult
To summarize, we have now access to effective regimens for younger pts with MCL. Still we need to remember that ¾ of the patients are older than 70, and for this large group, there is no established standard therapy.

12. What is the optimal regimen?
PFS>
PFS>
Favorable OS
Low risk MIPI
PFS and tolerance
>R-CHOP 38 37 36 34 33 26 19 7
Number at risk 10 20 30 40 50 60 70 80
Months from Treatment
Overall Survival
R-Bendamustine?
R-CHOP + R?
VR-CAP?
R-Lenalidomide?
Rummel, Lancet 2013
Ruan, Blood 2018
PFS>
OS >R-CHOP
PFS>
OS >R-FC
For this large group of patients, there are at least 4 good options. R-bendamustine is what I prefer for the majority of patients. In a randomized trial, this showed superior PFS and less toxicity compared to R-CHOP.
Still R-CHOP is a very well documented regimen, and R-CHOP + R maintenance has shown superior OS compared to R-FC (which should probably not be used).
VR-CAP is a more toxic regimen than R-CHOP (causes more thrombocytopenia), but is also ass with superior OS.
Rituximab-lenalidomide has not been compared to other regimens in a randomized trial, but in a phase 2 trial of mainly low and intermediate MIPI , PFS at 3 years was 80% - a possible option for frail patients.
Robak, Lancet Oncol 2018
Kluin-Nelemans, NEJM 2012

13. ENRICH – Rituximab & Ibrutinib vs Rituximab & CHemotherapy
UK + Nordic Lymphoma Group
IR/R Intervention
R-CHEMO/R Standard care
Ibrutinib daily + Rituximab (every 21/28 days) for 8 cycles
R-CHEMO (every 21/28 days) for 6-8 cycles
Rituximab (every 56 days) for 2 years
Ibrutinib daily + Rituximab (every 56 days) for 2 years
Ibrutinib to continue until disease progression
Follow-up until disease progression R
140/400 pts randomized
Together with the British group, we are currently studying another chemo-free regimen, ibrutinib+rituximab, in a randomized trial, compared to either R-CHOP or R-Bendamustine, according to the investigator. This trial is called the ENRICH trial, and we hope to have enrolled all patients some time in 2020.

14. The genetic landscape of MCL
Cyclin-D1
SOX11
TP53
ATM
In the next part of my talk, I will discuss the clinical importance of genetic aberrations in MCL, with focus on four genes: CyclinD1, SOX11, ATM and TP53.

15. t(11;14) – the genetic hallmark of MCLRB
CDK4/6 inhibition?
Palbociclib
17 pts R/R MCL
18% ORR
Abemaciclib
22 pts R/R MCL
22% ORR
Few PD M G1
cdk4/ cyclin D1 G2
The presence of a t(11;14) is the hallmark of MCL, and causes overexpression of CyclinD1.
CyclinD1 binds to CDK4 or 6 and is necessary to phosphorylate RB, and regulate the progression to S-phase.
During the last years, several inhibitors of CDK4/6 have been developed, especially for use in breast cancer.
It would seem like a good idea to use CDK4/6 inhibitors also in MCL. Two agents have been tested, palbociclib and abemaciclib. For both agents, the response rate is modest, around 20%, but there is also a high number of patients with stable disease, so it seems as these agents are able to put a brake on the cell cycle, and may be combined with other agents. S
RB P

16. The importance of SOX11 Diagnostic
SOX11- negative – related to leukemic, indolent MCL
SOX11 is a neuronal transcriptional factor. By unknown mechanisms, this is highly expressed in most cases of MCL, and can be a helpful diagnostic marker. It may also be of clinical use, as the more indolent, leukemic form of MCL often is SOX11-negative.
WHO classification 2017

17. The importance of ATM mutation
Ataxia telangiectatica
Extreme sensitivity to radiation
Low-dose RT (2 x 2 Gy)
Very effective local palliation in MCL
May postpone the use of systemic therapy
The most commonly mutated gene in MCL is the ataxia telangectatica mutated gene, ATM. This hereditary condition is associated to extreme sensitivity to radiation, and may be tempting to speculate that ATM mutation may explain why MCL is also very radiosensitive. We usually use low dose radiotherapy, 2 x 2 Gy, and achieve local control in virtually every patient, without side effects. Both in previously untreated patients and at relapse, this can postpone the use of systemic therapy for several years.

18. Mutational profiling – NORDIC MCL2+3
182 pts
We have performed sequencing of lymphoma samples from bone marrow from patients enrolled in the Nordic MCL2 and MCL3 trials. Also here, ATM was the most commonly mutated gene, and in 10% , there was a mutaion of TP53 present at diagnosis.
In addition, 16% presented with aTP53 deletion.
Eskelund C et al, Blood 2017

19. mutations more important than deletions?
The importance of TP53
PFS
mutations more important than deletions?
We found that even with very intensive therapy including high dose cytarabine and autologous stem cell transplant, patients with a TP53 mutation had a very poor outcome. Interestingly, a TP53 deletion did not have the same prognostic impact.
Eskelund C et al, Blood 2017

20. NORDIC-MCL6 PHILEMON Treatment scheduleCT
CT, PET
MRD
CT, PET
MRD L L L L L L L L L L L L
Ibrutinib 560 mg daily
Maintenance until progression
Weeks
The most recently concluded nordic trial was the MCL6, or Philemon trial, for relapsed MCL, investigating the triple combination of ibrutinib, lenalidomide and rituximab.

21. NORDIC MCL6 –PHILEMON - Rationale
R-lenalidomide effective and well tolerated in untreated MCL
Ruan et al, NEJM ORR 92%, CR 64%, 2-year PFS 85%
Ibrutinib in R/R MCL
Wang et al, Blood ORR 67%, CR 23%, 2-year PFS 31%
Inhibits interleukin-2 inducible tyrosine kinase (ITK) and NK cell activity
Antagonizes rituximab-induced ADCC in vitro
Our idea was that lenalidomide may counteract the inhibitory effect on NK-cells exerted by ibrutinib, which at least in vitro partly antagonizes the activity of rituximab ?
IBRUTINIB
LENALIDOMIDE

22. Tailor treatment according to TP53 mutational status – CLL style?
NORDIC MCL2/3
NORDIC MCL6 PHILEMON
IBRUTINIB-LEN-R
p=0.49
In this relapsed population, 20% of patients had a TP53 mutation. With this combination, we did not see the same poor outcome among patients with a TP53 mutation. This is in contrast with the very poor outcome with chemotherapy as in the MCL2/3 protocol. One may speculate that, as in CLL, TP53-mutated MCL should be treated with something else than chemotherapy.
On the other hand, in a series of patients progressing on ibrutinib, a gain of TP53 mutation was found in 2 out of 5 cases, indicating that this may also play a role in ibrutinib resistance. The sad truth may be that we do not have effective agents for this population.
Perhaps not so simple:
5 paired samples pre and post ibrutinib progression
2 of 5 showed gain of TP53 mutation - Jain BJH 2018

23. Upcoming Nordic MCL trials
Explore an MRD-driven approach
To minimize side effects
To minimize cost of drugs
Relapsed MCL
Venetoclax-Lenalidomide-Rituximab
Untreated MCL
Acalabrutinib-Rituximab
MCL7 -VALERIA
A problem with many novel agents are that they are given until progression, which can be for a very long time. In the most recent Nordic MCL trials, we are exploring another concept, an MRD driven approach, to try to minimize both side effects and costs. Our ongoing trial, MCL7 Valeria is for relapsed MCL, using the novel combination of venetoclax-lenalidomide and rituximab. For untreated elderly patients with MCL, we are planning a trial with acalabrutinib and rituximab.
MCL8 -ALTAMIRA

24. NORDIC MCL7 - VALERIA
Aim – to explore efficacy and safety with venetoclax- lenalidomide-rituximab in relapsed MCL (including ibrutinib refractory)
Primary endpoint – ORR at 6 months (compared to R2)
Explore an MRD driven strategy
9-24 pt phase 1
50 pt phase 2 - R/R MCL
15 pt untreated (frail/elderly) – exploratory subset
Total pts
Start – 9 patients enrolled in phase 1
The Valeria trial includes a phase 1 portion, to assess the maximally tolerable dose of this combination. The first 3 cohorts have been enrolled, and we will start the phase 2 part later this year, also including a group of untreated elderly patients.

25. VALERIA - MRD driven treatment
VLR
3 months
STOP
MRD+
MRD+
MRD+
MRD-
MRD-
MRD-
MRD-
This is the schedule for the MRD driven strategy. Patients will receive treatment for 3 months, and if MRD negative in blood, will continue for another 3 months. If still negative, both in blood and bone marrow, they will stop treatment.
PET-CT (for primary endpoint)

26. NORDIC MCL8 - ALTAMIRA
Elderly patients with untreated mantle cell lymphoma
Acalabrutinib 100 mg x 2 p o daily for up to three years
Rituximab 375 mg/m2 i v day mg sc or 375 mg/m2 iv every 28 days for another 5 doses, then every 56 days for three years.
Stop acalabrutinib after molecular remission at 6 months or later, confirmed 3 months later
Randomized MRD driven vs treatment until progression
88 pts
Acalabrutinib – no ITK and NK-cell inhibition
The MCL8 Altamira trial, will be a trial for untreated elderly patients, using a combination of acalabrutinib and rituximab. Acalabrutinib does not inhibit NK cell function, and is a more attractive partner with CD20 antibodies than ibrutinib. This will be a randomized trial, comparing an MRD driven strategy to treatment until progression.

27. Future prospects in MCL
BTK inhibitors in 1st line?
Tailor treatment based on TP53 mutation?
Non-chemo combinations 1st line for elderly patients?
MRD driven strategies?
CD20-ab
Chemo
BTKi
Len
BCL2i
CDKi
To summarize, what can we expect in future treatment of MCL? I think that we may start adding BTK inhibitors to primary treatment. I also believe that we will start testing tumors for the presence of TP53 mutations, and treat these differently, although I cannot say how. We may also start using chemotherapy free combinations in elderly patients first line, and we will see if MRD driven strategies can save toxicity and money.