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Mantle cell Lymphoma:

Current treatment strategies

Mathias J. Rummel
Med. Klinik IV - Hematology
Hospital of the Justus-Liebig-University Giessen, Germany
MCL - Therapeutic Advances

Chemotherapy
Younger patients HD Ara-C + R ± APBSCT
Elderly patients Bendamustine + R ± AraC

Targeted therapy
Anti-CD20 Rituximab
Microenvironment Lenalidomide
Proteasome Bortezomib
M-TOR Temsirolimus

New compounds
BTK-inhibitor Ibrutinib

APBSCT, autologous peripheral blood stem cell transplantation; HD Ara-C,


Ara-C, high-dose cytarabine
Ara-C,
Nordic
AraC, Rituximab
„Nordic“ scheme
Nordic Lymphoma Group MCL2 Trial
www.nordic-lymphoma.org

Long-term progression-free survival in Mantle Cell


Lymphoma following front-line intensive immuno-
chemotherapy with in-vivo purged stem-cell support

Using the MCL1 (previous nordic MCL trial) results as historic control,
Rituximab plus high-dose AraC was included In the MCL-2 protocol
aiming to improve:
EFS, PFS, OS, and the proportion of PCR-negative stem cell products

Geisler CH, et al. Blood. 2008;112: 2687-2693.


Treatment:
MCL-1 TRIAL 1996-2000
INDUCTION RE- STEM-CELL
STAGE HARVEST REINFUSION

B
Maxi Maxi Maxi Maxi E
C C C C
A
H H H H
O O O O M/C
P P P P
Week: 1 4 7 10 13 14

MCL-2 TRIAL 2000-2006


INDUCTION RE- STEM-CELL
STAGE HARVEST REINFUSION

R R RR B
Maxi A Maxi A Maxi A E
C r C r C r
H H H A
a a a
O C O C O C M/C
P P P
Week: 1 4 7 10 13 16 19 20

AraC: 4 Infusions: ≤ 60 years 3 g/m 2, > 60 years 2 g/m 2


Nordic MCL Project

NLG
Response Compared to MCL1

Response Pretransplant
No. Eval. CR / CRu ORR

MCL--1 TRIAL 1996


MCL 1996--2000
MCL1: INDUCTION RE--
RE
STAGE HARVEST
STEM--CELL
STEM
REINFUSION
41 27% 76%
B

CHOP Maxi
C
H
O
Maxi
C
H
O
Maxi
C
H
O
Maxi
C
H
O
E
A
M/C
P P P P
Week:: 1
Week 4 7 10 13 14

MCL2: INDUCTION
MCL--2 TRIAL 2000
MCL 2000--2006
RE--
RE
STAGE HARVEST
STEM--CELL
STEM
REINFUSION
160 54% 96%
R-CHOP Maxi
C
A
r
Maxi
C
R
A
r
R
Maxi
C
RR
A
r
B
E
A
H H H

+ R-AraC
a a a
O C O C O C M/C
P P P
Week:: 1
Week 4 7 10 13 16 19 20
AraC:: 4 Infusions: < 60 years 3g/m2, > 60 years 2g/m2
AraC P = 0.001 P = 0.0005

Geisler CH, et al. Blood. 2008;112: 2687-2693.


Nordic MCL Project

NLG
EFS and OS as an Intent-to-Treat Analysis
Events: 61 (38%)

Relapse/PD 48 (30%)

Non-relapse events 13 (8%)


Off due to: Toxicity 7
Harv. fail. 4
Graft fail.1
Pulm emb 1

Deaths: 39 (24%)

Lymphoma 31
Non-relapse deaths 8�
Infection 3 NRM: 5%
Vasc. Inc.2
Graft fail. 1
Pulm. emb. year + 5: 1

Geisler CH, et al. Blood. 2008;112: 2687-2693.


Nordic MCL project

NLG EFS According To:

Disease Specific Variables


E F S ac c o rd ing to ki-6 7 e xp re s s io n EFS according to cytological variant
EFS according to Lymphoma Growth Pattern
100
100 100
90 < 10 (n= 10) 90
90
Percent survival

80

Percent survival
80 80
70 70

Percent survival
70 Non-Diffuse (n=70)
60 10-29 (n= 60) 60 Common (n=129) 60
50 50 50
> 29 (n= 50) Blastoid (n=31) Diffuse (n=81)
40 40 40
30 30 30
20 20 20
10 10 10
P =0 .0 0 8 0
P=0.069 P=0.012
0 0
0.0 2.5 5.0 7.5 10.0 0.0 2.5 5.0 7.5 10.0 0.0 2.5 5.0 7.5 10.0
EFS EFS EFS
Nordic MCL2: six-year follow-up: long survival but late relapses do occur

Geisler C et al. British Journal of Haematology, 2012, 158, 355–362


Rigshospitalet
NLG
Nordic MCL2 trial – 2016
- Median follow-up: 11.4 years
• Median OS: 12.7 years – Median PFS: 8.5 years

15-year follow-up of the Nordic MCL2 trial Christian W. Eskelund


R-CHOP vs R-FC

R-Erhaltung vs IFN
Rituximab

in combination for induction (established)

and also as maintenance (not for all)


R-CHOP Versus R-FC
Followed by Maintenance with
Rituximab Versus Interferon-Alfa
Outcome of the First Randomized Trial for Elderly Patients
with Mantle Cell Lymphoma

Oral presentation by Kluin-Nelemans et al.


Blood 2011;118(21):
First RCT for MCL Elderly
8 countries, n=560 (Jan 2004 - Oct 2010)
Kluin-Nelemans et al. N Engl J Med 2012;367:520-31

Newly diagnosed, >60-65 years; Performance 0-2,


Stages II-IV, Central PA review

8 x R-CHOP 6 x R-FC
PR, CR

IFN-α maintenance Rituximab


(3 x 3 M IU/week) maintenance
or Peg-IFN (all 2 months)
(1mg/kg week)
MCL Elderly: Baseline Characteristics 1st randomization

Parameter R-CHOP (%) R-FC (%)

Age median (range) 70 (61-87) 70 (60-85)


% male 68 72
Stage IV 83 81
% pos. BM 76 75
B-Symptoms 38 38

Performance 0-1 92 93

Elevated LDH 44 43
MIPI low risk 7 9

MIPI intermediate risk 43 39


MIPI high risk 50 52

n 280 280

Kluin-Nelemans et al. Blood 2011;118(21)


MCL Elderly: Responses (per protocol)

R-CHOP R-FC
Documented 251 268
Early stop 19 8% 25 9%
Evaluable 232 243
ED 9 4% 8 3%
PD 12 5% 35 14%
SD 10 4% 11 5%
PR 86 37% 61 25%
CRu 36 16% 31 13%
CR 79 34% 97 40%
CR/CRu 115 50% 112 53%
CR/CRu/PR 201 87% 168 78% P=0.0508*

* adjusted for interim analyses


MCL Elderly: Overall survival

R-CHOP

R-FC

Kluin-Nelemans et al., NEJM 2012; 367(6): 520-31


MCL Elderly
Elderly:: Causes of Death

R-CHOP (n=232) R-FC (n=243)


64 98 % of
Total (28%) % of deaths (40%) deaths
Lymphoma 41 64% 56 57%
Infection 7 11% 15 15%
Cardiac 6 9% 4 4%
Secondary Tumor 2 3% 2 2%
Secondary AML 0 0% 2 2%
Pulmonal 2 3% 5 5%
Cerebral Bleeding 1 2% 0 0%
Leukoencephalopathy 0 0% 2 2%
Unknown 5 8% 12 12%
MCL elderly study toxicity R-CHOP vs R-FC
100
80
60
100 4 0
90 100
20
80 90
70 800
60 70 Hb W BC Lym pho N e u tr o p h i l s P l a te l e ts
50 60 p = 0 .0 1 6 p = 0 .0 0 5 p = 0 .0 1 1 p = 0 .2 5 p < 0 .0 0 1
40 50
30 40 R -C H O P G ra d e 3 -4 R -C H O P G ra d e 1 -2
20 30 R -F C G ra d e 3 -4 R -F C G ra d e 1 -2
10 20
0 10
0
Mucositis Cardiac Pulm Neuropathy Alopecia Infections Febrile
M uc os itis Ca rdiafunction
function c P ulm Ne uropa thy Alope c ia Infe c tions Fe brile
neutropenia
func tion func tion ne utrope nia
p=0.063 p=0.70 p>0.99 p<0.001 p<0.001 p=0.004 p=0.085
p=0 .0 6 3 p=0 .7 0 p>0 .9 9 p<0 .0 0 1 p<0 .0 0 1 p=0 .0 0 4 p=0 .0 8 5

R-CHOP Grade 3-4 R-CHOP


R -C H O P G rade 3-4
Grade 1-2
R -C H O P G rade 1-2
R-FC Grade
R -FC 3-4 3-4 R-FC
G rade Grade
R -FC 1-2 1-2
G rade
MCL Elderly: Overall survival

Rituximab
IFN

Kluin-Nelemans et al., NEJM 2012; 367(6): 520-31


MCL elderly - Remission duration related to induction

R-CHOP R-FC

p=0.18 for interaction of induction and maintenance


Kluin-Nelemans et al., NEJM 2012; 367(6): 520-31
22-10-2011
Overall survival Rituximab vs IFN

Rituximab

IFN

22-10-2011
Overall survival with respect to induction regimen

After R-CHOP After R-FC

p=0.0223 for interaction of induction and maintenance


Kluin-Nelemans et al., NEJM 2012; 367(6): 520-31
Abstract # 145 ASH 2016
LyMa trial

Inclusion Randomization
N=299 N=240

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

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) Abstract # 145 ASH 2016
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
PFS from inclusion

mFU : 54.4m (52.7-59.2)

PFS
24m: 79.5 % (95%CI; 74.5-83.7)
36m: 73.4 % (95%CI;68-78.1)
48m: 67.8 % (95%CI; 62.1-72.8)

PFS (months) from inclusion


EFS from Randomization

mFU:: 50.2m (46.4-54.2)


mFU

EFS
Obs (95%CI) vs Rituximab (95%CI)
24m: 77.3 % (68.7-83.9) 91.7 % (85.1-95.7)
36m: 69.4 % (60.2-76.9) 85.8 % (78.7-90.9)
48m: 61.4 % (51.3-69.9) 78.9 % (69.5-85.6)

EFS (months) from randomization


PFS from Randomization

mFU:: 50.2m (46.4-54.2)


mFU

PFS
Obs (95%CI) vs Rituximab (95%CI)
24m: 79.8 % (71.5-86.0) 93.3 % (87.1-96.6)
36m: 72.8 % (63.7-79.9) 89.1 % (82.0-93.5)
48m: 64.6 % (54.6-73.0) 82.2 % (73.2-88.4)

PFS (months) from randomization

Abstract # 145 ASH 2016


Duration of Remission

months events
N = 122 (median) (n)
Observation 57.1 25
R maint. 67.9 20

Hazard ratio, 0.76 (95% CI 0.42 - 1.35)


p = 0.3486

Pts at risk
Observ 62 52 44 32 15 6 1
R maint 60 46 41 38 24 8 1
OS from Randomization

mFU:: 50.2m (46.4-54.2)


mFU

OS
Obs (95%CI) vs Rituximab (95%CI)
24m: 93.3 % (87.0-96.6) 93.3 % (87.1-96.6)
36m: 85.4 % (77.5-90.7) 93.3 % (87.1-96.6)
48m: 81.4 % (72.3-87.7) 88.7 % (80.7-93.5)

OS (months) from randomization

Abstract # 145 ASH 2016


Overall survival (58.6 months median follow-up
follow-up))

N = 122

months events
(median) (n)
Hazard ratio, 1.51 (95% CI 0.70 – 3.25) Observation n.y.r. 11
R maint. n.y.r. 15
p = 0.2974

Pts at risk
Observ 62 58 57 52 43 21 8
R maint 60 59 53 44 38 23 5
CONCLUSIONS

• The LyMa design (R-DHAP/R-BEAM) provides:

• high CR/CRu before and after ASCT (Le Gouill et al. ASH 2013)
• Longterm disease control (PFS and EFS)
• Prolonged OS

• Final analysis shows that Rituximab maintenance after ASCT prolongs:

• EFS: 78.9% vs 61.4% at 4 years (HR=0.457; 0.27-0.74; p= 0.0016)


• PFS: 82.2% vs 64.6 % at 4 years (HR=0.4; 0.23-0.68; p= 0.0007)
• OS : 88.7% vs 81.4 % at 4 years (HR=0.502; 0.25-0.98; p= 0.0454)

• Rituximab maintenance (375mg/m2 every 2 months for 3 years)


should be recommended to transplanted MCL patients

• Ancilary studies:
• Genomic (Le Bris et al. ASH 2016 Saturday, abstract 1745)
MCL Elderly: Overall Survival
With Respect to Induction Regimen
After R-CHOP

P = .0223 for interaction of induction and maintenance


Kluin-Nelemans HC, et al. N Engl J Med. 2012;367(6):520-531.
Toxicity of IFN and rituximab

9 0
8 0
7 0
6 0
5 0
4 0
3 0
2 0
1 0
0

10 0
H b W B C L ym p h o N e u tro P la t e le t s
9 0 p = 0 .9 4 p = 0 .0 0 2 p = 0 .0 5 4 p = 0 .2 0 p = 0 .0 0 1
8 0
7 0 IF N G r a d e 3 - 4 IF N G r a d e 1 - 2
6 0 R G ra d e 3 -4 R G ra d e 1 -2
5 0
4 0
3 0
2 0
1 0
0
D e p r e s s io n F a t ig u e In f e c t io n s
p = 0 .1 6 p < 0 .0 0 1 p = 0 .0 2 2

IF N G r a d e 3 - 4 IF N G r a d e 1 - 2
R G r a d e 3 -4 R G r a d e 1 -2
Conclusions
� R-CHOP superior to R-FC:
- Improved OS at 4 years: 62% vs 47%, p = 0.005
- Less toxicity

� Rituximab maintenance doubles the remission duration in patients


responding upon initial therapy with R-CHOP

� Rituximab maintenance improved OS in pts with response to R-CHOP


- at 4 years 87% vs 63%, p = 0.005

� For any future trial:


R-CHOP followed by maintenance therapy with rituximab should
become the standard to which new induction regimens are compared

Kluin-Nelemans et al. Blood 2011; 118(21)


Kluin-Nelemans et al., NEJM 2012; 367(6): 520-31
Conclusions

� R-CHOP superior to R-FC:


- Improved OS at 4 years: 62% vs 47%, p = 0.005
- Less toxicity

� Rituximab maintenance doubles the remission duration in patients


responding upon initial therapy with R-CHOP

� Rituximab maintenance improved OS in pts with response to R-CHOP


- at 4 years 87% vs 63%, p = 0.005

Kluin-Nelemans et al. Blood 2011; 118(21)


Kluin-Nelemans et al., NEJM 2012; 367(6): 520-31
R-CHOP Versus R-FC Followed by Maintenance with
Rituximab Versus Interferon-Alfa
Patients and regimen Results
�Stage II-IV MCL >60 yrs; N=560 �CR rates after R-FC and R-CHOP were
similar
– (38 vs 34% CR, 52 vs 50% CR/Cru
�Induction therapy: 8 x R-CHOP-21 vs 6 x
�OS was significantly inferior after R-FC
R-FC-28
– (40 vs 64 months; p=0.0072)
�Maintenance therapy: Interferon-alpha vs
Rituximab �R maintenance almost doubled remission
duration vs IFN
– (at 4-yrs 57% vs 26% in remission; HR
Conclusions 0.54, 0.35-0.87; p=0.0109)
�R-FC is discouraged for elderly patients �OS did not differ; significant advantage
with MCL after R maintenance in R-CHOP-treated
�R-CHOP induction and R maintenance – (4-yr OS 87% vs 57% after IFN;
p=0.0061)
should be considered the new standard for
elderly MCL patients

Oral presentation by Kluin-Nelemans et al. Blood 2011;118(21): Abstract 439


Bortezomib
Bendamustine plus AraC,
and Rituximab
Bendamustin
Bendamustine

Less aggressive but very effective approach

also in combination with Ara-C


Bendamustine plus Rituximab (B-R) in relapsed lymphomas

Rummel, et al. Robinson, et al. J


Clin Oncol 2005 J Clin Oncol 2008

Patients,
Patients, no. 63 66
Male, % 63 59
Median age, y 64 (40-81) 60 (40-84)
Entities,
Entities, %
Follicular 32 61
Mantle cell 25 18
Small lymphocytic 27 18
Marginal zone 10 3
Stages III/IV, % 98 89
Prior therapies 1/2/3, % 62/21/17 62/15/21
Prior rituximab,
rituximab, % - 56

ORR, total group (%) 90 92


PFS (median, months)
months) 24 23

ORR, mantle cell (%) 75 90


PFS, mantle cell (median, months)
months) 18 19
Relapsed/Refractory MCL

Agent Regimen Outcomes


25 pts with recurrent disease
Cladribine Single agent [1] ORR: 46%; CR: 21%
Median PFS: 5.4 mos

16 MCL patients
Bendamustine + Rituximab [2] ORR: 75%; CR: 50%
Bendamustine Median PFS: 18 mos
12 MCL patients
Bendamustine + Rituximab [3] ORR: 92%; CR/CRu: 59%
Median DOR: 19 mos

1. Inwards DJ, et al. Cancer. 2008;113:108-116.


2. Rummel MJ, et al. J Clin Oncol.
Oncol. 2005;23:3383-3389.
3. Robinson KS, et al. J Clin Oncol.
Oncol. 2008;26:4473-4479.
Bendamustine plus Rituximab versus CHOP plus Rituximab in the First-Line
Treatment of Patients with Indolent and Mantle Cell Lymphoma –
Final Results of a Randomized Phase III Study of the
StiL (Study Group indolent Lymphomas, Germany)

Mathias J. Rummel, N. Niederle, G. Maschmeyer,


Maschmeyer, G. A. Banat, U. von Grü
Grünhagen,
C. Losem, G. Heil, M. Welslau, C. Balser, U. Kaiser, H. Ballo, E. Weidmann,
H. Dürk,
rk, D. Kofahl-Krause, F. Roller, J. Barth, D. Hoelzer, A. Hinke,
and W. Brugger .

on behalf of the StiL .

J Clin Oncol 30, 2012 (suppl


(suppl;; abstr 3)
B-R vs CHOP-R - Hematotoxicity grades 3+4

B-R (n=1.450) CHOP-R (n=1.408)


(% of cycles)
cycles) (% of cycles)
cycles) P value

Leukocytopenia 12,1 38,2 < 0.0001

Neutropenia 10,7 46,5 < 0.0001

G-CSF administered 4,0 20,0 < 0.0001

Thrombocytopenia 0,7 1,2

Anemia 1,4 1,9


B-R vs CHOP-R - Toxicities (all CTC-grades)

B-R (n=260) CHOP-R (n=253)


(no. of pts)
pts) (no. of pts)
pts) P value

Alopecia - +++ < 0.0001

Paresthesias 18 73 < 0.0001

Stomatitis 16 47 < 0.0001

Skin (erythema
(erythema)) 42 23 = 0.0122

Allergic reaction (skin) 40 15 = 0.0003

Infectious complications 96 127 = 0.0025

- Sepsis 1 8 = 0.0190
Results: B-R vs CHOP-R

92 patients with MCL evaluable for response, median observation 28 months

B-R CHOP-R
(n = 45) (n = 47)

Age (median) 71 67

ORR 91 % 96 %

CR 32 % 34 %
SD 7% 2%
Prim. refractory 2% 2%

PD / relapse n = 20 n = 29
Deaths n= 7 n= 8
J Clin Oncol 30, 2012 (suppl
(suppl;; abstr 3) MJR
Bendamustine-Rituximab (B-R) vs CHOP-R

StiL NHL 1-2003

Bendamustine-Rituximab
Follicular
Waldenströ
Waldenströms
Marginal zone
Small lymphocytic
R
R
Mantle cell (elderly
elderly))

CHOP-Rituximab

Bendamustine 90 mg/m 2 day 1+2 + R day 1, max 6 cycles,


cycles, q 4 wks.
wks. CHOP-R, max 6 cycles,
cycles, q 3 wks.
wks.
PFS: Mantle cell lymphoma (n=93) StiL NHL 1-2003

1.0
Median (months
(months))
0.9
B-R 35.4
0.8 CHOP-R 22.1

0.7

0.6

0.5

0.4

0.3

0.2
HR, 0.50 (95% CI 0.29 - 0.81)
0.1
p = 0.0061
0.0
0 12 24 36 48 60 72 84 96 months MJR

Rummel M et al, Lancet 2013; 381: 1203 –10


BRIGHT Trial: Primary Endpoint, IRC Assessment:
Complete Response by Lymphoma Type
Randomized: BR R-CHOP R-CVP P Value P Value
Indolent NHL (n = 187) (n = 81) (n = 105) CR Ratio (NI) (Sup)
CR 27% 23% 23% 1.16 0.1289 NA
(95% CI) (20.5-33.7) (14.8-34.2) (15.2-32.1) (0.81-1.65)
PR 67% 67% 60%
SD 3% 4% 11%
PD 0 0 0
Unknown 3% 6% 6%
OR of CR + PR 94% 90% 83%
(95% CI) (89.7-97.0) (81.5-95.6) (74.2-89.5)

Randomized: BR R-CHOP R-CVP P Value P Value


MCL (n = 37) (n = 23) (n = 14) CR Ratio (NI) (Sup)
CR 51% 30% 14% 1.95 0.0174 0.0180
(95% CI) (34.4-68.1) (13.2-52.9) (1.8-42.8) (1.01-3.77)
PR 41% 57% 36%
SD 3% 4% 21%
PD 3% 0 0
Unknown 35% 9% 4%
OR of CR + PR 92% 87% 50%
(95% CI) (78.1-98.3) (66.4-97.2) (23.0-77.0) Blood. 2014 May 8;123(19):2944-52
CI, confidence interval; CR, complete response; NA, not applicable; NI, noninferior;
noninferior; OR, overall response; PD, progressive disease,
PR, partial response; SD, stable disease; NI, noninferior;
noninferior; Sup, superior. 51
BRIGHT study: PFS in Mantle Cell Lymphoma

1.0
0.9

Survival Distribution Function


0.8
0.7
0.6
0.5
0.4
0.3 � 5-yr rate % (95% CI):
0.2 39.7 (22.8, 56.1) vs 14.2 (37.9, 31.3)
0.1
� HR = 0.40 (0.21-0.75; P = 0.0035)
0.0

0 2 4 6 8 10 12 18 24 30 36 42 48 54 60 66 72
At Risk
1. 37 36 34 32 32 31 31 27 26 21 20 17 17 15 12 3 0
2. 37 30 29 26 26 21 20 13 12 8 8 7 4 3 2 0 0

Progression-Free Survival (months)

*BR vs R-CHOP/R-CVP.

Presented by: Ian W. Flinn, MD, PhD


OS for Mantle Cell Lymphoma: B-R vs CHOP-R

1.0

0.9

0.8 B-R
CHOP-R
0.7
Probability

0.6

0.5

0.4

0.3

0.2

0.1

0.0
0 365 730 1095 1460 1825 2190 days

ASCO 2012 plenary session, J Clin Oncol 30, 2012 (abstr


(abstr 3) MJR
Bendamustine-Rituximab (B-R) vs Fludarabine-Rituximab (F-R)

StiL NHL 2-2003


relapsed disease

Bendamustine-Rituximab
90 mg/m2 Day 1+2, max 6 cycles,
cycles, q 4 wks
Follicular
Waldenströ
Waldenström’s
Marginal zone
Small lymphocytic
R
R
Mantle cell
Fludarabine-Rituximab
25 mg/m2 Day 1-3, max 6 cycles,
cycles, q 4 wks
Progression-free survival for subentities: B-R vs F-R

1.0 1.0
0.9 Follicular 0.9
0.8 0.8 Mantle cell
0.7 p = 0,0278 0.7
0.6 0.6
P = 0.0090
0.5 0.5
0.4 0.4
0.3 B-R 0.3
0.2 F-R 0.2
B-R
0.1 0.1 F-R
0.0 0.0
0 365 730 1095 1460 1825 2190 2555 0 365 730 1095 1460 1825 2190 2555

1.0 1.0 Waldenströ


Waldenström’s
Marginal zone
0.9 0.9
P = 0.1636
0.8 P = 0.4130 0.8
0.7 0.7
0.6 0.6
0.5 0.5
0.4 0.4 B-R
0.3 B-R 0.3
F-R
0.2 F-R 0.2
0.1 0.1
0.0 0.0
0 365 730 1095 1460 1825 2190 2555 0 365 730 1095 1460 1825 2190 2555

Rummel et al., ASH 2010, Annual meeting, abstract


B-R + Watch & Wait vs B-R + 2 years Rituximab

Randomized Phase II Study of the StiL

Bendamustine-Rituximab
+ Watch & Wait
Mantle cell
(not eligible for APBSCT)
R
R
Bendamustine-Rituximab
+ 2 years Rituximab
q 2 months
BAC-R
Rituximab-Bendamustine-Ara-C (R-BAC)
for patients with mantle cell lymphoma
not eligible for autologous transplant

EUDRACT 2009-009912-34
ClinicalTrials.gov NCT00992134

Department of Cell Therapy and Hematology, San Bortolo Hospital,


Vicenza (Director F Rodeghiero), Principal Investigator: Carlo Visco
MJR
Visco C et al. J Clin Oncol 2013, 31: DOI: 10.1200/JCO .2012.45.9642
Bendamustine and Cytarabine:
A highly synergistic combination
Classic MCL
Bendamustine (B) and Ara-C (A)
are strongly synergistic in-vitro when
cultured consecutively
on MCL cell lines (CI<0.01)

Blastoid MCL

Visco et al, BCMD 2012


Hiraoka et al, PLoS One 2014
R-BAC Treatment schedule
Bendamustine + AraC + Rituximab
1 2 3 4 +1 +2.. ...

Rituximab 375 mg/m2


Bendamustine 70 mg/m2
Ara-C 800 mg/m2
G-CSF 10 µg/kg

4 cycles (2+2) if CR or PR after 2 cycles. Stop if NR after 2 cycles.


6 cycles only if 1st line, <80 and good tolerance. Recycle every 28 days. MJR
Visco C et al. J Clin Oncol Apr 10, 2013:1442-1449
Hematologic Toxicity, 173 delivered cycles

Overall (173) Untreated (96) R / R (77)

Grade 3-4 event N cycles % N cycles % N cycles %

Leukopenia 83 48 31 32 52 68

Neutropenia 54 31 16 17 38 49

Febrile neutropenia 7 4 4 4 3 4

Thrombocytopenia 132 76 67 70 65 84

Anemia 85 49 41 43 44 57

Data refer to cycles with at least 1 day of grade 3-4 event

MJR
Visco C, et al. J Clin Oncol. 2013;31(11):1442-1449.
Hematologic Toxicity, 173 delivered cycles

Grade 3-4 event N cycles %


Leukopenia 83 48
Neutropenia 54 31
Febrile neutropenia 7 4
Thrombocytopenia 132 76
Anemia 85 49

Data refer to cycles with at least 1 day of grade 3-4 event

MJR
Visco C, et al. J Clin Oncol. 2013;31(11):1442-1449.
Response to R-BAC

CT scan / BM biopsy / PET (Cheson criteria,


criteria, J Clin Oncol 2007)

Line of therapy Patients ORR CR PR NR PD


(%) (%) (%) (%) (%)

Untreated 20 100 95 5 0 0

R/R 20 80 70 10 15 5

MJR
Visco C, et al. J Clin Oncol. 2013;31(11):1442-1449.
Overall Survival and Progression-free survival to R-BAC

Previously
Untreated

Relapsed /
Refractory

Visco C, et al. J Clin Oncol. 2013;31(11):1442-1449.


R-BAC Treatment schedule
Rituximab + Bendamustine + AraC

1 2 3 4 +1 +2.. ...

Rituximab 375 mg/m2


Bendamustine 70 mg/m2
Ara-C 500 mg/m2
G-CSF 10 µg/kg

4 cycles (2+2) if CR or PR after 2 cycles. Stop if NR after 2 cycles.


MJR
6 cycles only if 1st line, <80 and good tolerance. Recycle every 28 days.
days.
Rituximab, bendamustine and cytarabine (R-BAC-500)
as induction therapy in elderly patients with mantle cell
lymphoma: phase 2 study from Fondazione Italiana Linfomi

C. Visco1, A. Chiappella 2, S. Franceschetti 3, C. Patti4, S. Ferrero5, D. Barbero5, A. Evangelista 6, M.


Spina7, A. Molinari 8, L. Rigacci9, M. Tani10, A. Di Rocco11, G. Pinotti12, A. Fabbri13, R. Zambello14,
S. Finotto1, M. Gotti15, A. M. Carella 16, F. Salvi17, S. A. Pileri18, M. Ladetto 17, F. Zaja19, G.
Gaidano3, U. Vitolo2, F. Rodeghiero1.

Visco C et al, abstr ICML, Lugano, Jun 2015


Rituximab, Bendamustine, Cytarabine (R-BAC-800)
ORR CR
(%) (%)

Untreated 100 95
Visco C et al, JCO 2013
Median age 72 (65-82)
MIPI high in 60%
Median F/U 60 months (45-72)
PFS OS
1 1

,8 ,8

,6 ,6

5-years PFS 66% 5-years OS 73%


,4 ,4

,2 ,2

0 0

0 10
0 10 20 30 40 50 60 70 80 Visco 20
C et al,30abstr40ICML,
50 60
Lugano, 70
Jun 80
2015
Months Time Visco C et al. Unpublished data
Study Details
• Single arm, phase 2, two-stage multicenter trial
• Cytarabine dose reduction to 500 mg/m2

• Introduction of MRD and CGA assessment

• Central pathology revision

Inclusion Criteria and enrollment


• Previously untreated >65 years or 60-65 unfit
• No history of indolent disease
• 1st patient 2 May 2012, last 25 Feb 2014
Design and Objectives

Bryant and Day two-stage design (Bryant J and Day R. Biometrics 1995;51)
Total number of patients n=57
Stage I: 19 patients (stop if <8 CR, or if >7 patients with toxicity)
Stage II: 38 patients
-------------------------------------------------------------------------------------------------------------------
Primary objectives:
- CR rate (Cheson criteria 2007) and safety of RBAC500

Secondary objectives:
- The rate of molecular response (characterized by labs of the FIL)
- The PFS, OS, and DOR
Protocol Flow Chart
Baseline PET+MRD

Intermediate MRD
(before cycle 3)

Final PET+MRD
(End of treatment )

MRD +6, +12, +24


Overall (57) %
Age, years
median (range) 71 (61-79)

Gender
male 43 75 R-BAC-500
Performance Status
0-1 54 94
Patients
AAS
III-IV 52 91 Demographics
MIPI risk category and Disease
low 9 16
intermediate 23 40 Characteristics
high 25 44
at Baseline
BM involvement 36 63
Elevated LDH 20 35
Histology
Classic 43 75
Pleomorphic 8 14
Blastoid 6 11
Ki-67 (%)
median (range) 20 (5-85)
Study Flow
57 patients enrolled
from 29 Centers.
303 delivered cycles

57 patients had at least 2 cycles

4 patients dicontinued
due to toxicity/AE
53 patients had at least 4 cycles
93%
11 patients dicontinued
due to toxicity/AE; 1 PD
PD;
5 doctor/patient decision
decision;
36 patients had 6 cycles 63%
Overall premature interruptions

Patients Details
Adverse Febrile neutropenia* (2), relevant hemato-toxicity* (9),
15 (26%) atrial fibrillation (1), sepsis (2), CMV reactivation (1)
events
Progressive
1 (2%) After 4th cycle
disease

Other 5 (9%) Doctor or patient decision

Overall 21 (37%)

*Stop Treatment Criteria: Febrile neutropenia lasting for more than 3 consecutive days or
Grade 4 cytopenia lasting for more than 6 days or
Grade 3-4 non-hematological toxicity, occuring in 2 consecutive cycles

Visco C et al, abstr ICML, Lugano, Jun 2015


Hematological Toxicity R-BAC-500
Delivered cycles: 303
Overall
Grade 0 1 2 3 4

Leukopenia - 30% 26% 17% 27%


Neutropenia - 15% 36% 14% 35%
Febrile neutropenia 5% 1%
Thrombocytopenia - 14% 34% 16% 36%
Anemia 21% 24% 43% 12% <1%

Platelet transfusion 89 of 303 (29%)


Platelet transfusion per patient: 28 of 57 (49%)
Febrile neutropenia: median duration 3.4 days (1-10)
Grade ≥3 toxicity cycle 1-3 vs 4-6 (chi-square test p=0.507)
Data refer to cycles with at least 1 day of event.
Patients were monitored every other day between day +8 and +12, or until resolution of cytopenia after the end of cycles.
Hematological Toxicity R-BAC-500
Delivered cycles: 303
Overall
Grade 0 1 2 3 4

Leukopenia - 30% 26% 17% 27%


Neutropenia - 15% 36% 14% 35%
Febrile neutropenia 5% 1%
Thrombocytopenia - 14% 34% 16% 36%
Anemia 21% 24% 43% 12% <1%

Platelet transfusion 89 of 303 (29%)


Platelet transfusion per patient: 28 of 57 (49%)
Febrile neutropenia: median duration 3.4 days (1-10)
Grade ≥3 toxicity cycle 1-3 vs 4-6 (chi-square test p=0.507)
Data refer to cycles with at least 1 day of event.
Patients were monitored every other day between day +8 and +12, or until resolution of cytopenia after the end of cycles.
Non-hematological Toxicity
occurring in more than 1 patient
All grades Grade 3 Grade 4
Event N patients % N patients % N patients %

Nausea/vomiting 12 21 0 0 0 0
Stomatitis 3 5 0 0 0 0
Constipation/Dhyarrea 6 10 0 0 0 0
Infusion related/TLS 12 21 1 2 0 0
Fatigue 14 25 1 2 NA NA
Documented infections 5 9 5* 9 2** 4
g-GT/GOT-GPT elevation 7 12 1 2 0 0
Alopecia 3 5 0 0 0 0
Rash/desquamation 5 9 0 0 0 0
Cardiac 3 5 2^ 3 1*** 2
*HZV reactivation, infection of the surgical wound, CMV reactivation (2), fungal infection; **Pseudomonas Aeruginosa and
Gram+ sepsis; ***Myocardial infarction with cerebral ischemia; ^Atrial fibrillation, chest pain.
Response rates to R-BAC-500
After 2 % End of %
cycles treatment**
treatment
N=57 N=57
ORR 57 100 55 96
CR 21 37 53 93
PR 36 63 2** 3
SD - - - -
PD - - 2 4
93% PET-negative CR
* 36 (63%) patients after 6 cycles; 6 (10%) after 5; 11 (19%) after 4; 4 (7%) after <4.
** Had 2 and 3 cycles respectively (withdrawn for toxicity)
Survival curves
PFS OS
Kaplan-Meier Cum. Survival Plot for PFS Kaplan-Meier Cum. Survival Plot for OS

1 1

,8 ,8

,6 ,6
2-yrs PFS 80±5% 2-yrs OS 89±4%
,4 ,4

,2 ,2

0 0

0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40
Time (months) Time (months)

Median follow-up 22 months (15-38)


Visco C et al, abstr ICML, Lugano, Jun 2015
Survival curves
Grouping Variable: MIPI score Grouping Variable: Histology
1 1

,8 ,8

,6 ,6
PFS

,4 ,4
MIPI high Classic
,2 MIPI interm ,2 Pleomorphic
P=0.02 MIPI low P<0.001 Blastoid
0 0

0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40
Time (months) Time (months)

Grouping Variable: Ki67 Grouping Variable: N of cycles (*PD excluded)


1 1

,8 ,8

,6 ,6
PFS

,4 ,4
>4
,2 ≤20% ,2 4
P<0.001 >20% P=0.06; P<0.001 2 or 3
0 0
0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40
Time (months) Time (months)
MRD results (nested-PCR)
MRD MRD-
Enrolled Marker: N Samples
No marker Timepoints BM/PB
patients Bcl1 or IgH
After cycle 2 44 55%/63%
57 46 11
End of Therapy 39 51%/77%
81% + 6 months 29 59%/76%

Grouping Variable:: End of Tx, BM Grouping Variable: End of Tx, PB


1 1
MRD- MRD-
,8 ,8
MRD+ MRD+
,6 ,6

,4 ,4
PFS

,2 ,2

P = .03 P = .16
0 0

0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40
Time (months) Time (months)
Conclusions

• The R-BAC-500 regimen can be safely administered


as first line therapy to elderly patients with MCL.
• Hematological toxicity is substantially reduced
compared to the previous used R-BAC-800.
• With 93% of FDG-PET negative CR,
and a projected 2-years PFS of 80%
without R-maintenance therapy,
R-BAC-500 is a highly effective treatment for MCL pts

Visco C et al, abstr ICML, Lugano, Jun 2015


BR but not R-HCVAD is a feasible induction
regimen prior to auto-HCT in frontline MCL:
results of SWOG Study S1106

Robert W. Chen, Hongli Li, Steven H.Bernstein, Samir Kahwash, Lisa M.Rimsza, Stephen
J. Forman, Louis Constine, Thomas C. Shea, Amanda F.Cashen, Kristie A. Blum, Timothy
S.Fenske, Paul M. Barr, Tycel Phillips, Michael Leblanc, Richard I.Fisher, Bruce D.Cheson,
Sonali M.Smith, Malek Faham, Jennifer Wilkins, John P. Leonard, Brad S.Kahl and
Jonathan W. Friedberg

US intergroup S1106: SWOG, CALGB/Alliance, ECOG

RW. Chen, et al. BJH 2016


Mantle Cell Lymphoma

� Optimal treatment is unknown

� Build intensive platform for future trials in younger pts

� R-hyperCVAD is an effective regimen (Khouri I et al, JCO 1998)


�High dose ARA-C important
(Romaguera JE et al , JCO 2005, Geisler CH et al Blood 2008, S0213)
�ASCT possible after short course of R-hyperCVAD
(Vose et al, ASCO abstract 2006, Till B et al, Leuk and Lymphoma 2008)

� Bendamustine-R (B-R) is superior R-CHOP


(Rummel M et al, Lancet 2013)

� R-CHOP followed by ASCT is superior to maintenance interferon


(Dreyling M et al, Blood 2005)

RW. Chen, et al. BJH 2016


Schema
Registration

Randomise for Induction

R-HCVAD cycle 1
R-MTX/AraC cycle 2 B-R x 4 cycles

Restaging Restaging

<PR ≥PR ≥PR <PR

OFF STUDY R-HCVAD Cycle 3 OFF STUDY


Follow for survival Stem cell collection B-R x 2 cycles Follow for survival

R-cyclophosphamide 3 gm/m2
R-MTX/AraC cycle 4
Stem Cell Collection

Restaging

STEM CELL TRANSPLANT


Second
<61 yrs: BCV, BEAM or TBI/VP16/Cy
Registration
61-65 yrs: BCV or BEAM

RW. Chen, et al. BJH 2016


Objectives

Objectives
� Primary: Estimate 2-year PFS
� Secondary: ORR, OS, toxicity and tolerability
� Value of MRD monitoring

Statistics
� Targeted 2-year PFS at least 75%, 1-sided, p=0.05 level test
� S0213 (R-HyperCVAD) and S0601 (RCHOP + bortezomib)
suggested 2-year PFS of 68% and 62%
� 160 patients total, 80 in each arm
� Either arm would be unacceptable if stem cell collection failure is ≥10%.
If 4 out of 20 patients on either arm fails then the arm will close

RW. Chen, et al. BJH 2016


Patient Demographics
Characteristics R-HCVAD(n=17) B-R(n=35) P-value
Age 59(44-66) 57(33-64) 0.23
Male/Female 9(53%)/8(47%) 32(91%)/3(9%) 0.003
Performance status
  0 11(65%) 26(74%) 0.52
  1 6(35%) 9(26%)
Disease Stage
  Ⅲ 1(5.9%) 3(8.5%) 1.00
  Ⅳ 16(94.1%) 32(91.4%)
Bulky disease 1(6%) 3(9%) 1.00
B symptoms 6(35%) 10(29%) 0.75
BM involvement 14(82%) 30(86%) 1.00
Extranodal involvement 15(88%) 32(91%) 1.00
Elevated LDH 5(29%) 9(26%) 1.00
Ki-67(46)
  <10% 20% 10%
0.58
  10-30% 60% 68%
  >30% 20% 22%
MIPI Score
  Intermediate/High 6(35%) 13(37%) 1.00
  Low Risk 11(65%) 22(63%)
RW. Chen, et al. BJH 2016
Off-Treatment

Reasons for discontinuing


R-HyperCVAD(pts=17) B-R(pts=35)
treatment/stopping before Auto-
12/17 14/35
SCT
Failure to collect stem cells 5 2
Thrombocytopenia 5  
Patient choice   4
Progressive disease   2
Pancytopenia 1  
Neutropenia   1
Allergy   1
Seizure   1
Insurance denial   1
Others 1 2
R-H ASCT: 9(53%), 4 off protocol
B-R ASCT: 23(66%), 2 off protocol

RW. Chen, et al. BJH 2016


S1106:Progression Free Survival

100%

80%

60%

40%

2-year
20% At Risk Failed Estimate
B-R 35 8 81%
R-HCVAD/MTX/Ara-C 17 4 82%
0%
0 12 24 36 48
Months After Registration

RW. Chen, et al. BJH 2016


S1106:Overall Survival

100%

80%

60%

40%

2-Year
20% At Risk Deaths Estimate
B-R 35 4 87%
R-HCVAD/MTX/Ara-C 17 2 88%
0%
0 12 24 36 48
Months After Registration
B-R: PD 3, unknown 1
R-HCVAD: PD 1, suicide 1
RW. Chen, et al. BJH 2016
NGS-based Minimal Residual Disease(MRD)Assessment

MRD prior to MRD post


induction chemo induction/prior to ASCT

Patient on trial

� NGS-based method instead of flow.


� Genomic DNA extracted from FFPE or BM mononuclear cells (Primary tumor)
� PCR amplification of IGH-VDJ, IGH-DH, and IGK (Adaptive Biotechnologies Corp)
� DNA from peripheral blood mononuclear cells and plasma amplified and sequenced
� 27 patients consented to optional MRD assessment
� 12 paired samples (prior to and post induction)

RW. Chen, et al. BJH 2016


MRD results

B-R (n=9):
� 8 (89%) patients with baseline positive MRD converted to MRD negative status.
� 3 additional patients were missing MRD status at baseline but were MRD
negative post induction.
� 2 year PFS is 100% for all 11 patients MRD negative at end of induction.
(3 did not go to ASCT)
� 1 patient MRD negative at baseline and remained negative at end of induction

R-H (n=2):
� 2/2 MRD positive at baseline and achieved MRD negative status

RW. Chen, et al. BJH 2016


Conclusions

�R-hyperCVAD is not an ideal platform for building future multicenter


trials in MCL with ASCT (marrow toxicity, inadequate stem cells).

�B-R arm achieved an 89% MRD negative rate on all paired samples and
all patients who converted from positive to negative status remain in
remission.

�B-R can achieve a deep remission and should be the future platform but
needs to be confirmed in a larger trial.

RW. Chen, et al. BJH 2016


StiL proposal for elderly MCL: R-B vs R-BAC

Randomised Phase III Study

B-R

Mantle cell
elderly, not eligible
for HDT + APBSCT
R
R
B-R plus AraC
In mantle cell lymphomas

Ongoings studies combine Bendamustine with

- Bortezomib
- Cytarabin
- Lenalidomide
- Ibrutinib
Bendamustine combination therapies

- Bendamustine-R + Rituximab maintenance


- Bendamustine-R + Bortezomib
- Bendamustine-R + Cytarabine (AraC)
- Bendamustine-R + Lenalidomide
- Ibrutinib +/- Bendamustine +/- R
ECOG 1409/SWOG/CALGB:
Randomized Phase 2 Study

For previously untreated pts with MCL


> 65 or 60-64 years of age, not ASCT candidates

• Arm A = Bendamustine-R ⇒ Lenalidomide/Rituximab


• Arm B = Bendamustine-R ⇒ Rituximab
• Arm C = Bendamustine-Bortezomib-R ⇒ Lenalidomide/Rituximab
• Arm D = Bendamustine-Bortezomib-R ⇒ Rituximab

ASCT, autologous stem cell transplantation.


B-R + Watch & Wait vs B-R + 2 years Rituximab

StiL NHL 7-2008 - M AINTAIN

Bendamustine-Rituximab
+ Watch & Wait
Mantle cell
for patients not R
R
eligible for APBSCT)

Bendamustine-Rituximab
n = 168 + 2 years Rituximab
q 2 months

Rummel et al, ASCO 2017


Two Years Rituximab Maintenance vs. Observation
after 1st-line treatment with Bendamustine plus
Rituximab in pts with Mantle Cell Lymphoma

Results of a prospective, randomized, multicentre phase 2 study


(a subgroup study of the StiL NHL7-2008 M AINTAIN trial)

Mathias Rummel, Wolfgang Knauf, Martin Goerner,


Goerner, Ulrike

Soeling,
Soeling, Elisab.
Elisab. Lange, Bernd Hertenstein,
Hertenstein, Jochen Eggert,
G. Schliesser,
Schliesser, R. Weide, Kl. Blumenstengel,
Blumenstengel, N. Detlefsen,
Detlefsen,
Axel Hinke, Frank Kauff, Juergen Barth on behalf of StiL

Lymphomas,, Giessen, Germany


Study group indolent Lymphomas
StiL NHL 7-2008: Rationale and study design

� Bendamustine plus Rituximab (B-R) is an effective treatment in MCL


(StiL NHL 1-2003: Rummel,
Rummel, Lancet 2013; Flinn,
Flinn, Blood 2014; Chen, Lugano 2015)

� Rituximab maintenance in MCL


- improved PFS and OS after R-CHOP
- failed to improve outcome after R-FC
(H. Kluin-Nelemans et al. NEJM 2012)

� No data available for R-maintenance after B-R

� R-maintenance as an attempt to further prolong disease control after B-R

� Prospective, randomized, multicentre phase 2 study (a subgroup study


of the StiL NHL7-2008 M AINTAIN trial) for hypothesis generating

� Primary and Secondary objectives: PFS and OS, DoR, TTNT, Toxicity
StiL NHL7-2008 (subgroup Mantle Cell Lymphoma)

� Cooperative Study group indolent Lymphoma (StiL)

� 81 centers in Germany and Austria

� NCT00877214 (ClinTrials.gov)

� Investigator initiated trial

� Funding by Roche Pharma AG

� 168 patients with MCL registered between Apr 2009 and Jul 2012

� Median follow-up 58.6 months


B-R + Watch & Wait vs. B-R + 2 years Rituximab

StiL NHL 7-2008 - M AINTAIN

Observation
(n = 62)

MCL B-R ≥ PR R
R
patients
not eligible up to SD, PD
for APBSCT 6 cycles off study n = 122
Rituximab
2 yrs, q 2 mo
(n = 60)
Inclusion criteria

� Patients with histological proven mantle cell lymphoma

� No pretreatment with chemotherapeutics, Interferon or Rituximab

� Histology not older than 6 months

� Stage III or IV or II with bulky disease

� Patients aged 18 - 80 years who were not eligible for high-dose therapy

� ECOG 0-2

� Written informed consent of the patient

MJR
Patient disposition
* Patients not eligible for randomization:
3 died prior to randomization
- 2 sepsis, - 1 unknown
Patients: n = 168
9 failed to respond (6 x PD, 3 x SD)
6 Rituximab intolerance

Patients randomized: n = 122 * 3 toxicity


- 2 cytopenia
- 1 inflammatory syndrome
13 withdrew consent
R maintenance Observation 3 violation of protocol
n = 60 n = 62 - concurrent breast cancer disease
- no randomization due to p ts wish
- CLL accord.
accord. reference pathology
Patients analyzed (n = 122) 4 secondary malignancies
2 infections during induction
3 other reasons
- lost for follow up
- doctor’
doctor’s decision (Coombs +ve
+ve))
- suspected Guillain Barre
Baseline characteristics of randomized patients

all pts R+ R-

Total (n) 122 60 62

Age (median) 71 70 71

Pts aged >70 years 65 (53%) 31 (52%) 34 (55%)

Stage III 12 (10%) 4 (7%) 8 (13%)

Stage IV 103 (84%) 53 (88%) 50 (81%)

B-symptoms 38 (31%) 20 (33%) 18 (29%)

Bulky disease 23 (19%) 12 (20%) 11 (18%)

Bone marrow involved 91 (75%) 46 (77%) 45 (73%)

LDH >240 45 (37%) 22 (37%) 23 (37%)


Baseline characteristics (cont.)

all randomized pts R+ R-

MIPI low 19 (16%) 9 (15%) 10 (17%)

intermediate 55 (46%) 31 (52%) 24 (41%)

high 45 (38%) 20 (33%) 25 (42%)

MIPI-b * low - - -

intermediate 36 (47%) 18 (44%) 18 (51%)

high 40 (53%) 23 (56%) 17 (49%)

Ki-67 ** < 30% 48 (61%) 23 (56%) 25 (66%)

30% - 50% 28 (35%) 17 (41%) 11 (29%)

> 50% 3 (4%) 1 (2%) 2 (5%)

* MIPI-b:
MIPI-b: including Ki-67; ** Ki-67 available for 79 (65%) patients
Response rates following B-R induction

140 patients evaluable for response evaluation

ORR 119 (85%)

CR 38 (27%)

PR 81 (58%)

SD 9 (6%)

PD 7 (5%)
Early death 5 (4%)
MJR
Progression free survival (58.4 months median follow-up
follow-up))

N = 168
Median: 64.2 months

Pts at risk 168 133 110 94 70 38 11


Progression free survival (56.3 months median follow-up
follow-up))

*
N = 106

Median: 43.2 months

Pts at risk 106 75 65 55 36 20 6

* All patients including non-responders and randomization failures (n=44)


plus all responding patients subsequently randomized to observation only (n=62)
Progression free survival (58.6 months median follow-up
follow-up))

months events
N = 122 (median) (n)
Observation 54.7 29
R maint. 72.3 21

Hazard ratio, 0.71 (95% CI 0.41 - 1.23)


p = 0.2267

Pts at risk
Observ 62 57 49 40 26 13 5
R maint 60 58 45 39 24 18 5

Rummel et al, ASCO 2017


Overall survival (58.6 months median follow-up
follow-up))

N = 122

months events
(median) (n)
Hazard ratio, 1.51 (95% CI 0.70 – 3.25) Observation n.y.r. 11
R maint. n.y.r. 15
p = 0.2974

Pts at risk
Observ 62 58 57 52 43 21 8
R maint 60 59 53 44 38 23 5

Rummel et al, ASCO 2017


Causes of death
R-maintenance Observation
n = 60 n = 62

OS events,
events, n (%) 15 (25%) 11 (18%)

− Lymphoma 10 (67%) 2 (18%)


− Infection 4 (27%) 2 (18%)
− Cardial reasons - 3 (27%)
− Secondary malignancy - 1 (9%)
− Suicide 1 (7%) -
− Accident - 1 (9%)
− Other / unknown - 2 (18%)

15 deaths in R-maintenance arm: only 1 completed 2 yrs,


yrs, 9 stopped early due to progression
Median of 4 administered Rituximab cycles in these 15 patients
MJR
10 lymphoma deaths:
deaths: 8 have stopped R-maintenance because of disease progression
Cross study comparison
StiL NHL7 NEJM 2012
2012**
n = 122 n = 274

Age (median) 71 70

Sex m 83 (68%) 193 (70%)

Stage III 12 (10%) 34 (12%)

IV 103 (84%) 223 (81%)

B-symptoms 38 (31%) 103 (38%)

ECOG 2 4 (3%) 13 (5%)

Bone marrow involved 91 (75%) 202 (74%)

LDH >240 45 (37%) 99 (36%)

MIPI low 19 (16%) 26 (9%)

intermediate 55 (46%) 129 (47%)

high 45 (38%) 119 (43%)

* Kluin-Nelemans et al. NEJM 2012


Duration of Remission

months events
N = 122 (median) (n)
Observation 57.1 25
R maint. 67.9 20

Hazard ratio, 0.76 (95% CI 0.42 - 1.35)


p = 0.3486

Pts at risk
Observ 62 52 44 32 15 6 1
R maint 60 46 41 38 24 8 1
Cross study comparison

StiL NHL 7-2008 Kluin-Nelemans et al


n = 122 (of 168) n = 184 (of 280)
Rate of randomized patients 73 % 66 %

B-R B-R CHOP-R CHOP-R


+R + INF +R
Remission duration
median (months
(months)) since randomization 57 68 23 n.y.r
rate at 72 months (estimated
(estimated)) 49% 40% 12% 50%

OS
median (months
(months)) since randomization n.y.r.
n.y.r. n.y.r.
n.y.r. 64 n.y.r.
n.y.r.
rate at 72 months (estimated
(estimated)) 70% 66% 50% 71%
Overall survival B-R +/- R-maintenance (5 yrs follow-up
follow-up))

N = 122

OS at 48 mo
mo:: 85%

months events
(median) (n)
Hazard ratio, 1.51 (95% CI 0.70-3.25) Observation n.y.r. 11
R maint. n.y.r. 15
p = 0.2974

Pts at risk
Observ 62 58 57 52 43 21 8
R maint 60 59 53 44 38 23 5
OS from Randomization

mFU:: 50.2m (46.4-54.2)


mFU

OS
Obs (95%CI) vs Rituximab (95%CI)
24m: 93.3 % (87.0-96.6) 93.3 % (87.1-96.6)
36m: 85.4 % (77.5-90.7) 93.3 % (87.1-96.6)
48m: 81.4 % (72.3-87.7) 88.7 % (80.7-93.5)

OS (months) from randomization

Abstract # 145 ASH 2016


B-R +/- R maintenance: Summary, conclusion

� High activity of B-R in elderly MCL patients confirmed

� R-maintenance did not improve PFS or OS after B-R

� B-R without R-maintenance appears equal and comparable


to R-CHOP plus R-maintenance (PFS and OS)

� No statistical evidence supporting benefit of R-maintenance


in elderly MCL patients following induction with B-R

� Attempts to further improve B-R


- Cytarabine,
Cytarabine, addition (R-BAC) or following B-R (Armand et al. Br J Hem 2016)
- Ibrutinib,
Ibrutinib, addition plus / or maintenance (NCT01776840)
- Lenalidomide,
Lenalidomide, maintenance (NCT00963534, ECOG 1409)
- Bortezomib,
Bortezomib, addition (ECOG 1409)
StiL NHL 7-2008 for MCL

Subgroup analyses
Exposure to Rituximab maintenance

� 33 out of 60 (55%) patients received all planned 12 cyles R (2 years)

� Median number of given R cycles is 12

� 27 patients stopped R-maintenance early:


- 12 progression o f disease
- 5 patients wish
- 6 infection or cytopenia
- 2 secondary malignancy
- 1 apoplex
- 1 suicide
Salvage regimens after failing initial treatment

R maintenance Observation
n = 60 n = 62

PFS events,
events, n (%) 21 (35%) 29 (47%)

Salvage treatments 15 (71%) 23 (79%)

− No treatment yet 6 6
− APBSCT 2 (13%) 3 (14%)
− B-R - 7 (30%)
− CHOP-R 5 (33%) 3 (14%)
− DHAP-R 2 (13%) -
− Temsirolimus 2 (13%) -
− Radiatio 1 (7%) -
− Other 3 (20%) 10 (43%) MJR
Progression free survival: MIPI low vs. intermed. vs. high

N = 119

MIPI low
MIPI intermed.
MIPI high
Overall survival: MIPI low vs. intermed. vs. high

N = 119

MIPI low
MIPI intermed.
MIPI high
Progression free survival: Ki67 ≤ 30 vs. Ki67 > 30

N = 79

months
(median)
Hazard ratio, 0.39 (95% CI 0.11 – 0.75) Ki67 ≤ 30 n.y.r.
p = 0.0128 Ki67 > 30 24.6

Pts at risk
Ki67 ≤ 30 58 56 48 39 31 14 6
Ki67 > 30 21 18 8 7 5 3 0
Overall survival: Ki67 ≤ 30 vs. Ki67 > 30

N = 79

months
(median)
Hazard ratio, 0.38 (95% CI 0.09 – 0.94) Ki67 ≤ 30 n.y.r.
p = 0.0393 Ki67 > 30 n.y.r.

Pts at risk
Ki67 ≤ 30 58 56 55 47 40 19 7
Ki67 > 30 21 20 14 12 9 4 1
Progression free survival: CR vs. PR

months
N = 114 (median)
CR 75.4
PR 72.3

Hazard ratio, 0.80 (95% CI 0.43 - 1.48)


p = 0.4894

Pts at risk
CR 35 33 26 25 21 16 4
PR 79 76 64 50 37 14 6
Overall survival: CR vs. PR

N = 114

months
(median)
Hazard ratio, 0.94 (95% CI 0.39 - 2.27)
CR n.y.r.
p = 0.8939 PR n.y.r.

Pts at risk
CR 35 34 31 28 25 19 6
PR 79 76 72 62 53 24 7
Progression free survival: pts ≤ 70 vs. >70 years

months events
N = 122 (median) (n)
Pts ≤ 70 n.y.r. 20
Pts > 70 65.6 30

Hazard ratio, 0.67 (95% CI 0.39 - 1.18)


p = 0.1675

Pts at risk
Age ≤ 70 57 54 46 40 32 18 5
Age > 70 65 61 48 39 28 13 5
Overall survival: pts ≤ 70 vs. >70 years

N = 122

months events
(median) (n)
Hazard ratio, 0.23 (95% CI 0.13 - 0.61)
Pts ≤ 70 n.y.r. 5
p = 0.0013 Pts > 70. 73.2 21

Pts at risk
Age ≤ 70 57 56 54 50 44 25 7
Age >70 65 61 56 46 37 19 6
Progression free survival: only pts with CR

months events
N = 35 (median) (n)
Observation n.y.r. 6
R maint. 75.4 7

Hazard ratio, 0.87 (95% CI 0.29 – 2.59)


p = 0.8086

Pts at risk
Observ 18 17 13 13 10 7 7
R maint.
maint. 17 16 13 12 11 9 6
Overall survival: only pts with CR

N = 35

months events
(median) (n)
Hazard ratio, 0.37 (95% CI 0.09 – 1.73)
Observation n.y.r. 2
p = 0.2168 R maint. n.y.r. 5

Pts at risk
Observ 18 17 16 16 14 10 4
R maint.
maint. 17 17 15 12 11 9 2
Progression free survival: only pts with PR

months events
N = 79 (median) (n)
Observation 53.8 19
R maint. 72.3 14

Hazard ratio, 1.31 (95% CI 0.66 – 2.59)


p = 0.4408

Pts at risk
Observ 39 37 35 26 16 6 3
R maint.
maint. 40 39 29 24 21 8 3
Overall survival: only pts with PR

N = 79

months events
(median) (n)
Hazard ratio, 0.56 (95% CI 0.21 – 1.49) Observation n.y.r. 6
p = 0.2492 R maint. n.y.r. 10

Pts at risk
Observ 39 37 37 33 28 11 4
R maint.
maint. 40 39 35 29 25 13 3
Ibrutinib
Ibrutinib

Single agent activity


Future also in combination
Ibrutinib for relapsed Mantle Cell Lymphoma
111 patients with rel/ref MCL
median 3 prior tx, refract 45%
Ibrutinib 560 mg orally daily

Results
� Predominantly grade 1 or 2
toxicity included transient
diarrhea, fatigue, and nausea
– ORR: 68%
– Median PFS: 13.9 mo
– Median DOR: 17.5 mo

� The response was independent


of prior Bortezomib exposure
Wang ML, et al. N Engl J Med. 2013;369(6):507-16
Ibrutinib,, Bendamustine and
First-line Ibrutinib
Rituximab (B-R): phase 3 study design
Age ≥65 years

N = ~ 520
B-R + Placebo R + Placebo
Bendamustine 90mg/m 2
day 1&2 Rituximab 375m2/kg
R Rituximab 375mg/m day 1
2 if CR or PR
PR** q8 wks for up to 2 years
A q4 wks 6 cycles +
N + Placebo (4 caps daily)
D Placebo (4 caps daily) until PD or unacceptable toxicity
O 1:1
M
I B-R + Ibrutinib R + Ibrutinib
Z Bendamustine 90mg/m 2
day 1&2 Rituximab 375m 2/kg
Rituximab 375mg/m day 1
2 if CR or PR
PR** q8 wks for up to 2 years
E
q4 wks 6 cycles +
+ Ibrutinib 560mg qd (4 caps daily)
Ibrutinib 560mg qd (4 caps daily) until PD or unacceptable toxicity

* If SD - continue with ibrutinib/placebo only


* If PD - discontinue study treatment 2-Feb-18
Dreyling M et al. Hematol Oncol. 2013;31(Suppl 1):142.
Mantle cell lymphoma: Summary and Conclusions

� Survival almost doubled within the past 3 decades,


even though MCL is still considered to be a noncurative disease

� Progress has been achieved by


- High-dose cytarabine (most relevant)
- Stem cell transplantation (younger pts)
- Bendamustine (pts not eligible for ASCT)

� Bendamustine plus Rituximab for patients not eligible for high dose treatment
- B-R can be further improved by adding cytarabine (concurrent or subsequent)

� Ibrutinib,
Ibrutinib, Bortezomib,
Bortezomib, and Lenalidomide available for relapsed MCL

� Ibrutinib new promising active agent showing high single agent activity in
relapsed / refractory MCL, currently under investigation in combination regimens
DISCLAIMER
Konten ini telah diunggah atas izin peneliti sebagai pemilik konten atau pemegang hak
cipta dan hak guna, yakni Prof. Dr. Mathias Rummel. Dexa Group tidak bertanggung
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akan dikenakan sanksi sesuai dengan hukum yang berlaku.