Mantle cell Lymphoma treatment First line

Mantle cell Lymphoma treatment

First line

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Pr Olivier Hermine MD, PhD

Department of Hematology and CNRS UMR 8147

Red cell Labex

Hôpital Necker

Paris, France

[email protected] or [email protected]

http://www.zoologi.su.se/education/phd-biology/europa.GIF

mailto:[email protected]

4

Multicenter Evaluation of MCL

Annency Criteria fulfi l led

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

y ears

0

0,25

0,5

0,75

1

p

single agent

comb. no anthra.

comb. with anthra.

event free interval after chemotherapy in stages III + IV

Dreyling, ASCO 1999 Nickenig, Cancer 2006

CR/Cru 25%

European MCL Network Clinical course

Clinical risk factors: MIPI

Hoster, Blood 2008

Univariate risk factors

• age

• ECOG performance status

• B-symptoms

• spleen involvement

• tumor size

• leukocyte or lymphocyte count

• LDH

• hemoglobin

• albumin

• beta2-microglobulin

(PALL: PS, age, LDH, leucocyte count, Ki67)

6 ©2008 by American Society of Hematology

Proliferation index in MCL

Determann O et al. Blood 2008;111:2385-2387

7 ©2008 by American Society of Hematology

Proliferation index in MCL

Determann O et al. Blood 2008;111:2385-2387

Indolent ?

Conventional vs Indolent MCL Clinical Characteristics

Clinical data Conventional

MCL (15)

Indolent

MCL (12)

Age at diagnosis 67 (30-83) 58 (41-75)

Gender (M/F) 11/4 7/5

ECOG≥2 70% 0+

Intermediate/High MIPI 46% 0+

Lymphadenopathy (>1cm) 15/15 2/12+

Lymphocytosis (≥5x109/L) 9/11 4/9

Evolution

Median Follow-up 15 m (0.5 - 79) 70 m (25-121)

Chemotherapy 15 0

5-year Overall Survival 49% 100%*

+ p <0.05

* p=0.002 Fernandez V et al Cancer Res 2010

SOX11 Cyclin D1

Conventional

MCL

Indolent MCL

SOX11 Protein Expression in MCL

Courtesy of E Campo

Overall Survival in MCL patients according to SOX11 Expression

Sox11 -

Sox11 +

P< 0.001

0 2 4 6 8 10 12 14 16

YEARS

0

.2

.4

.6

.8

1

PR

OB

AB

ILIT

Y

SOX11 negative (N=15; dead: 4)

SOX11 positive (N=97; dead: 68)

Fernandez V et al Cancer Res 2010 Courtesy of E Campo

11

Prognosis score : IPI – SUVmax :

SSE Favorable (n= 9):

NO relapse No death

Intermediate (n=13):

SSE median : 37 mo

SG mdian : 40 mo

Unfavorable (n=9):

SSE median = 22 mo

SG median = 22 mo

Touzeau et al. Euroepan J of N Medecine

Results – Analysis of prognosis factors

12

MCL with Indolent Clinical Behavior

OS from diagnosis OS from treatment

Martin P et al JCO 2009

Optimal treatment in mantle cell lymphoma ?

Induction ? Consolidation ?

maintenance

SCT

=> eradication => tumor reduction

Treatment Strategy

• Depend on age Old (60%) vs Young

(40%) with a 65 years old cut off

• Physiological status and comorbidity

more relevant

• High dose vs standard chemotherapy

Mantle cell lymphoma in young patients

• 40% < 60 yr

• Treatment with high dose chemotherapy and autologous SCT is possible

• Treatment with Allogeneous stem cell transplantation is feasible


SCT


Autologous SCT ?

Allogenous SCT ?


SCT


Autologous SCT ?

European MCL Network

ASCT vs. IFN

PR, CR

Interferon-a

maintenance

Cyclo 120mg/kg

+ TBI

autologous PBSCT

RELAPSE

DexaBEAM (stem cell harvest)

6x CHOP-like chemotherapy

2 cycles

consolidation

Dreyling, Blood 2005 (updated)

1st-line treatment of MCL in the R era: Pooled ASCT vs. IFN

Overall survival

Hoster et al, ASH 2009


Induction ? Consolidation

SCT


Role of Rituximab in MCL induction CHOP vs. R-CHOP

First Line Therapy

eval pts.: 60 62

CR: 7% 34% (p =0.00024)

PR: 67% 60%

MR: 14% 3%

SD: 4% 0%

PD: 7% 2%

EX: 0% 2%

PR+CR: 74% 94% (p=0.005)

CHOP R-CHOP

CHOP vs. R-CHOP: MCL

Time to treatment failure

Hoster, ASH 2008

Bibliography

• Tam CS, Bassett R, Ledesma C, et al. Mature results of the M.

D. Anderson Cancer Center risk-adapted transplantation

strategy in mantle cell lymphoma. Blood. 2009;113(18):4144-

52.

• Schulz H, Bohlius JF, Trelle S, et al. Immunochemotherapy

with rituximab and overall survival in patients with indolent or

mantle cell lymphoma: a systematic review and meta-analysis.

J Natl Cancer Inst. 2007;99(9):706-14.


R+CHOP ? Consolidation

SCT


day 1 day 21

Rituximab + HyperCVAD/M-A in MCL

alternate cycles 1 and 2 every 21 days

Rituximab 375mg/m2

(day 1)

Methotrexate 200mg/m2

i.v. 2 hours (day 2)

Methotrexate 800mg/m2

i.v.continuous 22 h (day 2)

Cytarabine 1,000/3,000mg/m2

i.v. 2x 2h (days 3–4)

cycle 1, 3, 5, 7

R-hyperCVAD cycle 2, 4, 6, 8

R-M-A

antifungal, antibacterial, antiviral prophylaxis: G-CSF !!!

Romaguera, JCO 2005

Surv

ival pro

babili

ty

Rituximab + hyperCVAD/M-A in MCL:

Failure-free survival according to age

Months

•

80706050403020100

1

.9

.8

.7

.6

.5

.4

.3

.2

.1

0

> 65 y rs - 32 pts, 19 f ailed

<= 65 y rs - 65 pts, 24 f ailed

p = 0.03

<= 65 y rs

> 65 y rs

••• •

Rituximab + HyperCVAD/M-A in MCL

Failure-Free Survival according to age

Months

Romaguera JE, et al. J Clin Oncol 2005; 28:7013–7023.

Hyper CVAD

2 year PFS 63%

40% treatment arrest

High toxicity

SWOG 0213: R-HyperCVAD/MTX-AraC in Patients

With Newly Diagnosed MCL

Nordic MCL Project: MCL1 + 2

Protocol MCL1

Week 0 3 6 9 12 15 18 21

Rituximab 375mg/m2

BEAM

Eligible: MCL, stage II-IV, <66 years

PBSC

harvest

PBSC

infusion

Protocol MCL2

Week 0 3 6 9 12 15 18 21

PBSC

harvest

PBSC

infusion

Maxi-CHOP

HD ara-C

Geisler et al, Blood 2008

Mantle cell lymphoma

R-CHOP/High dose Ara-C => ASCT

B: Survival

0.0 2.5 5.0 7.5 10.00

20

40

60

80

100

MCL1 (n=41)

P<0.001

MCL2 (n=160)

Years

Perc

en

t su

rviv

al

A: Event-free Survival proportions

0.0 2.5 5.0 7.5 10.00

20

40

60

80

100

MCL1 (n=41)

MCL2 (n=160)

P<0.0001

Years

Perc

en

t su

rviv

al

Geisler Blood 2008

0.0 2.5 5.0 7.5 10.0 12.50.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Low (80)

Event-free Survival according to MIPI

P<0.0001Int. (41)High (37)

Years

Fra

cti

on

su

rviv

al

0.0 2.5 5.0 7.5 10.0 12.50.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Low(80)

Survival according to MIPI

Int (41)High (37)P<0.0001

Years

Fra

cti

on

su

rviv

al

NLG

MCL2: Outcome by MIPI

EFS OS

Geisler et al, ICML 2011

32

PR, CR

Cyclo 120mg/kg

+ TBI 12 Gray

PBSCT

PR, CR

(2+1) x R-

CHOP/R-DHAP

alternating

stem cell mobilization

after course 6

PBSCT

TBI 10 Gray

Ara-C 4x1.5 g/m2

Melphalan 140 mg/m2

4 x R-CHOP

2 x R-CHOP

DexaBEAM (stem cell mobilization)

MCL younger Protocol Design

33

Response Rates after induction PP

R-CHOP

R-CHOP/

R-DHAP

Stop without staging 6 3% 9 4%

Evaluable 206 199

ED 0 0% 0 0%

PD 10 5% 8 4%

SD 10 5% 3 2%

PR 103 50% 78 39%

CRu 29 14% 38 19%

CR 54 26% 72 36% p=0.032

CR or CRu 83 40% 111 55% p=0.0028

CR or CRu or PR 186 90% 188 94% p=0.14

Update November 19, 2010, European MCL Network, V0.3 26.11.2010

34

Time to treatment failure PP

p=0.0382 (one sided sequential test)

Hazard Ratio 0.68

MCL Younger: Remission Duration after ASCT

Update April 7, 2013, European MCL Network, V1.0 22.05.2013

36

MCL Younger: Cumulative incidence of

treatment failure, ITT


37

MCL Younger:

TTF ITT – MIPI

Low risk Intermediate risk High risk

• no different treatment effect according to MIPI score

(interaction p=0.92)

MIPI and TTF/RD

Ki-67 in MIPI Low

European MCL Network

MRD Response to Treatment

UK SH

midterm end of induction

MRD- MRD-

source PB BM PB BM

R-CHOP 20(22%) 14(18%) 44(46%) 20(26%)

R-DHAP 51(61%) 32(43%) 69(80%) 43(68%)

Over all 71(40%) 46(30%) 113(62%) 63(45%)

n = 192

Remission Duration according to Clinical

Response and MRD Status after Induction

CR BM+

PR BM-

PR BM+

CR; MRD-

Cru/PR; MRD-

Cru/PR; MRD+

CR; MRD+

CR BM- CR BM+

PR BM-

PR BM+

p=0.0013

n = 128

42

Achievement of MR post Induction is an Independent Prognostic Factor

variable HR 95% CI p

Molecular response 4.2 (1.8-9.8) 0.001

MIP score 1.9 (1.2-3.1) 0.01

CR 1.0 (0.5-2.2) 0.1

Treatment arm 0.5 (0.2-1.2) 0.98

R-CHOP R-DHAP

Impact of ASCT on MRD Status

PB BM PB BM 0

25

50

75

100

% M

RD

ne

ga

tive

51%

70%

p = 0.03 p = 0.008

33%

61%

82%

90%

77%

88%

ns ns

* *

* *

Remission Duration according to MRD Status

after ASCT - Pooled trials -

n = 161

*

% M

RD

ne

ga

tive

*p < 0.0001

R-CHOP R-CHOP/ R-DHAP

0

25

50

75

100

51%

83%

*


45

MCL Younger: Overall Survival

PP population

ARM 24 36 48

R-DHAP 88% 83% 80%

R-CHOP 83% 76% 74%


R+high dose ARAC

RCHOP/RDHAP ?

Consolidation

SCT



R+high dose ARAC

RCHOP/RDHAP ? Maintenance ?

SCT


TBI ? MCL2 vs EMCL (ASH 2013)

>PR (EBMT)

LYMA trial

SCT

=> MRD => MRD, FDG-PET

4X DHAP-R R

No R

n=199

Median FU for living patients: 22,1 months

OS at 6 months: 97% (94.6-99.4)

OS at 1y: 90.4% (86.3-94.7)

OS at 2y: 86.3% (81.2-91.6)

Overall Survival of the 199 patients


SCT


Allogeneous SCT ?

Nonmyeloablative allogeneic transplantation

Khouri et al, JCO 2003

60 48 36 24 12 0

Months after SCT

1,0

0,8

0,6

0,4

0,2

0,0

Cu

m S

urv

iva

l

FL n=726

MCL n=321

DLBC n=579

p<0.001

Allogeneic SCT for B-cell NHL: overall survival

European Group

for Blood and Bone Marrow Transplant

Months

60 48 36 24 12 0

1,0

0,8

0,6

0,4

0,2

0,0

Allogeneic SCT for MCL: OS by conditioning

RIC n=220

Conventional n=95

European Group

for Blood and Bone Marrow Transplant (2001-2004)

S. Robinson

Years 1 2 3 4 5

At Risk: Auto 212 136 66 Allo 31 24 12

0

Pro

bility,

%

100

0

20

40

60

80

100

0

20

40

60

80 Auto (N=251)

Probability of Overall Survival "Early MCL“ = CR1/PR1

P<0.001 at 1 year (93% vs 69%) P=0.057 at 3 years (76% vs 62%) p=0.941 at 5 years (62% vs 61%)

(Source: Jc11_21) LY08-02-11_11.ppt

RIC/NST (N=50)

Allogeneic SCT for MCL: OS by disease status

60 48 36 24 12 0

Months

1,0

0,8

0,6

0,4

0,2

0,0

CR1 n=56

Others n=133

Refrac / Relapse / Progr n=140

European Group

Blood and Bone Marrow Transplant (2001-2004)

Allogeneous Stem

Transplantation in MCL

• GVL effect occurs

• Curative procedure

• Not in first line except in patients

with poor prognosis that remain to

be determined (hıgh MIPI,

MRD+,blastoıd ?)

• In relapsing setting in responding

patients (CR or PR)

Mantle cell lymphoma is also a

disease of the ederly patients or unfit

patients

• 60% >40 yr

• Treatment with high dose chemotherapy and autologous/allo SCT is not possible (70 y)

Update April 7, 2013, European MCL Network, V1.0, 23.05.2013


4 x R-CHOP

IFN-a maintenance

(3 x 3 M IU/week)

or Peg-IFN

(1mg/kg week)

4 x R-CHOP

PR CR

3 x R-FC

Rituximab

maintenance

(all 2 months)

3 x R-FC

MCL Elderly:

Randomization and Treatment


MCL Elderly: Time to treatment failure

ITT

n Events PD SD Rel ED DRem

ALL 550 327

R-FC 276 167 36 13 74 8 36

R-CHOP 274 160 15 17 104 12 12


MCL Elderly: Overall survival ITT


MCL Elderly: RD R vs. IFN - PP

Hazard Ratio 0.54

p adjusted for interim analyses


MCL Elderly: RD ITT

• R-CHOP • R-FC

p=0.0249 for interaction of induction and maintenance


MCL Elderly: RD PP

Cumulative Incidence

• R-CHOP • R-FC

p=0.0015

p=0.0342

p=0.0001

p=0.0322


MCL Elderly: OS of responders

• R-CHOP • R-FC

p=0.0021 for interaction of induction and maintenance

MCL in Ederly

• RCHOP + R is the new standard

• However room to improve prognosis

(increase CR)

• Chemotherapy of induction ?

• Improve maintenance

• New drugs ?

New Drugs to improve response

before Allogeneous Stem cell

transplantation ?

Bendamustine

Bortezomib (FDA approval)

Thalidomide/Lenalidomide

Temsirolimus (EMEA approval)

Others new compounds

Bendamustine in indolent NHL

upfront therapy, 18% MCL

549 patients with indolent lymphoma, German STiL group,

MJ Rummel et al

R 375 mg/m2 d 1

B 90 mg/m2 d 1-2

Repeat day 28

ASH 2009

Treatment schedule

R-BAC

R-BAC PROTOCOL VI-1903

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.

R-BAC PROTOCOL VI-1903

Untreated

R/R

OS and PFS in Patients with untreated (20)

or R/R MCL (20) (N = 40)

Median f/u 23 months (7-36)

0

.2

.4

.6

.8

1

0 5 10 15 20 25 30 35

Time (months)

0

.2

.4

.6

.8

1

0 5 10 15 20 25 30 35

Time (months)

OS

PF

S

Drug targets

in MCL (in preparation

for allo)

B cell receptor signalling pathways

Perez-Galan et al, Blood 2010

Drug targets

in MCL (in preparation

for allo)

B cell receptor signalling pathways

Bruton‘s tyrosine kinase

Perez-Galan et al, Blood 2010

PI3K

mTOR

Drug Target Response rate

Bortezomib & co Proteasome 33-58%

PCI-32765 BTK 77% (CR 44%)

Cal-101 PI3K 67% (CR 0%)

Temsirolimus & co mTOR 30-40%

Lenalidomide & co sIPI >1 42-53% (CR

20%)

Drug targets in MCL (in preparation for allo)

CDK inhibitors (flavopiridol), BH3 mimetics, HDAC inhibitors (vorinostat), HSP90 inhibitors, Bispecific mTOR and PI3 kinase: Too preliminary or ineffective

CCI 779 +Rituximab Ansell et al ASH 2009 (abs 1665)

• 71 pts atleast two prior therapies

• 30% Rituximab refractory

• ORR 47% CR 20% PR 28%

• PFS 9.5 m

• Use of combination T3 (RFC,

RCHOP, RDHAP)

77

0

0.2

0.4

0.6

0.8

1

0 100 200 300

PFS (days)

Su

rviv

al

pro

ba

bil

ity

Zinzani ASH 2008

Lenalidomide maintenance (n = 39) Progression-free survival

78

Treatment – Maximum of 24 months or until Toxicity, PD or Consent Withdrawal

1st line induction

RCHOP vs

RCHOP/RHDArac

Lenalidomide = Rituximab (15 mg daily d1-21, q28 days)

Rituximab

PR / CR

(90%) ® B

A

MCL-003 proposal: Study Design

Phase 3, 1:1 Randomized, comparative, maintenance study post-completion of standard chemotherapy

Newly Diagnosed MCL Patients with PR or CR after Initial Chemotherapy

Transplant ineligible

Primary endpoint: PFS

Global Participation in Study: Europe, US, other countries around the world

Ibrutinib phase II study in relapsed MCL

560 mg orally, once daily, until PD

115 patients, 40-84 years old

Median number of previous treatments: 3 (range 1-6)

Efficacy Bortezomib-naïve

(n=63)

Bortezomib-exposed

(n=46)

Total (n=109)

ORR 65.1% 67.4% 66.1%

CR 19% 19.6% 19.3%

PR 46% 47.8% 46.8%

Wang et al, ASH 2012 # 624

First line Elderly MCL

International trial (Jand J)

MCL

BR

BR-I

Conclusıon

• MCL prognosıs has ımproved and cure ıs

now a goal to achıeve

• Hıgh dose Arac/Rıtuxımab contaınıng

regımen

• Stem cell transplantatıon ın young

• Maıntenance ın ederly

• New drugs, probably best ıf used ın

combınatıon, are now avaılable that may

change these paradıgms

Original Concept

Dose reduction for good risk

R-CHOP/

R-DHAP

+/- BTK ? x6

R- ASCT

Maintenance

(new drug BTK ) Ibrutinib (R?)

PI M. Dreyling and EU-MCL network

R- ASCT

Maintenance

(new drug BTK Ibrutinib) (R?)

(R?)

Thank you Med V

Heidelberg

M Rieger

U Hegenbart

S Dietrich

AD Ho

Nordic LG

C Geisler

E Kimby

LWP

P Dreger

A Sureda

JJ Luan

H Finel

O Hermine

S Montoto

J Robinson

N Schmitz

H Schouten

A Boumendil

Slides

M Dreyling

T Fenske

C Geisler

B Glass

P Hari

O Hermine

S Montoto

S Robinson

N Schmitz

A Sureda

R Storb

Update November 19, 2010, European MCL Network, V0.3 26.11.2010

84

Aknowledgments

M Dreyling EMCL coordinator

• The support of the EMCL network including the

GELA , GLSG, and Polish lymphoma group.

• All the investigators and their staff from 129

centers in 4 countries (Germany 82 , France

35, Belgium 11 and Poland 1)

• The EMCL pathology review Panel (W Klapper,

N Brousse)

• The MRD group (C Pott, EA Macintyre, K

Beldjord, MH Delfau)

• The Data Center of Munich (E Hoster, M

Unterhalt) for data processing and statistics

• The GELA and GELA-RC, GLSG and PLSG

teams for organization, monitoring, data

cleaning

Treatment frail elderly MCL

patients

• Aim at optimal palliative treatment:

– Rituximab + chloorambucil

– Rituximab alone: not effective

– R-CVP

– (low dose) radiotherapy

– Small molecules (Lenalidomide,

Temsirolimus)?

Documents

Mantle cell Lymphoma treatment First line