dr. campo mcl

Elias Campo

Hospital Clinic, University of Barcelona

Biology and Pathology of

Mantle Cell Lymphoma

Mantle Cell Lymphoma

14 der(14) 11 der(11)

IGH/CCND1

Years

Pro

bability

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8

Complete Response 25% (6-50%)

Duration of CR 1.5 yrs (0.5-2.5 yrs)

Median Survival 3-4 years

Cyclin D1

Herrmann, A. et al. J Clin Oncol; 27:511-518 2009

Improvement in Survival of Patients

with non-blastoid MCL

1996 to 2004

1975 to 1986

• New diagnostic tools and management measures

• Application of new therapeutic regimens

MCL Pathogenesis

• Cell Cycle Dysregulation

• Dysruption of DNA damage

response pathway

• Cell survival pathways

Mantle Cell Lymphoma: Cytological Variants

Classical Small cell

Blastic Pleomorphic

MCL Phenotype

CD20

Cyclin D1 CD5

CD3

Prognostic Value of Proliferation in MCL

Ki-67 Ki-67

MIPI-b

Hoster, E. et al. Blood 2008;111:558-565 Katzenberger, T. et al. Blood 2006;107:3407

ARF-INK4a Locus

p16ink4a

CDK4 / Cyclin D

Rb

p14/p19arf

MDM2

p53

BMI-1

Cell Cycle Regulatory Pathways

G1 S G2 M APOPTOSIS G1 S

Mutated (30%)

Amplified (10%)

Amplified (10%)

Deleted (30%)

9

17

Deleted (<5%)

DNA Damage Response Pathways

ATM

DNA damage Replication

stress

11

ATM

protein

R23stop

FS32stop

M1L

R3008H

D2725V

K2717M

FS564stop

FS1349stop

p53

binding

c-Abl

binding

b-adaptin

binding

PI3-kinase

domain Rad-3

homology

Truncated protein Conserved residue

substitution

Genetic Stability

YEARS

PR

OB

AB

ILIT

Y

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10

No gain (n=8)

1 to 4 gains (n=28)

>4 gains (n=6)

P=0.02

Activated pathways in MCL without

apparent genetic alterations

Wnt Pathway

PI3K, AKT, mTOR

Pathway

NFkB Pathway

Navarro et al Sem Hematol 2011

Proteasome Inh

CD20

CD40L

CD40

CD40L

CD40

TRAIL-R

TRAIL

AbaDR4

AbaDR5

CXCR4

SDFa1

PI3K

Akt

mTOR

NF-KB

BCL-2 Inh

IAPs

Antagonists

IL6 TNFa

IAPs

PI3K/Akt/mTOR

Axis Inh

NF-KB Inh

Mitochondria

stromal cells

nurse-like cells

folicullar dentritic cells

macrophages

Nucleus

IL-4

Nucleus

B cell neoplasm

BAFF

APRIL

TACI

BCMA

HSP-90

HSP90

Inhibitors

SrcK

CD38

CD31

BCR

BAFF-R

PK Inh

AbaCD20

AbaCD38

T Lymph

VEGF

VEGF-R

ImiDS

IL10 ImiDS

DNMT/HDAC

Inhibitors

Nucleoside

Analogs

Saborit-Villarroya et al, Curr Drug Targets. 2010;11:769-80.

Naive B

lymphocyte

Increased

Genomic

Instability

ATM

CHK2

Early

MCL

Classical

MCL

t(11;14)

Cyclin D1

Rb p27

Molecular Pathogenesis in MCL

Blastoid

MCL

p16/CDK4/Rb

ARF/MdM2/p53

High

Proliferation

Bcl-2/other

Cell

Survival

Jares P et al Nat Rev Cancer 2007

IGH Somatic Hypermutations in 807 MCL

Hadzidimitriou A et al Blood 2011

Highly mutated 111 (13%)

Minimally/borderline mutated 458 (57%)

Truly Unmutated 238 (30%)

MCL: From Naive to an Antigen Selected Cell ?

Antigen Selection

Ig Somatic Mutations

Class Switch

Naïve

V D J cμ cγ

T Cell-Independent Response

HyperMutated-MCL

UnMutated-MCL

Boderline Mutated-MCL

CD5 CD3

CD20

Cyclin D1 p27

Cyclin D1 Negative MCL Variant

Cyclin D1

Cyclin D3 Cyclin D2

Fu et al, Blood 2005

MCL, n=89

MCL

CCND1-

n=6

SOX11

CCND1

SOX11

CCND1

BL, n=33 DLBCL, n=46 PMBL, n=20 FL, n=44

SOX11 mRNA Expression in non-HL

is Highly Specific of MCL

Mozos et al Haematologica 2009

CyclinD1 negative MCL

MCL Cyclin D1 (SP4) Sox11

Sox11 Protein Expression in MCL

Mozos et al Haematologica 2009

SOX11 Expression is Highly Specific of MCL

and Recognizes Cyclin D1 Negative tumors

* weak

Lymphoma Sox11 +

MCL CCND1- 39/41

MCL 97/112

DLBCL 0/63

SMZL 0/9

MZL 0/11

FL 0/22

CLL 0/12

BL 2/8 (3)*

B/T LBL 8/8

Lymphoma Sox11 +

cHL 1/36

NLPHL 0/5

PTCL NOS 0/15

AILT 0/5

Hepatosplenic 0/3

ALK+ 0/3

ALK- 0/3

T-PLL 2/3

T/NK Nasal type 0/3

Mozos A et al Haematologica 2009, updated

SOX11

Cyclin D1

Classical MCL

CCND1

SOX11 SOX1

1

p27

MCL with Indolent Clinical Behavior

OS from diagnosis OS from treatment

Martin P et al JCO 2009

Conventional vs Indolent MCL Clinical Characteristics

Clinical data Conventional

MCL (15)

Indolent

MCL (12)

Chemotherapy 15 0

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

5-year Overall Survival 49% 100%*

ECOG≥2 70% 0+

Intermediate/High MIPI 46% 0+

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

Lymphocytosis (≥5x109/L) 9/11 4/9

+ p <0.05

* p=0.002 Fernandez V et al Cancer Res 2010

SETMAR HMGB3

FARP1

HDGFRP3

DBN1

PON2

CNN3

SOX11 KIAA1909

RNGTT

CNR1

CDK2AP1

CSNK1E LGALS3BP

Supervised analysis

Indolent and

conventional MCL

iMCL and cMCL Have a Distinct Gene Expression Signature

Fernandez V et al Cancer Res 2010

SOX11 Cyclin D1

Conventional

MCL

Indolent MCL

SOX11 Protein Expression in MCL

Can SOX11 expression recognize a subtype of MCL with

different clinicopathological features and outcome?

Clinical data SOX11 -

(n = 15)

SOX11 +

(n = 97)

High MIPI 33% 46%

Lymphn nodes (>1cm) 53% 99% *

Splenomegaly 92% 48%*

WBC ≥ 10x109/L 57% 18%*

Lymphocytosis (≥5x109/L) 83% 24% *

Ki67 high >50% 20% 28%

Adriamycin-Regimens 67% 72%

Complete Response 40% 54%

5-year OS (%) 78% 36%*

+ p <0.01 Fernandez V et al Cancer Res 2010

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

Cyclin D1

Cyclin D1 SOX11

Cyclin D1 SOX11

“In situ” MCL (17 cases )

• Location at diagnosis

– Solitary LN 10

– LN several sites 2

– Extranodal 5

– Bone Marrow, Peripheral blood 3/7

• SOX11+ 7/16 (44%)

• Follow-up

– 9 W&W

• 2 Progression to overt MCL (4 years)

• 4 Alive with stable (2) or no disease (2) (med 8 yr; range 1-19)

• 1 Dead, unrelated cause (1.4 y, 84 year-old)

– 4 Chemotherapy Alive No Disease 4 yr

– 2 Rx Alive no Disease > 2 yr

• 1 incidental finding 3 yr after overt MCL in complete remission

Carvajal-Cuenca et al Haematologica 2011

Classical MCL

t(11;14)

Blastoid MCL

Genomic Instability

Unmutated Ig

Leukemic/ non-nodal type MCL

Genetically Stable

Hypermutated IG

(del)17p

“In situ” MCL

SOX11-

SOX11+

Conclusions

- MCL pathogenesis integrates alterations in cell cycle, DNA damage

response and survival pathways that may be targeted by new

therapies

- Antigen selection may play a role in the pathogenesis of at least a

subgroup of MCL

- Cyclin D1 negative MCL can be recognized by SOX11 expression

and seem to have similar clinical and genetic characteristics to

conventional MCL.

- Some MCL have an indolent clinical course and may benefit of a

more conservative clinical management. A subset of them seems to

correspond to a different biological subtype.

- We may recognize early steps in MCL lymphomagenesis that

should be managed with caution.

Acknowledgments

Hospital Clínic-University

of Barcelona

Silvia Bea

Cristina Royo

Alba Navarro

Guillem Clot

Alejandra Martinez

Eva Giné

Gonzalo Gutierrez

Verònica Fernàndez

Dolors Colomer

Neus Villamor

Pedro Jares

Armando Lopez-Guillermo

S. Orsola-Malpighi Hospital-Bologna

Claudio Agostinelli

Stefano A Pileri

Addenbrooke’s Hospital-Cambridge

Nicola Trim

Wendy Erber

University Hospital

Schleswig-Holstein-Kiel

Chistiane Pott

Itziar Salverria Reiner Siebert University Hospital Munich-Grosshadern-Munich

Martin Dreyling

National Institute of Health

Bethesda

Adrian Wiestner

Wyndham Wilson

Elaine Jaffe

Institute of Pathology-Würzburg

Elena Hartmann

Andreas Rosenwald

Abteilung für Klinische-Pathologie-

Stuttgart

German Ott