Lymphomes de la zone marginale (MALT et non MALT) DES/DES … · Lymphomes de la zone marginale...

Lymphomes de la zone marginale

(MALT et non MALT)

Catherine Thieblemont

Hôpital Saint-louis, Paris - France

DES d’hématologie

14 Février 2014

Cas clinique 1

• Mme. M., 87 ans, présente un oedème de la paupière gauche

• PS = 0

• Aucun antécédent, en particulier oculaire

• IRM : infiltration des tissus mous à gauche. Oeil droit est normal.

- Infiltrat diffus de cellules centrocytes monomorphes de

petite taille sans différentation plasmocytaire

-Immuno : CD5 neg CCND1 neg CD10 neg and bcl6 neg

= Lymphome de MALT

Cas clinique 1

• Quel bilan d’extension recommendez-vous?

1. Scanner TAP seul

2. Scanner TAP et BOM

3. Colonoscopie, gastroscopie

4. Scanner TAP, BOM, gastroscopie

• Quel traitement proposez – vous?

1. Radiotherapie sur la partie résiduelle post-biopsique

2. Chlorambucil

3. R-CVP

4. Antibiotiques

5. surveillance

6. autre

Cas clinique 2

Mme. M., 79 ans, est adressée pour douleur du flanc gauche associée à une

thrombopenie. Elle n’a aucun antécédent. Le PS est à 1. L’examen clinique retrouve

une SMG à 3 cm du rebord costal.

Cas clinique 2

• Quel est votre bilan pour porter le diagnostic de lymphome de la zone

marginale splénique ?

• Quel est votre bilan d’extension ?


– Observation et surveillance

– Rituximab seul

– R-CHOP

– R-FC

– Splenectomie

– Splenectomie suivie par du Rituximab or R-chimio

•

Marginal zone

Secondary follicule

• Mainly present in spleen

• Present in extranodal MALT (Peyer patches, crypt epithelium of tonsils)

• Rare in nodes

• Immune response

• T- dependant or T- independant response :

-> innate and adaptative immune response

Ly B m

Marginal zone Marginal zone B-cells

Memory B-cells

Immune response for a protective response

against highly pathogenic encapsulated

bacteria that do not trigger classical T-

dependent responses

Naive B cells

Weill JC, Weller S, Reynaud CA. Human marginal zone B cells. Annu Rev Immunol. 2009

Marginal zone B-cells

WHO Classification 2008

Marginal Zone B-Cell Lymphomas

Extranodal Marginal Zone Lymphoma of mucosa-associated lymphoid-tissue (MALT Lymphoma)

~ 8% of all NHLs

Splenic Marginal Zone Lymphoma ~ 2% of all NHLs

Nodal Marginal Zone Lymphoma ~ 1% of all NHLs

Small cell

2,4%

T-cell Large L.

3,4%

T cells small cell

5,4%

T small cell L. (angioim.)

0.5%

Lymphoblastic L.

0,5%

Burkitt

0,5%

DLBCL

38,0%

FL

8,8%

MALT

7,3%

MZL

18,5%

SLL

6,3%

MCL

4,9%

Waldenstrom

3,4%

MZL

30%

MZL

17%MCL

6%

DLCL

31%

LL

1%BL

3%

HIV/PTL

2%

Unclassified

2%SLL/LPL

10%CTCL

1%

FL

21%

ALCL

1%

PTCL

6%

MALT 43% MZL

17%

Chez l’ adulte Chez le sujet âgé > 80 ans

2ème lymphome chez le sujet très âgé

Nathwani 1999; Sonoki 2001; Berger F 2000; Thieblemont C. 2007

MZL : A frequent disease

Auto-antigens - Thyroid Hashimoto thyroiditis

- Salivary gland Myoepithelial sialoadenitis +/ - Sjögren S.

- Lung Lymphoid interstitial pneumopathy

MZL: associated with a chronic antigenic stimulation

MALT Lymphomas

Site Infectious agents

- Stomac Helicobacter pylori

- Intestin Campylobacter jéjuni

- Ocular adnexa Chlamydia psittaci

- skin Borrelia burgdorferi

Hepatite C Virus

Microbial pathogens

1.

2.

+

Splenic Nodal

Lung : Achromobacter (Alcaligenes) Xylosoxidans in BALT-Lymphoma?

HELICOBACTER PYLORI in STOMACH

chronic antigen stimulation -> chronic inflammation

chronic antigen stimulation -> chronic inflammation

INFECTION AUTOANTIGEN

Acquisition of MALT

Ag-dependant

MALT lymphoma

Ag-independant

MALT lymphoma

Epithelium of

extranodal sites

MALT CONCEPT

C.Thieblemont et al. Semin Cancer Biol. 2014

Isaacson P, Wright DH. Cancer 1983

lymphoma progression

antibiotic-resistant gastric lymphoma

rare t(1;14)

BCL10 deregulation

common t(11;18) API2/MALT1

fusion

at non-GI sites t(14;18) MALT 1

deregulation

NF-kB

activation

Different chromosomal translocations affecting the same signalling pathway in MALT lymphoma

more recently

described

t(3;14) FOXP1

overexpression

poorer outcome

and higher risk

of histological

transformation

?

Wild-type MALT 1 synergizes with BCL 10 to activate NF-B

<5% ~35% ~15%

A20 (TNFAIP3)

a negative

regulator of BCL10-mediated NF-kB activation

deleted or mutated

in up to 40%

~10% ?

Chromosomal abnormalities in marginal zone lymphoma

+3, +18, + 12, del 6q

- No diagnostic value

- No pronostic value

- Therapeutic implication for t(11;18) / ATB , Alkylating agents

Review in Gascoyne RD, Hematology 2005

MALT lymphoma

Mucosal sites Non mucosal sites

Gastro-Intestinal tract

- Stomach

- Intestin

Respiratory tract

- lung

- pharynx, larynx

Urinary tract

Breast

Thyroid

Salivary Gland

- Skin

- Meninges

- Orbit

Very diverse sites of involvement

Thieblemont C. Hematology Am Soc Hematol Educ Program. 2005

Thieblemont C. et al. J Clin Oncol 1997

Non GIT: 50% GIT : 50%

non GIT

3%

Lung

9%

Breast

3%

Orbit

10%

Head and Neck

11%

Thyroid

4%

Skin

10%

Stomach

34%

Intestin

8%

Stomach + Intestin

4% GIT + non GIT

4%

SKIN

GIT = Gastro - Intestinal tract

THYROID

LUNG

ORBIT

STOMACH

INTESTIN

Very diverse sites of involvement

Endoscopic aspects Gastric MALT lymphoma

Pseudogastritis

30%

Nodular

infiltration

25%

Ulcers

45%

JC Delchier – Henri Mondor Hospital, Créteil

Endoscopic aspect of gastric MALT lymphoma

In the non-gastric sites

Skin Lung Thyroid Orbit

- Conjonctiva

- Lacrymal gland

- Soft tissue

Clinical presentation at initial diagnosis

• Indolent disease

• Good performance status

• Absence of B-symptoms

• Normal LDH and B2-microglobulin

• Localized disease : 70%

• Dissemination : 30%

– multiple mucosal and non mucosal extranodal sites

– Nodal involvement : 25%

– Bone Marrow involvement : 20%

Thieblemont et al , Blood 2000 Zucca et al, Blood 2003 Raderer et al, JCO 2006

de Boer et al. Haematologica 2008 Papaxoinis et al , Ann Oncol 2008

Sretenovic et al, Eur J Haematol. 2009

The dissemination does not confer a worse prognosis

Localized disease

Disseminated disease

Years

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25

p NS 0.0

0.2

0.4

0.6

0.8

1.0

5 10 15 20 25

Years

p NS

Localized disease

Disseminated disease

Overall Survival Progression free survival

C Thieblemont, Blood 2000

N=158 patients

Transformation into DLBCL

• In 3-18% of the MALT lymphomas

• At first recurrence or at further relapses

• Genetic alterations

– p53 allelic loss and mutation

– Hypermethylation of p15 and p16

– p16 deletion

Thieblemont C et al. 1997 – Zucca E et al. 2003 – Thieblemont C et al. 2000

Du M. et al. Blood1995 – Martinez-Delgado et al. Leukemia 1998 – Neumiester P et al. Gastroenteroly 1997

STAGING procedures

for MALT lymphoma

Dreyling M, Thieblemont C. et al. ESMO guidelines Ann Oncol 2013

Lymphoma Specific to the organ

Mandatory • physical exam

• complete blood counts

• basic biochemical studies (renal and liver

function, LDH and β2MG, serum protein

immunofixation)

• HIV, HCV and HBV serology

• CT of the chest, abdomen and pelvis

- GASTRIC : Gastroduodenal endoscopy with multiple

biopsies taken from each region of the stomach,

duodenum, gastro-esophageal junction and from any

abnormal-appearing site;

• H. pylori status must be evaluated in gastric L.

- SMALL INSTESTINE (IPSID – Immuno-Proliferative

Small Intestinal Disease): Campylobacter Jejuni search in

the tumor biopsy by PCR, immunohistochemistry or in situ

hybridization may be performed.

- LARGE INTESTINE : colonoscopy

Recommended • bone marrow aspirate and biopsy • If clinically indicated, head & neck MRI studies and other

imaging are to be realized

Optional • petscan : weak avidity (50%)

high in non-gastric lesions ?

Management of MALT lymphoma recent attempts to overcome the controversies

ESMO Guidelines Consensus Conference at 11-ICML, Lugano, June 2011 (Dreyling, Thieblemont et al. Ann Oncol 2013)

MALT lymphoma Dependant to a pathogen Traitement séquentiel :

IPP double dose + amox 2g/j x 5j

Puis 5j : IPP dble dose

+ métronidazole 500mg x 2/j

+ clarithromycine 500 mg x 2/

2 months

3 months

/ 6 months – 2 years

/ 18 months after

Antibiotics and MALT lymphoma

• No response to antibiotics in H. pylori-negative

gastric MALT Lymphoma

• No response to antibiotics in extragastric MALT

lymphoma in patients infected with H. pylori

• Efficacy of antibiotics in H.pylori-positive gastric

DLBCL

Steinbach G et al. Ann Intern Med 1999

Grünberger B et al. J Clin Oncol 2006

JC Delchier et al. IELSG 2011; Kuo SH et al. Blood 2012

Stage I and II

– Radiation

– R-Alkylant

– Rituximab

Stage III and IV

– R-Alkylant

– Rituximab

MALT lymphoma non-Dependant to a pathogen

– Multiple therapeutic options

– Proved efficacy with non-randomized trials

RT in localized MALT lymphoma

Author n RT dose (Gy) FFP Schechter, 1998 17 28-43 100% at 2 yr Tsang, 2001 9 20-30 100% at 5 yr Yahalom, 2002 51 30 median 89% at 4 yr Hitchcock, 2002 9 34 median 78% (100% local) Goda JS, 2010 25 25-30 79% at 5 yr

Between 20 to 35 Gy

Gastric

Chemo and R-chemo in MALT lymphoma

Authors N cases Treatment CR Follow-up Previous

treatment

Hammel 1995 24 Clb or CPM 75% 5-y EFS = 50% no

Levy* 2005 21 Clb or CPM

42%

89%

t(11;8)+

t(11;8)-

no

Jäger, 2002 25 Cladribine 84% 3-y FFP = 89% no

De Boer, 2012 14 Fludarabine 79% 7-y F-up: 3 relapse no

Aviles* 2005 83 CHOP/CVP 87% - no

Whorer 2005 5 MCP 80% myelodysplasies Yes

Raderer 2003 7 Rituximab 33% 0% relapse Yes / No

Conconi 2003 25 Rituximab 48% - No

Martinelli 2005 26 Rituximab 46% 10% relapse No

Woehrer 2007 7 R-CHOP 71% 0% relapse Yes / No

Salar 2009 10 R-fludarabine 100% t(11;18)+ no

Levy 2010 13 R-Chlorambucil 100% 2adenoK

t(11;8)+

Yes / No

Troch 2012 40 R-cladribine 58% - No

Zucca, 2012 400 Phase III

clb vs R-Clb vs R 78% 5-y EFS 68% No

Chemotherapy in MALT lymphoma

Only one randomised trial (Zucca et al, 2010)

Single alkylating agents: 100% ORR (75%CR) (Hammel 1995)

Cladribine: 100% ORR (84% CR); higher CR rate in gastric than extragastric (important hematologic toxicity grade and increased risk of secondary MDS) (Jaeger 2002 and 2006)

Chlorambucil plus Mitoxantrone and Prednisone as well as Fludarabine in combination with Mitoxantrone and the classic CVP are active and well-tolerated regimens (Wohrer 2003; Zinzani

2004)

Aggressive anthracycline-containing regimens to be reserved for cases with transformation or bulky masses (Thieblemont 2005)

Zucca E, et al. Lugano ICML 2013

IELSG-19 Randomised Study:

R-Chlorambucil vs chlorambucil vs R alone in MALT lymphoma

IELSG-19 Randomised Study:

R-Chlorambucil vs chlorambucil vs R alone in MALT lymphoma

Zucca E, et al. Lugano ICML 2013

Splenic Marginal zone lymphoma

Clinical presentation

Most of the patients

• Asymptomatic

• Abnormal blood cells count

° Lymphocytosis

° Cytopenia (autoimmune or by hypersplenism)

• No B symptoms

• Good performance status (PS <2) : 85%

• Median age : 65

• Clinical examen : SPLENOMEGALY

C. Thieblemont et al. , 2003 – K Viala et al., 2008 – Troussard X et al., 1996 – J Chacon et al. 2002 – N Parry-Jones et al., 2003

Clinical presentation

In case of advanced disease :

• Asthenia : PS > 2

• Cachexia

• Pain of left hypochondrium : large splenomegaly

• Abnormal blood cell count

° Lymphocytosis

° Cytopenia +++ (autoimmune or by hypersplenism)


Diagnosis

Mandatory • Full blood count and Blood cytology • Blood Flow cytometry : CD5−, CD10−, CD19+, CD23− CD27+, CD43−, FMC7±, kappa / lambda

Optional • Caryotype / FISH CCND1 • IgVH Mutated 2/3 - Biased usage VH1.2, VH1–2, VH3–23, VH4–34

• In the future : BRAF mutation 0% - MYD88 : 0% - NOTCH2 : 30%

The diagnosis of SMZL at present does not strictly require a splenectomy

Dreyling M, Thieblemont, C. ESMO guidelines 2013

Matutes E et al. Leukemia 2007. Bikos V et al. Leukemia 2012 Kalpadakis etal Anticancer Res2009

Associated with Immune disorders

M component (IgM) 46%

Marked hyperviscosity and hyperglobulinemia = uncommon

Immune disorders 20% - Hemolytic anemia 10%

- Positive Coombs test 16%

- Thrombocytopenia 5%

- Coagulation (VW, Cardio lupic) 3%

- cold agglutinin

- Angioedema: acquired deficit in C1-esterase inhibitor

- Neuropathy (radiculopathy, axonal, demyelinating)


STAGING procedures

for SMZL

Dreyling M, Thieblemont C. et al. ESMO guidelines Ann Oncol 2013

Mandatory

• physical exam

• complete blood counts

• Cytology

• Immunophenotype

• basic biochemical studies (renal and

liver function, LDH and β2MG, serum

protein immunofixation)

• HIV, HCV and HBV serology

• CT of the chest, abdomen and pelvis

at initial diagnosis

Optional

• cytogenetic

• Petscan : + 50% Median SUV 2,2

Tsukamoto et al. , 2007 Cancer 110:652-9

• Splenectomy

• Chemotherapy

• Rituximab alone

• Combined R-Chemotherapy

Therapeutic options

• Improvement in PS

• Correction of cytopenia

Benefit of the splenectomy

Thieblemont et al, Lancet Oncol 2003

• Decrease of bone marrow infiltration Associated with a decrease of lymphocytosis

• Median time to next treatment > 8 years

Authors n Status of disease

Response Rate (PR)

PFS

(At n years)

OS

(At n years)

Mulligan et al.

1983

20 - 95% 79% (4y) 74% (4y)

Troussard et al.

1996

28 - 75% 71% (5y)

Thieblemont et al.

2002

48 1rst line 100% 48% (5y) 77% (5y)

Ianitto et al.

2004

21 - 91% Median 4 years 70% (5y)

Tsimberidou et al. 2006

10 - - 80% (3) 89% (3)

Kalpadakis et al.

2012

27 1rst line

80% 58% (1.3)

7% (1.3)

Lenglet et al.

2013

100 1rst line 100% 61% (5)

46% (10)

84% (5)

67% (10)

Splenectomy

Survie globale Survie sans progression

5 a : 61% 10 a : 46% 5a : 84% 10a : 67%

100 SMZL patients treated with splenectomy

10 (48%) NON LIES AU

LYMPHOME

1 pneumocystose

3 PNP non documentées

2 autres cancers

1 LAM

1 AVC

1 AVP

1 insuffisance cardiaque

1 cause indeterminée

11 (52%) DECES LIES

AU LYMPHOME

21 DECES

n =100

Lenglet J., et al. Leuk & lymphoma 2013

Chemotherapy

• After splenectomy: benefit not established

– If high LDH level and/or presence of B symptoms?

– No impact on the risk of relapse, survival

• Agents

– Alkylating agents (clb, cyclophosphamide)

– Purine analogs (fludarabine; bendamustin)

– Rituximab

• Multidrug combination if

– Transformation in high grade lymphoma

Thieblemont et al, Blood 2005

Before Rituximab era Fludarabine

Retrospective series

Authors n Status of disease Response Rate

CR PFS

Bolam, et al.

1997

4 Relapsed

(after clb)

100% 100% Outcome

2 died at 22 and 25 mo

2 Alive at 6 and 10 mo

Yasukawa et al.

2002

1 Relapsed

(after CDDP)

100% 100% Alive at 15 mo

Lefrere et al.

2004

10 2 first line

8 second line

100% 70% 42% at 4.7 y

Bolam et al, Br J haematol 1997

Yasukawa et al, Eur J haematol 2002

Lefrere et al, Leukemia 2004

Authors Schedule n Status of disease

Response Rate

CR

/CRu

PR PFS

(At n years)

OS

(At n years)

Rituximab alone

Tsimberidou et al.

2004

R once/W x 4 or 8

26 1rst line 88% 43% 46% 86% (3y) 95% (3y)

Kalpadakis et al.

2007

R once/W x 6 16 1rst line 100% 79% 11% 92% (2.1y) 100% (3y)

Bennett et al.

2005

R once/W x 4 14 1rst line 78% 57% 21% 60% (6y) 80% (6y)

Kalpadakis et al.

2013

R once/W x 6 85 1rst line 95% 71% 24% 92% (5y) 73% (5y)

Rituximab and Chemotherapy

Tsimberidou et al. 2004

R-FMD or RFC 6 1rst line 83% 34% 50% 100% (3) 100% (3)

Arcaini et al.

2004

R-CVP 3 1rst line 100% - - 100% (1.3)

100% (1.3)

Cervetti et al.

2004

2-Cda 50 1rst line or relapsed

63% 62% - 83% (2) NA

Rituximab and R-Chemo

Splenic MZL : associated with Hepatitis C virus

Treatment IFN ou IFN + ribavarin

Disappearance of lymphocytosis and

splenomegaly

E2 E1

B-cell of Marginal Zone

CD81

+ MALT lymphoma

+ Nodal MZL

O. Hermine et al. NEJM 2002

Nodal Marginal Zone Lymphoma

Definition • Primary nodal B-cell lymphoma that shares morphologic,

immunophenotypic, and genetic characteristics with extranodal MZL and splenic MZL, but without those specific localizations at presentation

• 1986 : « nodal monocytoid B-cell lymphoma » • 1987 : « parafollicular B-cell lymphoma » • 1988 : relationship established with marginal zone • 1990 : included in the revised kiel classification • 2001 : REAL classification • 2008 : WHO classification

Sheibani et al. Am J Pathol 1986 - Cousar et al. Am J Clin Pathol - 1987 Piris M et al. Histopathology. 1988

Lennert K, Feller AC. Berlin: Springer Verlag; 1990 – Jaffe E. et al. REAL classification 1990 -Swerdlow et al WHO classification

Very rare lymphoma : 1.5% to 15% of the NHL series

Morphology

• Heterogeneous – Infiltration : marginal zone / perifollicular, or interfollicular, perisinusoidal,

follicular via colonization of reactives follicules or diffuse

– Cell : several types of cells : small cells, small cells with a plasmocytoid differentiation, plasma cells, variable content of medium to large cells, monocytoid B-cell

• Proportion of large cell is usually high and mitotic index is high – Is NZML a low grade lymphoma?

– No correlation between number of large cell and outcome

Traverse-Glehen et al. Oncology 2012

Immunophenotype

• sIgM+/-D/G+ , cIg+/-

• CD19+, CD20+, CD79a+

• Pax5+, CD5-, CD10-, CD23-, BCL2+, CyclinD1-

• Sometimes CD5+ , CD23+ , CD43 +

• Plasmacytic differentiation : CD38+, CD138+, MUM1 +

Traverse-Glehen et al. Oncology 2012 – Dreyling M, Thieblemont C. ESMO guidelines Ann Oncol 2013

Cytogenetic / Molecular features

• No characteristic cytogenetic profil for NMZL

• Recurrent clonal abnormalities : +3, +19, -7, +12, del 6q

• No translocation characteristic of MALT L.

• CGH : del6q23, del13q14, +3q13-q28, +6p, and + 18q

inactivation of A20

NK-KB

• Biaised usage : VH4-34

• Gene Sequencing : Mutation of MYD88 : 0% (/LPL)

Dierlamm J, et al. Blood.1996 - Slovak ML, et al Hum Pathol. 1993 - Callet-Bauchu E, et al. Leukemia. 2005

Rinaldi A, et al. Blood. 2011 - Novak U, et al. Br J Haematol. 2011 - Novak U, et al Blood. 2009- Gachard N, et al 2013

Clinical features

• Median age : 50-62 years

• Disseminated nodal involvement (peripheral and visceral)

• Bone marrow 28% - 44%

• M-component unfrequent < 10%

• Rare cytopenia

Nathwani et al Semin Diag 1999 – Armitage J Clin Oncol, 1998 – Berger et al. Blood 2000 –

Camacho et al. Am J Surg Pathol 2003 – Arcaini Cancer 2004 - Traverse-Glehen et al.

Histopathology 2006 – Petit et al. Haematoligica 2005 – Oh et al. Ann Hematol 2006 – Kojima

Cancer Sci 2007 – Gachard N et al. Leukemia 2013

Clinical features

Nathwani Armitage Berger Camacho Arcaini Traverse-Glehen

Petit Oh Arcaini Kojima Gachard

1999 1998 2000 2003 2004 2006 2005 2006 2007 2007 2013

N pts 20 25 37 22 9 21 12 36 47 65 11

Male (%) 44 64 43 32 44 64 33 72 36 20 -

Age Med 59 58 54 62 62 54 68 50 63 64 -

ECOG>2 0 7 12.5 - 22 14 - 17 6 6 -

Stage III/IV 71 82 68 41 99 76 75 44 77 78

pnodal % 100 - 95 95 100 98 - - 98 - 100

BM % 28 32 43 29 44 62 44 19 45 0 27

Spleen % - - 0 - 0 0 0 - 0 - 4

LDH>Nl% 36 40 40 43 22 48 - 19.4 15 12 -

Mcomp+ - - 8 - 11 33 10 - 15 5 0

HCV+ % - - - 20 22 0 - 2.8 21 - -

PFS Medy - - - - 2.8 1.3 - 1.3 2.6 - -

5-y OS % 56 57 55 79 - 64 - 82 69 85 -

A more aggressive disease but a good outcome

Thieblemont, C. 2005

Time to progression Overall survival

CHLS data

Treatment

No standardized treatment

Similarly treated as FL

• Rare localized cases: Radiation Therapy

• Stage II to IV

- R – Anthracyclin based-regimen (CHOP, CHOP like)

- R - Bendamustine

• Relapsed setting, high risk, in eligible patients

- Intensive chemotherapy plus ASCT

Dreyling M, Thieblemont, C. ESMO guidelines 2013 – Rummel Lancet 2013

New drugs in MZL

• Bendamustine

• Imids

• Targeted therapies

• Role of Maintenance Therapy

R-bendamustine

After 3 cycles ! CRR : 75% - stop at 4cycles

After 6 cycles : ORR 100% - CR 95%

SMZL

Troch M et al. Haematologica 2009; Conconi AR et al. Ann Oncol 2011

Rationale : To target NFKB activation

Gastric and non-gastric cases

Relapsed MALT lymphoma

Bortezomib

Authors n dose Response Survival Toxicity

Troch

2009

16 1.5 mg/m2 i.v.,

on days 1, 4, 8, and 11

, for up to six 21-day cycles

ORR : 80%

CR : 43%

4 relapses

(median F-

up=23 mo)

Neuropathy : 44%

Diarrhea : 50%

Conconi

2011

32 1.3 mg/m2 i.v.,

on days 1, 4, 8, and 11

, for up to six 21-day cycles

ORR : 48%

CR : 28%

2-y PFS = 50% Neuropathy : 65%

High rate of

toxicity

Lenalidomide

www.clinicaltrial.gov

Targeted therapies

Scientifique Background • BCR and TLR signaling pathways are recurrently

targeted by genetic changes in MZL

BCL10

TARGET

GENES

NF-kB

IKBKB

Non-canonical

NF-κB pathway

Canonical

NF-κB

pathway

TNFAIP3

BCR

PKCβ

TLR

MY

D88

TRAF6

IRAK1/4

X

CD40

BAFFR

RANK

LTBR

TRAF2 TRAF3

BIRC3 MALT1

TRADD

RIPK1 TRAF2

CARD11

TAB2

TAK1 NEMO

p50

RelA

p50

RelA IkBα

P

TNFR

MAP3K14

IKK

p100

RelB

p52

RelB

Mutations MALT L. SMZL NMZL

CARD11 - 7- 8.8%

CD79A - 2%

BCL10 4-9% -

MALT1 20-40% -

Rossi et al. J Exp Med 2012

Yan et al. Haematologica. 2012

Du M. Histopathology 2011 (for review)

BTK inhibitor

rr MZL (MALT L., Splenic, nodal)

Phase II international trial

Prognostic factors in MZL

MALT lymphoma SMZL NMZL

0

t(11;18)

response to ATB

and alkylating

agents

Scores… 0

Hemoglobin < 9.5 g/dl

platelet count < 80x103/µl.

LDH level high

Extrahilar lymphadenopathy

Montalban et al. 2013

Biological markers / targeted therapies

0.00

0.25

0.50

0.75

1.00

41 22 13 6 3 2 1 0 0HPLLs/C

311 219 140 86 48 28 13 10 5HPLLs/B

198 147 98 47 25 11 6 2 1HPLLs/A

Number at risk

0 24 48 72 96 120 144 168 192Months

HPLLs/A HPLLs/B

HPLLs/C

MCL CCND1 +

SLL/CLL

Borderline

cases

CCDN1 -

Lplasmocytic L./

Waldenström

Hairy cell leukemia

(/ variant)

• Splenic

• MALT

• Nodal

- Villous L.

- / HCV

Splenic Red

pulp L with VL

Lymphoproliferative diseases = derived from a cell of the Marginal Zone

New discriminant markers !

MZL

Differential diagnosis

Immunophenotype Cytogenetic Next generation sequencing (NGS)

MZL

CD20+ CD19+ CD79a+

CD5- CD23- CD10-CD43v

BCL2+

Matutes Score < 3

Splenic MZL

NOTCH2

30%

LPL/Waldenström CD22+f CD25+ CD103- del6q

+4 +3 +18

MYD88 L265P

90%

Hairy cell leukemia CD103 CD11c CD25 (HC-2/) CD123 (=IL-3R)

Score RMN 3 ou 4 / 4

5q13 +5 del(5)

del(7)(q32) del(17)(q25)

t(11;20) t(2;8)

BRAF V600E 100% Absent in HCL-V and HCL

IGHV4-34

LLC/ SLL

CD20+

CD5+ CD23+ CD43+

CD10- FMC7- CD79b-

Matutes Score 4 ou 5 / 5

13q(del) 60%

+12 15-20%

11q (del) 30%

17pdel 2-30%

-

Swerdlow SH. et al. IARC 2008; Kiel et al. 2012; Rossi D et al. 2012; Tiacci E et al. 2011; Treon SP. et al.

7q (del) 45% +3/+3q

MALT L. : t(11;18), t(14;18),

t(1;14), t(3;14)

Take home messages

• Heterogeneous disease

• Physiopathology : Microbial pathogens

• No standard treatment

• CLINICAL TRIAL !!

• New drugs

Mo AB, Bendamustine, ibrutinib, lenalidomide

Cas clinique 1

• Mme. M., 87 ans, présente un oedème de la paupière gauche

• PS = 0

• Aucun antécédent, en particulier oculaire

• IRM : infiltration des tissus mous à gauche. Oeil droit est normal.

- Infiltrat diffus de cellules centrocytes monomorphes de

petite taille sans différentation plasmocytaire

-Immuno : CD5 neg CCND1 neg CD10 neg and bcl6 neg

= Lymphome de MALT

Cas clinique 1

• Quel votre bilan d’extension recommendez-vous?

1. Scanner TAP seul





1. Radiotherapie sur la partie résiduelle post-biopsique

2. Chlorambucil

3. R-CVP

4. Antibiotiques

5. surveillance

6. autre

Cas clinique 1

• Quel votre bilan d’extension recommendez-vous?

1. Scanner TAP seul




5. Sérologie chlamydhia? Recherche chlamydhia sur la tumeur?

6. Serologie HCV


1. Radiothérapie sur la partie résiduelle

2. Chlorambucil, associé au R

3. R-CVP : non

4. Antibiotiques : Essai clinique !

5. surveillance : non

6. autre

Cas clinique 2

Mme. M., 79 ans, est adressée pour douleur du flanc gauche associée à une

thrombopenie. Elle n’a aucun antécédent. Le PS est à 1. L’examen clinique retrouve

une SMG à 3 cm du rebord costal.

Cas clinique 2

• Mme. M., 81 ans, est adressée pour douleur du flanc gauche associé à une

thrombopenie. Elle n’a aucun antécédent. Le PS est à 1. L’examen clinique

retrouve une SMG à 3 cm du rebord costal.

SMZL

Cas clinique 2

• Quel est votre bilan pour porter le diagnostic de lymphome de la zone

marginale splénique ?

• Quel est votre bilan d’extension ?


– Observation et surveillance

– Rituximab seul

– R-CHOP

– R-FC

– Splenectomie

– Splenectomie suivie par du Rituximab or R-chimio

•

Cas clinique 2

• Sept 2008 . 81 ans. La patiente refuse la splénectomie

Elle reçoit 8 cycles de Rituximab

– R once / Week x 4 (start : Feb 2009)

– R once / month x 4 (end : August 2009)

• Evaluation clinique: reponse partielle

– Examen : SMG at 1 cm / rebord costal

– Biologie : Normale

– Echographie : SMG=13 cm

• Juin 2010 : 83 ans. Reprogression

Splénectomie le 17/06/2010

Sept 2013

Lymphomes de la zone marginale (MALT et non MALT) DES/DES … · Lymphomes de la zone marginale...

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Transcript of Lymphomes de la zone marginale (MALT et non MALT) DES/DES … · Lymphomes de la zone marginale...