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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 ?
• Quel traitement proposez – vous?
– 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
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)
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
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)
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
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
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 1
• Quel votre bilan d’extension recommendez-vous?
1. Scanner TAP seul
2. Scanner TAP et BOM
3. Colonoscopie, gastroscopie
4. Scanner TAP, BOM, gastroscopie
5. Sérologie chlamydhia? Recherche chlamydhia sur la tumeur?
6. Serologie HCV
• Quel traitement proposez – vous?
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 ?
• Quel traitement proposez – vous?
– Observation et surveillance
– Rituximab seul
– R-CHOP
– R-FC
– Splenectomie
– Splenectomie suivie par du Rituximab or R-chimio
•
Cas clinique 2
• Quel est votre bilan pour porter le diagnostic de lymphome de la zone
marginale splénique ?
• Quel est votre bilan d’extension ?
• Quel traitement proposez – vous?
– 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
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