S. LuminariModena
LNHmarginale
extranodale
Linfoma marginale extranodale
● Definizione● Epidemiologia● Peculiarità biologiche● Caratteristiche cliniche/stadiazione● Terapia● Conclusioni
Linfomi marginali extranodali
● I linfomi marginali rappresentano l’8-10% dei LNH ecomprendono:– SMZL ca. 20%– NMZL ca. 10-15%– EnMZL ca. 65%
● Età medio-avanzata● Maggiore frequenza nelle donne● Andamento clinico indolente delle forme extranodali
– Ridotta tendenza alla disseminazione– Ridotta tendenza alla trasformazione
Extranodal NHL, survival by histologyand site in the IELSG series
(NON-SPLENIC) B-CELL MARGINAL ZONE LYMPHOMASModena Cancer Registry, years 1997-2006
(NON-SPLENIC) B-CELL MARGINAL ZONE LYMPHOMASModena Cancer Registry, years 1997-2006
Males FemalesNumber of cases 79 74
Percentage of all neoplasms 0,4 0,4
Crude rate (per 100,000) 2,5 2,2
Age-standardized rate* (per 100,000) 1,9 1,4
Age-standardized rate** (per 100,000) 1,4 1
Cumulative risk (0-74yrs) 0.15% 0.12%
Median age 66 69
Mean age 62,1 67,3
*according to the European standard population**according to the World standard population
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5years after diagnosis
RSR
(%)
Males Females M+F
LNH marginali ENTassi età specifici e trend temporale
Modena Cancer Registry, years 1997-2006
0
0,5
1
1,5
2
2,5
3
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
Age
Eu
ro
pe
A
ge
-sta
nd
ard
ize
d ra
te (p
er
100,0
00)
Males
Females
0
2
4
6
8
10
12
14
0-45-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-8485+
Age
ra
te (
pe
r 1
00
,00
0)
Males
Females
The MALT concept
● MALT acquisitosedi prive di tessuto linfoide “nativo” (e.g., Sjögren,Hashimoto, gastrite da H. pylori)
● MALT nativopresenza “fisiologica” di tessuto linfoide insedi EN (e.g., Peyer’s patches)
● MALT Lymphomadescritto per la prima volta nello stomaco da Isaacson eWright nel 1983; può originare nelle sedi di MALT acquisito
Elementi a favore di un meccanismoimmunomediato nella linfomagenesi dei
MALTomi
● Caratteristiche istologiche (componenteplasmocellulare, lesioni linfoepiteliali,….)
● Pattern mutazionale dei geni delle Ig● Associazione con stati infettivi cronici e/o
processi autoimmuni (H.pylori gastritis,Hashimoto, Sjogren…)
● Efficacia terapeutica degli antibiotici.
VH - N-DH(-DH)-N - JH
FR1 CDR I FR2 CDR II FR3 CDR III FR4
Molecular evidence of an antigen-drivengrowth in MALT lymphoma
● Somatic hypermutation and intraclonal variation of theimmunoglobulin heavy chain gene suggest positive antigenselection and derivation from post-germinal center B-cells
Bertoni et al, 1997
● The tumor Ig does not usually recognize H pylory but severalautoantigens
Zucca et al, 1998
Primary extranodal sites(excluding bone marrow and spleen)
Luminari et al, 2007
Primary non-GI MALT lymphoma locations
Thielblemont et al, 2000Zucca et al, 2003
Presentazione clinica● Stadio localizzato nel 60-70% dei casi● Coinvolgimento di più organi nel 10-15% dei casi● Interessamento linfonodale nel 10-20%● Coinvolgimento midollare:
– IHC 10%– CFM 30%– Biol mol 30%
● Pattern di disseminazione:– Interessamento bilaterale (Orbite, gh salivari, polmone, mammella)– Accoppiamento d’organo (diagnosi e f-up):
• Waldeyer + siti multipli• Polmone + GI• Gh salivari + GI
Necessità di stadiazioneestensiva…possibile ruolo della PET?
Trattamento
● Trattamento della malattia mediata da infezione● Trattamento della malattia localizzata● Trattamento della malattia sistemica/refrattaria
Reference n staging CR rate time to CR relapses procedure (%) (mos.) (n)
Savio, 1996 12
CT 84 2-4 0Pinotti, 1997 45 CT 67 3-18 2
Neubauer, 1997 50 CT±EUS 80 1-9 5
Nobre Leitao, 1998 17 CT+EUS 100 1-12 1
Steinbach, 1999 23 CT±EUS 56 3-45 0
Montalban, 2001 19 CT±EUS 95 2-19 0
Ruskone-Formestraux, 2001 24 CT+EUS 79 2-18 2
LY03 interim analysis, 2000 190 CT 62 3-24 15
Response to antibiotics and PPIin stage I gastric MALT lymphoma
Bacterial infections andnon-gastric MALT lymphomas
● Analogous to H. pylori the in the stomach:
– Borrelia burgdorferi infection, may represent thebackground for the development of cutaneous MZL
Roggero et al, 2000
– Campylobacter jejuni may be associated with IPSID Lecuit et al, 2004
– Chlamydophila psittaci may contribute to thepathogenesis of ocular adnexa lymphomas
Ferreri et al, 2004
Prospective trial of doxycycline in OAL
● 27 OAL patients treated with a 3-week course ofdoxycycline:–15 newly diagnosed and 12 pretreated–11 C. psittaci -positive and 16 negative
● Doxycycline was well tolerated and at a median follow-upof 14 months:– 6 CR and 7 PR (ORR = 48%)–Lymphoma regression observed in both Cp+ (7 of 11)
and Cp- patients (6 of 16)
Ferreri et al, 2006
Bacteria-eradicating therapy inOAL vs. gastric MALT lymphoma
Stomach1 Ocular adnexa2
Tumor regression Slow & gradual Slow & gradualORR ~75% ~50%Time to response up to >24 mos up to 36 mosMolecular predictors of CR t(11;18)… ???Lymph node involvement poor response OR 3/3Reinfection rare ???Infection assessment easy
& standardized ???
1Ferrucci & Zucca, 20072Ferreri et al, 2006
● Terapia eradicante>90% eradicazione di H.Pylori≈ 50-100% RC istologiche>10% recidive ?
(Quale definizione della recidiva?)
● Come trattare la malattia persistente dopoterapia eradicante?
Gastric MALT lymphoma:Terapia di prima linea
Most patients with minimal histologicalresiduals of gastric MALT lymphoma after
eradication of H. pylori remain stable and can bemanaged safely by a watch and wait strategy
– median follow up 42 months– favourable outcome in 94%– minimal residual disease in
62%– 4 local PD in 4 patients,
1 histological tranformation
– median follow-up 76 months– 25 had histological score
fluctuations and 13 had stableresidual MALT lymphoma
– 1distant PD, 2 trasformations– 5-year OS is 92%. Only one
patient died for lymhpomaafter histologic trasformationFischbach et al, 2007
Pinotti et al, 2008
Abs # 361
Radioterapia nei MALT extranodali
● Opzione generalmente riconosciuta per il trattamento diprima linea della malattia localizzata
● Analisi retrospettiva su 69pts canadesi (Tsang et al2001)– Ampia rappresentatività d’organo– Dose mediana 30Gy (range 17,5 – 35Gy)– 66/69 RC– Nessuna recidiva dei MALTomi della tiroide e dello stomaco
(5aa DFS 97% vs 67%: p=0.006)– Controllo locale ottenuto nel 97%. Osservate recidive
controlaterali o a distanza.
Terapia sistemica
● Chi trattare?● Quando trattare?
–Correlazione non certa tra estensione di malattia eprognosi
–Ruolo della malattia persistente● Come trattare?
–Varietà di opzioni terapeutiche–Approccio empirico/aneddotico.
PZ ad alto rischio con MALToma?
● Ridotta prevalenza dei fattori prognostici noti:–LDH > VN 5-10%–PS non ambulatoriale 1-5%–Sintomi sistemici 5-10%–Beta 2 microglobulina > VN 15-30%
● Outcome eccellente● Ruolo dell’estensione di malattia
0 5 10 15 years0.00
0.25
0.50
0.75
1.00
Overall Survival
Stage IV, including bone marrow and nodal disease (N=40)
Log rank test, P=0.0001
Pro
babi
lity
IELSG Study of non-gastric MALT lymphomaStage I-II (N=131)
Stage IV, multiple mucosal sites only (N=9)
Zucca et al, 2003
● Criteri di indolenza– Nessuno dei seguenti
• Sintomi sistemici• Bulky• Interessamento BM
diffuso• Tempo di raddoppiamento
<12m• Anemia e/o piastirnopenia
Characteristics Patients’ number SL/LP SMZ/NMZ and
extranodal non
gastric MALT
P-value
Age > 60 years 139 55% 78% 0.007
Stgage III/IV 139 98% 90% 0.064
Nodal are as
involved (> 4)
139 8% 3% 0.262
Spleen
involvement
139 18% 46% 0.001
Extranodal sites
involved (>1)
139 25% 49% 0.005
Bone marrow
involve ment
139 87% 85% 0.812
FLIPI (3 -5) 129 17% 28% 0.144
Hb (<12 g/dL) 139 18% 22% 0.673
LDH (> 1) 129 9% 11% 0.788
Patients who
achieved CR
37 50% 73% 0.285
Characteristics Patients’ number SL/LP SMZ/NMZ and
extranodal non
gastric MALT
P-value
Age > 60 years 139 55% 78% 0.007
Stgage III/IV 139 98% 90% 0.064
Nodal are as
involved (> 4)
139 8% 3% 0.262
Spleen
involvement
139 18% 46% 0.001
Extranodal sites
involved (>1)
139 25% 49% 0.005
Bone marrow
involve ment
139 87% 85% 0.812
FLIPI (3 -5) 129 17% 28% 0.144
Hb (<12 g/dL) 139 18% 22% 0.673
LDH (> 1) 129 9% 11% 0.788
Patients who
achieved CR
37 50% 73% 0.285
CRITERIA FOR DEFINING DISEASE-PROGRESSION IN INDOLENT NON FOLLICULAR LYMPHOMA.THE GRUPPO ITALIANO STUDIO LINFOMI (GISL) PROPOSAL.
S. Molica, S. Luminari, L. Baldini, C. Stelitano, M. Goldaniga, F. Merli, A. Pastorini, D. Vallisa, A. M. Sirotti, V. Franco, S. Pileri, F. Morabito, M. Federico and V. Callea on Behalf of Gruppo Italiano Studio Linfomi (GISL).
10 ICML 2008
0.0
00.2
50.5
00.7
51.0
0
Proportion T
FT
T
0 12 24 36 48 60 72 84 96 108 120
Time, months
Marginal Zone SLL/LP-IC
TTFT studio LLIND per istotipo
10 ICML 2008
CRITERIA FOR DEFINING DISEASE-PROGRESSION IN INDOLENT NON FOLLICULAR LYMPHOMA.THE GRUPPO ITALIANO STUDIO LINFOMI (GISL) PROPOSAL.
S. Molica, S. Luminari, L. Baldini, C. Stelitano, M. Goldaniga, F. Merli, A. Pastorini, D. Vallisa, A. M. Sirotti, V. Franco, S. Pileri, F. Morabito, M. Federico and V. Callea on Behalf of Gruppo Italiano Studio Linfomi (GISL).
Chemioterapia nei maltomi
● Chlorambucil based:– CRR 75%, 5Yr EFS e OS; 50% 75%(Hammel et al JCO 1995)
● Nessun vantaggio con le antracicline(Baldini et al. JCO 2003)
● Ruolo del Rituximab● Ruolo di nuovi farmaci
34 pts, 11 with previuos CT, 15 gastric, 20 stage IV
response n %
ORR 25 73 SD 6 18 PD 3 9
Rituximab activity in MALT lymphoma
26 pts with gastric MALTomas resistant/refractory to antibiotics orwith no clinical evidence of H. pylori infection.
CR 46% (95% C.I. 27%-66%)ORR 77% (95% C.I. 56%-91%)The t(11; 18)(q21; q21) was not a predictive marker of response
No priorchemotherapy
Priorchemotherapy
ORR 87% 45%
CR 48% 36%
Martinelli et al, 2005
IELSG phase II studyConconi et al, 2003
Chlorambucil weeks 1-6 // 9-10 // 13-14 // 17-18 // 21-22(6 mg/m2 /d)
Chlorambucil weeks 1-6 // 9-10 // 13-14 // 17-18 // 21-22(6 mg/m2 /d)
1 8 15 22 42 56 70 84 98 112 126 140 154
Rituximab ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑(375 mg/ m2 )
Control arm
Study arms
day
1 8 15 22 42 56 70 84 98 112 126 140 154
Rituximab ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑(375 mg/ m2 )
day
INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP
IELSG-19 ongoing randomized trial
Antibiotic-resistantgastric lymphoma
raret(1;14)BCL10
deregulation
commont(11;18)
CagA+ strainsAPI2/MALT1
fusion
at non-GI sites t(14;18)
MALT 1deregulation
NF-kB activation
Different chromosomal translocationsaffecting the same signalling pathway in MALT lymphoma
more recentlydescribed
t(3;14)
FOXP1overexpression
poorer outcomeand higher riskof histologicaltransformation
?
othergenetic
alterations
?
<5%
INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP
IELSG-25 ongoing phase II trial of bortezomibin relapsed/refractory MALT lymphoma
Follow-up, 17 m
CR 27%, PR 37% SD 27% and PD 9%
Tossicità simile a quanto osservato per ilMieloma Multiplo e per altri LNH (neuropatiaperiferica e affaticamento).
Conconi et al, 2008
Abs # 368
Phase II Study of oxaliplatin for treatment ofpatients with MALT lymphoma
N=16 pts, non pretrattati
L-OHP 130mg/m2 q21 x6
ORR 15/16, CRR 9/16(56%)
F-up mediano 19 mesi– 1 recidiva a +12 m
– 2 progressioni a +4m e +6m
Raderer et al, 2005
Linfomi marginali extranodaliConclusioni
Presentazione clinica eterogenea
Andamento indolente
Atteggiamento terapeutico meno invasivopossibile (esordio e f-up)
Adesione a trial clinici
“treatment must be as simple as possible but not simpler”