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

ielsg@ticino.com

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”