AnastasiosStathis,M.D.PhaseIandLymphomaUnit

OncologyIns6tuteofSouthernSwitzerlandBellinzona,Switzerland

Treatment:GastricMALTlymphoma

GastricMALTlymphoma

• MALTlymphomas:approximately7%ofallNHLs•  Atleast1/3presentasaprimarygastriclymphoma

•  2/3ofcasesassociatedwithH.pyloriinfec6on

ESMOClinicalPrac>ceGuidelines,2013

Openques>onsinthemanagementofgastricMALTlymphoma

•  stagingprocedures•  H.pylorieradica6ontoallpa6ents?•  secondlinetreatments

Openques>onsinthemanagementofgastricMALTlymphoma

•  stagingprocedures•  H.pylorieradica6ontoallpa6ents?•  secondlinetreatments

MandatorystagingproceduresinMALTlymphomaatanysite

•  Historyandphysicalexam(includinglymphnoderegions,eyeandENTareas,liverandspleen)

•  Completebloodcountsandbasicbiochemicalstudies(includingrenalandliverfunc6on,LDHandβ2MG,serumIFE,HIV,HCVandHBVserology)

•  CTofthechest,abdomenandpelvis.•  bonemarrowaspirateandbiopsyrecommended•  ThevalueofPETiscontroversialandhasuncertainclinicalu6lity

ESMOConsensusConference,AnnOncol2013

RecommendedproceduresingastricMALTlymphoma

•  EGDwithmul6plebiopsies•  histochemicalexamina6onforH.pyloriandserologystudiesifhistologyisnega6ve

•  endoscopicultrasoundtoevaluatetheregionallymphnodesandgastricwallinfiltra6on

•  op6onal:FISHforthet(11;18)transloca6on

EGILSConsensusReport,2011ESMOClinicalPrac>ceGuidelines,2013

§  The value of PET is controversial and has uncertain clinical utility

§  multifocal disease in ≥25% of cases

§  variable FDG-avidity (higher in non-gastric lesions!)

§  pooled PET/CT detection rate, 71% (95% CI: 61-80%) in a literature meta-analysis

Staging of MALT Lymphoma

Treglia et al. Hematol Oncol. 2015

Lower FDG-avidity in gastric & OA lesions

Treglia et al. Hematol Oncol. 2015 Sep;33(3):113-24

Openques>onsinthemanagementofgastricMALTlymphoma

•  stagingprocedures• H.pylorieradica>ontoallpa>ents?•  secondlinetreatments

MostgastricMALTlymphomasregressaLerH.pylorieradica>on

Bertoni & Zucca, Lymphomas: Essentials for Clinicians 2015: 55-60

Theproblemoftheresponsedefini>on

Score Descrip>on HistologicFeatures

CR CompleteRemission NormaloremptyLPand/orfibrosis withabsentorsca]eredplasmacellsand lymphoidcellsintheLP;noLEL

pMRD ProbableMinimal EmptyLPand/orfibrosiswithaggregatesofResidualDisease lymphoidcellsorlymphoidnodulesinthe LP/MMand/orSM;noLEL

rRD Responding FocalemptyLPand/orfibrosis;dense,diffuseResidualDisease ornodularlymphoidinfiltrate,extending aroundglandsintheLP.FocalLELorabsent

NC NoChange Dense,diffuseornodularlymphoidinfiltrate withLEL(LEL‘‘maybeabsent’’)

GELAscoreforlymphomaresponseevalua>onaLerHpylorieradica>on

Copie-Bergmanetal,Gut2003;Copie-Bergmanetal,BrJHaematol2012

LP=laminapropria;LEL=lymphoepitheliallesions;MM=muscularismucosa;SM=submucosa

Endoscopicandhistologicalremissiondoesnotmean“cure”

•  54pa6entswithmonoclonalityatdiagnosis•  42(77%)histologicremission

–  56%molecularremission(byPCR)–  44%sustainedmolecularremission(medianf-up,2years)–  6(14%)histologicrelapses(4/6inthepresenceofmoleculardisease)

•  clinicalandprognos6crelevanceofmolecularremissions6lltobeascertained

Bertonietal.Blood2002

Long-termoutcomeaLerH.pylorieradica>on(IOSIandVareseseries)

A.Stathisetal.AnnOncol,2009

• N=105,stageIE•  f-up,76mos

•  Remissionrate,76%

•  Long-termclinicalcontrolinmostcases:

• 43%ofrespondershadhistologicalscorefluctua6ons

• 57%hadstableMRD

• 5-yearOSis92%.

Long-termsurveysaLerH.pylorieradica>on

Wundischetal.JCO,2005Fischbachetal.Gut,2007

Stathisetal.AnnOncol,2009Nakamuraetal.Gut2012

•  notonlypa6entswithmolecularresidualdiseasemayremainstablebutalsothosewithminimalhistologicalMALTlymphomaresiduals

•  Awatchandwaitpolicyseemssafeinpa6entswithminimalhRDorhistological-onlylocalrelapse

HPeradica>onisthestandardini>altreatmentforlocalizeddisease

EGILSConsensusReport,2011ESMOClinicalPrac>ceGuidelines,2013

WhytotreatHP-nega>vepa>ents?

•  Falsenega6vediagnos6ctest•  Othermicroorganismsinvolved(H.heilmannii)

•  Responsesin14of72publishedcases(19%)EGILSConsensusReport

HPeradica>onisthestandardini>altreatmentforlocalizeddisease

•  H.pylorieradica6ontherapymustbegiventoallgastricMALTlymphomas,independentlyofstage

•  Responsesmayrequireupto12monthsormore

•  HP-nega6vepa6entswithgastricMALTlymphomamayalsoreceivean6-Hpyloritreatment

•  Lymphomaswitht(11;18)andthosewithlymphnodeinvolvementareunlikelytoregressamerHPeradica6on EGILSConsensusReport,2011

ESMOClinicalPrac>ceGuidelines,2013

Openques>onsinthemanagementofgastricMALTlymphoma

•  stagingprocedures•  H.pylorieradica6ontoallpa6ents?•  secondlinetreatments

SameoutcomeaLerdifferenttreatmentsinstageIEgastricMALTlymphoma

Treatment N°ofpts CRrate 5-yearsOS(95%Cl)

An6bio6cs 45 67% 94%(65-99)Localtreatmenta 14 100% 92%(57-99)Chemotherapy 8 50% 75%(32-93)Combinedmodality

b 5 100% 80%(20-97)

Total 72 74% 89%(76-96)

asurgery±RTbsurgery+adjuvantchemotherapy Pino=etal,LeukLymphoma1997

Bertoni&Zucca.Lymphomas:Essen6alsforClinicians2015

RTisveryac>veinMALTlymphoma

Bertoni&Zucca.Lymphomas:Essen6alsforClinicians2015

RTisveryac>veinMALTlymphoma

• op>malRTvolume,doseandtechnique?• doesthisreallytranslatetocure?• inaveryindolentcondi>on,isthepoten>altoxicityacceptable?

• longtermsafety?(malignancy,gastricandrenaltoxicity)

Long-termoutcomeofgastricMALTlymphomaaLerRT:Theretrospec>vemul>-centreIELSG-22study

WirthAetal.AnnOncol2013

medianRTdosetostomach,40Gy(26–46Gy)

Chemotherapy in MALT lymphomas

Treatment Nr. pts ORR CR Author

Alkylators 24 pts 100% 75% Hammel P. J Clin Oncol 1995

R-CHOP/CNOP 7 pts 100% 100% Raderer M. Ann Oncol 2002

Cladribine 26 pts 100% 84% Jäger G. J Clin Oncol 2002

Oxaliplatin 16 pts 93% 56% Raderer M. J Clin Oncol 2005

Fluda-Mito 20 pts 100% 100% Zinzani PL. Cancer 2004

R-cladribine 39 pts 81% 58% Troch M. Haematologica 2013

responsen%ORR 2573 SD 618PD 39

Rituximabac>vityinMALTlymphoma

IELSGphaseIIstudy,Conconietal.Blood2003

34pts,11withpriorchemotherapy,15gastric,20stageIV

401evalua

blepa>

ents

IELSG-19 Randomised Study Treatment Schedule 19

E. Zucca E et al. J Clin Oncol 2017 Epub

E. Zucca E et al. J Clin Oncol 2017 Epub

IELSG-19 Randomised Study Final Results 19

E. Zucca E et al. J Clin Oncol 2017 Epub

IELSG-19 Randomised Study Outcome by Primary Site 19

AnyroleforR-maintenance?IELSG-38:studydesign38

•  Single arm phase II study

•  R-Chlorambucil for 6 mos followed by 2-yrs maintenance with Rsc

•  Accrual completed with 112 newly diagnosed MALT pts in need of systemic treatment

Response-adapted1stlineR-Benda(GELTAMOMZLphase-2trial)

A. Salar et al, Lancet Oncol, 2014

Targeting BTK with ibrutinib in r/r MZL

NoyAetal.Blood2017

Median, 14 months

62% at 18 months

80% at 30 months

PhaseIIstudiesinMALTlymphoma

Take-homemessages

•  H.pylorieradica6onisstandardfront-linetreatment

•  PersistentMRDnotclearlyassociatedwithprogression

• Watchfulwai6ngissafeincaseofstableMRDortransientlocalhistologicalrelapses

•  ThebesttreatmentnotyetdefinedforHP-nega6vecasesandan6bio6cfailures

LY03trialofgastricMALTlymphoma

B.Hancock,etal.BrJHaematol,2009

chlorambucil vs. observation after anti-Helicobacter therapy

•  CRtobeconfirmedin2subsequentinves6ga6ons

•  PRandSDandrelapsestobeclinicallymanagedonanindividualbasis:

–  ifnosignsofendoscopicorclinicalprogressionareevident,a‘watchandwait’strategycanbeadopted

–  pa6entswithdistantdissemina6onand/orgrossendoscopictumourshouldreceiveoncologicaltreatment.

EGILSrecommenda>onsforrestagingandfollow-up

EGILSConsensusReport

•  ClearevidenceofEUSu6lityasastagingprocedurebutlessstrongevidenceinfollow-up

•  Breathtest±EGDat~3mos.ameran6bio6csthenEGDwithbiopsiesq6msx2years,thenq12mos

•  Molecularstudiesnotneeded

HowtofollowupaLeran>bio>cs?

EGILSConsensusReport

HowlongtofollowupaLeran>bio>cs?

Life-long?Pa6entswithgastricMALTlymphomahavea66meshigherriskforgastricadenocarcinomaincomparisonwiththegeneralpopula6onandtheriskishighestinpa6entsyoungerthan60

Capelleetal.EurJCancer,2008