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in lymphoma tBD @bout

in Lymphomas IBD: Mythsand Realities
(and how to communicate your patients) to
FAGP Davld T. Rubln, irD,FAcc,AGAF,
Alrelalr Pretltror of Madlclna Borcl Dlsa$ Co{lEclor, Intlammrtoly Canlar

. Patients IBDhave increased with an baseline riskof lymphoma . Males females at increased for risk and are lymphoma IBD in . Anti-TNF increase riskof the therapies in lymphoma IBD . Lymphoma isthe mostdangerous risk aspect for of treatment IBD

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population in lymphomas general

. Non-Hodgkin (NHL) (90%), (10%) Hodskin's disease lymphomas . Epldemloloticaltrends slnce 1970s1 the tr Frank lncrease Western in countrles (x2 O Maleprcdomlnence vs femalesl for dlsease NHL and tr lmpactof a8edifferent Hodgkln's . Hodgkln; Incldence, noInfluence a8e wlth of low . NHL: of Inddile x 40betw*n ths8g33 20.nd80ys6 0 Rare fdmlllalclusters . Cumulatlve0-74 year risk in a male (France, 2000)2

Epstein-Barr Virus(EBV)-associated lymphomas

[2.5%lymphoma cancer - Sb !4.8%colorectal

a Cdbh Fts ffi t.JdAdd q,.!ymOI kMilol:3@ (wMb.trt

Virus Epstein-Barr
. Widespread gamma-herpes whichinfects virus almost the all population the during in mostcases life, before ageof 30 human years . lnfection during EBV usually occurs asymptomatically childhood. persists a lifelonglatentinfection the memoryBin as lymphocyte compartment . Whenprimary infection delayed is untiladolescence, may symptomatic mononucleosis occur (<10% population), a subsequent foldincrease the in 5-6 with infection the lymphocytes) of riskof NHL(dueto massive

PersistentEBVinfection in B-lymphocytes . 80 lyticreplication proteins, responsible for virus dissemination . Only latency proteins, for 8 targets immune surveilla by specifi T-cytotoxic nce c (lym rol if lymphocytes phop iferation impaired : )
proteins (EBNA LP) !6 nuclear 1,2,3A,3B.,3C, proteins (LMPl,LMP2) !2 membrane

arthritispatients What canwe learnfrom rheumatoid treatment? and an6-TNF lymphoma about
(1998-2005) diseases . National data bankfor rheumatic and biologics 58% received enrolled,55% . Nearly 2o,ooopatients receivedMTX
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without in lBDpatients immunosuPPressants

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GPROI 6605cD, 10391Uc (8.6%wltl lS) il6an FU: 3.8YE SIR=1.20

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cEsAilE2 515:tCD, 5557UC wlthout lS'z l{odlan Fu: 2.9YE SIR='1.43

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and infl lBD,intestinal ammation lYmPhomas

Mayo clinic,l 1985-2000 . 18 lymphomas . 9 (50%)with intestinalinvolvement(6 under lS) CESAME2 lymphomas) . 23 incidentlymphomas(22 Non-Hodgkin . 6 (260/"1 with intestinalinvolvement IBD -5 in intestinalsegmentsinvolvedby -4 u n d e rl S - 3 EBV+

cohort CESAME and lBD,lymphomas thiopurines:

ThloPurlnetheraPY ongolng E Dllcontlnud El N'vsrroc'lved <50years 51F65 Yeara >65Years

114 ?39 538 2,375

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cohort CESAME and lBD,lymphomas thiopurines:

lYmPhomas Drug-induced to ageandtreatmentduration NNHaccording

I I GsnoralPopulatlon AZA-IBD

of Duratton IBD(psr l'year Incrsase)

(r.0F1.08) 1.04
c c c oo c

thorapyr Thlopurlne N6verrecolved' Dlscontlnusd Contlnulng

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ud swnmts6 dulto rmtrn p** 6b wtf .nvl Th. Md .r-* bbFtu. ;h ilEr Gw ldtrd ! Nsrt6dd ffi Mrd

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Matter? Doesa FHof Lymphoma

. Swedish (1505 cases population-based control case and 1229controls) . Explored of confounders risk as exposures potential with FH in cell NHL/HL/B Lymphoma patients of
- Smoking - Uv exoosures use of drugs(ever/never - Medicationsincludingimmunosuppressive or cyclophosphamide, methotrexate, cyclosporine, azathioprine, at chlorambucil) least2 yearsprior to entry data - Occupational

in of Elements riskof lymphoma IBD

X 40 beyond the age of 20 Prevlous hlstory of symptomatlc mononucloosls

X 3-5 va non expoaed

. Noneweresignificantly with associated increased risk!

Chang, et al.l Nad Gncer Inst zm5j97:145574

Young malea seronogatlve for EBV:

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populations patients maybe at of Specific than others more riskof lymphoma

lymphomas lmmunosuppressant-associated WhataboutMTXandanti-TNF?

MTX . No information IBD in . Sporadic of but earlylymphomas no overt excess cases reversible of arthritis with rheumatoid of in cancers the population patients Anti.TNF . In l B D , e can atthi sti me,noconcl usi on be madebecau s mos tof the patients co-treated with thiopurinesl are

0.1-18.4 0.1-19.1

. No overt excess lymphomas to attributable anti-TNF of in hugeRAcohorts2

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+ Riskof NHLwith anti-TNF lM treatment disease for Crohn's

results Meta-analysis . 8905 patientsrepresenting of 20,602patient-years exposure patient-years 13 NHL) 5.1 per 1O,O0O . Mean age 52 years,62oy'o male . 10/13exposed lM' (thisis reallya studyof combination Rx) to g\

lymphomas T-cell Hepatosplenic

p** {n.o. . Main features: iferation fatallymphoprol - Rapidly 5-$

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e
1
10' 6"

SEER databass, all ageg lM alone AnII-TNF + IM Ys SEER Antl-TNF + lM vs lil alons 'notrepnoin)\ tit\ -\""rtEd&mury Suddll.no Inddmo &

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6.1 6.'l $*'
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-Youngmen thiopurines anti-TNF -Combination / or (morerarely, with thiopurines monotherapy anti-TNF) -Not relatedto EBV

t.23 1 .7

1.5-6.9

0.s7.1

u: lmmunomoduhbri sEA: Dd Endtulb;sfR:.bd.dbd

. Veryrare(<1/5000)- case the CESAME in no cohort

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H It's not how many, it's how often

+ Anti-TNF 6MP/AZA

are Smallnumbers difficultto interpret

(quantitative literacy) Numeracy . /, of patients were unableto convert: lT%to 10in 1000 . 8O%o patients were unableto convert: of to fl1 in 1000 0.7% . Patients whichis determining havedifficulty the higherrisk: 1 nl in 27versus in 37
dlb d il. gchs.d 1s9fi127t86r72 u .r .t lr, lrbro M a0 Pl g n o n .t. E C/rhcl2002;5:35 Sb i l d .n 9 L I

Oec06 . . . In 2006 ) In 2008 )

Mar07

Sept07

Apr 08

Dec08

Mar09

Apr 10

130,000IBDpatientstreated with infliximab 170,000IBDpatientstreated with infliximab

worldwide over l million patientstreated with anti-TNFs

6UP: a hrclplopudn.;B:.ablopdn. Ontocoi

Tipsfor clearcommunication
. Absoluterisksbetterthan relativerisk . Avoiddecimals (0.06%) . Keepcommondenominators (X/10,000) . Visual into pictures) aidshelp(turn numbers . Giveperspective other diseases life and to risks

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disease due to are The highestrisksin Crohn's poorly controlleddisease and corticosteroids
. . . Database) Retrospectivecohort from UK (General PracticeResearch 5,539 patients with crohn's;41,624 controls Evaluatedmortality associatedwith Crohn'sitself,prednisone, i mmu n o mo d u l a to rs(mostlyAZA and 6MP) Biologicsnot included in analysis ^

Patients willingto taketheserisks are

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E Progresslve multlfocal lukoencephalopathy (PML)

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E 0.8 I n" 'P o.s I 0.5 a 0.4 o H 0.s f 0.2 ! 0.r =o

Moderate ModeElelo to mlld remlsslon Severslo moderatq Sevsr to mlld Ssverto remlsslon

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Summary
with . Anti-TNF therapyin combination havea verysmallabsolute maY ;il;";s in increase the riskof lYmPhoma the datato understand . We don't haveenough alone iytPhot. riskof anti-TNFs (andlife)are . Risks poorlytreateddisease of the iigft", t'han riskof lYmPhoma .lfcommunicatedclearly,patientsarewillingto the accept riskof lYmPhoma

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