Azathioprine: LongAzathioprine: Long--Term Term Side EffectsSide Effects

Edward V Loftus, Jr, MDEdward V Loftus, Jr, MDDivision of Gastroenterology and HepatologyDivision of Gastroenterology and Hepatology

Mayo Clinic College of Medicine Mayo Clinic College of Medicine Rochester, MNRochester, MN

OverviewOverview•• ““Real world” experiences with AZAReal world” experiences with AZA•• ITPA polymorphismsITPA polymorphisms•• Hematological Hematological –– Drug interactionsDrug interactions•• Teratogenicity/Pregnancy SafetyTeratogenicity/Pregnancy Safety•• HepaticHepatic•• InfectiousInfectious

–– Combination therapy with infliximabCombination therapy with infliximab•• Neoplastic (e.g., lymphoma)Neoplastic (e.g., lymphoma)

AZA/6MP Tolerance: RCT AZA/6MP Tolerance: RCT ExperienceExperience

•• Experience in Experience in RCTsRCTs for Crohn’s disease for Crohn’s disease generally favorablegenerally favorable

•• Pooled odds ratio of study withdrawal Pooled odds ratio of study withdrawal due to AZA/6MP adverse events was 5.3 due to AZA/6MP adverse events was 5.3 (95% CI, 2.2(95% CI, 2.2--12.6)12.6)

•• Withdrawals due to adverse events Withdrawals due to adverse events ranged from 0% to 15%ranged from 0% to 15%

–– Average rate was 9% (vs. 2% in placebo)Average rate was 9% (vs. 2% in placebo)

Pearson DC et al, Ann Intern Med 1995;123:132Pearson DC et al, Ann Intern Med 1995;123:132--4242

““Real World” Experiences With Real World” Experiences With AZA/6MP in 2002AZA/6MP in 2002--44

SettingSetting NN % Withdrawal% WithdrawalDue to AEDue to AE

Olmsted Co, MNOlmsted Co, MN 102102 25%25%Canterbury, NZCanterbury, NZ 216216 26%26%Oxford, UKOxford, UK 622622 28%28%Groningen, NLGroningen, NL 318318 23%23%NijmegenNijmegen, NL, NL 5050 22%22%

Loftus CG et al, Am J Gastroenterology 2003 abstractLoftus CG et al, Am J Gastroenterology 2003 abstractGearryGearry et al, Pharmacoepidemiol Drug Safety 2004;13:563et al, Pharmacoepidemiol Drug Safety 2004;13:563--77Fraser AG et al, Gut 2002;50:485Fraser AG et al, Gut 2002;50:485--99WeersmaWeersma RK et al, Aliment Pharmacol Ther 2004;20:843RK et al, Aliment Pharmacol Ther 2004;20:843--5050deJongdeJong DJ et al, DJ et al, EurEur J J GastroenterolGastroenterol HepatolHepatol 2004;16:2072004;16:207--1212

Inosine Triphosphate Pyrophosphatase Inosine Triphosphate Pyrophosphatase (ITPA): Role in AZA/6MP Metabolism(ITPA): Role in AZA/6MP Metabolism

AZAAZA 6MP6MP 66--thiothio--IMPIMP

66--thiothio--IDPIDP66--thiothio--ITPITP

ITPAITPATPMTTPMT

XOXO

6MMP6MMP

66--thiothio--uric aciduric acid MeMe--66--thiothio--IMPIMP

TPMTTPMT

IMPDHIMPDH66--TGNsTGNs

Marinaki et al, Pharmacogenetics 2004;14:181Marinaki et al, Pharmacogenetics 2004;14:181--77

HPRTHPRT

Inosine Triphosphate Pyrophosphatase (ITPA) Inosine Triphosphate Pyrophosphatase (ITPA) Polymorphisms May Explain Some Polymorphisms May Explain Some

“Idiosyncratic Reactions” to AZA/6MP“Idiosyncratic Reactions” to AZA/6MP•• 62 IBD pts with adverse reactions to 62 IBD pts with adverse reactions to

AZA, 68 pts who tolerated > 3 monthsAZA, 68 pts who tolerated > 3 months•• ITPA polymorphism (94C>A) ITPA polymorphism (94C>A)

significantly associated with adverse significantly associated with adverse events overall events overall

•• 94C>A 17% allele frequency vs. 4% in 94C>A 17% allele frequency vs. 4% in controls (OR, 4.2, 95% CI 1.6controls (OR, 4.2, 95% CI 1.6--11.5)11.5)

–– FluFlu--like symptoms: OR 4.7, 1.2like symptoms: OR 4.7, 1.2--18.118.1–– Rash: OR, 10.3, 4.7Rash: OR, 10.3, 4.7--62.962.9–– Pancreatitis: OR, 6.2, 1.1Pancreatitis: OR, 6.2, 1.1--32.632.6

Marinaki et al, Pharmacogenetics 2004;14:181Marinaki et al, Pharmacogenetics 2004;14:181--77

Do ITPA Polymorphisms Account for Do ITPA Polymorphisms Account for Leucopenia Following AZA/6MP?Leucopenia Following AZA/6MP?•• 41 CD patients with leucopenia and 100 41 CD patients with leucopenia and 100

controls tested for ITPA mutationscontrols tested for ITPA mutations–– Prevalence of 94C>A was 15% in leucopenia Prevalence of 94C>A was 15% in leucopenia

group vs. 10% in controlsgroup vs. 10% in controls•• 254 IBD patients and 129 healthy volunteers 254 IBD patients and 129 healthy volunteers

testedtested–– Leucopenia seen in 11% of IBD ptsLeucopenia seen in 11% of IBD pts–– 94C>A seen in 25% of 94C>A seen in 25% of leucopenicleucopenic pts but only pts but only

10% of controls10% of controls–– 94C>A did NOT predict 94C>A did NOT predict hepatotoxicityhepatotoxicity or or

pancreatitispancreatitisAllorgeAllorge D et al, Gut 2005;54:565D et al, Gut 2005;54:565ZelinkovaZelinkova Z et al, Gut 2004;53(Suppl VI):A49 (UEGW abstract)Z et al, Gut 2004;53(Suppl VI):A49 (UEGW abstract)

Hematological Adverse EventsHematological Adverse Events

•• Variations in TPMT activity may explain Variations in TPMT activity may explain only a small proportion of leucopenia, only a small proportion of leucopenia, usually only early eventsusually only early events

•• TPMT deficiencies explained only 27% TPMT deficiencies explained only 27% of of leucopenicleucopenic events in a French studyevents in a French study

•• Role of ITPA mutations remains unclearRole of ITPA mutations remains unclear•• Continued indefinite need for periodic Continued indefinite need for periodic

monitoring of WBC even if counts have monitoring of WBC even if counts have been stablebeen stable

ColombelColombel JF et al, Gastroenterology 2000;118:1025JF et al, Gastroenterology 2000;118:1025--30.30.

AZA/6MP Drug Interactions: AZA/6MP Drug Interactions: Sulphasalazine and 5Sulphasalazine and 5--ASAASA

•• 34 Crohn’s patients on stable doses of 34 Crohn’s patients on stable doses of AZA/6MP with serial 6TGN levels before and AZA/6MP with serial 6TGN levels before and after introduction of SASP or 5ASAafter introduction of SASP or 5ASA

•• Leucopenia (WBC < 3.5) occurred over the Leucopenia (WBC < 3.5) occurred over the next 8 weeks in:next 8 weeks in:

–– 5/10 mesalamine 4 g/d (50%)5/10 mesalamine 4 g/d (50%)–– 6/11 sulphasalazine 4 g/d (54%)6/11 sulphasalazine 4 g/d (54%)–– 2/10 balsalazide 6.75 g/d (20%)2/10 balsalazide 6.75 g/d (20%)

•• Serum 6Serum 6--TGN levels rose significantly after TGN levels rose significantly after introduction of mesalamine or sulphasalazineintroduction of mesalamine or sulphasalazine

Lowry et al, Gut 2001;49:656Lowry et al, Gut 2001;49:656--64.64.

AZA/6MP Drug Interactions: AZA/6MP Drug Interactions: InfliximabInfliximab

•• 32 Crohn’s patients with serial 6TGN serum 32 Crohn’s patients with serial 6TGN serum levels before/after infliximablevels before/after infliximab

•• Median AZA dose 2.8 mg/kg (0.6Median AZA dose 2.8 mg/kg (0.6––3.6)3.6)BeforeBefore 11--3 Weeks3 Weeks 3 Months3 Months

TGNTGN 277277 442 442 †† 279279WBCWBC 4.34.3 3.6 3.6 †† 4.14.1MCVMCV 96.196.1 98.3 98.3 †† 95.395.3†† p<0.01 compared to other 2 time pointsp<0.01 compared to other 2 time points

Roblin et al, Aliment Pharmacol Ther 2003;18:917Roblin et al, Aliment Pharmacol Ther 2003;18:917--25.25.

AZA Effects on Fertility in MalesAZA Effects on Fertility in Males

•• 18 men with IBD on AZA for > 3 months18 men with IBD on AZA for > 3 months–– Semen quality as measured by total Semen quality as measured by total

sperm county, density, motility, and sperm county, density, motility, and morphology was normalmorphology was normal

•• 11 men with IBD started on AZA after 11 men with IBD started on AZA after first semen analysisfirst semen analysis

–– Baseline parameters slightly decreasedBaseline parameters slightly decreased–– No worsening in parameters after mean No worsening in parameters after mean

11 months AZA treatment11 months AZA treatment•• 6 men on AZA fathered 7 healthy 6 men on AZA fathered 7 healthy

childrenchildrenDejaco et al, Gastroenterology 2001;121:1048Dejaco et al, Gastroenterology 2001;121:1048--53.53.

AZA/6AZA/6--MP TeratogenicityMP Teratogenicity•• Metabolites can cross the placentaMetabolites can cross the placenta•• Biggest/best studies in transplant and Biggest/best studies in transplant and

rheumatology (SLE) literaturerheumatology (SLE) literature•• 146 kidney transplant recipients on 146 kidney transplant recipients on

AZA/steroids or AZA aloneAZA/steroids or AZA alone–– Low birth weights in 39%Low birth weights in 39%–– Premature births in 52%Premature births in 52%–– Congenital anomalies in 4% (background Congenital anomalies in 4% (background

rate = 3%)rate = 3%)•• IBDIBD--specific studies are hampered by specific studies are hampered by

small numberssmall numbersArmenti et al, Transplantation 1994Armenti et al, Transplantation 1994

AZA/6MP During Pregnancy in IBDAZA/6MP During Pregnancy in IBDNew York 1950sNew York 1950s--19971997

Francella et al.Gastroenterology 2003;124:9Francella et al.Gastroenterology 2003;124:9--17 17

AA B1B1 B2B2 CC NormalNormalPregnancies, nPregnancies, n 8484 6161 1515 165165

Full term (%)Full term (%) 63%63% 72%72% 67%67% 75%75%

Prematurity (%)Prematurity (%) 5%5% 5%5% 27%27% 4%4% 7.1%7.1%

Spontaneous abortion (%)Spontaneous abortion (%) 23%23% 16%16% 7%7% 19% 15%19% 15%––40%40%

Congenital abnormalities (%)Congenital abnormalities (%) 4%4% 3%3% 7%7% 4%4% 2%2%––5%5%

Neonatal/child infections(%) Neonatal/child infections(%) 1%1% 2%2% 13%13% 1%1% 2%2%––12%12%

Neoplasia in childNeoplasia in child 0%0% 2%2% 0%0% 0% 0.1/100% 0.1/1066/yr/yr

Multivariate analysis: successful pregnancy outcome on 6MP, 0.8 Multivariate analysis: successful pregnancy outcome on 6MP, 0.8 (0.5(0.5--1.5)1.5)

AA=conceived after 6=conceived after 6--MP; MP; B1B1==stopped 6stopped 6--MP when pregnant; MP when pregnant; B2B2=continued =continued 66--MP while pregnant; MP while pregnant; CC=pregnancy before starting 6=pregnancy before starting 6--MP(control)MP(control)

Pregnancy Following 6MP, New York, 1982Pregnancy Following 6MP, New York, 1982--9797

Group 1Group 1 Group 2Group 2 Gen popGen popn = 29n = 29 n = 75n = 75

PregnanciesPregnancies 7272 140140Live BirthsLive Births 51 (71%)51 (71%) 120 (86%)120 (86%) 85%85%SpontSpont AbsAbs 16 (22%)16 (22%) 18 (13%)18 (13%) 12%12%StillbirthsStillbirths 1 (1%)1 (1%) 2 (1%)2 (1%) 1%1%EctopicEctopic 2 (3%)2 (3%) 00 2%2%PrematurityPrematurity 4 (8%)4 (8%) 8 (7%)8 (7%) 11%11%Low Birth WeightLow Birth Weight 4 (8%)4 (8%) 8 (7%)8 (7%) 7%7%Cong AnomalyCong Anomaly 3 (6%)3 (6%) 4 (3%)4 (3%) 5%5%Fetal demiseFetal demise 29%29% 14%14% 15%15%ComplicationsComplications 15%15% 10%10% 16%16%ZlatanicZlatanic J et al, J J et al, J ClinClin GastroenterolGastroenterol 2003;36:3032003;36:303--9.9.

Azathioprine and 6MP in PregnancyAzathioprine and 6MP in Pregnancy--North Jutland, Denmark, 1991North Jutland, Denmark, 1991--20002000

FirstFirst EntireEntire NotNot OR, All OR, AZA/6MPOR, All OR, AZA/6MPTrim.Trim. PregPreg ExposedExposed ControlsControls ControlsControlsn=9n=9 n=10n=10 n=19,418n=19,418 (95% CI)(95% CI) (95% CI)(95% CI)

Low Low Birth weightBirth weight 22%22% 30%30% 4.4%4.4% 3.8 (0.43.8 (0.4--33)33) 2.3 (0.42.3 (0.4--14)14)PrePre--termtermBirthBirth 22%22% 30%30% 5.5%5.5% 6.6 (1.76.6 (1.7--26)26) 2.8 (0.42.8 (0.4--19)19)CongenitalCongenitalAnomaliesAnomalies 22%22% 20%20% 3.7%3.7% 20 (2.520 (2.5--161)161) 3.2 (0.23.2 (0.2--57)57)Perinatal Perinatal DeathDeath 11%11% 10%10% 0.6%0.6% 6.7 (1.46.7 (1.4--32)32) 7.7 (0.67.7 (0.6--102)102)

Norgard et al, Aliment Pharmacol Ther 2003;17:827Norgard et al, Aliment Pharmacol Ther 2003;17:827--3434

AZA/6MP: Infectious ComplicationsAZA/6MP: Infectious Complications•• Lenox Hill Hospital 1980Lenox Hill Hospital 1980--99 (n = 410)99 (n = 410)•• Infections, not necessarily related to Infections, not necessarily related to

leucopenia, may occur in up to 14%leucopenia, may occur in up to 14%•• Pneumonia 4%Pneumonia 4%•• Herpes zoster 3%Herpes zoster 3%•• Cytomegalovirus infections (colitis, Cytomegalovirus infections (colitis,

hepatitis, systemic illness) < 1%hepatitis, systemic illness) < 1%•• Upper respiratory infections 7%Upper respiratory infections 7%WarmanWarman JI et al, J JI et al, J ClinClin GastroenterolGastroenterol 2003;37:2202003;37:220--5.5.

Combination Combination PurinePurine Analog and AntiAnalog and Anti--TNF TNF Therapy: Does It Synergistically Increase Therapy: Does It Synergistically Increase

Infection Risk?Infection Risk?•• Many Many centrescentres advocate combination therapy to advocate combination therapy to

reduce formation of antibodies to infliximabreduce formation of antibodies to infliximab•• Does this increase infection risk?Does this increase infection risk?•• 217 IBD patients from Stockholm217 IBD patients from Stockholm

–– 18 severe infections (8%)18 severe infections (8%)–– 2 sepsis deaths2 sepsis deaths

•• 500 Crohn’s patients from Mayo500 Crohn’s patients from Mayo–– 41 infections (8%)41 infections (8%)–– 2 sepsis deaths, 2 pneumonia deaths2 sepsis deaths, 2 pneumonia deaths

LjungLjung T et al, Gut 2004T et al, Gut 2004ColombelColombel JF et al, Gastroenterology 2004JF et al, Gastroenterology 2004

AZA/6MP AZA/6MP HepatotoxicityHepatotoxicity•• Overall prevalence of biochemical Overall prevalence of biochemical

abnormalities: 3abnormalities: 3--4%4%•• Most of these are doseMost of these are dose--dependentdependent

–– Related to overRelated to over--accumulation of 6MMP accumulation of 6MMP due to high TPMT? Controversialdue to high TPMT? Controversial

–– May resolve spontaneously or with dose May resolve spontaneously or with dose reductionreduction

•• 66--thioguanine: fewer allergic side thioguanine: fewer allergic side effects, more effects, more hepatotoxicityhepatotoxicity (up to 26%)(up to 26%)

DubinskyDubinsky MC et al, Gastroenterology 2002;122:904MC et al, Gastroenterology 2002;122:904--1515

DubinskyDubinsky MC et al, Gastroenterology 2003;125:298MC et al, Gastroenterology 2003;125:298--303303

AZA/6MP AZA/6MP HepatotoxicityHepatotoxicityLess common but more serious:Less common but more serious:

Nodular regenerative hyperplasiaNodular regenerative hyperplasiaVenoVeno--occlusive disease of liverocclusive disease of liver

HoltmannHoltmann M et al, Dig M et al, Dig DisDis SciSci 20032003Daniel F et al, Gut Daniel F et al, Gut 2004;532004;53((SupplSuppl VI):A221VI):A221

True incidence ofTrue incidence ofthese events these events remains unknownremains unknown

ReticulinReticulin stainstain

Baseline Risk of Lymphoma in IBDBaseline Risk of Lymphoma in IBD

•• Studies from referral centers indicate Studies from referral centers indicate a twofold to six fold increase in riska twofold to six fold increase in risk

–– Referral bias?Referral bias?–– Risk increases with increased Risk increases with increased

severity?severity?•• PopulationPopulation--based studies indicate based studies indicate

little or no increased risk, with few little or no increased risk, with few exceptionsexceptions

PopulationPopulation--Based Studies of Lymphoma in IBDBased Studies of Lymphoma in IBDAuthorAuthor SettingSetting PatientsPatients RR RR (95% CI)(95% CI)EkbomEkbom UppsalaUppsala CD 1655CD 1655 0.4 0.4 (0 (0 -- 2.4)2.4)

UC 3121UC 3121 1.2 1.2 (0.5 (0.5 -- 2.4)2.4)PerssonPersson StockholmStockholm CD 1251CD 1251 1.4 1.4 (0.4 (0.4 -- 3.5)3.5)KarlenKarlen StockholmStockholm UC 1547UC 1547 1.2 1.2 (0.3 (0.3 -- 3.5)3.5)LoftusLoftus Olmsted CoOlmsted Co CD 216CD 216 2.4 2.4 (0.1 (0.1 -- 13)13)

UC 238UC 238 00 (0 (0 -- 6.4)6.4)PalliPalli FlorenceFlorence CD 231CD 231 2.52.5 (0.3 (0.3 -- 9)9)

UC 689UC 689 9.3*9.3* (2.5 (2.5 -- 24)24)BernsteinBernstein ManitobaManitoba CD 2857CD 2857 2.42.4 (1.2 (1.2 -- 5)5)

UC 2672UC 2672 1.01.0 (0.5 (0.5 -- 2.2)2.2)LewisLewis GPRD, UKGPRD, UK CD 6605CD 6605 1.41.4 (0.5 (0.5 -- 3.4)3.4)

UC 10391UC 10391 1.21.2 (0.7 (0.7 -- 2.1)2.1)AsklingAskling Mult SwedishMult Swedish CD 20120CD 20120 1.31.3 (1.0 (1.0 -- 1.6)1.6)

cohortscohorts UC 27559UC 27559 1.01.0 (0.8 (0.8 -- 1.3)1.3)* Hodgkin lymphoma (RR not signif elevated for non* Hodgkin lymphoma (RR not signif elevated for non--Hodgkin)Hodgkin)Ekbom,Ekbom, Cancer 1991; Persson,Cancer 1991; Persson, Gastroenterology 1994; Karlen, Am J Gastroenterol 1999; Gastroenterology 1994; Karlen, Am J Gastroenterol 1999;

Loftus, Am J Gastroenterol 2000; Palli, Gastroenterology 2000; BLoftus, Am J Gastroenterol 2000; Palli, Gastroenterology 2000; Bernstein, Cancer 2001; ernstein, Cancer 2001; Lewis, Gastroenterology 2001; Askling, Gut 2005Lewis, Gastroenterology 2001; Askling, Gut 2005

Lymphoma Risk in IBD Patients on Lymphoma Risk in IBD Patients on AZA/6MP: MetaAZA/6MP: Meta--AnalysisAnalysis

StudyStudy SettingSetting NN ObsObs ExpExp SIR SIR (95% CI)(95% CI)KinlenKinlen U.K.U.K. 321321 22 0.160.16 12.512.5 (1.2 (1.2 -- 46)46)ConnellConnell LondonLondon 755755 00 0.520.52 00FarrellFarrell DublinDublin 238238 22 0.050.05 37.5 37.5 (3.5 (3.5 -- 138)138)FraserFraser OxfordOxford 626626 33 0.650.65 4.6 4.6 (0.9 (0.9 -- 13.7)13.7)KorelitzKorelitz New YorkNew York 486486 33 0.610.61 4.94.9 (0.9 (0.9 -- 14.5)14.5)LewisLewis GPRDGPRD 14651465 11 0.640.64 1.61.6 (0.001 (0.001 -- 9)9)PooledPooled 38913891 1111 2.632.63 4.24.2 (2.1 (2.1 -- 7.5)7.5)Sensitivity analyses: when papers with highest or lowest SIRs weSensitivity analyses: when papers with highest or lowest SIRs were re

excluded, results remained significant (range, 3.5 excluded, results remained significant (range, 3.5 -- 5.2)5.2)Kandiel et al, DDW abstract 2004 and Gut 2005 (in press)Kandiel et al, DDW abstract 2004 and Gut 2005 (in press)

EpsteinEpstein--Barr Virus and LymphomaBarr Virus and LymphomaBB--cell lymphomacell lymphoma

EBV inEBV in--situ hybridizationsitu hybridizationDayharsh et al, Gastroenterology 2002;122:72Dayharsh et al, Gastroenterology 2002;122:72

EBV Virus LoadEBV Virus Load138 Crohn’s patients138 Crohn’s patientswith serial EBV viral with serial EBV viral load measurementsload measurements

2 pts had viral loads in2 pts had viral loads indangerous range (i.e., dangerous range (i.e., risk for lymphoma)risk for lymphoma)

No clear relationshipNo clear relationshipbetween immunobetween immuno--suppressive therapysuppressive therapyand EBV loadsand EBV loads

Reijasse et al, InflammReijasse et al, InflammBowel Dis 2004;10:85Bowel Dis 2004;10:85

RiskRisk--Benefit of AZA/6MP for Benefit of AZA/6MP for Crohn’s: Decision AnalysisCrohn’s: Decision Analysis

•• Markov model of qualityMarkov model of quality--adjusted life year gain of AZA adjusted life year gain of AZA for Crohn’s in a 35 yearfor Crohn’s in a 35 year--old patientold patient

•• Base case assumed 3 fold increased lymphoma risk Base case assumed 3 fold increased lymphoma risk and a 50% reduction in Crohn’s related mortalityand a 50% reduction in Crohn’s related mortality

•• 10 years of AZA resulted in gain of 1.25 quality10 years of AZA resulted in gain of 1.25 quality--adjusted monthsadjusted months

•• AZA was no longer beneficial if:AZA was no longer beneficial if:–– Risk of death from severe flare < 0.06%Risk of death from severe flare < 0.06%–– Lymphoma risk is > 8 times normalLymphoma risk is > 8 times normal–– Background risk of lymphoma in Crohn’s > 4 times normalBackground risk of lymphoma in Crohn’s > 4 times normal–– Fear of AZAFear of AZA--related lymphoma results in > 1% decrease in related lymphoma results in > 1% decrease in

utility (proxy for QOL)utility (proxy for QOL)

Lewis JD et al, Gastroenterology 2000;118:1018Lewis JD et al, Gastroenterology 2000;118:1018--24.24.

Does Prolonged Leukopenia Does Prolonged Leukopenia Increase Cancer Risk With 6MP?Increase Cancer Risk With 6MP?

•• 600 IBD pts treated with 6MP at Lenox Hill 600 IBD pts treated with 6MP at Lenox Hill Hospital, New YorkHospital, New York

•• 31 pts developed sustained leukopenia (WBC 31 pts developed sustained leukopenia (WBC < 4 for at least 2.5 wks)< 4 for at least 2.5 wks)

•• 93 matched controls without leukopenia93 matched controls without leukopenia•• 8 developed cancers (26%) versus 8% in 8 developed cancers (26%) versus 8% in

controls (p = 0.017)controls (p = 0.017)–– Leukemia in 2Leukemia in 2–– NonNon--Hodgkin lymphoma in 1Hodgkin lymphoma in 1–– No colorectal cancersNo colorectal cancers

DiSanti et al, Am J Gastroenterol 2004;99:S252 (ACG abstract)DiSanti et al, Am J Gastroenterol 2004;99:S252 (ACG abstract)

Risk of Other Cancers With AZA/6MPRisk of Other Cancers With AZA/6MP

•• NonNon--melanoma skin cancer, especially melanoma skin cancer, especially squamous cell cancersquamous cell cancer

–– In transplant literature, RR is 6 to 65In transplant literature, RR is 6 to 65–– Might increase further with addition of Might increase further with addition of

ciclosporinciclosporin•• Many IBD cohort studies show Many IBD cohort studies show

increased risk of colorectal cancer increased risk of colorectal cancer following AZA/6MP, but this is to be following AZA/6MP, but this is to be expected given the extent and duration expected given the extent and duration of colitisof colitis

Conclusions (1)Conclusions (1)•• Tolerance of AZA/6MP in the “real world” may Tolerance of AZA/6MP in the “real world” may

not be as good as RCT data (22 not be as good as RCT data (22 –– 28% 28% withdrawal rates)withdrawal rates)

•• “Newer” polymorphisms such as ITPA may “Newer” polymorphisms such as ITPA may explain some toxicity such as fever and explain some toxicity such as fever and pancreatitispancreatitis –– data are conflictingdata are conflicting

•• Drug interactions between AZA/6MP and 5Drug interactions between AZA/6MP and 5--ASA or infliximab may result in leucopeniaASA or infliximab may result in leucopenia

•• Data on safety in pregnancy are sparse Data on safety in pregnancy are sparse –– may may be a small but real risk of adverse outcome be a small but real risk of adverse outcome ––discuss with the patientdiscuss with the patient

Conclusions (2)Conclusions (2)•• Most Most hepatotoxicityhepatotoxicity is mild and is mild and

reversible but rarely more serious injury reversible but rarely more serious injury may occurmay occur

•• Most populationMost population--based studies of based studies of lymphoma in IBD suggest little to no lymphoma in IBD suggest little to no increased relative riskincreased relative risk

•• Relative risk of lymphoma with AZA/6MP Relative risk of lymphoma with AZA/6MP use is likely increased, up to fourfold use is likely increased, up to fourfold --absolute risk remains lowabsolute risk remains low

•• EpsteinEpstein--Barr virus typically found in Barr virus typically found in lymphomas in IBD pts on AZA/6MPlymphomas in IBD pts on AZA/6MP