Current Diagnosis and Management of Immune Related Adverse Events

14 Pages·2017·0.36 MB·English

by  Abhinav B. Chandra

MINIREVIEW
published:08February2017
doi:10.3389/fphar.2017.00049
Current Diagnosis and Management
of Immune Related Adverse Events
(irAEs) Induced by Immune
Checkpoint Inhibitor Therapy
VivekKumar1,NehaChaudhary2,MohitGarg1,CharalamposS.Floudas1,ParitaSoni1
andAbhinavB.Chandra3*
1DepartmentofMedicine,MaimonidesMedicalCenter,Brooklyn,NY,USA,2DepartmentofPediatrics,MaimonidesMedical
Center,Brooklyn,NY,USA,3MedicalDirector,YumaRegionalCancerCenter,Yuma,AZ,USA
The indications of immune checkpoint inhibitors (ICIs) are set to rise further with the
approval of newer agent like atezolimumab for use in patients with advanced stage
urothelial carcinoma. More frequentuse of ICIs has improved our understanding of
their unique side effects, which are known as immune-related adverse events (irAEs).
The spectrum of irAEs has expanded beyond more common manifestations such as
Editedby:
RaquelAbalo, dermatological, gastrointestinaland endocrine effects to rarer presentations involving
KingJuanCarlosUniversity,Spain
nervous, hematopoietic and urinary systems. There are new safety data accumulating
Reviewedby:
on ICIs in patients with previously diagnosed autoimmune conditions. It is challenging
JamesM.Rae,
UniversityofMichiganHealthSystem, for clinicians to continuouslyupdate their working knowledge to diagnose and manage
USA these events successfully.If diagnosed timely, the majority of events are completely
RobertA.Rollins,
reversible, and temporary immunosuppression with glucocorticoids, infliximab or other
PfizerInc.,USA
agents is warranted only in the most severe grade illnesses. The same principles of
*Correspondence:
AbhinavB.Chandra management will possibly apply as newer anti- cytotoxic T lymphocytes-associated
[email protected]
antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1/PD-L1) antibodies
are introduced. The current focus of research is for prophylaxis and for biomarkers
Specialtysection:
Thisarticlewassubmittedto to predict the onset of these toxicities. In this review we summarize the irAEs of ICIs
PharmacologyofAnti-CancerDrugs, and emphasize their growing spectrum and their management algorithms, to update
asectionofthejournal
FrontiersinPharmacology oncologypractitioners.
Received:16August2016
Keywords:immunerelatedadverseevents,checkpointblockade,irAEs,nivolumab,pembrolizumab,ipilimumab
Accepted:23January2017
Published:08February2017
Citation: INTRODUCTION
KumarV,ChaudharyN,GargM,
FloudasCS,SoniPandChandraAB Recent advances in cancer immunotherapy are notable for the introduction of a novel class of
(2017)CurrentDiagnosisand drugs known as immune checkpoint inhibitors (ICIs). These agents inhibit negative regulatory
ManagementofImmuneRelated
components of the immune response, such as the cytotoxic T lymphocytes-associated antigen 4
AdverseEvents(irAEs)Inducedby
(CTLA-4)andtheprogrammedcelldeathprotein-1anditsligand(PD-1/PD-L1),whichleadto
ImmuneCheckpointInhibitorTherapy.
Front.Pharmacol.8:49. enhancedTcellactionagainstthecancercells(Hodietal.,2010).Ipilimumabisananti-CTLA-4
doi:10.3389/fphar.2017.00049 antibodyandwasthefirstagenttoreceivefoodanddrugadministration(FDA)approvalforuse
FrontiersinPharmacology|www.frontiersin.org 1 February2017|Volume8|Article49
Kumaretal. ManagementofirAEsSecondarytoICIs
against advanced-stage melanoma1. Since then anti- CTLA-4 Timing
antibody tremelimumab, anti-PD-1 antibodies pembrolizumab The majority of toxicities appear temporally, with skin
and nivolumab and PD-L1 antibodies, atezolizumab and manifestations the earliest to appear at 2–3 weeks after the
durvalumab, have shown beneficial effects in several cancers 1st dose of ipilimumab. Immune-mediated colitis and hepatitis
(Wolchok et al., 2010; Topalian et al., 2012, 2014; Ribas et al., appear approximately 5–10 and 12–16 weeks after the 2nd
2013b; Larkin et al., 2015; Robert et al., 2015a; Postow et al., and 3rd dose, respectively. Endocrine dysfunctions present
2015;Fehrenbacheretal.,2016;Ferrisetal.,2016;Massardetal., fromthe9thweekonwardsfollowingthe4thdose(Hodietal.,
2016; Reck et al., 2016; Rittmeyer et al., 2017) (Table1). In 2010; Ryder et al., 2014). Immune-mediated pneumonitis is
contrast to conventional chemotherapy, boosting the immune seen 8–14 weeks after treatment initiation (Hodi et al., 2010).
systemleadstoauniqueconstellationofinflammatorytoxicities Immune-mediated nephritis appears much later, after 14–42
known as immune-related adverse events (irAEs) that may weeks on immunotherapy (Izzedine et al., 2014). However,
warrantthediscontinuationoftherapyand/ortheadministration similartemporalassociationoftheappearanceofirAEshasnot
of immunosuppressive agents (Gangadhar and Vonderheide, beendescribedforPD-1/PDL-1antagonists(Naidooetal.,2015).
2014; Cousin and Italiano, 2016). The use of these agents is
General Principles of Management
set to increase due to their dramatic impact on survival in a
variety of advanced-stage cancers (Horvat et al., 2015). Thus, Current guidelines are formulated by manufacturers in
it is imperative for personnel involved in the care of oncology collaboration with the FDA and are based on the experience
patientstobewellversedwiththeheterogeneouspresentationsof from clinical trials examining the efficacy of ICIs and expert
irAEsintermsofrecognitionandmanagement.Here,wereview consensus. The guidelines are incorporated in the packaging
thecurrentliteratureonappropriatestepsinpatientevaluation inserts of these agents2,3,4,5. Although anti-PD-1/ anti-PDL-1
for the prompt diagnosis of irAEs and describe strategies for antibodies may be less toxic than anti-CTLA-4 antibodies, the
optimizingpatientoutcomewithsuitabletreatment. approachtomanagingirAEsduetotheseagentsissimilar,with
slight variations (Postow and Wolchok, 2016). The severity of
adverse events is graded using Common Terminology Criteria
Incidence
forAdverseEvents(CTCAE)onascalefrom1to5(1=mild,
The incidence of any grade irAEs is reported to range from 15
2 = moderate, 3 = severe, 4 = life threatening, and 5 = death
to 90% (Hodi et al., 2010; Eggermont et al., 2016; Ferris et al.,
related to toxicity) (National Cancer Institute, 2009). However,
2016) in single agent trials. The rate of severe irAEs requiring
the grading of irAEs may be challenging, due to arbitrary
immunosuppression and withdrawal of immunotherapy is
distinctionsbetweengrade2and3toxicities,suchasthenumber
estimated to be 0.5–13% (Hodi et al., 2010; Wolchok et al.,
ofstoolsinaday,maybeaffectedbyrecallbias.Thus,thissystem
2010; Topalian et al., 2012, 2014; Ribas et al., 2013b; Larkin
of grading may not be entirely suitable to grade ICIs toxicities
et al., 2015; Postow et al., 2015; Robert et al., 2015a; Ferris
(Horvat et al., 2015). Therefore, it is prudent to use clinical
etal.,2016;TableS1)1.Thehighincidencereportedinarecent
judgment rather than strictly adhering to the guidelines. We
studywasattributedtosubjectivityintoxicityevaluationsamong
haveoutlinedseveralgeneralprinciplesthatshouldbefollowed
investigators and the accumulation of experience leading to irrespectiveofaffectedorgans2,3,4,5.
early diagnosis (Horvat et al., 2015). The risk of severe grade
adverse events increased from 7 to 25% with an increase in â The ICIs are interrupted in moderate (grade 2) irAEs and
the dose of ipilimumab from 3 mg/kg to 10 mg/kg9. This was areresumedwhensymptomsand/orlabvaluesdecreasebelow
mostlyduetoincreaseintheepisodesofdiarrhea.However,this grade 1. Glucocorticoids (prednisone 0.5–1 mg/kg/day or
patternwasnotobservedwhennivolumabdosingwasincreased equivalent) should be started if symptoms persist beyond 1
from 0.3 mg/kg to 10 mg/kg10. Severe grade toxicities with week.
pembrolizumabwerealsosimilaratdosesof10mg/kgevery2or â For grade 3/4 toxicities, high doses of glucocorticoids
3weeksanditsFDA-approveddosageof2mg/kgevery3weeks (prednisone 1–2 mg/kg/day or equivalent) should be given.
(Herbst et al., 2016). Thus, it may be argued that toxicities due The glucocorticoids should be tapered gradually when
toanti-CTLA-4antibodiesaredosedependentwhereastoxicities symptoms subside to grade 1 or less. The eligible patients
withanti-PD-1/anti-PDL-1antibodiesareindependentofdoses. (those on prednisone 20mg or equivalent doses for at least
Ipilimumab,aCTLA-4inhibitorisassociatedwithhigherratesof 4 weeks) should also receive appropriate prophylaxis against
gastrointestinal (GI) toxicities, pruritus, rash, and hypophysitis Pneumocystisjiroveciiaspertheestablishedguidelines6.
whereasuseofPD-1/PD-L1antagonistsisassociatedwithhigher 2http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761034s000lbl.pdf
risk of vitiligo, dysthyroidism, hepatotoxicity, and pneumonitis 3Yervoy(cid:13)R [packageinsert].Princeton,NJ:Bristol-MyersSquibbCompany,2016.
(Hamidetal.,2013;WeberJ.S.etal.,2013;Brahmeretal.,2015; Available online: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=
Eggermont et al., 2015, 2016; Herbst et al., 2016; Table1 and 2265ef30-253e-11df-8a39-0800200c9a66
4Keytruda(cid:13)R [package insert]. Whitehouse Station, NJ: Merck, and Co.,
Table S1). The data on toxicities from newer agents continue
Inc.,2016.Availableonline:http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?
to accumulate. The irAEs in select clinical trials have been
setid=9333c79b-d487-4538-a9f0-71b91a02b287
summarizedinTableS1. 5Opdivo(cid:13)R [packageinsert].Princeton,NJ:Bristol-MyersSquibbCompany,2016.
Available online: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=
1Drugs@FDA:FDAApprovedDrugProducts.Availableonlineatwww.Accessdata. f570b9c4-6846-4de2-abfa-4d0a4ae4e394
fda.gov/scripts/cder/drugsatfda/index.cf. 6http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf.
FrontiersinPharmacology|www.frontiersin.org 2 February2017|Volume8|Article49
Kumaretal. ManagementofirAEsSecondarytoICIs
d)
e
∼Durvalumab(Massard)etal.,2016 PD-L1inhibitor Undertrial =AllIII ∼234–5 3–40 NRNR NRNR 9–100 00 None NR 00 (Continu
c
atier
∧Atezolizumab(Fehrenbacheretal.,2016;Rosenbergetal.,2016;Rittmeyer)etal.,2017 PD-L1inhibitor FDAapprovedinmetastnon-smallcelllungcanc(2016)andurothelialcarcinoma(2016). =AllIII ∼16–215 <12–141 <151 NRNR 18–201–2 <<11 2–30 2–30 1–21 <2–41 <11 <<11 <2.61
PembrolizumabHamidetal.,2013;(Garonetal.,2015;Robertetal.,2015b;Herbstetal.,2016;Nandaetal.,2016;Recketal.,2016;)Seiwertetal.,2016 PD-L1inhibitor FDAapprovedinrecurrentormetastaticheadandneckcancer(2016),first-linetreatmentformetastaticnon-smallcelllungcancerinselectedpatients(2016),metastaticnon-smallcelllungcancer(2015),advancedmelanoma(2014). =AllIII 40–457–12 11–211 10–212 <9*1 8–201 1–21–2 <2–8*1 3–10*1 <1–2*1 <8–10*1 <3–4*1 <<11 4–6*1–2
er
gd
Bermanstin
#seEvents. &Pidilizumab(etal.,2008;Aretal.,2013;Weetal.,2014) PD-1inhibitor Undertrial =AllIII$None None None None None None
er
sandimmune-RelatedAdv Nivolumab(Topalianetal.,2012,2014;WeberJ.S.etal.,2013;Borghaeietal.,2015;Brahmeretal.,2015;Larkinetal.,2015;Rizvietal.,2015;Robertetal.,2015a;Ferris)etal.,2016 PD-1inhibitor FDAapprovedinHodgkin’slymphoma(2016),Headandneckcancer(2016),advancedlungcancer(2015),metastaticrenalcellcarcinoma(2015),advancedmelanoma(2014). =AllIII 30–453–7 <171 <151 <10–111 <8–161 1–31 <1–21 <1–21 1–21 <4–51 <0–31 <<11 1–50–2
or
unecheckpointinhibit @Tremelimumab(Tarhinietal.,2012;Ribasetal.,2013b;Calabroetal.,2015;)Kindleretal.,2016 CTLA-4inhibitor Tremelimumabwasgrantedorphandrugstatusin2015forthetreatmentofmalignantmesotheliomabutisnotFDAapprovedyet. =AllIII ∼∼145 30–321 32–342 NRNR }30–405–10 NRNR NRNR 11 }51 21 None
TABLE1|Mechanismofactionofimm Ipilimumab(Hodietal.,2010;Wolchoketal.,2010;Ibrahimetal.,2011;Eggermontetal.,2015,2016;Horvatetal.,2015;Larkinetal.,2015;Postowetal.,2015;Robert)etal.,2015b MechanismofCTLA-4inhibitoraction TherapeuticFDAapprovedtoreduceStatustheriskofmelanomarecurrenceaftersurgery(2015),andlatestagemelanoma(2011). =AdverseEventsAllIII Grades(%)55–6510–18 SKIN <Pruritus25–30*1 Rash33–34*2–3 Vitiligo3–40 GASTROINTESTINAL Diarrhea36–38*6–7 Colitis8–10*5–6 HEPATIC <<IncreasedALT11 <IncreasedAST1–21 <<Hepatitis11 ENDOCRINE <Hypothyroidism1–21 <Hyperthyroidism0–21 Hypophysitis2–3*2–3 <<Pneumonitis11
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Kumaretal. ManagementofirAEsSecondarytoICIs
â Alternativeimmunosuppressiveagentsshouldbeconsidered
∼∧PembrolizumabDurvalumabAtezolizumab((Hamidetal.,2013;Fehrenbacheretal.,Massard(Garonetal.,2015;2016;Rosenbergetal.,2016)Robertetal.,2015b;etal.,2016;Rittmeyer)Herbstetal.,2016;etal.,2017Nandaetal.,2016;Recketal.,2016;)Seiwertetal.,2016 <<11None1–21 <<11NoneNR e;AST,aspartateaminotransferase;NR,notreported.YearofFDAapprovaliswritteninthe ntswereincludedonlyiftheywerereportedasimmunerelatedoradverseeventsofspecial&675,206.FormerlyMDV9300.HasbeentestedindiffuselargeB-celllymphomaandmultiplemmunotherapyhavetestedthreeagents,ipilimumab,nivolumabandpembrolizumab.Dataon ââcââirc(ig2erwtaeo4a2rIfoieeuxFGIGnnnlCrniwunpqxwcamtodttIrrflchiiieuealnsersoaaec--aoiyqpsbeitPeddxiccrtmgciuktitsgkareibieeDliorhPmsniiriemnsopavtnra2o-Dsg2fycddtata1daoo–ieuioeslnb-seiftcneprr4eelsea1tmoyoden2ectasnp4/so.ai5,rt3rtasttetd3ihcecaaeniteoT,rtsbtdupol4nminstrmtni.sehc,oouelxoiiedo5dsa-s.Ioierdxiagcn:cPntroccnrteie/ilsbiflDaccdmoteekrnttrgeripssieiiangltet-nxies.elaayyi;nLtuasssineuscrmt,toy1tctsottefmmchoio,mipoInlaaopawClcaryenbegaannppobtnciIdsnhttsperseo5ftohbt1tdiwyoa.pndiiemse0btmocrhhtsoiiiopotosnmesoetrhg6cine.dpdneud/uigritishmkocwslmecssudooglssa/d3peamedrantleobtsrrmdnatekheioecserymeddaseaovoonisatmninnulmtweonttlyoioleeldnorsgdiyudptt7brfhhnletwpe.besioo5eoitopneeeniinnsmltldlogeaghuocrtrn1cceeoghirppatn2erpgianepedepn.manedrtrewrtniaHmfhtehreenoit1-esaend-opeoulassevCpldrnatwpiwneoke.maotTideewsniitesantceniLoovofhtiinfttnAinnefiuooiielstnnrgyeecrrrss-),
TABLE1|Continued @&Nivolumab(Ipilimumab(HodiTremelimumabTopalianPidilizumab(Bergeretal.,2010;Wolchoketal.,2012,2014;etal.,2008;ArmandTarhinietal.,2012;(etal.,2010;IbrahimWeberJ.S.etal.,etal.,2013;WestinRibasetal.,2013b;)etal.,2011;2013;Borghaeietal.,2014Calabroetal.,2015;)Eggermontetal.,etal.,2015;BrahmerKindleretal.,20162015,2016;Horvatetal.,2015;Larkinetal.,2015;Larkinetal.,2015;Rizvietal.,2015;Postowetal.,2015;Robertetal.,2015;Robertetal.,2015a;Ferrisetal.,2015betal.,2016)) <RenalFailure11None1–3*0–2None <<<<Neurological11None11None CTLA-4,cytotoxicT-lymphocyteantigen4;PD-1,programmeddeath;PD-L1,programmeddeathligand-1;ALT,alanineaminotransferasbracket.$#Currentdatasuggestthatthesetoxicitiesaremorecommonlyassociatedwiththisparticularagent.Eventdidnotoccur.Adverseeve*@interest(AESI).Headtoheadtrialstocomparetoxicitiesamongdifferentagentshavenotbeenconductedyet.Formerlyticilimumab,CP-∧∼myeloma.Immunerelatedadverseeventsdidnotoccurineitherstudy.FormerlyMPDL3280A.Formerlymedi4736.Majorityoftrialsonithetoxicitiesofnewercheckpointinhibitorsarestillaccumulating. ia2tibgbeBBhi1igatpeCrOESFoIoTtmnnroooemttnnle07yeafaaihATyancxflcxvointtva0)tradapmenooaswriiLiiEnamlelle5gepgeccae.ffy.dmitmAE,esau,)eniimutameCsaneatt.aui2fep2n-siteyymbemdrtcfmnsE0s4temr0et(nIok.nctefiaer,o0CinrrA1esaweseoistTsiuef-tfi5tanwr0rucstcrtnarpChpiahAnrnS)sltt)cdkoploahohia.ushreol.AeoAotneEmfpaneowpeiicserHtdsndfclbhgMarsadreettsuoherete,eeiotaldrmoyayivorsbspmnsgsdi1sandrwenaeocctctspneapeonrwvAictshriesdsenoereor.sitdieoianesopveesbfismtanenEltlleclttsoesrhttesoiespecoscmono(iirdpmseenloonir,Sauh(eaavEeeermrhreHlbapartlIedssadeon.vffioiairmisier,htonmnoanuoktheoenneGovcgprfptevwaxbn2ocauemwiveprderItsibnpee0tcrnniteaohsroiahtieasyre1ettdtuthetsouhneoelIss1psioiileotsmsefycnxe;aelriufentssfnintrmiosonuctsekpsscItteinhaSmrtpmedtrteiCastiipuyilhtndcmeivohat-.yiatiIpdh,iiueiRCnlgwwsoisnuettv.mtliiet,oifiam2nseiTnanhcoirdoecnfss0luolrttdofLntet2a,sare1ieaplrnoavlrtAtnn0esaaear3lheaobhoeoesa1sdrst-)opplxseotitfitit54.oblnhcornsorahueib)itpcieeeeerneagtHrn.ioraeodicspAambtrtnleebctmsoeyetnaiiiaetTntEepgmiptdneapfiitoartAeasihtbivsnhrsmtllynl,lsrmdreaeosba.oeietdk,dnemomwuetrrevyd(toaeiroetecnkhAesvohirur2ioatvirufenritenksnwarot0sneimsssispootsetsadti,i(1biierkooa(oirrtsBtaaoe4p1eolWdsthCplnxcsabnofeo)c7r(oiieepis..rDoncoeaecAseactfmwp4Ieiditp(bant1vCtnitOeA0IiairnioGeta7etvLtoaooe%lIiiirnnnnhdd7.aaerss--Itff,,
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Kumaretal. ManagementofirAEsSecondarytoICIs
2009; Hodi et al., 2010; Ibrahim et al., 2011; Tarhini et al., Gastrointestinal
2012; Calabro et al., 2015; Larkin et al., 2015; Kindler et al., Diarrhea and colitis are more common with anti-CTLA-4
2016) and 16–24% of patients treated with anti-PD-1/anti-PD- antibodies and are reported in 30–40% of patients treated with
L1antibodiesinsingle-agenttrials(Borghaeietal.,2015;Garon ipilimumab(Hodietal.,2010).Grade3/4diarrheaisseeninup
et al., 2015; Rizvi et al., 2015; Robert et al., 2015a,b; Nanda to 10% of patients on ipilimumab therapy and 1–2% of cases
et al., 2016; Reck et al., 2016; Rosenberg et al., 2016; Seiwert treated with anti-PD-1/anti-PD-L1 antibodies alone (Weber,
et al., 2016). This fatigue is usually mild, and the presence 2009; Ibrahim et al., 2011; Tarhini et al., 2012; Borghaei et al.,
of severe fatigue should trigger an assessment for underlying 2015; Calabro et al., 2015; Garon et al., 2015; Rizvi et al., 2015;
disorders such as endocrinopathies2,3,4,5. Infusion reactions, Robert et al., 2015b; Kindler et al., 2016; Nanda et al., 2016;
including fever and chills, are more common with CTLA-4 Rosenberg et al., 2016; Seiwert et al., 2016). Enteritis without
inhibitors accounting for AEs in phase III studies (Momtaz colonicinvolvementleadingtosmallbowelobstructioncanalso
et al., 2015). They are rarely high grade and may be managed beseen.Colitispredominantlyaffectsthedescendingcolon(Oble
supportivelywithantipyreticsandantihistamines(Villadolidand et al., 2008). Patients with significant diarrhea/colitis during
Amin,2015). ipilimumabtreatmenthavesubsequentlybeentreatedwithanti-
PD-1/anti-PD-L1antibodieswithoutdevelopingdiarrhea/colitis
Dermatological (Naidooetal.,2015).
Skinmanifestations,suchasrash/pruritusandmucositis,arethe Grade 1 gastrointestinal events are classified as increase in
most common irAEs associated with ICIs. Approximately 47– stool frequency of less than 4 per day or mildly increased
68% of patients treated with anti-CTLA-4 antibodies and 30– ostomy output from baseline (Table2). Mild cases should
40%patientstreatedwithanti-PD-1/anti-PD-L1antibodiessuffer be managed symptomatically with loperamide, oral hydration
skin toxicities of any grade (Weber, 2009; Hodi et al., 2010; and electrolyte replacement (Weber et al., 2015). Other
Wolchok et al., 2010; Ibrahim et al., 2011; Tarhini et al., 2012; etiologies such as infection with Clostridium difficile or other
Topalian et al., 2012; Ribas et al., 2013b; Topalian et al., 2014; viral/bacterial pathogens should be excluded (Du-Thanh et al.,
Postow et al., 2015; Borghaei et al., 2015; Calabro et al., 2015; 2015). The American Dietary Association colitis diet may
Garon etal.,2015;Larkinet al.,2015;Rizvietal.,2015;Robert also be beneficial2,3,4,5. Treatment with glucocorticoids is
et al., 2015a,b; Ferris et al., 2016; Kindler et al., 2016; Nanda indicated for worsening of symptoms or persistence beyond
et al., 2016; Rosenberg et al., 2016; Seiwert et al., 2016)1. The 3 days. Grade 2 severity events are 4–6 stools per day
characteristic rash is faintly erythematous and maculopapular, over baseline or a moderate increase in ostomy output.
involves the trunk and extremities and may be pruritic (Jaber These events are managed by oral diphenoxylate, atropine
etal.,2006).Vitiligoisalsocommonandhasdelayedappearance or budesonide, in addition to symptomatic treatment. It is
after several months of treatment with ICIs (Weber, 2012). important to rule out colitis by performing a colonoscopy
Histologicalanalysisshowsperivascularlymphocyticinfiltration in persistent grade 2 or grade 1 diarrhea with hematochezia.
deep in the dermis with CD4+ and CD8+ T cells in close Grade 2 diarrhea with bleeding/ulceration should be treated
proximitywithmelanocytes(Jaberetal.,2006).Thetreatmentof with oral glucocorticoids and interruption of immunotherapy.
symptomaticcaseswith topicalglucocorticoids (betamethasone Grade 3 events include diarrhea with 7 or more stools
0.1% cream) or urea-containing creams and oral antipruritic per day above the baseline, incontinence or severe increase
agents(diphenhydramine,hydroxyzine,GABAagonists,orNK- in ostomy limiting self-care activities. Grade 4 is any life-
1 receptor antagonists) for troublesome pruritus is usually threatening complication, such as bowel perforation, requiring
sufficient (Weber, 2012; Horvat et al., 2015). The majority of acute intervention. Grade 3 and 4 events should be treated
skin eruptions are mild, and immunotherapy can be continued with intravenous glucocorticoids in addition to symptomatic
in most patients (Weber, 2012). Severe (Grade 3 defined as treatment2,3,4,5.
papules and/or rash covering >30% BSA) cases should be The symptomatic improvement should be noted in 48–
treatedwithoralglucocorticoidsfor3–4weeks,withtemporary 72h.Hospitalizationiswarrantedforparenteralglucocorticoids
discontinuation of ICIs (Table2). Permanent discontinuation with fluid and electrolyte management in cases refractory to
should be considered in more severe cases, such as Stevens– oral glucocorticoids (Weber, 2012; Weber et al., 2015). If
Johnsonsyndrome,butfortunatelysevereirAEsarerare.Patients the symptoms fail to resolve after 3 days on intravenous
who fail to respond to steroids or have bullae formation merit glucocorticoids (methylprednisolone 2 mg/kg or equivalent),
dermatologic evaluation and skin biopsy. Oral mucositis and then infliximab should be given at a dose of 5 mg/kg every 2
dryness are seen more frequently with anti-PD-1/anti-PD-L1 weeks2,3,4,5. The use of infliximab for this indication is based
antibodies than with anti-CTLA-4 antibodies (Weber, 2009; onitsefficacyinCrohn’sdisease(Minoretal.,2009).However,
Ibrahim et al., 2011; Tarhini et al., 2012; Borghaei et al., therecommendationsarenotclearfornon-resolvingsymptoms
2015; Calabro et al., 2015; Garon et al., 2015; Rizvi et al., oninfliximabtherapy,andprolongedcoursesofglucocorticoids
2015; Robert et al., 2015b; Kindler et al., 2016; Nanda et al., are preferred. These patients should be cautiously observed
2016; Rosenberg et al., 2016; Seiwert et al., 2016). Topical for GI complications, including perforation and obstruction.
glucocorticoids and lidocaine are used for treatment. These The prompt intervention is mandatory because colitis related
lesions may mimic oral candidiasis, which should be ruled mortality has been attributed to delayed reporting and lack of
out2,3,4,5. ICI withholding (Naidoo et al., 2015). The efficacy of matrix
FrontiersinPharmacology|www.frontiersin.org 5 February2017|Volume8|Article49
Kumaretal. ManagementofirAEsSecondarytoICIs
TABLE2|Summaryofmanagementofselectedimmunerelatedadverseevents(irAEs).
S.N. Organsystem Manifestations Management
1. Dermatological Immunemediateddermatitis q Diagnosis:Mucocutaneousexamination.
q Mostcommonmanifestationandearliestto Grade*1:Rashaffecting<10%BSA. q Treatment:Continueimmunotherapy
occur. MostlyAsymptomatic Symptomatictreatmentwithoralantihistaminic
q Seenin2–3weeksafterinitiationoftreatment drugs.
withipilimumab. Topicalsteroids.
q Commonlyseenafterthefirstdose.
q Manifestsasmaculopapularrash,erythema, Grade2:Rashaffecting10–30%BSA. q Diagnosis:clinicalexaminationandlabtesting
pruritus,dryskin,alopeciaorhypertrichosis, forLFTs,KFTs,serumtryptaseandIgElevels
lichenoidkeratosisandvitiligo. q Treatment:Withholdimmunotherapy**.
MorecommonwithCTLA-4inhibitors.Seenin Resumeaftertoxicityimprovestograde1or
upto47–68%patientonanti-CTLA-4therapy lower@.
and30–40%patientsonanti-PD-1/anti-PD-L1 Symptomatictreatmentwithoralantihistaminic
therapy.Mucositisandvitiligoaremorecommon drugs.
inpatientsreceivinganti-PD-1/anti-PD-L1 OralPrednisone0.5–1mg/kg/dayorequivalent
agents taperover4weeksifsymptomsresolve.
Grade3/4:Rashcovering>30%BSA. q Diagnosis:Asingrade2plusskinbiopsy
Severelifethreateningsymptoms q Treatment:Withholdimmunotherapy.
Generalizedexfoliative/ulceratedrash ConsultDermatologist.
Resumeaftertoxicityimprovestograde1or
lower.
Symptomatictreatmentwithoralantihistaminic
drugs.
OralPrednisone#1–2mg/kg/dayorequivalent
taperover4weeksifsymptomsresolve.
Consideralternativeimmunosuppressiveagent
(Cyclophosphamide,Mycophenolatemofetil,or
Infliximab)ifsymptomsdon’timproveafter48h.
2. Gastrointestinal Immunemediatedcolitis q Diagnosis: stool microscopic examination for
q Seen5–10weekslatertypicallyafter2nddose Grade1:=4stools/dayoverbaseline.Mild ova,parasitesandstoolculture.Stoolantigenfor
ofipilimumab. abdominalsymptoms c.difficileifsuspectedclinically.Labtestingfor
q Manifestsasincreaseinstoolfrequency,diarrhea LFTsandKFTs.
orconstipation,bloodormucusinstool, q Treatment:Continueimmunotherapy.
abdominalpain/cramping,nauseaandvomiting. Symptomatictreatmentandmonitorforfluid
q Morecommonwithanti-CTLA-4therapy electrolytesbalance.AmericandietAssociation
(30–40%).Grade3and4toxicities1n10% (ADA)colitisdiet,loperamideoratropinesulfate.
patientsagainst1–2%onanti-PD-1/anti-PD-L1 Budesonidecanbetriedifsymptomspersist
therapy beyond2–3days.
Grade2:Moderatenewsymptoms. q Diagnosis: As above in grade 1. Evaluate for
4–6stools/dayoverbaseline. othercauseslikeprogressionofprimarydisease.
Colonoscopymaybebeneficialinselectedcases.
q Treatment:withholdimmunotherapy.If
symptomsimprovetogradeIresume
immunotherapy.
Symptomatictreatment.
Ifsymptomsarepersistentbeyond5–7days
startoralprednisone1mg/kg/dayorequivalent.
Taperover4weeksifsymptomsimprove.Start
Infliximab5mg/kgevery2weeksifsymptoms
don’timproveafter3daysonsteroidtreatment.
Grade3/4:Severegrade.=7stools/dayover q Diagnosis:Ruleoutinfectiousandothercauses
baseline. asabove.
Severeandpersistentabdominalpain,fever, GIconsultandendoscopyinselectedcases
ileus. q Treatment:Discontinueimmunotherapy
Lifethreateningcomplicationslikeintestinal I.V.Methylprednisone2–4mg/kg/dayor
perforationandperitonitis equivalenttaperover4weeksifsymptoms
resolve.
Consideralternativeimmunosuppressiveagent
(Cyclophosphamideormycophenolatemofetil)if
symptomsdon’timproveafter48h.Monitorfor
intestinalperforation.
(Continued)
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Kumaretal. ManagementofirAEsSecondarytoICIs
TABLE2|Continued
S.N. Organsystem Manifestations Management
3. Hepatic Immunemediatedhepatitis q Diagnosis:LFTs.
q Appears12–16weeksafterinitiationof Grade1:Asymptomatic/mildlysymptomatic q Treatment:Continueimmunotherapyif
treatmentwithipilimumab. AST/ALTof2.5×ULN asymptomatic.
q Typicallyseenafterthe3rddoseofcheckpoint TotalBilirubinof1.5×ULN MonitorLFTsuntilresolution
inhibitortreatment. Grade2:Symptomatic. q Diagnosis: Rule out viral, drug induced or
q Mostlyasymptomaticelevationofliverenzyme. AST/ALTof2.5–5×ULN autoimmunecauses.
Fever,fatigueandjaundicemaybeseeninsome TotalBilirubinof1.5–3×ULN Monitor LFTs daily till resolution followed by
patients. weeklytesting.
q Manifestsin<10%patientsonanti-CTLA-4 q Treatment:Withholdimmunotherapy.
therapybutin∼20%patientsoncombination Resumeaftertoxicityimprovestograde1or
(anti-CTLA-4plusanti-PD-1/anti-PD-L1)therapy. lower.
OralPrednisone1mg/kg/dayorequivalenttaper
over4weeksifsymptomsresolve.
Consideralternativeimmunosuppressiveagent
(tacrolimus,cyclophosphamideor
mycophenolatemofetil)ifsymptomsdon’t
improveafter48h.Infliximabiscontraindicated
duetopotentialhepatotoxicity.
Grade3/4:Symptomsasabove. q Diagnosis: Asingrade2plusimagingtorule
AST/ALTof5×ULN out malignant etiology. Monitor LFTs daily till
TotalBilirubinof3×ULN resolution.
q Treatment:Discontinueimmunotherapy
I.V.Methylprednisone2–4mg/kg/dayor
equivalenttaperover4weeksifsymptoms
resolve.
Ifnoimprovementafter5–7days,add
tacrolimus0.10–0.15mg/kg/day(troughlevel
5–20ng/mL).Consideralternativeagents
(cyclophosphamideormycophenolatemofetil),if
noresponsedespitetherapeuticlevels.
Infliximabiscontraindicated.
4. Pulmonary Immunemediatedpneumonitis q Diagnosis: Radiological imaging using High
q Seenafter8–14weeksof1stdoseof Grade1:Asymptomatic,onlyradiological resolutioncomputedtomography(HRCTchest).
ipilimumab. changes. RepeatCTbeforeeverycycle
q Asymptomaticappearanceofinfiltratesonlung q Treatment:Withholdimmunotherapyfor2–4
imagingismorecommon. weeks.
q Symptomaticpneumonitisisseenin=1%. Monitorforsymptomsevery3days.
Morecommonwithanti-PD-1/anti-PD-L1than Ifnewsymptomsdevelop,treatashighergrade.
anti-CTLA-4therapy
Grade2:Mild/Moderatenewsymptoms q Diagnosis: As above plus microbiological
limitinginstrumentalactivitiesofdailyliving. assessment like sputum examination and
cultures.
q Treatment:withholdimmunotherapy.If
symptomsimprovetograde1within72h
resumeimmunotherapyotherwisediscontinue
immunotherapy.AlsoDiscontinuetherapy
inrecurrentgrade2pneumonitis.
Monitorforsymptomsdaily.
Oralprednisone1mg/kg/dayorequivalent.
Taperover4weeksifsymptomsimprove.
Grade3/4:Severesymptomslimitingself-care q Diagnosis: Rule out infectious and other
activitiesofdailyliving.HypoxiaorRespiratory pulmonarycauses.
failurerequiringurgentinterventionslike Pulmonaryconsultandbronchoscopy
endotrachealintubationortracheostomy. q Treatment:Discontinueimmunotherapy
I.V.Methylprednisone2–4mg/kg/dayor
equivalenttaperover4weeksifsymptoms
resolve.
Considerprophylacticantibiotics.Consider
alternativeimmunosuppressiveagent
(CyclophosphamideorInfliximab)ifsymptoms
don’timproveafter48h.
(Continued)
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Kumaretal. ManagementofirAEsSecondarytoICIs
TABLE2|Continued
S.N. Organsystem Manifestations Management
5. Endocrine Immune-mediatedendocrinopathies q Diagnosis: Complete blood count,
q Generallyseen9weeksafterinitiationof Grade1:Asymptomaticormildsymptoms; comprehensive metabolic profile. Consult
ipilimumabtreatment. clinicalordiagnosticobservationsonly; endocrine
q Immunerelatedthyroiditis interventionnotindicated Thyroiditis: TSH. If TSH is below 0.5 × ULN
Hypothyroidism/Hyperthyroidism: orabove2×ULNorconsistentlyoutofnormal
Fatigue,weakness,asthenia,newonsetatrial rangeinsubsequentcyclesconsideraddingfree
fibrillation,constipation/diarrhea,cold/heat T3andT4.
intolerance,dryskin/excessivediaphoresis, Adrenalitis: ACTH, Morning serum cortisol-if
weightgain/weightloss. abnormalCosyntropinstimulationtest.
q Immune-mediatedadrenalitis:Asthenia, Hypophysitis: LH/FSH/Testosterone, Prolactin.
failuretothrive,anorexia,nausea,vomiting,fever, MRI brain with pituitary cuts and visual field
coma,hypotension,hypoglycemia,eosinophilia. testingifindicated.
q Immune-mediatedhypophysitis: q Treatment:Continueimmunotherapy.
Headache,visualfielddefects,blurringofvision, Monitorforsymptoms.Ifworsenstreatashigher
impotence,amenorrhea grades.
Treatforhyperorhypothyroidismifindicated
Hypothyroidismismorecommonwithanti-CTLA-4 Grade2:Moderate;minimal,localor q Diagnosis:Asaboveingrade1.
whilehypophysitisandhyperthyroidismisseen noninvasive;interventionindicated;limiting q Treatment:
morecommonlywithanti-PD-1/anti-PD-L1therapy age-appropriateinstrumentalADL 1.Hyper/Hypothyroidism-continue
immunotherapy
2.Adrenalitis:continueimmunotherapy.
3.Hypophysitis$:Withholdimmunotherapy.
Prednisone1–2mg/kg/dayorequivalent.Taper
over>4weeksbeforeresumingimmunotherapy.
Replacedeficienthormone.Ifpatientdeveloped
hypophysitisonipilimumab,itcanbereplaced
withpembrolizumabfromnextcycle.
Grade3:Severeormedicallysignificantbutnot q Diagnosis:Asaboveingrade1.
immediatelylife-threatening;hospitalizationor q Treatment:
prolongationofexistinghospitalization 1.Hyper/Hypothyroidism:continue
indicated;disabling;limitingADLandself-care immunotherapy.Treatmentof
hypo/hyperthyroidismasperstandard
guidelines.
2.Adrenalinsufficiency:withhold
immunotherapy.Prednisone1–2mg/kg/dayor
equivalent.Taperover>4weeksbefore
resumingimmunotherapy.
3.Hypophysitis:permanentlydiscontinue
immunotherapy.Prednisone1–2mg/kg/dayor
equivalent.Taperover>4weeks.Fewpatients
mayrequirehormonereplacementtherapyfor
life.
Grade4:Life-threateningconsequences; q Diagnosis:Asaboveingrade1.
urgentinterventionindicated q Treatment:
1.Hyper/Hypothyroidism:continue
immunotherapy.Treatmentof
hypo/hyperthyroidismasperstandard
guidelines.
2.Adrenalinsufficiency:Permanently
discontinueimmunotherapy.Prednisone
1–2mg/kg/dayorequivalent.Taperover>4
weeksbeforeresumingimmunotherapy.
Ifinadrenalcrisisstabilizethepatientpriorto
endocrinework-up.Ruleoutsepsis.Ifinshock,
startwithstressdosesteroids,antibioticsandiv
fluids.
3.Hypophysitis:permanentlydiscontinue
immunotherapy.Prednisone1–2mg/kg/dayor
equivalent.Taperover>4weeks.Fewpatients
mayrequirehormonereplacementtherapyfor
life.
(Continued)
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Kumaretal. ManagementofirAEsSecondarytoICIs
TABLE2|Continued
S.N. Organsystem Manifestations Management
6. Renal ImmunemediatedRenaldysfunction q Diagnosis:KidneyFunctionTests,Urineanalysis
q Seen14–42weeksafterinitiationoftreatment. Grade1:↑creatinineabovethebaselinebut q Treatment:Continueimmunotherapy.
q Rarewithbothanti-CTLA-4and =1.5ULN Symptomatictreatmentandmonitorforfluid
anti-PD-1/anti-PD-L1therapy electrolytesbalance.
Grade2and3:creatinine1.5–6mg/dlULN q Diagnosis: As in grade 1. Monitor creatinine
every2–3days.Considerrenalbiopsy.
q Treatment:Withholdimmunotherapy.
OralPrednisone0.5–1mg/kg/dayorequivalent,
ifnoresponse↑to1–2mg/kg/dayand
discontinueimmunotherapypermanently.If
elevationpersists=7daystreatasgrade4.
Grade4:creatinine>6mg/dlULN q Diagnosis:Asingrade1.Monitorcreatinine
everyday.Considerrenalbiopsy.Consult
nephrology
Treatment:Withholdimmunotherapy.
OralPrednisone1–2mg/kg/day.Taperatleast
over4weeks.
7. Neurologic Immune-mediatedneurologicaladverse q Diagnosis:Clinicalexamination
Headache,fever,stiffness,memoryproblem, reactions q Treatment:Continueimmunotherapy.
confusion,drowsiness,hallucinations,seizures, Grade1:Asymptomaticormildlysymptomatic Monitorforprogressionofdisease.
peripheralneuropathy
Rarewithbothanti-CTLA-4and Grade2:Newonsetmoderatesymptoms q Diagnosis:Monitorforprogressionofdisease.
anti-PD-1/anti-PD-L1therapy limitinginstrumentalactivitiesofdailyliving. q Treatment:Withholdimmunotherapy.
Considerconsultingneurology.Oralprednisone
0.5–1mg/kg/dayorequivalent.Ifnoresponse
treatasgrade3and4.
Grade3and4:Newonsetseveresymptoms q Diagnosis: MRI brain, lumbar puncture, nerve
affectingself-careactivitiesofdailyliving.Life conduction velocity, electromyography, skin,
threatening. nerveormusclebiopsyasclinicallyindicated.
q Treatment:Permanentlydiscontinue
immunotherapy.Consultneurology.
Prednisone1–2mg/kg/dayorequivalent.Taper
overatleast4weeks.Ifworsensoratypical
presentationconsiderotherimmunosuppressive
agents.
ADL,activitiesofdailyliving;ALT,alanineaminotransferase;AST,aspartateaminotransferase;BSA,bodysurfacearea;CTLA-4,cytotoxicT-lymphocyteantigen-4;FSH,follicular
stimulatinghormone;KFT,kidneyfunctiontest;LFT,liverfunctiontests;LH,luteinizinghormone;MRI,magneticresonanceimaging;PD-1,programmedcelldeath;PD-L1,programmed
celldeathligand-1;TSH,thyroidstimulatinghormone;ULN,upperlimitofnormal.
ForReferencesseetext.
*CommonTerminatingCriteriaforAdverseEventsGrading.
#Patientsreceivingprednisone=20mg/dayorequivalentdosesforatleast4weeksarecandidatesforpneumocystisjiroveciiprophylaxisasperNationalComprehensiveCancer
NetworkNCCNguidelines.
**Treatmentwithcheckpointinhibitorsispermanentlydiscontinuedingrade2toxicityifitpersistsbeyond6weeks.HoweverPD-1inhibitorscanbecontinuedwithhormonereplacement
inendocrinopathies.
@Nivolumabispermanentlydiscontinuedifprednisonecan’tbetaperedto<7.5mg/dayorequivalentwithoutrecurrenceofsymptomsandipilimumabisdiscontinuedifprednisone
can’tbetaperedbelow10mg/kg/dayorequivalentdose.
$Prednisonedoseinhypophysitisiscontroversial.Newdatasuggeststhatphysiologicaldoseisaseffectiveashigherdosesadvocatedpreviously.Seetext.
budesonide for prophylaxis against colitis has not been proven cycleofimmunotherapy.Thepatientsshouldalsobemonitored
andisnotrecommended(Weberetal.,2009). regularly during the post-treatment period. An asymptomatic
elevation of hepatic transaminases and hyperbilirubinemia is
Hepatic common, and concomitant fever can also occur (Weber,
Hepatotoxicity can be caused by both anti-CTLA-4 and 2012). Liver biopsy is reserved for unclear cases and reveals
anti-PD-1/anti-PD-L1antibodies.Hepatotoxicityoccursin2–9% prominent sinusoidal histiocytic infiltrates and central vein
of patients (Weber, 2009; Ibrahim et al., 2011; Tarhini et al., damage with endotheliitis suggestive of ipilimumab-associated
2012; Borghaei et al., 2015; Calabro et al., 2015; Garon et al., hepatitis (Johncilla et al., 2015). Grade 2 reactions require
2015;Rizvietal.,2015;Robertetal.,2015b;Kindleretal.,2016; interruption of cancer treatment, with daily or alternate-day
Nanda et al., 2016; Rosenberg et al., 2016; Seiwert et al., 2016). monitoring of liver enzymes until they decrease, and then
Liver function should be tested at baseline and prior to each subsequent weekly assessments (Table2). Grade 3 or greater
FrontiersinPharmacology|www.frontiersin.org 9 February2017|Volume8|Article49
Kumaretal. ManagementofirAEsSecondarytoICIs
irAEs involve AST/ALT levels >5 times upper limit of normal emergency that mandates hospitalization, evaluation by an
(ULN)orbilirubin>3timesULN.Severehepatotoxicityrequires endocrinologist and treatment with methylprednisolone.
high-dose intravenous glucocorticoids for 24–48 h followed It is important to distinguish this condition from
by a slow taper for the next 30 days. The glucocorticoids sepsis, and prompt testing with cultures is mandatory
should be switched to mycophenolate 500mg every 12h if the (Table2).
liver enzymes are still elevated after 48 h of treatment2,3,4,5.
Pulmonary
The use of infliximab is contraindicated due its potential
hepatotoxicity. The differential diagnoses of immunotherapy- Grade 3 or higher pneumonitis has been reported in 5–7% of
induced liver damage include metastasis to the liver, viral NSCLC patients treated with nivolumab and pembrolizumab
hepatitis and other drug toxicity meriting extensive analysis. (Langer,2015;Abdel-RahmanandFouad,2016).Theincidence
Hepatitis persisting for longer periods requires prolonged or of symptomatic pneumonitis is only 1% with ipilimumab
repeatedglucocorticoidstapering(≥4weeks)and/oradditional (Barjaktarevic et al., 2013). The risk increased in patients
immunosuppression2,3,4,5. with prior thoracic radiation. There have been reported
granulomatous reactions similar to sarcoidosis (Berthod et al.,
Endocrine 2012). The presence of infiltrates on chest radiographs or
Endocrinopathies can occur secondary to inflammation of the CT imaging is more common and resolves rapidly after
pituitary, thyroid and adrenal glands or may be related to withholding the drug. Pneumonitis should be excluded by CT
development of type-1 diabetes mellitus. Clinical presentation imaging in any patient with cough, shortness of breath, and
is confounded by nonspecific symptoms such as behavioral fever2,3,4,5. A bronchoscopy may reveal diffuse lymphocytic
changes, nausea, headache, fatigue and visual complaints infiltration and should be performed in moderate to severe
(Corselloetal.,2013).Hypophysitisandhypothyroidismarethe cases to exclude infections. Severe cases should be treated with
most common endocrinopathies seen in up to 10% of patients glucocorticoidsusing2mg/kgintravenousmethylprednisolone.
treatedwithanti-CTLA-4andanti-PD-1/anti-PD-L1antibodies Immunotherapy should be permanently discontinued in cases
(Weber, 2009; Hodi et al., 2010; Wolchok et al., 2010; Ibrahim withrecurrentgrade2–4irAEs(Table2)2,3,4,5.
etal.,2011;Topalianetal.,2012,2014;Tarhinietal.,2012;Ribas
Rare Events
et al., 2013b; Borghaei et al., 2015; Calabro et al., 2015; Garon
Ocular
et al., 2015; Larkin et al., 2015; Postow et al., 2015; Rizvi et al.,
Common ocular manifestations include episcleritis,
2015;Robertetal.,2015a,b;Ferrisetal.,2016;Kindleretal.,2016;
Nandaetal.,2016;Seiwertetal.,2016;Rosenbergetal.,2016)1. conjunctivitis and uveitis. The incidence of these events is
higherwithipilimumabbutremainslessthan1%(Huillardetal.,
Hypophysitis with pituitary dysfunction requires testing
2014;AbuSamraetal.,2016).Thepatientshouldbereferredto
for thyroid stimulating hormone (TSH), serum cortisol,
anophthalmologistandtreatmentwithtopicalglucocorticoidsis
adrenocorticotropichormone(ACTH),growthhormone(GH),
requiredinmostcases.Theuseoforalglucocorticoidtherapyis
prolactin, luteinizing hormone (LH), and follicular stimulating
reservedforsevereevents.
hormone (FSH) in women or testosterone levels in men.
Diagnosis is based on clinical symptoms with radiographic
Renal
abnormalities (pituitary enlargement with enhancement) and
ICIscancauseacutekidneyinjurythatpresentssimilartoother
biochemical test results (low tropic hormones)2,3,4,5. The role
drug-induced tubulointerstitial nephritis. The median duration
of high dose glucocorticoids (1 mg/kg prednisone daily) is
for the appearance of the kidney injury is 13 weeks (Cortazar
controversial in cases with suspected hypophysitis. The use of
etal.,2016).Inadditiontonephritis,granulomatouslesionsand
physiological replacement doses has been suggested, and high
thrombotic microangiopathy can also be seen on renal biopsy.
doses should be reserved for patients with symptoms related
A previous study demonstrated that renal function partially
to mass effects such as severe headaches or visual disturbances
improved after glucocorticoid treatment, and that one-third of
(Albareletal.,2015).ArecentstudyreportedthatTSHandFSH
patients required dialysis (Cortazar et al., 2016). Grade 2 or
normalized after a follow-up period of 33 months. However, higher toxicity is treated with glucocorticoids (Table2). The
ACTHremainedlow,withpersistentpituitaryabnormalitieson
immunotherapy should be withheld for Grade 2–3 events and
MRIirrespectiveofglucocorticoiddose(Albareletal.,2015;Min
permanentlydiscontinuedforGrade4eventsorresistantGrade
etal.,2015).
2–3irAEs2,3,4,5.
Theroutinemonitoringofthyroidfunctionisindicatedbefore
each dose of ipilimumab. Hypothyroidism is more common Pancreatic
than hyperthyroidism. It is important to distinguish primary Routinemonitoringofamylase/lipaseinotherwiseasymptomatic
hypothyroidism (low free T4 with high TSH) from secondary individuals is not recommended. Asymptomatic elevation does
disease(lowfreeT4withlowTSH)causedbyhypophysitis.The notrequiretreatment.Thesignificanceofelevatedamylaseand
treatment of hypo and hyperthyroidism should be consistent lipaseinalargenumberofpatientsremainsunclear(Ribasetal.,
withstandardguidelines(Table2)2,3,4,5.Immunotherapycanbe 2013b;Postowetal.,2015;Herbstetal.,2016).
continuedwithhormonereplacement.
Hypophysitis2,3,4,5 with clinically significant adrenal Neurological
insufficiency(hypotension,dehydration,anddyselectrolytemia) The reported neurologic complications of immunotherapies
is equivalent to adrenal crisis and is a medical include posterior reversible encephalopathy syndrome (Maur
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