Risk Stratification for Fungal Infections in Hematological ...€¦ · Antifungal resistance in...

LivioPagano,AlessandroBusca,AnnaCandoni,ChiaraCattaneo,SimoneCesaro,

RosaFanci,GianpaoloNadali,LeonardoPotenza,DomenicoRusso,Mario

Tumbarello,AnnamariaNosari,FrancoAversa

onbehalfSEIFEMGroup

RiskStratificationforFungalInfectionsin

HematologicalMalignanciesPatients:SEIFEMrecommendations

SEIFEM

Butnotonly……

AML MDS ALL CLD MPN PEDIATR AUTO ALLO

AnnaCandoni

RosaFanci

ChiaraCattaneo

LeonardoPotenza

GianpaoloNadali

SimoneCesaro

DomenicoRusso

AlessandroBusca

FedericaLessi(Padova)

MariannaCriscuolo(UCSC)

FrancescaFarina(Monza)

MariaChiaraTisi(UCSC)

GloriaTurri(Verona)

AngelicaBarone(Parma)

AngelicaSpolzino(Parma)

MarcoSanna(Cagliari)

IlariaDelPrincipe(TorVergata)

AngelamariaQuinto(Padova)

RobertaDiBlasi(UCSC)

LauraMaracci(Ancona)

BenedettaCambò(Parma)

AnnaPegoraro(Verona)

FrancescoMarchesi(IFO-Roma)

LuciaPrezioso(Parma)

MitjaNabergoj(Padova)

SilviaPascale(Pescara)

AngelaPassi(Brescia)

MelaniaCarlisi(Palermo)

NicolaPolverelli(Bologna)

BarbaraBeggia(S.Giovanni-RM)

BenedettaRambaldi(Brescia)

Anancientsayingsays:“inthedarknessallcatsappeargray”

UNDERLYINGCONDITIONØ neutropeniaØ progressivecancerØ chemotherapyØ T-cellsuppressorØ GVHDØ Steroids

INNATEIMMUNESTATUSØ Toll-likerec.polymorphismØ Plasminogenpolymorphism

Ø MannosebindinglectinØ Otherpolymorphism

ENVIRONMENTØ climateØ constructionworksØ tobacco,cannabisØ placeofresidenceØ pets,pottedplantsØ gardening

COMORBIDITIESØ diabetes

Ø ironoverloadØ trauma,burns

Ø renalimpairmentØ metabolicacidosis

Ø priorrespiratorydisease

Ø Hematol.malignancyØ Transplantprocedures

AdaptedfromHerbrechtetal.2012AGE !!

RiskofInvasiveFungalInfection

Molds Yeasts1.   AGE≥50y2.   PERFORMANCESTATUS>23.   DIABETES4.   COPD5.   LIVERDISEASE6.   SMOKING7.   COCAINE8.   HIGHRISKJOB9.   HIGHRISKHOBBY10.   HOUSERENOVATION

0.015<0.0010.0050.005---

0.0210.006<0.0010.017<0.001

------------0.05---------------

v  <0.5 x 109/l: risk of infection v  <0.1 x 109/l: high risk of IFI

Neutrophils X 109/l

Time (days)

0.5 0.1

maximum risk

2 4 6 8 10 12

ModifiedfromBodeyetal,AnninternMed1966

Neutropenia:acommonriskfactorforIFI

DysplasticvsnormalPMN:↓fungicidalactivityagainstyeasts

↑susceptibilitytoinfectionsinmyelodysplasia

10

102

103

104

105

106

8 h 24 h 48 h 72 h Time of incubation

CFU

LMMoC AR AR LMMoC LMMoC LMMoC LMMoC AR AR AR AR AR AREB AREB AR ARSA Controllo Controllo+SD Controllo -SD

Fianchi et al, Leuk Res 2012

Lower microbicidal response rates for bacteria but not fungi in CLL patients than in age-matched controls

NeutropeniaisnolongertheonlyprimaryriskfactorforIFIinaploidenticalorT-

depletedHSCT

VanBuriketal,AnninternMed1966

RiskofIAafterreceivingprednisoloneinstratifieddosesandtimeintervals

Thurskyetal,BMT2004

Notonlyhighdosesbutalsoprolongedtreatment

Leukemicpatients=HEAVELYTRANSFUSEDIRONOVERLOAD=highavailabilityoffreeiron(FI)

FreeIron:

v Actasafreecalalysercausingmucositisv Hasnegativeeffectonantimicrobialfunctionsofneutrophils,monocytes,NKandmacrophagesv Isusedbyfungitopromotetheirgrowth 18%

70%

0%

20%

40%

60%

80%

100%

Controls Pts with IA

BoneMarrowIronStoresscore≥3

p-value<0.0001

Theuseofairfiltersreducestheincidenceofinvasiveaspergillosis

THE PAST-PAST

Martino&Viscoli,BrJHaematol2006THE PAST

AML-BASELINE (Risk assessment 1)

HIGH RISK INTERMEDIATE RISK LOW RISK

Fluconazole Prophylaxis and DD-AFT

Fluconazole Prophylaxis No Serial GM Mold Active Azole Prophylaxis

Host factors AML related factors

Treatment related factors Fungal Exposure

DINAMIC RISK ASSESSMENT in AML

AML-DAY 15 BM (Risk assessment 2)

HIGH RISK

PERSISTENCE OF BM BLAST CELLS

Nucci et al, Blood 2014

AN INTRIGUING PRESENT

WhyariskstratificationofIFIisnecessary?

•  Costsfordiagnosisandtreatment•  Antifungalresistance•  Drug-druginteractionbetweenantifungal,

antineoplasticandimmunosuppressiveagents

•  Needforarisk-adaptedprophylaxis,diagnosticworkupsandtreatments(empiricvspre-emptive)

Buscaetal.

Antifungalresistanceinpatientswithhaematologicalmalignanciesdoesnotappeartorepresentarelevantproblem,atleastatpresent.Itis

temptingtospeculatethatthewidespreaduseofantifungalprophylaxiswithextended-spectrumazoleshinderingtheeffectivedetectionof

isolatesmightcontributetounderstatetherealmagnitudeofresistancetoantifungalagentsinhaematologicalpatients.

AnandaRajahetal,AAC2011

Issuestobeaddressed

•  RiskfactorsinHMsotherthanAMLsandHSCTs.

•  Riskfactorsindifferentphasesoftreatments(i.e.AMLsinconsolidationorresistant-relapse).

•  Riskfactorsmaychangeday-by-day(“dynamicrisk”)

Methodology AsystematicliteraturereviewwasperformedusingthePubMed

databaseforpublicationsuntilSeptember2015forthefollowingMeSHterms:neutropenia,treatment,hematological

malignancies,stemcelltransplantation,fungalinfection,aspergillosis,candidema,riskfactors.

TheattentionwasfocusedontheepidemiologyandriskfactorsforIFI

Thegroupco-authoringreviewedallthepublicationsidentifiedandpreparedaslidesetcomprisingevidence-basedstatementsandrecommendationspresentedtotheplenarysessiononthe

annualSEIFEM-Groupmeeting,10th2015.Afterrevisionaccordingtotheresultsoftheplenarydiscussion,asummarizing

slidesetwasmade.

Topictreated:RiskfactorsforIFIin

•  AML • MDS •  ALL• MPN•  CLD

•  autologousHSCT•  allogeneicHSCT

•  Pediatricsubset

Reference StudyType PhaseofLeukemia Patient’scharacteristics TypeofInfection IFI-Incidence

Glasmacher2006randomized,prospective,multicentric

Inductionandconsolidation

248(ALL13,7%,AML69,0%,CMLBC4,4%,Lymphoma

10,1%,MM0%,other2,8%)

InvasiveAspergillosis(IA),provenIFI,suspectedIFI(notavailableEORTC

criteria)

proven1,6%(IA0,8%,candidiasis0,4%,other0,4%),suspected8,9%

246(ALL10,6%,AML76,9%,CMLBC2,8%,

Lymphoma5,7%,MM0,8%,other3,3%)

proven2,0%(IA1,2%,candidiasis0,4%,other0,4%),suspected11,4%

Cornely2007randomized,prospective,multicentric

induction 304(AML84%,MDS16%) possible/proven/probable(EORTC2002)

proven/probable2%(1%moulds,1%yeast)

298(AML87%,MDS13%) proven/probable 8%(7%moulds,<1%yeast)

240(AML88%,MDS12%) proven/probable 8%(7%moulds,<1%yeast)

58(AML83%,MDS17%) proven/probable 10%(moulds)

Pagano2007 prospective,multicentric NA 237AML proven/probableIA 12,7%

Pagano2012 prospective,multicentric induction 576AML possible/proven/probable 22,3%

Caira2015 prospectivemulticentric 881AML

possible/proven/probable

24,2%

Mattiuzzi2009 prospectivemonocentric

Inductionandreinduction 71(77%AML,23%MDS) proven/probable

(EORTC2002) 0%

Vehreschild2010 prospectivemonocentric induction 77AML possible/proven/probable

(EORTC2002) 3,9%(2,6%IA;1,3%candidiasi)

Tang2015 prospectivemonocentric induction 298AML possible/proven/probable 5,7%proven;5%probable;23,9%possible

EpidemiologyofIFIinAML(1)

EpidemiologyofIFIinAML(2)Reference StudyType Phaseofleukemia Patient’s

characteristics TypeofInfection IFI-Incidence

Bohm2005 retrospectivemonocentric

inductionandconsolidation 82AML(induction) proven/probable 19,5%(13,4%IA;6,1%

candidiasis)

44AML(consolidation) proven/probable 0%

Pagano2006 retrospectivemulticentric

Induction,reinduction,consolidation 3012AML proven/probable 12,3%(7,9%molds;4,4%

yeast)

Nihtinen2008 retrospectivemonocentric

inductionandconsolidation 847AML acuteorchronic

candidainfections 8,7%

242AML 8,7%

induction 157AML 11%candidiasis,1%IA

Inductionandreinduction

52(75%AML,25%MDS) 4%

Michallet2011 retrospectivemonocentric induction 121AML possible/probable 3,2%posaconazolo,12,1%no

prophylaxis

Barreto2013 retrospectivemonocentric

Inductionandconsolidation 165AML(12%MDS) possible/proven/probable 14,5%

Heng2013 retrospectivemonocentric consolidation 106AML provenprobable 2%

Neofytos2013 retrospectivemonocentric induction 254AML possible/proven/probable 48,4%

Gomes2014retrospectivemonocentric

induction 125AML proven/probable 16,8%

Kung2014 retrospectivemonocentric

inductionandreinduction 130AML possible/proven/probable 10,8%

Girmenia2014 retrospective induction 198AML proven/probable 17,2%

APL AML p-valueNopts 103 881 Meanage 51 55 0.01CVC 52(50%) 687(78%) <0.0001Meandurationofdeepneutropenia(<500/mm3) 17.5days 24days 0.04Antifungalprophylaxis 94(91%) 837(95%) 0.1Topicalantifungalprophylaxisonly 17(17%) 60(7%) 0.0005DruginprophylaxisØ fluconazoleØ itraconazoleØ posaconazoleØ other

33(32%)13(12%)38(37%)1(1%)

168(19%)117(13%)513(58%)23(3%)

0.0020.8

<0.0001

IFIsØ allcasesØ proven/probable

8(7%)4(4%)

214(24%)

77(9%)

0.0001

0.08moldsØ allcasesØ proven/probable

8(7%)4(4%)

191(22%)55(6%)

0.00060.4

yeasts 0 23(3%) <0.0001Antifungaltreatment 11(11%) 275(31%) 0.0001Overallmortalityat30days 8(8%) 110(12%) 0.1IFD-Mortalityat30days 1(1%) 25(3%) 0.5

RiskofIFIinAPL:

SEIFEM-Dregistry

Paganoetal,

BrJHaem2015

Nomyelosuppressivetreatments.Noprolongedneutropeniaparticularlyforthosethatrecived

ATO-ATRA

AML-RiskfactorsforIFI

-FACTORS-Leukemia

RelatedHost

RelatedTreatmentRelated

FungalExposure

LowerProbabilityofCR(AdverseCytogenetic/genemutationprofiles;WBC>50.000/µL;SecondaryAML).

Age>65yrs

Expectedtreatmentrelatedsevereandprolongedneutropenia(ANC<100/µLfor>10d)

RoomswithoutHEPAfiltrationBuildingconstrutionsorrenovations

BaselineNeutropeniawithANC<500/µLfor>7d,MDS-relatedphagocyticdysfunction.

OrgandysfunctionwithHighcomorbidityindexorPS>2

Highlymucotoxicregimen

AirwayColonizationByAspergillusspecies

LeukemiaStatus:Relapse-Refractory>FirstInduction>Consolidation

ChronicObstructivePulmonaryDiseaseSmoking,HighexposureJob

Mucositisgrade>3for>7days,especiallyifinvolvinglowergut.

PriorAspergillosis

Day15BMBlasts>5% Immunitypolymorphism Esophagitisgrade>2WHO

MultisitecolonizationbyCandidaspecies.

NoCRbyendofInduction Pharmacogenomicsofantineoplasticdrugs

SEIFEM

AML-RiskfactorsforIFI

-TIME-Pre-treatment

RISKFACTORSPost-treatmentRISKFACTORS

LowerProbabilityofCR(AdverseCytogenetic/genemutationprofiles;WBC>50.000/µL;SecondaryAML

Expectedtreatmentrelatedsevereandprolongedneutropenia(ANC<100/µLfor>10d)

BaselineNeutropeniawithANC<500/µLfor>7d,MDS-relatedphagocyticdysfunction.

Highlymucotoxicregimen

LeukemiaStatus:Relapse-Refractory>FirstInduction>Consolidation

Esophagitisgrade>2WHO

Age>65yrs Day15BMBlasts>5%

OrgandysfunctionwithHighcomorbidityscoresorPS>2 NoCRbyendofInduction

Smoking,COPD,Highexposurejob(construction,farming,gardening,floristshopemployer,forestrywork)

PriorAspergillosis

AirwaycolonizationbyAspergillussp.NoHEPAfiltration/BuildingorHouseconstruction-renovation

Immunitypolymorphism

Pharmacogenomicsofantineoplasticdrugs

SEIFEM

Considerations1.  «The risk for IFIs is higly variable in AML and result from interactions

betweennetstateofimmunosupression,organdysfunction,andexposuretoopportunistfungi».

2.  «PROTECTIVEEFFECT»ofCRstatusandimpact/importanceofBMBLASTCLEARANCE.

3.   FACTORS: Risk Factors related to AML, HOST, FUNGAL EXPOSURE,TREATMENT.

4.   TIME:PRE-TREATMENTandPOST-TREATMENTassessmentofRiskforIFD

RISKFACTORS+TIMEDYNAMICRISKASSESSMENTDYNAMICRISK=DYNAMICADAPTEDANTIFUNGALSTRATEGY

SEIFEM

PopulationPeriodStudy

Treatment

N°cases Incidence References Comment

CALGBprot.9221191MDSdefinedbyFAB:150AZA(includingcrossover)vs92BSCRetrospective

6CandidainfectionsduringAZAtreatment

0.04patientwithevent/

patient-yearofexposure

SilvermanLetal.JCO2006Vol.24No.24

0.07patientwithevent/

patient-yearofexposure(3Candida

infections)amongBSC

101MDS(IPSS>0.5)

2008-2009

Prospective

Decitabine

12/97 12% LeeJ-H.etalHaematologica

2011

97febrileepisodesrequiring

hospitalizationduring489treatmentcycles

SEIFEM

EpidemiologyofIFIinHigh-RiskMDStreatedwithHypomethylatingAgents

Population N°cases Incidence References Comment

157MDS,27AML

2008-2011

Retrospective

AZA

6/124 4,8%, MerkelD.etalAmericanJournalofHematology2012

153infectiouseventduring928treatmentcycles,124/153underwentcompletemicrobiologyworkup

64MDS/AML2009-2012Retrospective

AZA

6Aspergillosis2Candida(8outof23microbiologicallydocumentedinfection)

25%inpriorICvs

2%infrontline(Riskdifference,

22.4%)

FalantesJFetalClinicalLymphoma,

Myeloma&Leukemia2014

InvasiveAspergillosissignificantlyhigherinpriorICthanfrontlineAZA

149MDSamong173cases2008-2011Prospective-randomized

AZA

2(pneumoniaandGI)

4.3%(Outof46infectiousevents)

OfranYetal.ClinicalLymphoma,Myeloma&

Leukemia,2015

Infectiouseventssignificantlymorefrequentafter7days,than5daysofAzacitidine

SEIFEM

EpidemiologyofIFIinHigh-RiskMDStreatedwithHypomethylatingAgents

RiskFactorsofIFIinMDStreatedwithHypomethylatingAgents

Population Riskfactor References Comment

149MDSamong173cases(IPSS>1.5)

Plt<20000/mmc,poorcytogeneticsNeutropeniaAZA7days

OfranYetal.ClinicalLymphoma,Myeloma&Leukemia,2015Vol.15

Infectiouseventssignificantlymorefrequentafter7days,than5daysofAzacitidine

64MDS,523AZA AZAasSalvagetherapyafterintensiveregimens

FalantesJFetalClinicalLymphoma,

Myeloma&Leukemia2014

PreviousIC

157MDS,27AML

LowHblevel,LowPLTcount,Unfavorable

cytogenetics

AZA7days

MerkelD.etal,AmericanJournalofHematology2012

Lowneutrophilcountonlyinunivariateanalysis.Higherriskduringthefirst2courses

101MDS(IPSS>0.5)

NumberofDecitabinecourses

LeeJ-H.etalHaematologica2011

28,7%duringthefirst3coursesversus9,6%duringthe4thto8thcourses,p<0.001

SEIFEM

Falantes JF, et al. Clinical Lymphoma Myeloma and Leukemia 2014, 80 - 86

Merkel D, et al.American Journal of Hematology, 2013, 88, 130-134,

Higherriskduringthefirst2-3cyclesofAZAtherapy

RISKFACTORSOFIFIINMDSØ MDSwithhighIPSSrisk(>1.5)treatedwithazacitidine75mg/m(2)for7daysØ Higher–riskMDS(bonemarrowblasts>10%orIPSSintermediate-2orhigh)receivingazacitidineafterintensiveregimensØ HigherIFIriskduringthefirst2-3cyclesofAZA/Decitabinetherapy

SEIFEM

EpidemiologyofIFIinPh-ALL(last5-10years)

Population N°cases IncidenceIFI References Comment

<40y(median26) 54pts 6(11%)possible Rijneveld,Leukemia2011

HOVON70(pediatriclike,noDMZ)

>40y(median57) 60pts 5(8.3%) Daenen,Leukemia2012

HOVON71(DMZ)

Olderadolescents(15-18)

45pts 0% Pui,JCO2011 Pediatricprotocols

Olderadults(55-65)

100pts 9-10% Sive,BJH2012 MRCUKALL

≥60y 122pts †1.6%fungi†4.9%fungi+bacteria

O’Brien,Cancer2008 HyperCVAD/MTX-AraC<60y:†0.7%fungi+bacteria

≥55y 30pts 7/30(23%)induct12/24(8.3%)induct2

Hunault-Berger,AmJHematol2015

HDDMZprephase+ind1GRASPALL/GRAALL

≥55y 60pts(Ph-) 11/60(18.3%)(ind)(8IPA+3

candidemia)

Hunault-Berger,Haematologica2011

RPeg-DoxvsCI-DoxHDDMZ

SEIFEM

EpidemiologyofIFIinPh-ALL(last5-10years)


18-83y(median40)

68pts(Ph-) 2.9% Thomas,Cancer2010

HyperCVAD/MTX-AraC(Rstandardvsintensif)

18-60(median37)

85pts(Ph-) 10.6%(induct) Storring,BJH2009 Pediatricregimen

15-72y(median28)

32pts 12.5%proven/prob Henden,LeukLymph2013

HyperCVAD/MTX-AraC

16-73y(median33)

31pts 6.5%(fatalIFI) Barba,AmJHematol2012

Clofarabine-basedregimens

22-69y(median42)

37pts 4/40(10%)(3candida,1aspergillus)

Kadia,AmJhematol2015

Ph±,MOpAD±TKI(meto+vcr+pASP+DMZ)

SEIFEM

EpidemiologyofIFIinPh+ALL(last5-10years)


15-59y(median45)

45 1/31DIV(3.2%)(1IPA)noneHAMI

DeLabarthe,Blood2006

PoorearlyrespàDIV:IM+DEXA+VCR(GRAAPH2003)

>55(median66) 30 Ind:6.7%(2IPA)consol:1IPA

Delannoy,Leukemia2006

Consol:IM+CHT(noDMZ)(GRAALstudy)

44(8-62) 30 1/30(3.3%) Ribera,Haematologica2010

IFIduringintensifiedinduction(IM+mito+Ara-

C)

45(20-66) 53 2/53(3.8%) BassanJCO2010 ReducedintensityCHT

22-78y(median50)

56 0% Ottmann,Blood2002

IM

10-70y(median45)

31 6(19.4%)(3candidemia,3IPA)

Rea,Leukemia2006 IM+VCR+DMZ

SEIFEM

RiskfactorsofIFIinALLPopulation Riskfactor References Comment

1173ALLpts(retrospetivestudy)

Induction/reinduction Pagano,Haematologica2006

IFI6.5%(IM4.3%)

134ALLpts(prospectivestudy)

Induction/relapse;BMaplasia Nicolle,Haematologica2011

IA2.2%


CVC(yeasts);neutropenia(moulds)

Montagna,IntJMolSci2012

IFI4.2%(IM2.1%)


-- Pagano,AnnHematol2012

IFI4%


(AML/MDSinduction),previousIFI,neutropenia,malesex

Sun,TumorBiol2015 IFI2%

17ALLpts(retrospectivestudy)

(Intensivecht) Teng,Haematologica2015

IFI5/17(29.4%)

355ALLpts(randomizedstudy)

-- Cornely,ASH2014 IFI:11.7%placebovs7.9%L-AmB

37ALLpts(randomizedstudy)

-- Cattaneo,JAntimicrobChemother2011

IA:2.7%(yeasts,caspofunginallocation)

44ALLpts(retrospectivestudy)

Noprophylaxisduringbuildingwork,neutropenia,pulmonaryantecedents,(highriskAML)

Chabrol,Haematologica2010

IFI:6.8%(proven,probable,possible)

SEIFEM

CuatneousMucormycosis

Cunninghamellaberthollletiae

CMLCB AmJHematol.2009Jul;84(7):447-8.doi:10.1002/ajh.21289.CutaneouszygomycosiscausedbyCunninghamellabertholletiaeinapatientwithchronicmyelogenousleukemiainblastcrisis.MotohashiK1,ItoS,HagiharaM,MarutaA,IshigatsuboY,KanamoriH.

Arthritis Candidaspp CMLCB AnnHematol.2002Sep;81(9):529-31.Epub2002Aug16.Candidaarthritisinapatientwithchronicmyelogenousleukemia(CML)inblastictransformation,unresponsivetofluconazole,buttreatedeffectivelywithliposomalamphotericinB.TurgutB1,VuralO,DemirM,KaldirM.

Pneumonia CandidakruseiCandidaglabrata

CMLimatinib MedMycol.2008May;46(3):259-63.PneumoniacausedbyCandidakruseiandCandidaglabratainapatientwithchronicmyeloidleukemiareceivingimatinibmesylatetreatment.SpeletasM1,VyzantiadisTA,KalalaF,PlastirasD,KokoviadouK,AntoniadisA,KorantzisI.

Cerebralcriptococcosis

Criptococcusneoformans

CMLimatinib

LeukRes.2010Sep;34(9):1250-1.doi:10.1016/j.leukres.2010.05.019.Epub2010Jun19.Occurrencesofopportunisticinfectionsinchronicmyelogenousleukemiapatientstreatedwithimatinibmesylate.AnthonyN1,ShanksJ,TerebeloH.

candidemia CMLimatinib

Opportunisticinfectioninpatientswithchronicmyeloidleukemiareceivingimatinib,FalconeA.P.BodenizzaC.,SanpaoloG.,Dell'OlioM.,MelilloL.,NobileM.Scalzullip.CascavillaN

Cutaneouscriptococcosis

Criptococcus

CML JDermatol.2005Aug;32(8):674-6.Localizedcutaneouscryptococcosisinapatientwithchronicmyeloproliferativedisease.EbaraN,KobayashiN,AsakaH,ToyoharaM,YoshikawaM,MiyagawaS.

Pneumonia Pneumocystisjiroveci MFIruxolitinib

BMJCaseRep.2014Jun2;2014.-2014-204950.Pneumocystisjirovecipneumonitiscomplicatingruxolitinibtherapy.LeeSC1,FeenstraJ2,GeorghiouPR3.

Pulmonarycriptococcosis

Criptococcusneoformans

MFIruxolitinib

WyshamN,SullivanD,AlladaG.Anopportunisticinfectionassociatedwithruxolitinib,anoveljanuskinase1,2,inhibitor.Chest2013;143:1478–9.

Mucormycosis Mucorales

MFIruxolitinib

StansfieldLC,BegnaK,ToshP,etal.Mucormycosisinapatienttreatedwithruxolitinib.Blood2014;e-letterpublished31January.

EpidemiologyofIFIinMPNCaseReports

SEIFEM

EpidemiologyofIFIinMPNRegistrativestudies

Population N°cases Incidence References Comment

IRIS(ImatinibvsINF+AraC)

1106(553) 0 B.J.Drukeretal,NEJM2006

DASISION(DasatinibvsImatinib)

519(260) 0 E.Jabbour,Blood2014

ENESTnd(NilotinibvsImatinib)

846(563) 0 H.M.Kantarjianetal,Lancet

Oncology2011;G.Saglioetal,NEJM2010

COMFORTII(Ruxolitinibvs

BAT)

219(146) 0 C.Harrisonetal,NEJM2012

1pneumoniaandrespiratoryinfections(?)

SEIFEM

AtipicalinfectionsinCMLptstreatedwithDasatinibat140mg

Side effects

period of 38 months, seven patients are alive (Table 2). Themedian survival time in the 16 patients was 27Æ1 months(range: 2Æ5–37Æ6 months).

Haematological events recorded during treatmentwith dasatinibDuring treatment with dasatinib, mild to severe cytopeniadeveloped in a majority of our patients (Table 3). Especiallyin patients in whom disease-related cytopenia pre-existed,dasatinib was found to promote the pre-existing cytopenia.This cytopenia-promoting effect was particularly seen inpatients with pre-existing anaemia or pre-existing thrombocy-topenia. By contrast, in most patients in whom grade III orIV neutropenia developed, no substantial neutropenia wasdetectable before dasatinib (Table 3). All in all, grade IVcytopenia developed in 10 patients. Interestingly, in a fewpatients, dasatinib did not induce cytopenia. These patientsshowed a fast complete response with rapid regeneration ofnormal haematopoiesis. Haematological findings (cytopenia)are shown in Table 3.

Non-haematological events recorded duringtreatment with dasatinibNon-haematological adverse events were recorded in allpatients and included weight loss of at least 10% of bodyweight (6 ⁄ 16, 37Æ5%), pleural effusions grade II or higher (75%of all patients), fatigue (12Æ5%) and infections requiring antibi-otic therapy (75%). One patient in CML AP died from atypicalpneumonia caused by pneumocystis jirovecii ⁄ carinii (Table 4,Fig. S1). This patient also developed pleural effusions that wererecorded shortly before pneumonia was diagnosed. One patientdeveloped EBV-positive mucosal leukoplakia of the tongue(Fig. S2), one porphyria cutanea tarda (PCT), one late onsetrheumatoid arthritis (LORA), one a paresis of the N. facialisand one a permanent loss of function of the N. olfactorius(Table 4). In the patients with PCT and LORA and in the twopatients with neurological defects, no infectious agents weredetected. In three patients, a skin tumour was found (squamouscell carcinoma, n = 2; basal cell carcinoma, n = 1) (Table 4).Most events were recorded within the first year of therapy. In afew patients (n = 3), pleural effusions developed within the sec-ond year. Interestingly, all three skin tumours were detected inthe third year of therapy with dasatinib. Other nonhaematologi-cal toxicities were mild and tolerable. Specifically, no severecardiac event was recorded. Moreover, we did not record anysevere gastrointestinal, renal or hepatic events during treatmentwith dasatinib.

Effects of dasatinib on the number of immune cellsIn a subset of patients, the numbers of CD3+ and CD4+ T cellsand CD19+ B cells were recorded. In four of five patients exam-ined, a sustained decrease in CD19+ B cells, sometimes down tovery low or even undetectable counts, was seen (Fig. 1a,b), andin 4 ⁄ 4 patients recorded, a slight to moderate decrease in CD3+

and CD4+ T cells was found (Fig. 1c–f). Overall, CD19+ B cellsdecreased from a pretreatment level of 246 ± 311 lL)1 blood to75 ± 80 lL)1 blood at 3 months (P < 0Æ05), CD3+ T cells from1022 ± 190 lL)1 blood to 868 ± 323 lL)1 blood at 3 months,and CD4+ T cells dropped from a pretreatment value of614 ± 195 lL)1 blood to 495 ± 271 lL)1 blood at 3 months.During the same time, WBC and ANC also decreased substan-tially (ANC from 10 556 ± 9673 lL)1 before treatment to1587 ± 917 lL)1 at 3 months). In 2 ⁄ 4 patients, a decrease inCD3+ ⁄ CD56+ and CD3) ⁄ CD56+ NK cells was observed,whereas in two other cases, the numbers of CD56+ cellsincreased (Fig. 1g–j). Immunoglobulin levels (IgG, IgA, IgM)did not change during therapy with dasatinib (not shown).

The levels of serum tryptase, a marker that correlates withthe number of mast cells in healthy subjects and that is also pro-duced in immature CML basophils, decreased substantiallyduring dasatinib in most patients (from a pretreatment level of

Table 3 Haematological side effects

#No Phase

Toxicity grade (CTC)

Anaemia Thrombocytopenia Neutropenia

(pretreatment grading is shown in brackets)

#01 BP-my II (II) IV (I) II (III)

#02 AP IV (II) IV (IV) IV (0)

#03 AP III (II) IV (0) IV (0)

#04 AP III (I) IV (0) IV (0)

#05 AP I (II) III (I) IV (0)

#06 BP-my IV (I) IV (0) IV (0)

#07 BP-ly IV (II) IV (IV) IV (IV)

#08 CP IV (II) IV (IV) IV (0)

#09 CP II (I) 0 (0) 0 (0)

#10 CP III (II) III (I) 0 (0)

#11 CP III (I) III (0) 0 (0)

#12 CP IV (II) IV (0) II (0)

#13 AP 0 (0) 0 (0) 0 (0)

#14 AP IV (III) IV (IV) II (0)

#15 AP II (II) 0 (0) I (0)

#16 AP II (I) II (0) 0 (0)

CTC, National Cancer Institute (NCI) common toxicity criteria.

1102 ª 2009 The Authors. Journal Compilation ª 2009 Stichting European Society for Clinical Investigation Journal Foundation

C. SILLABER ET AL. www.ejci-online.com

51Æ2 ± 112Æ8 ng mL)1 to 6Æ0 ± 8Æ0 ng mL)1 at 3 months,P < 0Æ05) (Fig. 1k–n). Interestingly, during dasatinib, serumtryptase levels not only decreased to normal range, suggestingan effect on CML basophils, but further decreased, sometimesto undetectable levels (Fig. 1m–n), suggesting drug effects onnormal (mast) cells.

Dasatinib blocks TcR-dependent activation of T cellsand IgE receptor-dependent activation of basophilsin a subset of patientsRecent data suggest that dasatinib interferes with TcR-depen-dent activation of T cells and IgE receptor-dependent activationof basophils [18–20]. We examined T cell receptor-dependentactivation of ex vivo T lymphocytes and IgE receptor-dependentactivation of ex vivo blood basophils obtained from the periph-eral blood. Blood was drawn before and 2 h after dasatinibintake (70 mg p.o.) in four patients. Interestingly, in one patient,

a complete suppression of TcR-dependent activation of T cellsand IgE receptor-dependent activation of blood basophils wasfound after dasatinib intake. In particular, OKT3-inducedupregulation of CD69 on T cells and anti-IgE-induced upregu-lation of CD63 and CD203c on basophils was completelysuppressed after dasatinib intake (Fig. 2). In the other threepatients, receptor-dependent activation of T cells remainedunaltered. In two of these patients, basophil activation waspartially or completely blocked after dasatinib, whereas in onepatient, upregulation of CD63 was even more pronounced afterdasatinib intake compared with pretreatment levels (Fig. 2).These data suggest that dasatinib acts immunosuppressivein vivo in a subgroup of patients. We also asked whether theimmunosuppressive effect of dasatinib is a long-lasting effect.However, after several hours (after dasatinib intake), ex vivoT cells and basophils responded well to receptor-specificstimuli in all donors (data not shown).

Table 4 Non-haematological side effects

#No Phase

Pleural effusion

(CTC grade)

Infections

(CTC grade)

Weight loss

(CTC grade)

Fatigue

(CTC grade)

Skin

findings Other events

#01 II Pneumonia, diarrhoea n.k. III No No

#02 0 Urinary tract infection I No No Arthropathy

#03 II Bronchitis, pneumonia,

hairy leucoplakia

of tongue

II I–II Folliculitis, erythema

nodosum

Diarrhoea, loss of hearing,

cerebral bleeding

#04 V Pneumocystis

carinii pneumonia

n.k No Herpes labialis Multiorgan failure

#05 II Bronchitis No No Basal cell carcinoma No

#06 II Neutropenic fever n.k. No Herpes labialis No

#07 III Neutropenic fever,

suspected fungal

pneumonia

II II No

#08 II Onchymycosis III II PCT Headache

#09 I Bronchitis I No No Loss of olfactory function

#10 III Diarrhoea with fever III II SCC, exanthema Scrotal oedema,

paresis of N. facialis

#11 0 0 II No No LORA

#12 I 0 I SCC

#13 II 0 0 II No Headache, bone pain

#14 II 0 0

#15 III 0 II

#16 III Pneumonia 0 No No Vomiting and diarrhoea

CTC, National Cancer Institute (NCI) common toxicity criteria; n.k. not known; SCC, squamous cell carcinoma; PCT, porphyria cutanea tarda;LORA, late onset rheumatoid arthritis.

European Journal of Clinical Investigation Vol 39 1103

ADVERSE EVENT PROFILE OF DASATINIB

RecommendationsforIFIinMPNSEIFEM

ThereisnoevidenceofincreasedriskofIFIinpatientswithCMLinchronicphaseorMPNtreatedwithTKIs(Imatinib,Dasatinib,Nilotinib,Ruxolitinib)Bosutinib??Ponatinib???

LOWRISK

SEIFEM

0

0,5

1

1,5

2

2,5

3

3,5

4

4,5

5

SunTetal2015

PaganoLetal2006

NosariAMetal2014

KurosawaMetal2012

TakaokaKetal2014

TengJCetal2015

StanzaniMetal2013

2011 1999-2003 2004-2012 2006-2008 2006-2012 2009-2011 2009-2012

IFI%

NHL

0

0,2

0,4

0,6

0,8

1

1,2

1,4

SunTetal2015 PaganoLetal2006

NosariAMetal2014

KurosawaMetal2012

2011 1999-2003 2004-2012 2006-2008

IFI%

HL

IncidenceofIFIinNHLandHL

From0.2to4.3%

From0.7to1.2%

SEIFEM IncidenceofIFIinMM

0

2

4

6

8

10

12

OshimaKetal2011PaganoLetal2006 OffidaniMetal2011

NosariAMetal2014

LiJetal2015 TehBWetal2015 TengJCetal2015

1979-1998 1999-2003 2003-2009 2004-2012 2006-2012 2009-2011

IFI%

From0.5to10.8%

SEIFEM IncidenceofIFIinCLL

0

1

2

3

4

5

6

7

8

9

PaganoLetal2006 MoreiraJetal2013 TengJCetal2015

1999-2003 1999-2009 2009-2011

IFI%

CLL

Totale

From0.5to7.8%

RiskfactorsofNHLandHLSEIFEM

References Pts Inclusioncriteria

Infection

Riskfactors

Sun at al, TumorBiol2015*

1101/188* H e m a t o l o g i cmalignancies

Proven, probableandpossibleIFI

Univariate:gender;ECOG;Concomitantdisease;stage;CHT;Previous IFI; ANC and duration of neutropenia; Decreasedalbumin;ParenteralnutritionMultivariate: Male gender; ANC<500/mm3; inductionchemotherapy(vsotherlines);previousIFI;CVC;Decreasedalbumin;Antifungalprophylaxis

P a g a n o e t a l ,H a ema to l o g i c a2006*

3457/844* H e m a t o l o g i cmalignancies

P r o v e n o rProbableIFI

nd

Nosari et al, L&L2014*

626/158* C h r o n i c l y m p hmalignancies

Probable provenIFI

Severeandprolongedneutropenia(ANC<500>10days);Age

Kurosawaetal, IntJHematol2012*

1373/92* H e m a t o l o g i cm a l i g n a n c i e s(including auto andalloHSCT)

L H ; P r o v e n ,probableIFI

Neutrophilcountdecreased;CVC(forcandidiasis);GVHD

Takaokaetal,AnnHematol2014

_____ S e c o n d - l i n etreatment or moreadvancedlines

Proven, probaleandpossibleIFI

Univariateandmultivariate:primary refractoriness; twoormore previous treatment lines;minimumneutrophil countequaltoorlessthan500/μL

T e n g e t a l ,H a ema to l o g i c a2015

186 --_____________

Proven, ProbableandPossibleIFI

nd

Stanzani M et al,PlusOne2013

390 H e m a t o l o g i cmalignancies

_____ Univariate: prior IMD;Corticosteroids; Uncontrolledmalignancy; High risk CHT;Neutropenia; LymphocytedisfunctionMultivariate:Neutropenia; lymphocytopenia or lymphocytedysfunctioninASCT;malignancystatus;priorIMD*includingHL

RiskfactorsofMMSEIFEM

References Ptsn Inclusioncriteria

Infection

Riskfactors

Oshima K et al,AJH2011

52 c o n s e c u t i v e l yautopsied patientsaffectedbyMM

proven nd

Pagano et al,Haematologica2006

1616 Newly diagnosedMM

nd

Offidani M. etal,L&L2011

202 Previoustreatmentwith Thalidomide(44 pts underwentpriorSCT)

Univ: PLT < 130.000/mmc; CM>3 g/dl; newlydiagnosed;ISS:2-3;noantibioticprophylaxis.Multiv:lowPLT<andhighCM;DVT

Nosarietal,L&L2014

300 untransplanted Univariate:severeandprolongedneutropenia(<500for>10days);Age

Li J. et al, CellB i o c h e mBiophys2015

143 PrevioustreatmentwithBortezomib

Bortezomib therapy (expecially during firstcycle)vs.conventionalchemotherapywithoutBortezomib

Teh BW et al,Haematologica2015

237 nottransplanted

Univariate:Bortezomibtherapyand3ormorelinesoftherapy.Multivariate:3ormorelineswithin3years

T e n g e t a l ,Haematologica2015

251 IncludingASCT nd

RiskfactorsofCLLSEIFEM

References Ptsn Inclusioncriteria

Infection

Riskfactors

Paganoetal,Haematologica

2006

1104 Hematologicmalignancies

ProvenorProbableIFI

nd

Moreiraetal,Leukemia2013

174 Chroniclymphmalignancies

ProbableprovenIFI

nd

Tengetal,Haematologica

2015

51 --CLLpatients

Proven,ProbableandPossibleIFI

nd

IFIRiskFactorsinCLDSEIFEM

HodgkinDisease:NoRisk(evenifinGermanstudieswiththeuseof“escalatingBEACOPP”anincreasednumberoffungalmortalitywasobserved)

1.   Severe and prolonged neutropenia, the stage and state of the underlyingdiseasesandmore than two therapeutic lines result themost important riskfactorsforIFI

2.   Thepossibilitythatthenoveldrugs,andinparticulartheproteasomeinhibitorbortezomib, may increase the risks of such infections should be furtherinvestigated.

3.   Thevastmajorityofthestudiesareallretrospectiveandtheanalysisperformedare extremely heterogeneous. Epidemiologic perspective studies are urgentlyneeded to assess the current incidence of and risk factors for IFI in chroniclymphoproliferativedisorders

EpidemiologyofIFIinASCT(last10years)


25-65y(Medianage:51y)

1979pts(AML40.5%,ALL20%,MM12.5%,NHL8.5%,CML7.5%,

HD3%)

1.2% Pagano,CID2007 SEIFEMB2004

Observationalmulticenteritalianstudy(1999-2003)

0.3-79y(Medianage:49y)

9534pts 1.2% Kontoyiannis,CID2010

TRANSNETUSA(2001-2006).Prospectivesurveillance,includingpediatricpopulation


62pts(MM33,lymphomas20,

AL7,solidtumors2)

9.7% Post,TransplInfectDis2007

Retrospectivestudy2000-2003

16-67(Medianage:36y)

314pts:64NHL,64MM,16ALL,129HL,41AML

Incidence:3.2%forfungiand1%for

Aspergillusfumigatus.

Giletal,Infection2007

-PtsconditionedwithTBI-ptswithAL(mucosalbarrierdamageand

prolungedneutropenia)

SEIFEM




≤40y:41pts>40y:68pts

109pts(NHL39,HD36,MM34)

8% Gil,BMT2009 ProspectivePolandstudy2005-2007onASCTonly.MultivariateanalysisshowstheroleofapreviousFludarabine

treatmentastheonlyriskfactorforIFI


322pts(MM47.5%,HD19.6%,NHL15.5%,AML3.1%,ALL0.3%,other14%)

1.9% Nucci,ClinMicrobInfect2012

ProspectiveBrasilianstudy(2007-2009),includingpediatric

population

58-72y(Medianage:65)

135pts(MM100%)

2.2% Teh,Haematologica2015

Retrospectivestudy(2009-2011).AllpatientsunderwentaprevioustreatmentwithIMiDsorproteasomeinhibitors

SEIFEM



Medianage:37.7y±15.4

348pts(NHL35.9%,AML21.6%,MM20.7%,ALL4.9%,others

0.9%)

4%

Sun,BBMT2015

Prospectivechinesestudy(2011).

Multivariateanalysisshowstheroleofa

prolongedneutropeniaastheonlyriskfactor

forIFI

27.5-75.4y(Medianage:

58.7y)

382pts(MM100%)

0% Martino,BBMT2014

RetrospectiveitalianstudyGITMO(1998-2012)

NoIFIascausesof

re-admission

SEIFEM

Population RISKfactors REFERENCE Comment62pts:MM33,lymphomas20,

AL7,solidtumors2(Retrospectivestudy)

-  Colonizationwithcandidaspeciesinperiodpretrasplant

-  Durationofneutropenia

Postetal,TransplInfecDis

2007

IFI:9.7%

314pts:64NHL,64MM,16ALL,129HL,41AML

-PtsconditionedwithTBI-ptswithAL(mucosalbarrierdamageandprolungedneutropenia)

Giletal,Infection2007

Incidence:3.2%forfungiand1%for

Aspergillusfumigatus.

109pts:NHL39,HD36,MM34(Prospectivestudy)

-Prolongedneutropenia(>21days)- Useoffludarabine/rituximabinpretrasplantperiod- UseBMstemcellsinsteadofPBSC

Gil,BMT2009

IFI:8%

RiskfactorsOFIFIINASCTSEIFEM

Population RISKfactors Reference Comment

73pts:MM68.5%,lymphomas26%,AL1.4%,CL1.4%,MDS

1.4%,others5.5%(Multicentricprospectiveobservationalstudy)

-  Useofsteroid(75.3%)-  Relapse(60.3%)-  PriorHSCT(56.2%)

Neofytos,CID2009

- 77IFIs(IFIsnotmutuallyexclusive)

- themajorityofIFIs(68.5%)werereportedbyasinglecenter

- themajorityofASCTpatientshadarelapse,ahistoryofpriorHSCTandreceivedsteroids.

1355pts:626NHL,300MM,158HL,

271CLL(Monocentricretrospective

experience)

-Onlytreatmentwithfludarabinewasconfirmedatmultivariateanalysis.

Nosarietal,Leukemia&Lymphoma

2014

IFIin42(3%)

135pts:MM100%

(Retrospectivestudy)

-Cumulativeexposuretoimmunosuppressivetreatmentanddiseaseburden

Teh,Haematologica2015

IFI:2.2%

RiskfactorsOFIFIINASCTSEIFEM

HighRISK IntermediateRISK LowRISKPreviousIFI Allothers

>3linesoftherapy(diseaseburden)

Prolongedneutropenia(ANC<500/mm3formorethan14

days)

corticosteroidtherapy

ColonizationbyCandidaspp

PreviousFludarabinetreatment

SEIFEM IFIriskcategories(ASCT)

EpidemiologyofIFIinHSCTrecipients(last5-10years)

Reference Timeframe

No.Patients&typeofHSCT

IFDrateandmortality

MorganJ,MedMycolSuppl2005

2001-2002

4621patientsAuto2588-Allo2033

AutoIFD0.5%;AM54%Allo2.9%;AM85%(rateMSD2.3%;

MMRD3.2%;MUD3.9%)

Pagano,CID2007SEIFEM

1999-2003 3228patientsAuto60%-Allo40%

AutoIFD1.2%;AM14%Allo7.8%;AM77%

Garcia-Vidal,CID2008

1998-2002 1248patients;Allo-HSCT IMI13.1%

Mikulska,BMT2009

1999-2006 306patients;Allo-HSCT IA15%;AMIA67%

Neofytos,CID2009PATHAlliance

2004-2007 234patients;Auto31%-Allo69%

AMIA21.5%

TRANSNETCID2010

2001-2006

875patients;Auto-AlloHSCT

IFDrate:Auto1.2%MSD5.8%;MUD7.7%

Omer,BBMT2010 2000-2010 271patients;AlloHSCT IFD15%;AM33%

SEIFEM

EpidemiologyofIFIinHSCTrecipients(last5-10years)

Reference Timeframe

No.Patients&typeofHSCT

IFDrateandmortality

GirmeniaGITMOBBMT2014

2008-2010

1858PatientsAllo-HSCT

IFD8.8%AM19%

AtallaTID2015

2007-2009 345patientsAllo-HSCT

IMI8.1%

SunYBBMT2015

2011 1401patientsAllo75%Auto25%

Allo8.9%;Auto4.0%Proven31%;Probable22%

WalshTJMycoses2015


IA7.9%-Candidemia3.4%Others4%IA52%

LiuY-CJMicImmInf2015

2002-2013 421 PatientsAllo-HSCT

IFI7.4%AM80%

MontesinosPBMT2015


Post-engraftmentIFD11%NRMat1y:40%

SEIFEM

RiskfactorsofIFIinHSCTrecipients(1)RiskFactors

Pre-HSCTPost-HSCT

References Study/No.Patients

Comment

Age>36y

>50y

>30y>40y

PaganoCID2007PaganoCID2007

Garcia-VidalCID2008ParodyBMT2015

MontesinosBMT2015

Retrosp-1249

Retrosp-1248Retrosp-434Retrosp-404

Riskformoldinfection

RiskforIFD>40d

DiagnosisAML

Lymphoma

AtallaTID2015AtallaTID2015

Prosp-345Prosp-345

EarlyIMI(<40d)LateIMI(>40d)

DiseasestatusatHSCT

MikulskaBMT2009GirmeniaBBMT2014StanzaniPlos2013

Retrosp-306Prosp-1858

Retr(1709)-Prosp(1746)

InvasiveAspergillosisEarlyIFI(<40d)

TypeofHSCTMUD

UCB

Haplo/mismatch

SunBBMT2015PaganoCID2007

Garcia-VidalCID2008GirmeniaBBMT2014

GirmeniaBBMT2014

OmerBBMT2013AtallaTID2015

Prosp-1053Retrosp-1249Retrosp-1248Prosp-1858

Prosp-1858

Retrosp-272Retrosp-271

RiskforIMIearlyandlateIFI

earlyandlateIFI

SEIFEM


Pre-HSCTPost-HSCT


Comment

IronoverloadFerritin>500

>1000>1550>2000

Score>3

SucakTr.Proc2010OzyilmazBMT2010SivginTrAphSc2012Garcia-VidalCID2008KontoyiannisCancer2007

Retrosp-250Retrosp-148Retrosp-73Retrosp-1248Retrosp-66

pulmonaryinfectionpulmonaryinfection

RisKforIMI

GeneticTLR-4

Dectin-1PTX3

BochudNEJM2008CunhaBlood2010CunhaNEJM2014


MiscellaneousEnvironment

CD34+cellsinfusedEBMTscore

BOScore

CVCPreviousIFI

>1previousHSCT

WarrisJClinMic2003BittencourtBlood2002LiuJMicImmInf2015StanzaniPlos2013

PaganoCID2007

LiuJMicImmInf2015GirmeniaBBMT2014StanzaniPlos2013

MontesinosBMT2015WalshMycoses2015

ne


Retr(1709)-Pros(1746)

Retrosp-1249Retrosp-421Prosp-1858

Retr(1709)-Pros(1746)Retrosp-404Retrosp-378

(<3x10^6/Kg)

Durationneutropenia<500;previousIMI;diseasestatus;

lymphocytopenia

EarlyIFI

IFD>40d

SEIFEM

AdmissioninICU


Pre-HSCTPost-HSCT


Comment

GVHDAcutaII-IV

AcutaIII-IV

Cronica

GirmeniaBBMT2014OmerBBMT2013ParodyBMT2105

Garcia-VidalCID2008LiuJMicImmInf2015WalshMycoses2015

GirmeniaBBMT2014MikulskaBMT2009ParodyBMT2015

MontesinosBMT2015

Prosp-1858Retrosp-272Retrosp-434Retrosp-1248Retrosp-421Retrosp-378

Prosp-1858Retrosp-306Retrosp-434Retrosp-404

Late(40-100d)/verylateIFI

RiskforIMI

VerylateIFI(>100d)LateIA(>40d)

-IFD>40d

Immunosoppression Basilixmab

Alemtuzumab

ATG

steroids

SunBBMT2015

ThurskyBJH2005JuliussonBMT2006

Garcia-VidalCID2008OmerBBMT2013

Garcia-VidalCID2008MikulskaBMT2009

LiuJMicImmInf2015

Prosp-1053

Retrosp-217Prosp-69



RiskforIMI

RiskforIMILateIA

SEIFEM


Pre-HSCTPost-HSCT


Comment

ImmuneReconstitutionneutropenia

Monocytopenia<10

Lymphopenia<300

<50CD4+

NK<200/mcl

Neutrophilfunction(ROS)

SunBBMT2015

Garcia-VidalCID2008AtallaTID2015

MikulskaBMT2009MontesinosBMT2015Garcia-VidalCID2008

Garcia-VidalCID2008MikulskaBMT2009StanzaniPlos2013

StuehlerJID2015

StuehlerJID2015

Prosp-1053Retrosp-1248Prosp-345Retrosp-306Retrosp-404Retrosp-1248


Retr(1709)-Pros(1746)

Prosp-51

Prosp-51

<500neutroph.>14d

RiskforIMILate(>40d)IFI

IAIFD>40dRiskforIMI

RischioxIMIEarlyIA

ComorbidityDiabetes

CMVinfection

Parainfluenzaeipoalbuminemia

Garcia-VidalCID2008

SunBBMT2015Garcia-VidalCID2008ParodyBMT2015MikulskaBMT2009AtallaTID2015

MontesinosBMT2015Garcia-VidalCID2008WalshMycoses2015

Retrosp-1248Prosp-1053

Retrosp-1248Retrosp-434Retrosp-306Prosp-345Retrosp-404Retrosp-1248Retrosp-378

RiskforIMI

RiskforIMI

EarlyIA(<40d)LateIFI(>40d)

IFD>40dRiskforIMI

SEIFEM

GeneticTLR-4,Dectin-1,PTX3

HSCTMUD-CB

GVHD&

immunosuppressiveTx,ATG,

Alemtuzumab,AntiCD25

RiskFactors

IFI

Immunedefect

Inna

te

adap

tive

Ironoverload

Impairedimmuneresponse

DecreasedphagocitycfunctionDecreasedchemotacticfunctionofGNimpairedNKandmacrophagefunction

Activedisease

Steroids

CMV&antiviralTXganciclovir

ProlongedneutropeniaDelayedimmunerecovery

ProlongedneutropeniaDelayedimmunerecovery

ProlongedneutropeniaInhibitoryeffectonlymphoproliferation

Lymphopenia,monocytopeniaImpairedNKcytotoxicity-phagocytosis-

oxidativekillingDecreasedIL-2,TNF-alpha,IFN-gamma

Defectofimmuneresponse

RISKFACTORSFORIFIINPEDIATRICPATIENTSAuthor,yearJournal

Typeofstudy

N°ofpts AgeMedian(range)

Diagnosis

IncidenceofIFI

TypeofIFI

Riskfactors

DvorakCC,2005BMT

Retrospective(1998-2004)

120 8,7(0-20)

Allo-HSCT -Proven:11/120(9.2%)-probable:4/120(3.3%)-possible:5/120(4.2%)

Aspergillus,Candida,other

-  durationofneutropenia;-  age>10years;-  transplantforSAAorFanconi

anemia;-  high-dosecorticosteroidfor>10

days(univariateanalysis)

KobayashiR,2007JPHO


149 8(0-21) Allo-HSCT -Proven:1/149(0.7%)-probable:6/149(4.0%)-possible:5/149(3.4%).

Aspergillus -  cGVHD

HaleKA,2010BJH

Case-controlstudy(2002-2005)

106cases 5(0-18) Acuteleukaemia,HSCT

- Aspergillus,other

-  HR-LLA;-  relapseddisease;-  PICUadmission;-  GVHD

VillarroelM,2010PediatrInfectDis

Prospective 646high-riskfebrileneutropeniaepisodes

Children Malignantdisease

-Proven:7/646(1.2%)-probable:10/646(1.6%)-possible:18/646(3.0%)

? -  Feverpersistingatday4ofadmissiontogetherwithAMC<or=100andCRP>or=90

MorM,2011PedBloodCancer


1047 Children Hematologicormalignantdisease

-Proven:16/1047(1.5%)-probable:18/1047(1.7%)-possible:41/1047(4%)

Candida,other

-  AML;-  severeneutropenia;-  hightreatmentintensity

Author,yearJournal

Typeofstudy

N°ofpts

AgeMedian(range)

Diagnosis IncidenceofIFI

TypeofIFI Riskfactors

SrinivasanA,2013BiolBloodMarrowTransplant


759 9,4(0-21)

Allo-HSCT -Proven:75/759(10%)-probable:40/759(5,2%)

Aspergillus,Candida

-  severeaGVHD;-  cGVHD;-  olderage

SanoH,2013PediatricsInt

Prospective(2008-2010)

62 4(0-21) Hematologicormalignantdisease

8/62(12.9%) Aspergillus,other

-  relapseoforiginaldisease;-  AML;

HolJA,2014BMT

Prospective(2004-2012)

209 6,6(0,2-22,7)

Allo-HSCT -Proven:11/209(5.3%)-probable:14/209(6.7%)


-  apriorideterminedHSCTTRMrisk>20%;

-  high-dosesteroidspostHSCT

CastagnolaE,2014BiolBloodMarrowTransplant


198 8,4(3,4-12,1)

Allo-HSCT 31/134episodes(23.1%)

IFI -GradeofaGVHD

OzsevikSN,2015JPHO


253 Children Hematologicormalignantdisease

67/928febrileepisodes(7.2%)


-  prolongedandprofoundneutropenia(moldinfections);

-  CVC(invasiveyeastinfection)

SahbudakBZ,2015Mycoses


125 Children ALL Provenandprobable:30/125(24%)


- Prolongedandprofoundneutropenia

RISKFACTORSFORIFIINPEDIATRICPATIENTS

Evaluationatdiagnosis(literaturebased)

Pre-HospidalizationRiskfactorsforIFI

(i.e.lifestyle-work-comorbidities)

CommonriskfactorsforallHMs:

Neutropenia,lymphopenia,Steroids,Ironoverload,etc

HighRisk

SpecificRiskfactorsforAML,ALL,MDS,MPN,

CLD

StratificationforRiskfactors

IntermediateRisk LowerRisk

Re-evaluationofriskduringtreatmentonthebasisofunderlyingmalignancyresponse

(i.e.at15-21dforacuteleukemia,after2-4cyclesforCLD,MDS,etc)Ifresistantswitchriskcategory

NewriskevaluationatASCT(previousantifungaltreatment,

previouschemotherapy,underlyingmalignancystage)

NewriskevaluationatHSCT(asforASTCand,more,kindof

HSCT,etc)

Pre-engraftment Post-engraftment

«DYNAMIC»statificationusefulbothinadultsandchildrenConfirmatorystudiesarerequired!

Conclusion

Ø  a«dynamicriskscore»forallcategoriesofHMscanbedesignedonthebasisof:Ø epidemiology,Ø  riskfactorsreportedinthemorerecentliterature

Ø expertopinion

IFIriskstatificationinHMSEIFEM

HIGHRisk INTERMEDIATERisk LOWRiskAMLundergoingInductionCHTwithanyofthefollowingRiskFactors:Neutropeniaatbaseline,lowCRprobability(AdverseK,secondaryAML),age>65yrs,Significantpulmonarydisfunction,highe-TRMscore.AMLwithPriorIAAMLundergoingsalvageregimensforRelapsed/Refractorydisease.

AML not meeting criteria for High or Low Riskgroups.

AML<45yrs;Undergoingfirstremission-inductionorconsolidationCHTandwithoutRiskFactorsforIFIAPLtreatedwithATRA/ATO

AllogeneicStemCelltransplantation(from donors other than a matched siblingdonor, patients active HM, GVHD requiringhigh-dosesteroidsandhistoryofpreviousIFI)

AllogeneicStemCelltransplantation(frommatchedsiblingdonors,patients incompleteremissionwithnoevidenceofGVHDandnopreviousIFI)

MDS/AMLreceivingazacitidineassalvagetherapyafterintensiveregimens

MDSwithIPSS>1.5treatedwithazacitidine75mg/m(2)for7daysMDSduringthefirst2-3cyclesofAZA/Decitabine

Acute Lymphoblastic Leukemia: Elderlypatients (≥55y); Intensive pediatric regimens(induction); High Doses dexametazone;Previouslytreated(relapsed/refractory)

AcuteLymphoblasticLeukemia:Adults(30-54y);Standardinductionchemotherapy;Intensiveconsolidationtreatment;TKI+reducedcht(Ph+ALL)

AcuteLymphoblasticLeukemia:Youngeradults(30y);Maintainancetreatment(completeremission);TKI+steroids(Ph+ALL)

AutologousStemCellTransplantation:PreviousIFI;>3linesoftherapy(diseaseburden);Prolongedneutropenia(ANC<500/mm3formorethan14days);corticosteroidtherapy;ColonizationbyCandidaspp;PreviousFludarabinetreatment

MPN(ChronicMyeloidLeukemia,EssentialThrombocitemia,IdiopathicThrombocytosis,PolicytemiaVera)

CLLtreatedwithmultiplelinesofCTXMultipleMyelomain3ormorelinesorduringASCT.HD:ifreceived“escalatingBEACOPP”DLBCLrelapsed/refractory

LoworhighgradeNHL,CLL,MM,HDtreatedwithconventionalfrontlinechemotherapy

«Additional»riskfactorsforIFIinpediatricsPazients Riskfactors TypeofIFI

(N°ofstudies)

Allogeneicstemcelltransplantation

AcuteGVHD/severeGVHDChronicGVHDDoseofsteroid>1mg/kg/dayfor>7daysAprioriTRMrisk>20%Olderageattrasplant

Aspergillus(5)Candida(4)Other(3)

Malignancy High-riskALLin1°CRRelapsedALLAMLdiagnosisPICUadmissionCVCSevereandprolongedneutropeniaPersistentfever>4days,monocytopenia(<0.1x109/l),C-RP>90mg/dl

Aspergillus(5)Candida(4)Other(6)

IFIRISKTABLE:patientandenvironmentrelatedriskfactors

Legend:High:incidence>5%,riskfactorthatputpatientathighriskforIFIreportedinpreviousstudiesorriskfactorinthesettingofHSCTIntermediate:incidence2-5%,riskfactorknowninthissetting,butthatnotidentifyanhighorlowriskforIFI,reportedinpreviousstudiesLow:incidence<2%,riskfactorthatputpatientatlowriskforIFIreportedinpreviousstudiesHighe-TRMscore‡:PS(performancestatus),Age,Platelet,Albumin,secondaryAML,WBC,%blastinPB,creatinine(WalterRB,etal.JCO,Oct.2011)Environment‡‡:intensivecareunitadmission,buildingworks,tobacco,cannabis,residence,pet,pottedplants,gardening,roomwithoutHEPAfiltration,airwayscolonizationbyAspergillus

Categories RiskFactors HSCT ASCT AML MDS ALL MPN NHL/HD CLL MM

Patient Age>65

Age55-65

Age30-54

Malesex

Comorbidities PS>o=2

PreviousIFI

Ironoverload

Diabetes

priorrespiratorydisease

Hypoalbuminemia

Influenza/parainfluenzavirus

Mucositis>o=3per>7gg

Esophagitis>2(WHO)

CMVinfection

Candidamultiplecolonization

Highe-TRMscore‡

Immunitystatus Toll-likerec.Polymorphism

Plasminogenpolymorphism

Mannosebindinglectin

Otherpolymorphism(PTX3,Dectin-1)

Lymphocytesdysfunction

Prolonglymphocytopenia(<300cells/μL)

Environment‡‡

IFIRISKTABLE:diseaseandtreatmentrelatedriskfactorsCategories RiskFactors HSCT ASCT AML MDS ALL MPN

NHL/HD CLL MM

Disease Activedisease† FirstRemission Aggressivedisease/lowerprobabilityofCR††

Therapy NoAntifungalProphylaxis Manyprevioustreatmentlines HighdoseChemotherapy††† Salvageregimen FirstInduction Consolidation Maintenance Highdoseofsteroid T-cellsuppressors* B-cellsuppressors**

Hypomethylatingagents(notassalvagetherapy)

TBI TKI CVC Bortezomib Neutropenia Neutropeniaatbaseline

Neutropenia<500/μLfor>10gg

Transplantrelated

Typeofdonor(HLAmismatchedvsHLAmatchedMUDvsrelated)

Stemcellsource(UCBvsBMvsPB) Moderate-severeacuteorchronicGVHD >1HSCT Cellmanipulations

CMVserologystatus(R+/D-vsR+/D+vsR-/D+vsR-/D-)

ATG CD34+infused(<3x10^6/Kg) EBMTscore*** BOscore****

Pre-transplantdiagnosis(AMLearlyonset-Lymphomalateonset)

Latepost-transplantimmunerecovery

Legend:High:incidence>5%,riskfactorthatputpatientathighriskforIFIreportedinpreviousstudiesorriskfactorinthesettingofHSCTIntermediate:incidence2-5%,riskfactorknowninthissetting,butthatnotidentifyanhighorlowriskforIFI,reportedinpreviousstudiesLow:incidence<2%,riskfactorthatputpatientatlowriskforIFIreportedinpreviousstudiesActivedisease†:Day15blast>5%orNOCRbytheendofinductionAggressivedisease(lowerprobabilityofCR)††:Adversecytogenetic/genemutationprofile,WBC>50.000/μL,secondaryAMLHighdosechemotherapy†††:forALLispediatricconditioning,forHSCTinmyeloablativeconditioningT-cellsuppressors*:Fludarabine,Cyclosporine,Tacrolimus,MMF,ATG,AlemtuzumabB-cellsuppressors**:RituximabEBMTscore***:Age,diseasestage,timebetweendiagnosisandtransplant,donortype,donor/recipientsex(GratwohlA,etal.Cancer,Oct.2009)BOscore****:bronchiolitisobliteransCTscore(deJongPA,etal.Thorax,2006Sep;61(9):799-804

…butinlightofallthedifferencesappear!!

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