risk stratification for fungal infections in hematological ...€¦ · antifungal resistance in...
TRANSCRIPT
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)
Population N°cases IncidenceIFI References Comment
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)
Population N°cases IncidenceIFI References Comment
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%
136ALLpts(prospectivestudy)
CVC(yeasts);neutropenia(moulds)
Montagna,IntJMolSci2012
IFI4.2%(IM2.1%)
205ALLpts(prospectivestudy)
-- Pagano,AnnHematol2012
IFI4%
847ALLpts(prospectivestudy)
(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)
Population N°cases IncidenceIFI References Comment
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
20-64y(Medianage:56y)
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
EpidemiologyofIFIinASCT(last10years)
Population N°cases IncidenceIFI References Comment
19-67y(Medianage:45y)
≤40y:41pts>40y:68pts
109pts(NHL39,HD36,MM34)
8% Gil,BMT2009 ProspectivePolandstudy2005-2007onASCTonly.MultivariateanalysisshowstheroleofapreviousFludarabine
treatmentastheonlyriskfactorforIFI
0-82y(Medianage:37y)
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
EpidemiologyofIFIinASCT(last10years)
Population N°cases IncidenceIFI References Comment
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
2002-2011 378patientsAllo-HSCT
IA7.9%-Candidemia3.4%Others4%IA52%
LiuY-CJMicImmInf2015
2002-2013 421 PatientsAllo-HSCT
IFI7.4%AM80%
MontesinosPBMT2015
2001-2013 404patientsAllo-HSCT
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
RiskfactorsofIFIinHSCTrecipients(2)RiskFactors
Pre-HSCTPost-HSCT
References Study/No.Patients
Comment
IronoverloadFerritin>500
>1000>1550>2000
Score>3
SucakTr.Proc2010OzyilmazBMT2010SivginTrAphSc2012Garcia-VidalCID2008KontoyiannisCancer2007
Retrosp-250Retrosp-148Retrosp-73Retrosp-1248Retrosp-66
pulmonaryinfectionpulmonaryinfection
RisKforIMI
GeneticTLR-4
Dectin-1PTX3
BochudNEJM2008CunhaBlood2010CunhaNEJM2014
Retrosp-336Retrosp-205Retrosp-268
MiscellaneousEnvironment
CD34+cellsinfusedEBMTscore
BOScore
CVCPreviousIFI
>1previousHSCT
WarrisJClinMic2003BittencourtBlood2002LiuJMicImmInf2015StanzaniPlos2013
PaganoCID2007
LiuJMicImmInf2015GirmeniaBBMT2014StanzaniPlos2013
MontesinosBMT2015WalshMycoses2015
ne
Retrosp-212Retrosp-421
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
RiskfactorsofIFIinHSCTrecipients(3)RiskFactors
Pre-HSCTPost-HSCT
References Study/No.Patients
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
Retrosp-1248Retrosp-272
Retrosp-1248Retrosp-306Retrosp-421
RiskforIMI
RiskforIMILateIA
SEIFEM
RiskfactorsofIFIinHSCTrecipients(4)RiskFactors
Pre-HSCTPost-HSCT
References Study/No.Patients
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
Retrosp-1248Retrosp-306
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
Retrospective(1988-2006)
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
Retrospective(1998-2006)
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
Retrospective(1990-2009)
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%)
Aspergillus,Candida,other
- apriorideterminedHSCTTRMrisk>20%;
- high-dosesteroidspostHSCT
CastagnolaE,2014BiolBloodMarrowTransplant
Retrospective(2000-2009)
198 8,4(3,4-12,1)
Allo-HSCT 31/134episodes(23.1%)
IFI -GradeofaGVHD
OzsevikSN,2015JPHO
Retrospective(2010-2011)
253 Children Hematologicormalignantdisease
67/928febrileepisodes(7.2%)
Aspergillus,Candida,other
- prolongedandprofoundneutropenia(moldinfections);
- CVC(invasiveyeastinfection)
SahbudakBZ,2015Mycoses
Retrospective(2005-2013)
125 Children ALL Provenandprobable:30/125(24%)
Aspergillus,Candida,other
- 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!!