2018专家共识建议接受积极治疗的骨髓增生异常综合征患者感染控制.doc

2018专家共识建议接受积极治疗的骨髓增生异常综合征患者感染控制 Aepted ManuscriptInfection control in patients with myelodysplastic syndromes whoare candidates for active treatment:Expert panelconsensus-basedremendationsCorrado Girmenia,Anna Candoni,Mario Delia,RobertoLatagliata,Alfredo Molteni,Esther N.Oliva,Giuseppe A.Palumbo,Antonella Poloni,Prassede Salutari,Valeria Santini,Maria TeresaVoso,Pellegrino MustoPII:S0268-960X (18)30069-9DOI:doi:10.1016/j.blre.2018.10.002Reference:YBLRE555To appearin:Blood ReviewsPleasecite thisarticle as:Corrado Girmenia,Anna Candoni,Mario Delia,RobertoLatagliata,Alfredo Molteni,Esther N.Oliva,Giuseppe A.Palumbo,Antonella Poloni,Prassede Salutari,Valeria Santini,Maria TeresaVoso,Pellegrino Musto,Infection controlin patients withmyelodysplastic syndromeswho are candidates for active treatment:Expert panelconsensus-based remendations.Yblre (2018),doi:10.1016/j.blre.2018.10.002This isa PDFfile of an uneditedmanuscript thathas beenaepted forpublication.Asa serviceto ourcustomers weare providingthis earlyversion of the manuscript.Themanuscript willundergo copyediting,typesetting,and review of theresulting proofbeforeit ispublished inits finalform.Please notethat during the productionprocess errorsmaybe discoveredwhich couldaffect thecontent,and alllegal disclaimersthat applyto thejournalpertain.Infectioncontrolin patients withmyelodysplastic syndromeswhoarecandidates for active treatment:expert panelconsensus-based remendationsCorrado Girmenia,1,*girmeniabce.uniroma1.it AnnaCandoni,2Mario Delia,3Roberto Latagliata,1Alfredo Molteni,4Esther N.Oliva,5Giuseppe A.Palumbo,6Antonella Poloni,7Prassede Salutari,8Valeria Santini,9Maria TeresaVoso10and PellegrinoMusto111Dipartimento diEmatologia,Oncologia eDermatologia,Policlinico UmbertoI,Sapienza University of Rome,Italy2Clinica Ematologica,Centro Trapiantie TerapieCellulari,Azienda SanitariaUniversitaria Integratadi Udine,Italy3Hematology andBMT unit,Policlinic ofBari,Department ofEmergency andOrgan Transplantation,University ofBari,Italy4UnitComplessa diEmatologia,ASST Cremona,Italy5Grande OspedaleMetropolitano BianchiMelacrino Morelli,Reggio Calabria,Italy6Dipartimento diScienze MedicheChirurgiche eTeologie AvanzateG.F.Ingrassia,Universitdegli Studidi Catania,Italy7Clinica diEmatologia,AOU OspedaliRiuniti,Dipartimento diScienze Clinichee Molecolari,UniversitPoliteica delleMarche,Ancona,Italy8Dipartimento diEmatologia,Medicina Trasfusionalee Bioteologie,Ospedale SpiritoSanto,Pescara,Italy9MDS UNIT,Hematology,AOU-Careggi UniversityHospital,Department ofExperimental andClinical Medicine,Universitdegli Studidi Firenze,Florence,Italy10Department ofBiomedicine and Prevention,Universityof Rome TorVergata,Rome,Italy11Scientific Direction,IRCCS-CROB,Referral CancerCenter ofBasilicata,Rionero inVulture,(PZ),Italy*Corresponding authorat:Dipartimento diEmatologia,Oncologia eDermatologia,Policlinico UmbertoI,Sapienza UniversityofRome,Via Benevento6,00161Rome,Italy.ACCEPTED MANUSCRIPTACCEPTED MANUSCRIPTAbstract Theimprovement insupportive care and theintroduction of new therapeuticagents,including lenalidomideand hypomethylatingagents,in myelodysplastic syndromes haveimproved patientsoutes;however,at the same time,the frequencyand epidemiology of infectionshave changed.Therefore,the greatstrides in the indicationsand use ofnewtreatment strategiesfor myelodysplastic syndromes needa parallel progress in the best approach to prophylaxis and supportive therapyfor infections.Based on the recognitionthat theabove issuesrepresent anunmet clinicalneed inmyelodysplastic syndromes,an Italianexpert panelperformed areview of the literatureand poseda frameworkof thebest remendations for optimalinfection controlin patient candidates to receive active treatment formyelodysplasticsyndromes.In thisconsensus documentwe reportthe outesof thatreview andof theconsensus meetingsheld duringxx.The issuestackled in the projectdealt with:information tobe collectedfrom candidatesfor active treatment formyelodysplasticsyndromes;how tomonitor the risk of infection;antimicrobial prophylaxis;the roleof ironchelation and antiviral/antibacterial vainations.For eachof theseissues,practice remendationsare provided.Keywords:myelodysplasticsyndrome,infections,prophylaxis,vaination.ACCEPTED MANUSCRIPTIntroduction Myelodysplasticsyndromes(MDS)area group ofclonal myeloidmalignancies withvariable clinicalpresentation anddisease prognosis.In lower-risk MDS,erythropoiesis-stimulating agentsand lenalidomide are theremended treatments,whereas hypomethylatingagents(HMAs)are considered the standardof carein higher-risk MDS patients forwhom allogeneicstem cell transplant is not feasible.1-3Out of the HMAs azacitidine,decitabine and,very recently,guanecitabine actuallyazacitidine isthe mostwidely usedin higher-risk MDS patients.Infections historicallyrepresent amajor plicationin MDS patients;however,their frequencyand spectrumin thedifferent subgroupsof MDS patients receivingcurrent treatmentapproaches has not been specifically investigatedand infection-control strategies,in particularanti-infective preventionfor high-risk disease,have notbeen standardized.4-7Hence,the greatstrides in the treatmentof MDS patients needparallelprogressin thebestapproachtoprophylaxis andsupportivetreatment for infections.Based on these considerations,a panelof Italianexperts in the managementof MDS patients tookpart in a projectaimed atproviding usefulremendations for the riskstratification andprevention of infectious plications in MDSpatientcandidatesfor activetreatment.Methods Theexpert panelincluded12hematologists selectedbecause of their expertisein researchand clinicalpractice of MDS.An Advisory Committee chairedby fourclinicians(CG,RL,MTV,VS)with expertisein clinicalepidemiology ensuredthe propermethodology of the process.The goal of theproject was to developremendationsforinfection-control strategiesin patients with MDSwho werecandidatesfor activetreatmentother thanacute myeloidleukemia(AML)-like chemotherapyand allogeneichematopoietic stem celltransplant.The areasof majorconcern in the infection-control strategyin MDS patients wereselected bygenerating clinicalkey questionsusing thecriterion of clinical relevance,i.e.,impact on the managementof patients and risk of inappropriateness,through aDelphi process.8The Delphimethod isa structured,interactive municationtechnique whichrelies ona panelof expertsThe expertsanswer questionnairesin ACCEPTED MANUSCRIPT twoor morerounds.After eachround,a facilitatorprovides asummary of the expertsforecasts from the previousround as well as the reasonsthey providedfor theirjudgments.Thus,experts areencouraged torevise theirearlier answersin lightof thereplies ofother membersof theirpanel.It isbelieved thatduring thisprocess therange of the answerswill decreaseand thegroup willconverge towardsthecorrectanswer.The AdvisoryCommittee examinedthe currentstate ofknowledge regardinginfection-control strategiesinpatientcandidatesforactivetreatmentof MDS,identified keyquestions anddrafted statementsto addressthese questions.A systematicreviewof the literatureon theepidemiologyof infections in MDS populationswas performedusing thePubMed database,limiting thechoice toEnglish-language articles.Articles thatincluded largesingle centeror multicenterseries of MDS patients,as wellas reviewarticles andposition papersby otherexpert groups,were considered.During the first meeting in Februaryxx,the keyquestions proposedby theAdvisoryCommitteewere discussedand approvedby theexpert panel,and oneor morepanelists weregiven thetask ofproducing remendationsforaspecific keyquestion basedon literatureanalysis and their ownexperience.Each panelistscored theiragreement with the statementsmade by the otherpanelists andprovided suggestionsfor rephrasing.The ensuingments werecentrally binedforasubsequent roundof electronionsultation;agreement on the statementsand approvalof thefull bodyof remendationswere definitivelyreached duringa secondmeetinginDecemberxx.The overallgoalof the meetingswastoreach adefinite consensusover question-specific statementsfor whichthere wasdisagreement during the first-round postalphase.We usedthe nominalgroup technique9-agroupprocess involvingproblem identification,solution generation,and decisionmaking-through whichparticipants werefirst askedto mentin round-robin fashionon theirpreliminary votesand thento proposea newvote.First,every memberof thegroup gavetheir viewofthesolution,with ashort explanation.Then,duplicate solutionswere eliminatedfrom thelist ofall solutions,and themembers proceededto rankthe solutions,1st,2nd,3rd,4th,and soon.If an80%consensus onthe statementwas not achieved,the choiceswere discussedand afurther votetaken.If an80%consensus wasstill notattained,the issuewas declaredunresolved andno furtherattempt wasmade.A facilitator(CG)encouraged thesharing anddiscussion ofreasons forthe choicesmade byeach groupmember,thereby identifyingmon ground,andaplurality ofideas andapproaches.Remendations specificallyconsideredthecurrent MDSACCEPTED MANUSCRIPTtreatment strategies,which requireproper stratificationaording to the InternationalPrognostic ScoringSystem(IPSS)ortheIPSS-Revised(IPSS-R).2,3Epidemiology of infections in patients with MDS receivingcurrent therapyIn patients with MDS,infectious plicationshave a highly variableincidence aording to MDSsubtype,patient characteristicsand treatment.4,5Considering the MDS intrinsicimmune impairment,several patients have an infection at the onsetofthe disease beforestarting anytreatment.Although theobservation of aninfection in MDSpatients at the onsetofthe disease ismon in the clinicalpractice,specific prospectiveepidemiological studiesare scarcein thisphase andmost ofthe recentdata in MDS populationsare derivedfrom retrospectivestudies in patients atdifferent phasesofthedisease orfrom Phase IIIII clinical trials performedto testnew therapeuticagents forMDS;therefore,endpoints aredifferent fromincidence of infectious plications.Moreover,to date,the infectious risk in MDS and the realimpact of these plicationsonthesurvival of MDSpatientsare stillunclear.4In arecent reportfromtheDusseldorf registry,examining cause of deathin alarge cohortof3792patients with MDS,2877patients(75.9%)had deceasedatthetime ofanalysis.From1665patients with a clearlydocumented cause of death,449(27%)died asa result ofaninfection.10Table1shows the most recentprospective PhaseII andIII clinical trials testingnew drugsin MDS and reportinginformation on infectious adverseevents.11-21Table2shows theresults ofretrospective observationalstudies focusedon infectious plications in MDSpatients.5,7,22-26As detailed,infectious plicationshave avariable,but notnegligible,incidence,especially inclinical trialsenrolling higher-risk MDSpatients(including IPSS-R intermediateto veryhigh),in whichthe rate of grade3infections reaches58%of treatedcases.13Conversely,in studies involving lower-risk MDSpatients,infections andfebrile neutropeniaof grade3are lessfrequent,ranging from2%to21%of treatedcases.5,17-19The effectof HMA therapy inworsening cytopenia and inincreasing the risk of infection in MDS isstill poorlydocumented.In fact,in earlystudiesin patients with higher-and lower-risk MDS(CALBG8421,8921,9221trials)receiving azacitidine,there wasno increase in the infection rateduring azacitidiherapy pared with the“best supportive care”cohort.27However,more recent“real-world”studies haveACCEPTED MANUSCRIPTsuggested anincreaseininfectious eventsin higher-risk MDSpatients treated with HMAs,especially duringthe early(first23)cycles of therapy,before achieving a response,when thedrug-induced cytopeniais associated with active-phase MDS.4,25,26In addition,clinicaltrialsclearly showthat thepercentage ofinfectious eventsis high,not onlyin the therapeutic armbut alsoin thecontrol group,emphasizing that there isan inherentrisk of infection inMDS,regardless ofthe therapeuticapproach,due toboth neutropenia and thealtered functionof neutrophils.11-14,19-21When detailed,most reported infections inMDS ourin the presence of neutropeniaandare prevalentlyof bacterial origin,with subsequentpneumonia,bacteremia and/or sepsis.4,28,29Infectious riskassessment andmonitoring WhichMDSpatients eligible foractivetreatmentare at higher risk of infection,and whatinformation andtests areremended toidentify/stratify therisk ofinfection?Preliminary considerationsAlthough infectionsmay ourand causedeath independentlyof specificrisk factors,10,28-35baseline neutropenia,present in50%of higher-risk IPSS/IPSS-R and1520%of lower-risk MDS,is likelythe mainpredisposing factorin thesepatients.4,6,29,35Furthermore,several otherfunctional defectsof granulocytes,aswellas varioustypes ofB-,T-,natural killerand regulatoryT-cell abnormalities,have been reported toalso impairthe responseto infectiousmicroorganisms inthe absenceof neutropenia in patients with MDS.4,31The truecontribution of such abnormalitiesto the development of infections inMDS,however,has notbeenspecificallyinvestigated inthe clinicalsetting.Frailty,chronic infectionsor previoussevere infectiousepisodes,environmental(home,hospital),and patients(airways)bacterialorfungal colonizations,iron overload(IO),bone marrowreserve(cytopenias)and biologicalstatus ofthedisease(number ofblasts andgeic characteristics),have allbeen variablyassociated with an increased risk of infections andwith theirseverity.4-6,29,34,36-38Importantly,specific drugsand treatmentscurrently employedinMDS,which havedemonstrated efficacyin selectedsubtypes,can alsotransiently worsenor determinesevere neutropeniaand immunosuppression,thus possiblyplaying anadditional relevantrole inthedevelopmentof infections.In ACCEPTED MANUSCRIPT this setting,no evidenceofan increasedrisk ofinfection(in particularlife-threatening pneumoniaand sepsis)has been reported intwo prospective,randomized trialsparing azacitidio bestsupportivecare.11,27However,azacitidine inducedsustained neutropenia(grade34)in up to91%ofthesepatients,including those who hadbaseline grade02and shiftedto grade34neutropenia ontherapy(84%).Of interest,theinfectionrate in azacitidine-treated patientswas significantly lower than in those receiving low-dose cytarabineor intensive chemotherapy,resulting ina34%reduction inthe rateofinfection.11In aretrospective studyof184patients treated with azacitidine,themostrelevant prognosticfactors forinfections ina multivariateanalysis werelow plateletcounts(20109/L),poor riskcytogeics andlow hemoglobinlevels(10g/dL).26In thisstudy,absolute neutrophil counts beforeeach azacitidinecycle andmarrow blastpercentage(but notage,transfusion dependency,azacitidine doseor serumcreatinine)were alsofound tobe risk factors inthe univariateanalysis,but theydid notmaintain theirprognostic relevanceinthemultivariate model.Two studiesreported a higher risk ofinfectiousplicationsin patients treated with azacitidine75mg/m2for7days,thanin those receiving5days oftherapy eitherinthefirst cycle39or duringthe entiretreatment.40Notably,the rateofinfectiousevents tendedto declinewith sequentialazacitidine cycles(in particularafter thefirst threecycles).7,23,25,26,41,42This isprobably due to theprogressive resolutionof neutropenia in responders.In anotherretrospective study,febrile episodesappeared tobe more frequent ifintensive chemotherapyhad beenemployed beforeazacitidine,pared withwhen azacitidinewas usedfrontline.25In thisstudy,there wasno relationshipbetween neutrophilcounts lowerthan0.5109/L andprobability ofinfectiousplications;however,severe neutropeniawas associated with ahigher incidence of proven/probable invasivefungal diseases(IFDs)inMDSpatients receivingazacitidine.24Response toazacitidine impactsontheprobability ofinfections,with asignificantlylowerprevalence ofthese plicationsin patients who achievedat leasta hematologicresponse,paredwith those with progressive or stable disease.23In thisstudy,older agewas associated with anot significanthigher rateofinfections,whereas orbiditiesor IPSS-R hadno influence.Conversely,a veryhigh IPSS-R hasrecently beenidentified as an independentriskfactorforinfectionsinazacitidine-treated patients,witharelevant attributablemortality.7ACCEPTED MANUSCRIPTIn anotherreal-world Italianexperience in184MDSpatientstreated with azacitidine,higher plateletlevels werethe onlyfactor associated with an increased incidenceof febrileevents,whereas age,months fromdiagnosis,hemoglobin,white bloodcell andneutrophilcounts,bone marrowblasts,MDS orbidityindex,body massindex,IPSS andIPSS-R,azacitidine dose,and responsewere not.41Of note,atthetime ofthe events,disease remissionhad notbeen achievedin mostcases(only11%of eventsourred inresponsive patients);ahighrisk ofdeath dueto pneumoniaand bowelinfection wasalso observed.An infectiousevent wasthe attributablecause ofdeath mainlyin patientswithprogressiveorstabledisease.IFDs have beenreportedat ratesvarying between4%and12%inMDSpatients undergoingHMAtherapy.26,39,43,44The ratewas significantlyhigher in thosewhohad receivedprevious intensivechemotherapy,uptoabout25%.25Similar toother infections,therisk of IFDwas highestduringthefirst threetreatment cycles.Pulmonary infectionsare associated with poorprognosis inMDSpatientstreated withazacitidine.41,44Given thedifferent etiologies,interstitial pneumoniaassociatedwithazacitidine should be differentiatedfrom otherlung infections.45Specific dataontherisk ofinfections associatedwith decitabireatment inMDS arelimited.Overall,decitabine appearsto increasemyelotoxicity paredwithazacitidine.In particular,one parative,retrospective studyfound that patients whohad receiveddecitabine experiencedmorefrequentepisodes ofgrade3or4cytopenia andinfection thanthosereceivingazacitidine;this wasparticularly frequentin elderlypatients.43In aretrospective studyof85AML andMDSpatientstreated ina prospectiveclinical studyusing10-day cyclesof decitabine,culture resultswere available for163infection-related plicationsthat ourredin70patients.Infection-related deaths