FebrileNeutropenia–GuidelinesUpdateandApproachtoManagementofBothHigh-and

Intermediate-RiskPaBents

Bernardo Rapoport

TheMedicalOncologyCentreofRosebank,Johannesburg

andDepartmentofImmunology,FacultyofHealthSciences,UniversityofPretoria

SOUTHAFRICA

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•  Despitemajoradvancesinpreven1onandtreatment,FNremainsoneofthemostfrequentandseriouscomplica1onsofcancerchemotherapy

•  Majorcauseofmorbidity,healthcareresourceuse

•  Compromisedtreatmentefficacyresul1ngfromdelaysanddosereduc1onsofcancerchemotherapy

•  MortalityfromFNhasdiminishedsteadily,butremains

significant

Introduction

4

G.P. Bodey, Ann Int Med, 1966

The risk of infection increases with the severity and duration of neutropenia

Complications of Myelosuppressive Cancer Chemotherapy

Kuderer NM et al. Cancer 2006;106:2258–2266 Chirivella I et al. J Clin Oncol 2006;24;abstract 668

Bosly A et al. Ann Hematol 2007

Myelosuppressive chemotherapy

Febrile neutropenia (FN) Chemotherapy dose delays and dose reductions

Decreased relative dose intensity (RDI)

Complicated life-threatening infection and prolonged hospitalization

Neutropenia

Reduced survival

Short-termeffects Long-termeffects

Thereisaclearrela1onshipbetweentheseverityofneutropenia(whichdirectlyinfluencestheincidenceofFN)andtheintensityofchemotherapyCurrently,thedifferentregimensareclassified• Highrisk(>20%)

• Intermediaterisk(10%–20%)

• Lowrisk(<10%)ofFN

ESMO Guidelines Neutropenia Risk

•  Lymphoma R-ICE •  Adjuvantbreast FEC100•  Adjuvantbreast FEC100T•  Neo-adjuvantorAdjuvantbreast TAC•  BurkiXsLymphoma R-CODOX-M•  Bladder MVAC•  Sarcoma MAID•  Sarcoma Doxorubicin-ifosfamide•  Small-celllungcancer CAE•  Tes1cularcancer VIP

FNRiskof>20%

MorethanhalfoftheFNepisodesoccurinthefirstcycleofchemotherapy

•  Star1ngwiththefirstcycleandcon1nuingthroughsubsequent

cyclesofchemotherapyisrecommendedinpa1entswhohaveanapproximately20%orhigherriskforfebrileneutropeniaonbasisofpa1ent-,disease-,andtreatment-relatedfactors

•  PrimaryCSFtheprophylaxisshouldalsobegiveninpa1entsreceivingdose-densechemotherapywhenconsideredappropriate

PrimaryProphylaxiswithaCSF

FNRiskof10-20%

•  AgeplaysamajorroleintheriskofFNanditscomplica1ons

•  Olderpa1entshaveahigherriskofFNfollowingchemotherapy

•  Olderpa1entshavetheworsemorbidityandmortalityrates

•  RiskofFNanditscomplica1onsincreaseswhenoneorseveralco-morbidi1esarepresentinthepa1ent

ESMO Guidelines Age and co-morbidities

•  FNcanbeeffec1velypreventedbytheuseofG-CSFs•  ItisrecommendedtouseG-CSF’sinpa1entsreceiving

chemotherapieswitha10-20%riskofdevelopingFN

•  Seriousco-morbidi1esand/oraged>60years

•  Dosereduc1ondeemeddetrimentaltooutcome

FN Prophylaxis

Prophylac1cG-CSFforpa1entswithdiffuseaggressivelymphomaage65yearsandoldertreatedwithcura1vechemotherapy(CHOP-R)shouldbeconsidered,par1cularlyinthepresenceofcomorbidi1es

CSFforpaBentswithdiffuseaggressivelymphomaage65yearsandolder

MulBpleChronicCondiBons•  InthecaseofFN,observa1onalstudieshaveprovidedimportant

informa1onabouttheimpactofcomorbidity

•  A2014systema1creviewreportedthatthepresenceofcomorbidcondi1onsincreasedtheriskofFNamongpa1entswithcancertreatedwithchemotherapy

•  Comparedwithpa1entswithnocomorbidcondi1ons,pa1entswiththreeormorecomorbidcondi1onshadan81%increasedriskofFN

•  Thepresenceofrenal,hepa1c,andcardiovasculardiseasehaveeachbeenassociatedwithFNorFN–relatedhospitaliza1on

•  Advanceddisease•  HistoryofpriorFN•  Noan1bio1cprophylaxisorG-CSFuse•  Mucosi1s

•  PoorPS•  Cardiovasculardisease

ESMO Guidelines Neutropenia Risk

Other Risk Factors

•  Isrecommendedforpa1entswhoexperiencedaneutropenic

complica1onfromapreviouscycleofchemotherapy(forwhichprimaryprophylaxiswasnotreceived)

•  Areduceddoseortreatmentdelaymaycompromisedisease-freeoroverallsurvivalortreatmentoutcome

•  Inmanyclinicalsitua1ons,dosereduc1onordelaymaybeareasonablealterna1ve

SecondaryProphylaxiswithG-CSFs

G-CSFsshouldnotberou1nelyusedforpa1entswithneutropeniawhoareafebrileG-CSFsshouldnotberou1nelyusedasadjunc1vetreatmentwithan1bio1ctherapyforpa1entswithuncomplicatedfeverandneutropenia

G-CSFsinAfebrilePaBentsGuidelineRecommendaBons

G-CSFsshouldbeconsideredinpaBentswithFN

•  Prognos1cfactorsthatarepredic1veofpoorclinicaloutcomes•  High-riskfeaturesincludeexpectedprolonged(>10days)•  Profoundneutropenia(<0.1×109/L) •  Ageolderthan65years•  Uncontrolledprimarydisease •  Pneumonia•  Hypotensionandmul1organdysfunc1on(sepsissyndrome) •  Invasivefungalinfec1on•  Beinghospitalizedatthe1meofthedevelopmentoffever

HighRiskforInfecBon-AssociatedComplicaBons

KlasterskyJ,JClinOncol2000;18:3038–51.

MASCCIndex

•  Mul1na1onalAssocia1onforSuppor1veCareinCancer•  Prospec1velyvalidatedtooltorapidlyassessriskbefore

accesstoneutrophilcount•  Scores≥21areatlowriskofcomplica1onsMASCCscoring

index:–  Burdenofillness:noormildsymptoms5–  Burdenofillness:moderatesymptoms3–  Burdenofillness:severesymptoms0–  Nohypotension(systolicBP>90mmHg)5–  Nochronicobstruc1vepulmonarydisease4–  Solidtumour/lymphomawithnopreviousfungalinfec1on4–  Nodehydra1on3–  Outpa1entstatusatonsetoffever3–  Age<60years(notvalidinchildren<18years)2

MASCCScore=26

•  An1microbialshavebeenusedforalong1meforthepreven1onofepisodesofFNinchemotherapytreatedpa1ents

•  Thisapproachhasbeensomewhatsuccessful

•  Ledtotheemergenceofresistantstrains

•  Limi1ngitsefficacy

Chemoprophylaxis

•  GuidelinesfromtheEORTC&ASCOrecommendthatclinicianslimittheuseofan1bacterialprophylaxistopa1entsathighriskforFN

•  Cochranemeta-analysiss1llrecommendedtheuseofciprofloxacin

orlevofloxacinincancerpa1entsundergoingintensivechemotherapy

•  Othersrecommendavoidance

•  Fluoroquinolones,shouldbediscouraged

Chemoprophylaxis

•  Severalmeta-analysesindicatethatprimaryG-CSFprophylaxis(administeredaoercycle1)reducestheFNriskbyatleast50%insolidtumorspa1ents

•  GuidelinesrecommendG-CSFbeadministeredprophylac1callyifthe

riskofFNis>20%

•  FNintermediaterisk(10%–20%)considertheage,coexis1ngmorbidi1es,otherriskfactors

G-CSFprophylaxis

•  Autologousstem-celltransplant Common

•  Allogeneicstem-celltransplant Common

•  Duringgraofailure Common

•  AMLatDX 35%–48%

•  ALLduringALLinduc1on 30%

ESMO Guidelines FNinhigh-risksituaBons

•  Autologoustransplant 0%–10%

•  Allogeneictransplant highlyvariable

•  ALLduringinduc1on 2%–10%

•  AMLduringthefirst2months 20%–26%

•  Graofailure 80%

ESMO Guidelines FN-relatedmortalityinhigh-risksituaBons

•  Autologoustransplant Yes

•  Allogeneictransplant Yes

•  Graofailure Yes

•  AML No

•  MDS No

•  ALL Controversial

ESMO Guidelines G-CSF high-risksituaBons

TheUpdateCommiXeedidnotproviderecommenda1onsregardingtheuseofG-CSFsinadultswithacutemyeloidleukemiaormyelodysplas1csyndromes

AML+MDS

FN Management ESMO Clinical Practice Guidelines

Adapted from European Organisation for Research and Treatment of Cancer guidelines. FN, febrile neutropaenia; G-CSF, granulocyte colony-stimulating factor

Ann Oncol. 2016;27(suppl_5):v111-v118. doi:10.1093/annonc/mdw325

EvaluaBonPriortotheFirstCycleofChemotherapy

• Pegfilgras1matatotaldoseof6mg

• Equivalentdoseoffilgras1mis5μg/kg/dayfor∼10days

• EMA/FDAapprovedbiosimilarscanbeconsidered

G-CSFandpegfilgrasBmdoseschedule,routeofapplicaBon

G-CSFSideEffects

•  BonePain 25%

•  Painintheextremi1es 5-10%

G-CSFSideEffects

•  PrimaryprophylaxiswithG-CSFisnotindicatedduringchemoradiotherapytothechestduetotheincreasedrateofbonemarrowsuppressionassociatedwithanincreasedriskofcomplica1onsanddeath

•  ThereisalsoariskofworseningthrombocytopeniawhenG-CGFs

aregivenimmediatelybeforeorsimultaneouslywithchemotherapy

ESMOG-CSFContraindicaBons

FN risk ESMO ASCO NCCN Moderate to high (> 20 %)

Use G-CSFs Use G-CSFs Use G-CSFs

Intermediate (10-20 %)

Consider

Consider

Consider

Consider other risk factors

+++

++

++

Low (< 10 %)

Not

specified

Not

recommended

Not

recommended

Conclusion

ConclusionTakehomemessage

1.  Myelosuppresivechemotherapyisassociatedwithseveremorbidityandmortality

2.  ESMOGuidelines(ASCO&NCCN)recommendstheusageG-CSFtopreventFNandseriousinfec1vecomplica1onsassociatedwithchemotherapy

3.  Clinicalevalua1onofpa1entsriskfactorswitheverycycleofchemotherapyisimpera1ve

Thank You

PersonalisedCancerCare

542-03-#37

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