Profilassi e Terapia an.trombo.ca nel paziente onco‐ematologico · Profilassi e Terapia...
Transcript of Profilassi e Terapia an.trombo.ca nel paziente onco‐ematologico · Profilassi e Terapia...
ProfilassieTerapiaan.trombo.canelpazienteonco‐ematologico
Anna Falanga, MDUSC Immunoematologia e Medicina TrasfusionaleDipartimento Oncologia-EmatologiaOspedali Riuniti Bergamo
Corso Nazionale di Aggiornamento in Ematologia ClinicaBolzano, 18-19 giugno, 2009
CancerandVenousThromboembolism(VTE)
• VTEisafrequentcomplica.onofcancer:
– Es.matedriskis0.5%/yearor0.04%/month
– 6.5‐foldincreasedriskwithchemotherapy
• HeitJAetal,ArchInternMed,2000
• LeeAYY,BrJHaematol,2004
IncidenceofVTEinUSCancerPa.ents:1979‐1999
National Hospital Discharge Survey data.Stein PD et al. Am J Med. 2006;119:60-68.
0
1
2
3
4
1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999
VT
E In
cide
nce,
% Cancer No Cancer
4
Type of cancer Adjusted OR (95% CI)Hematologic 28 (4-199.7)
Lung 22.2 (3.6-136.1)GI 20.3 (4.9-83)
Breast 4.9 (2.3-10.5)Prostate 2.2 (0.9-5.4)
Copyright restrictions may apply.Blom, JAMA, 2005
RiskofVTEbySiteofCancer
5
RiskofInpa.entVTEbySiteofCancer
02468
101214
AllBrai
nLung
Stomach
Colon
Pancre
as
Other GI
Ovary
Endometr
ium/
cervix
Rat
e, %
Khorana AA et al. J Clin Oncol. 2006;24:484-490.
6
RiskofInpa.entVTEbySiteofCancer(cont’d)
Rat
e, %
0
1
2
3
4
5
6
7
All Leukemia NHL Hodgkin's Myeloma Breast
Khorana AA et al. J Clin Oncol. 2006;24:484-490.
• Commonly,venousthromboembolism(VTE)isconsideredmorefrequentinpa.entswithsolidtumors,whereashemorrhageduetoDICareconsideredmorefrequentinhematologicalmalignancies.
• HoweverrecentlargeepidemiologicalstudiesindicatethattherateofVTEinpa.entswithhematologicalmalignanciesisatleastashighas“highrisk”typesofsolidtumors.
Thrombosis in hematological malignancies
Thethrombo.criskinhematologicalmalignancies
• Hematologicalmalignanciescarryanintrinsicriskofthrombosis,duetothecancer.ssueprothrombo.cproper.es;
• Thisriskisincreasedbychemotherapy(inaddi.ontoothergeneralriskfactors,i.e.age,bed‐rest,surgery,etc.);
• Thrombosisratescanbees.matedin:
‐Mul.pleMyeloma ‐Lymphomas
‐AcuteLeukemias
Mul.pleMyelomaandThrombosis
• Mul.plemyeloma(MM)andotherplasmacelldyscrasiasarethrombogenicasaconsequenceoftheirmul.plehemosta.ceffects.
• Theoraldrugsthalidomideandlenalidomidehaveproducedmajortherapeu.cresponsesinpa.entswithMMwhenusedincombina.onwithoralsteroidsandchemotherapy,butsignificantlyincreasedtheriskofVTE.
• Availabledatasuggestthatthomboprophylaxiswithlow‐dosewarfarin,orLMWH,orAspirin,mayreduceVTErateassociatedtothalidomideandlenalidomide
Thalidomide
Lenalidomide
Figure 1
Falanga A, Marchetti M, JCO 2009, in press
Figure2
Lowfixeddosewarfarin
Warfarin(INR:2‐3)
LMWH
Beforeprophylaxis
Lowfixeddosewarfarin
Beforeprophylaxis
Beforeprophylaxis
LMWH
Aderprophylaxis(Lowfixeddosewarfarin)
Aderprophylaxis(Aspirin81mg/d)
Aderprophylaxis(LMWH)
LMWHLowfixeddosewarfarin
LMWH
Aspirin(100mg/d)
Aspirin(80‐325mg/d)
Lowfixeddosewarfarin
Aspirin(81mg/d)
Aspirin(325mg/d)
Thalidom
ide
Lenalidom
ide
Falanga A, Marchetti M, JCO 2009, in press
LymphomaandThrombosis
• Non‐HodgkinandHodgkinLymphomascarryasignificantriskforvenousandarterialthrombosis,par.cularlyduringchemotherapytreatments.
• Hemosta.caltera.onsunderlyingahypercoagulablecondi.onarecommonlyfoundinpa.entswithlymphomas.
Study StudytypePa.ents
(n)Pa.entswith
VTE(n)VTEincidence
(%)
Non‐HodgkinLymphomaClarkeetal,1990 Retrospec.ve 75 11 14.6
Khoranaetal,2006 Retrospec.ve 12977 650 5
Athaleetal,2008 Retrospec.ve 23* 3 13
Khoranaetal,2005 Prospec.ve 267 4 1.5
OFngeretal,1995 Prospec.ve 953 3 6.6
HodgkinDiseaseKhoranaetal,2006 Retrospec.ve 2042 79 3.9
Athaleetal,2008 Retrospec.ve 52* 6 11.5
Khoranaetal,2006 Prospec.ve 49 4 8.6
CNSLymphomaGoldschmidtetal,2003 Retrospec.ve 42 25 59.5
LargeB‐cellLymphomaKomrokjietal,2006 Retrospec.ve 211 17 8
VTEincidenceinLymphomapa.ents.
Dataarereportedaccordingtothetypeoflymphoma.*=pediatricpa.ents.CNS=centralnervoussystem;VTE=Venousthromboembolism.
Pa.entswithacuteleukemiaareunique
• Nearlyallpa.entswithcancershowevidenceofsubclinicalac.va.onofclohng,orchronicDIC.
• However,pa.entswithacuteleukemiaareuniqueinthattheymostodenpresentwith:
– awiderangeoflaboratoryabnormali.esconsistentwithDIC,and
– awiderangeofclinicalmanifesta.ons,fromlocalizedvenousorarterialthrombosistodiffuselife‐threateningbleeding
• RecentlargeepidemiologicstudiesindicatethattherateofVTEinpa.entswithhematologicmalignanciescanbecomparabletothatofothersolidtumortypesconsideredatthrombo.c‘highrisk’.
StudiesthathaveevaluatedtheincidenceofVTEinpa.entswithacuteleukemia(AL).
StudyStudydesign,Studyperiod
Totalpa.entswithAL(n)
Pa.entswithVTE(n)
VTEincidence
(%)
Pa.entswithspecificALtype
(n)
Pa.entswithVTE(n)
VTEincidence
(%)
Ziegleretal,2005
Retrospec.ve,1979‐2001
719 15 2.09
AML(534) 11 2.06
ALL(185) 4 2.16
APL(49) 3 6.12
Mohrenetal,2006
Retrospec.ve,1992‐2005
455 55 12.1
AML(310) 40 12.9
ALL(108) 14 13
APL(7) 3 42.86
Kuetal,2008
Registrydata,1990‐2000
7876 395 5*
AML(5394) 282 5.23
ALL(2484) 113 4.55
APL(337) 21 6.23
DeStefanoetal,2005
Prospec.ve,1994‐2003
379 21 6.3**
AML(310) 14 4.52
ALL(69) 7 10.14
APL(31) 5 16.13
Melilloetal,2007
Prospec.ve,1999‐2005
114 11 9.6
AML(70) 9 12.86
ALL(44) 2 4.55
APL(14) 4 28.57
Carusoetal,2006
Meta‐analysis,NA
‐ ‐ ‐ ALL(1752)° 91 5.2
Carusoetal,2007
Meta‐analysis,NA
‐ ‐ ‐ ALL(323)°° 19 5.9
AML=acutemyeloidleukemia;ALL=acutelymphoblas.cleukemia;APL=acutepromyelocy.cleukemia;VTE=Venousthromboembolism.°pediatricALLpa.ents.;°°adultALLpa.ents;*VTE+upperextremitythrombophlebiYs;**VTE+arterialthrombosis
Thethrombo‐hemorrhagicsyndromeofAPL
• Theincidenceofthesecomplica.onsvariesaccordingtothetypeofleukemiaandthephaseoftreatment.
• Thrombosisismorecommonthanpreviouslyappreciatedinindividualswithalltypesofadultacuteleukemias,includingpa.entswithAPL,inwhomhemorrhageisusuallypredominant.
• BleedingandThrombosiscanoccurconcomitantlyasapartofthesamethrombo‐hemorrhagicsyndrome(THS)ofAPL.
APLcoagulopathy
• InAPL,earlymortalitymostodenisduetoasevereandodencatastrophicbleeding,odenintracerebralinloca.on,andremainsamajorcauseoftreatmentfailure.
• Thrombosis,eitheratdiagnosisorduringthecourseoftreatment,maybeunrecognizedandreflectsthecomplexityofthecoagulopathy.
Coagulopathy of APL: Laboratory abnormalities
"Routine" clotting tests abnormalities:Hypofibrinogenemia, prolonged prothrombin and thrombin times,increased fibrinogen/fibrin degradation products (FDP).
elastase
TATF1+2FPA
COAGULATION FIBRINOLYSIS non-specificPROTEOLYSIS
ACTIVATION
u-PA
plasminogen
a-2-antiplasmin
D-dimerD-dimer
Hypercoagula.oninacuteleukemia
• Laboratoryabnormali.esofthebloodclohngsystemunderlyingtheclinicalpicturesofDICofacuteleukemias,areexacerbatedbytheini.a.onofchemotherapy.
• Studiesofhypercoagula.onmarkersclearlyshowthatthrombingenera.onisconstantlyongoing.
• TheincreaseofD‐dimer,theby‐productsofcross‐linkedfibrin,demonstratesongoinghyperfibrinolysisinresponsetoclohngac.va.on.
Baselineplasmalevelsofhypercoagula.onmarkersinpa.entswithAPL
Controls APLpa.ents P<
F1+2(nM) 1.1(0.5‐1.5) 11(3.0‐14.7) 0.001
TAT(ng/ml) 2.9(1.2‐5.2) 23(5.1‐78) 0.001
D‐dimer(microg/ml) 0.3(0.18‐0.60) 1.6(0.4‐3.2) 0.001
Fibrinogen(mg/dL) 270(184‐405) 94(65‐368) 0.001
Falanga et al, Blood, 1995Values are median (range)
ATRAandhemostasis
• TheadventofATRAfortheremissioninduc.ontherapyofAPLhasopenednewperspec.vesinthemanagementofthecoagulopathy.
• Differentlaboratorieshaveshownthedecreaseornormaliza.onofclohngandfibrinoly.cvariablesduringthefirstoneortwoweeksofATRAtherapy.
Plasmahypercoagula.onmarkersatONSET(T0)andduringATRAtherapy
*
*
*
=MeanControllevels *=p<0.05vsT0
DaysofATRATherapy DaysofATRATherapy
*
* *
Zhu J, et al, Leukemia 1999
Hemorrhageandthrombosisin54consecu.venewlydiagnosedAPLpa.ents
ONSETN (%)
INDUCTIONN (%) Total
Major fatal bleeding 1* (1.8) 2* (3.7) 5.5%
Major non fatal bleeding 0 5 (9.2) 9.2%
Fatal thrombosis 1* (1.8) 0 1.8%
Non fatal thrombosis 2 (3.7) 3 (5.5) 9.2%
*DeathsoccurredbeforestarYngATRAtreatment
Prospec.vetrialsofall‐transre.noicacid(ATRA)inacutepromyelocy.cleukaemia(APL).
CR,completeremission;ED,earlydeath;DFS,disease‐freesurvival.
Stein et al, Best Pract & Res Clin Haematol, 2009
The coagulopathy of acute promyelocytic leukemia revisited
Responseandinduc.onmortalityin732APLpa.entsenrolledinLPA96+LPA99studies
DeLaSerna,Blood2008
• 666morphologicCR(91%)• 66deaths(9%)
• Factorpredic.ngfatalhemorrhageinmul.variateanalysis:
• Abnormalcrea.ninelevel
• Peripheralblastcount>30*10^9/L
• Coagulopathy
Prognostic factor Odds Ratio P value
Fibrinogen < 170 mg/dL 2.86 0.001
M3 variant 3.14 0.002
Use of Tranexamic acid 1.96 0.049
Incidence of THSAt diagnosis + during induction = 5%
PETHEMA LPA96 & LPA99 Studies
ManagementofThrombohemorrhagicSyndromesinAcuteLeukemia
Pathogenesis
• Leukemiccell
• Chemotherapy
• Infec.ons
Intracoronarythrombuswith.ssuefactorexpressionheraldingacutepromyelocy.cleukaemia
Altweggetal.EurHeartJournal2007
A54‐year‐oldmansuddenlyexperiencedAMI.Nootherriskfactors,andnosignificantcomorbidity.
Bloodcountshowedapancytopenia:WBC640/uL,(neutrophils160/uL),platelets112000/uL,Hb9.1g/dL,Ht25%.Bloodsmear:pancytopenia,butotherwisenormal.PCIwasperformedandlargeamountsofthrombo.cmaterialcouldberemoved.Bonemarrowbiopsy(performedbecauseofpersis.ngpancytopenia)revealedhypergranularAPL.Peripheralbloodsmearthenwasshowing28%promyelocytes,containingin3%Auerrods,and0.5%wereblasts(PanelB;narrowarrows).Histologyofthethrombusexhibitedaregularpaternwithfibrinandplatelets,alotofredbloodcells,manyneutrophils,andfewmacrophages.Noblastswerefound.However,immunochemistryoftherecoveredthrombus(PanelC,redcolour;arrowheads)detectedabundantaccumula.onofTF,whichsuggeststhatthisprocoagulantplaysacrucialroleinthrombusforma.oninAPL.
floa.ngthrombuswithoutevidenceofaplaquerupture
MolecularGene.csofThrombohemorrhagicSyndromesAssociatedwithHumanTumors
Oncogene/Tumor Signaling Tumor VascularOutcomeSuppressorGene Pathway(geneproductsregulated)______________________________________________________________________________MET Tyrosine Hepatoma Thrombosis;DIC(PAI‐1;COX‐2) kinasereceptor
PTEN(TF) MEK/ERK Glioblastoma Thrombosis;pseudo‐palisadingnecrosis
K‐ras;p53 MEK/MAPK/ ColonCancer Angiogenesis(TF;VEGF;TSP) PI3K_____________________________________________________________________________
PAI-1 = plasminogen activator inhibitor-1; COX-2 = cyclooxygenase-2; TF =tissue factor; VEGF = vascular endothelial growth factor; TSP = thrombospondin
(Boccaccio et.al. Nature 2005;434:396; Rong et.al. Cancer Res 2005;65:1406; Yu et.al. Blood 2005;105:1734)
MolecularGene.csofThrombohemorrhagicSyndromes‐Leukemia
Disease Muta.on Hemosta.cEffect__________________________________________________________________________________________________________
APLAPL PML/RARPML/RARαα ↑↑TFTF((tt15‐1715‐17)) (Blastcell)(Blastcell)
__________________________________________________________________________________________________________APL=acutepromyelocy.cleukemia;PML/RARAPL=acutepromyelocy.cleukemia;PML/RARαα=promyelocy.c=promyelocy.cleukemia/re.noicacidreceptoralphagene;TF=.ssuefactor;leukemia/re.noicacidreceptoralphagene;TF=.ssuefactor;
Cheng et.al. Proc Nat Acad Sci (USA) 1999;Falanga et.al Blood 1998
Occurrenceofthrombo.ceventsinacutepromyelocy.cleukemiacorrelateswithconsistentimmunophenotypicandmolecularfeatures.
BrecciaMetal.Leukemia2007
• 124APLpa.entstreatedwiththeall‐transre.noicacidandidarubicinprotocol:
• Comparisonofclinico‐biologiccharacteris.csof11pa.entswhodevelopedthrombosiswiththoseof113pa.entswhohadnothrombosis.
• Pa.entswiththrombosis(ascomparedtothosewithout)had:
– highermedianwhitebloodcell(WBC)count(17x10(9)/l,range1.2‐56,P=0.002),prevalenceofthebcr3transcripttype(72vs48%,P=0.01),ofFLT3‐ITD(64vs28%,P=0.02),CD2(P=0.0001)andCD15(P=0.01)expression.
– Nocorrela.onwasfoundwithsex,age,French‐American‐Bri.shsubtype,all‐trans‐re.noicacidsyndromeorwiththrombophilicstatethatwasinves.gatedin5/11pa.ents.
• Thefindingssuggestthat,inAPLpa.entsbiologicfeaturesofleukemiacellsmaypredictincreasedriskofdevelopingthrombosis.
1.Doesac.va.onofbloodcoagula.onaffectthebiologyofcancerposi.velyornega.vely?
2.Canwetreattumorsmoreeffec.velyusingcoagula.onproteintargets?
3.Canan.coagula.onalterthebiologyofcancer?
Cancer and Thrombosis: Year 2009
State-of-the-Science Update
Key Questions
1. EpidemiologicevidenceissuggesYvethatVTEisabadprognos.csignincancer
2. ExperimentalevidenceissupporYveoftheuseofan.‐thrombo.cstrategiesforbothpreven.onofthrombosisandinhibi.onoftumorgrowth
3. Resultsofrecent,randomizedclinicaltrialsofLMWHincancerpa.entsindicatesuperiorityinpreven.ngrecurrentVTEandsuggestincreasedsurvival(notduetojustpreven.ngVTE)
4. Stronglinksbetweentheac.va.onofclohng(developmentofTHS)andtumorgrowthsuggestnewtherapeu.ctargets
Cancer and Thrombosis: Year 2009 State-of-the-Science UpdateTentative Answers
Preven.onandTreatmentofTHSinHematologicMalignancies
• Recommenda.onsextrapolatedfromexpertpanel:“Bleedingandthrombosisinacuteleukemia:Whatdoesthefutureoftherapylooklike?”– FRickles,AFalanga,PMontesinos,MASanz,B
BrennerandTBarbui
– ThrombRes(2007)120Suppl.2:S99
Preven.on
• Thrombosis• LMWH–worksbeterthanoralan.coagulantsin
pa.entswithvarietyofsolidandliquidtumors• Fondaparinux‐nodata?
• Neweran.‐Xaagents/DTIs–nodata?
• NeedRCTs
Preven.on
• Hemorrhage• ATRAisanexampleoftargeted,bifunc.onaltherapy
– Treatstheleukemiaatmolecularlevel
– Treatstheconsump.vecoagulopathyatmolecularlevel
– S.llneedtemporizingmeasures
• Suppor.vemeasures– Platelettransfusions
– Useofcoagula.onfactorconcentrates?
LPA96n = 175
LPA99n = 564
Lethal bleeding 9 (5%) 28 (5%)28 (5%) 37 (5%)37 (5%)
TOTALTOTALn = 739n = 739
PETHEMA LPA96 & LPA99 Studies
Antifibrinolytic prophylaxis
NoNo Yes
ManagementofThrombohemorrhagicSyndromesinHematologicMalignancies
1. Pathogenesis
2. Preven.on
3. Treatment
TreatmentofVenousThrombosisinHematologicMalignancies
• Noadhocstudiesorguidelinesareavailable
• Guidelinesforpa.entswithsolidtumors:–– Ini.altreatment:LMWHfulldose(100U/Kgx2/dor200U/Kg/d)for1Ini.altreatment:LMWHfulldose(100U/Kgx2/dor200U/Kg/d)for1
monthmonth
–– Long‐termtreatment:70‐80%oftheini.aldoseforatleast5monthsLong‐termtreatment:70‐80%oftheini.aldoseforatleast5months
• AdaptedtoHematologicMalignancies:–– Reducetheini.aldoseto70‐80%ifplateletsReducetheini.aldoseto70‐80%ifplatelets≤≤70X1070X1099/L/L
–– Reducetheini.aldoseto50%ifplateletsReducetheini.aldoseto50%ifplatelets≤≤50X1050X1099/L/L
–– StoptherapyifplateletsStoptherapyifplatelets≤≤220X100X1099/L/L
TreatmentofVTE(cont’d)
• VenousThromboembolism– LMWHx6months=minimum
• Doseadjustmentsvs.plateletcount,asonpreviousslide
• Frequentmeasurementofan.‐Xalevels
• Roleoffondaparinux,idraparinux,DTIsandneworalan.‐Xainhibitorsunknown
• Bleedingcomplica.onsmayberesponsivetorVIIa
– CVC‐relatedthrombosismaynotalwaysrequireRx;
– RoleofIVCfilters?
• Removablefiltersinselectpa.ents(e.g.plateletcount≤30x109)forshort‐termuse
Treatment
• Hemorrhage
– PlateletSupport
– ?TPO‐likedrugs– ?Coagula.onfactorconcentrates(e.g.rVIIaforsevere
bleeding–anecdotalevidence)
Managementofacutepromyelocy.cleukemia:recommenda.onsfromanexpertpanelonbehalfoftheEuropeanLeukemiaNet
Sanzetal,Blood2009
• Poichéunaquotasignifica.vadipazien.conLAPmuoreprimadell’iniziodellaterapiaodurantel’induzioneperemorragie(correlateallaDIC),siraccomanda:– InizioimmediatodiATRAancheprimadellaconfermadiagnos.cadi
LAP
– Poli.catrasfusionaleaggressiva(plasma,concentra.piastrinici,fibrinogeno)inmodomantenere:
• Plt>30000
• Fibrinogeno>150mg/dL
• Sopratutoinpzanziani,coniperleucocitosi,DICmoltoevidente,eaumentatacrea.nina
– Dubbial’u.litàdiacidotranexamico,eparina
Summary
•• NoRCTsorguidelinesavailabletoguidedecisionsNoRCTsorguidelinesavailabletoguidedecisionsregardingprophylaxisortreatmentofregardingprophylaxisortreatmentofTHSTHSininhematologicalmalignancies.hematologicalmalignancies.
•• Pa.entswithacuteleukemiasorotherPa.entswithacuteleukemiasorotherhematologicalmalignanciescarryahighriskofhematologicalmalignanciescarryahighriskofhemorrhage.hemorrhage.
•• ThisriskisaggravatedbyprolongedThisriskisaggravatedbyprolongedthrombocytopeniasecondarytointensivethrombocytopeniasecondarytointensivechemotherapyregimens.chemotherapyregimens.