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.