Profilassi e Terapia an.trombo.ca nel paziente onco ematologico

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1 Corso Nazionale di Aggiornamento in Ematologia Clinica Bolzano, giugno, 2009 Profilassi e Terapia an.trombo.ca nel paziente onco ematologico Anna Falanga, MD USC Immunoematologia e Medicina Trasfusionale Dipartimento Oncologia-Ematologia Ospedali Riuniti Bergamo

2 Cancer and Venous Thromboembolism (VTE) VTE is a frequent complica.on of cancer: Es.mated risk is 0.5%/year or 0.04%/month 6.5 fold increased risk with chemotherapy Heit JA et al, Arch Intern Med,2000 Lee AYY, Br J Haematol, 2004

3 Incidence of VTE in US Cancer Pa.ents: VTE Incidence, % Cancer No Cancer National Hospital Discharge Survey data. Stein PD et al. Am J Med. 2006;119:60-68.

4 4 Risk of VTE by Site of Cancer Type of cancer Adjusted OR (95% CI) Hematologic 28 ( ) Lung 22.2 ( ) GI 20.3 (4.9-83) Breast 4.9 ( ) Prostate 2.2 ( ) Copyright restrictions may apply. Blom, JAMA, 2005

5 5 Risk of Inpa.ent VTE by Site of Cancer Rate, % All Brain Lung Stomach Colon Pancreas Other GI Ovary Endometrium/ cervix Khorana AA et al. J Clin Oncol. 2006;24:

6 6 Risk of Inpa.ent VTE by Site of Cancer (cont d) Rate, % All Leukemia NHL Hodgkin's Myeloma Breast Khorana AA et al. J Clin Oncol. 2006;24:

7 Thrombosis in hematological malignancies Commonly, venous thromboembolism (VTE) is considered more frequent in pa.ents with solid tumors, whereas hemorrhage due to DIC are considered more frequent in hematological malignancies. However recent large epidemiological studies indicate that the rate of VTE in pa.ents with hematological malignancies is at least as high as high risk types of solid tumors.

8 The thrombo.c risk in hematological malignancies Hematological malignancies carry an intrinsic risk of thrombosis, due to the cancer.ssue prothrombo.c proper.es; This risk is increased by chemotherapy (in addi.on to other general risk factors, i.e. age, bed rest, surgery, etc.); Thrombosis rates can be es.mated in: Mul.ple Myeloma Lymphomas Acute Leukemias

9 Mul.ple Myeloma and Thrombosis Mul.ple myeloma (MM) and other plasma cell dyscrasias are thrombogenic as a consequence of their mul.ple hemosta.c effects. The oral drugs thalidomide and lenalidomide have produced major therapeu.c responses in pa.ents with MM when used in combina.on with oral steroids and chemotherapy, but significantly increased the risk of VTE. Available data suggest that thomboprophylaxis with low dose warfarin, or LMWH, or Aspirin, may reduce VTE rate associated to thalidomide and lenalidomide

10 Figure 1 Thalidomide Lenalidomide Falanga A, Marchetti M, JCO 2009, in press

11 Figure 2 Before prophylaxis Ader prophylaxis (Low fixed dose warfarin) LMWH Low fixed dose warfarin Ader prophylaxis (Aspirin 81mg/d) Before prophylaxis Thalidomide Before prophylaxis Ader prophylaxis (LMWH) LMWH Low fixed dose warfarin Low fixed dose warfarin LMWH Warfarin (INR: 2 3) Low fixed dose warfarin Lenalidomide Aspirin ( mg/d) LMWH Aspirin (100 mg/d) Aspirin (325 mg/d) Aspirin (81 mg/d) Falanga A, Marchetti M, JCO 2009, in press

12 Lymphoma and Thrombosis Non Hodgkin and Hodgkin Lymphomas carry a significant risk for venous and arterial thrombosis, par.cularly during chemotherapy treatments. Hemosta.c altera.ons underlying a hypercoagulable condi.on are commonly found in pa.ents with lymphomas.

13 VTE incidence in Lymphoma pa.ents. Study Study type Pa.ents (n) Pa.ents with VTE (n) VTE incidence (%) Non Hodgkin Lymphoma Clarke et al, 1990 Retrospec.ve Khorana et al, 2006 Retrospec.ve Athale et al, 2008 Retrospec.ve 23* 3 13 Khorana et al, 2005 Prospec.ve OFnger et al, 1995 Prospec.ve Hodgkin Disease Khorana et al, 2006 Retrospec.ve Athale et al, 2008 Retrospec.ve 52* Khorana et al, 2006 Prospec.ve CNS Lymphoma Large B cell Lymphoma Goldschmidt et al, 2003 Retrospec.ve Komrokji et al, 2006 Retrospec.ve Data are reported according to the type of lymphoma. *=pediatric pa.ents. CNS=central nervous system; VTE=Venous thromboembolism.

14 Pa.ents with acute leukemia are unique Nearly all pa.ents with cancer show evidence of subclinical ac.va.on of clohng, or chronic DIC. However, pa.ents with acute leukemia are unique in that they most oden present with: a wide range of laboratory abnormali.es consistent with DIC, and a wide range of clinical manifesta.ons, from localized venous or arterial thrombosis to diffuse life threatening bleeding

15 Recent large epidemiologic studies indicate that the rate of VTE in pa.ents with hematologic malignancies can be comparable to that of other solid tumor types considered at thrombo.c high risk.

16 Studies that have evaluated the incidence of VTE in pa.ents with acute leukemia (AL). Study Study design, Study period Total pa.ents with AL (n) Pa.ents with VTE (n) VTE incidence (%) Pa.ents with specific AL type (n) Pa.ents with VTE (n) VTE incidence (%) Ziegler et al, 2005 Retrospec.ve, AML (534) ALL (185) APL (49) Mohren et al, 2006 Retrospec.ve, AML (310) ALL (108) APL (7) Ku et al, 2008 Registry data, * AML (5394) ALL (2484) APL (337) De Stefano et al, 2005 Prospec.ve, ** AML (310) ALL (69) APL (31) Melillo et al, 2007 Prospec.ve, AML (70) ALL (44) APL (14) Caruso et al, 2006 Caruso et al, 2007 Meta analysis, NA Meta analysis, NA ALL (1752) ALL (323) AML= acute myeloid leukemia ; ALL= acute lymphoblas.c leukemia; APL=acute promyelocy.c leukemia ; VTE=Venous thromboembolism. pediatric ALL pa.ents.; adult ALL pa.ents; * VTE + upper extremity thrombophlebiys; ** VTE + arterial thrombosis

17 The thrombo hemorrhagic syndrome of APL The incidence of these complica.ons varies according to the type of leukemia and the phase of treatment. Thrombosis is more common than previously appreciated in individuals with all types of adult acute leukemias, including pa.ents with APL, in whom hemorrhage is usually predominant. Bleeding and Thrombosis can occur concomitantly as a part of the same thrombo hemorrhagic syndrome (THS) of APL.

18 APL coagulopathy In APL, early mortality most oden is due to a severe and oden catastrophic bleeding, oden intracerebral in loca.on, and remains a major cause of treatment failure. Thrombosis, either at diagnosis or during the course of treatment, may be unrecognized and reflects the complexity of the coagulopathy.

19 Coagulopathy of APL: Laboratory abnormalities "Routine" clotting tests abnormalities: Hypofibrinogenemia, prolonged prothrombin and thrombin times, increased fibrinogen/fibrin degradation products (FDP). ACTIVATION COAGULATION FIBRINOLYSIS non-specific PROTEOLYSIS TAT F1+2 FPA D-dimer u-pa plasminogen a-2-antiplasmin D-dimer elastase

20 Hypercoagula.on in acute leukemia Laboratory abnormali.es of the blood clohng system underlying the clinical pictures of DIC of acute leukemias, are exacerbated by the ini.a.on of chemotherapy. Studies of hypercoagula.on markers clearly show that thrombin genera.on is constantly ongoing. The increase of D dimer, the by products of cross linked fibrin, demonstrates ongoing hyperfibrinolysis in response to clohng ac.va.on.

21 Baseline plasma levels of hypercoagula.on markers in pa.ents with APL Controls APL pa.ents P < F1+2 (nm) 1.1 ( ) 11 ( ) TAT (ng/ml) 2.9 ( ) 23 (5.1 78) D dimer (microg/ml) 0.3 ( ) 1.6 ( ) Fibrinogen (mg/dl) 270 ( ) 94 (65 368) Values are median (range) Falanga et al, Blood, 1995

22 ATRA and hemostasis The advent of ATRA for the remission induc.on therapy of APL has opened new perspec.ves in the management of the coagulopathy. Different laboratories have shown the decrease or normaliza.on of clohng and fibrinoly.c variables during the first one or two weeks of ATRA therapy.

23 Plasma hypercoagula.on markers at ONSET (T0) and during ATRA therapy * * * * * * Days of ATRA Therapy Days of ATRA Therapy = Mean Control levels *= p<0.05 vs T0

24 Zhu J, et al, Leukemia 1999

25 Hemorrhage and thrombosis in 54 consecu.ve newly diagnosed APL pa.ents ONSET N (%) INDUCTION N (%) 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% * Deaths occurred before staryng ATRA treatment

26 The coagulopathy of acute promyelocytic leukemia revisited Stein et al, Best Pract & Res Clin Haematol, 2009 Prospec.ve trials of all trans re.noic acid (ATRA) in acute promyelocy.c leukaemia (APL). CR, complete remission; ED, early death; DFS, disease free survival.

27 Response and induc.on mortality in 732 APL pa.ents enrolled in LPA96 + LPA99 studies De La Serna, Blood morphologic CR (91%) 66 deaths (9%) Factor predic.ng fatal hemorrhage in mul.variate analysis: Abnormal crea.nine level Peripheral blast count >30*10^9/L Coagulopathy

28 PETHEMA LPA96 & LPA99 Studies Incidence of THS At diagnosis + during induction = 5% Prognostic factor Odds Ratio P value Fibrinogen < 170 mg/dl M3 variant Use of Tranexamic acid

29 Management of Thrombohemorrhagic Syndromes in Acute Leukemia Pathogenesis Leukemic cell Chemotherapy Infec.ons

30 Intracoronary thrombus with.ssue factor expression heralding acute promyelocy.c leukaemia A 54 year old man suddenly experienced AMI. No other risk factors, and no significant comorbidity. Blood count showed a pancytopenia: WBC 640/uL, (neutrophils 160/uL), platelets /uL, Hb 9.1 g/dl, Ht 25%. Blood smear: pancytopenia, but otherwise normal. PCI was performed and large amounts of thrombo.c material could be removed. Bone marrow biopsy (performed because of persis.ng pancytopenia) revealed hypergranular APL. Peripheral blood smear then was showing 28% promyelocytes, containing in 3% Auer rods, and 0.5% were blasts (Panel B; narrow arrows). Histology of the thrombus exhibited a regular patern with fibrin and platelets, a lot of red blood cells, many neutrophils, and few macrophages. No blasts were found. However, immunochemistry of the recovered thrombus (Panel C, red colour; arrow heads) detected abundant accumula.on of TF, which suggests that this procoagulant plays a crucial role in thrombus forma.on in APL. floa.ng thrombus without evidence of a plaque rupture Altwegg et al. Eur Heart Journa

31 Molecular Gene.cs of Thrombohemorrhagic Syndromes Associated with Human Tumors Oncogene/Tumor Signaling Tumor Vascular Outcome Suppressor Gene Pathway (gene products regulated) MET Tyrosine Hepatoma Thrombosis; DIC (PAI 1; COX 2) kinase receptor PTEN (TF) MEK/ERK Glioblastoma Thrombosis; pseudo palisading necrosis K ras; p53 MEK/MAPK/ Colon Cancer 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)

32 Molecular Gene.cs of Thrombohemorrhagic Syndromes Leukemia Disease Muta.on Hemosta.c Effect APL PML/RARα TF ) (Blast cell) (t APL = acute promyelocy.c leukemia; PML/RARα = promyelocy.c = promyelocy.c leukemia/re.noic acid receptor alpha gene; TF =.ssue factor; Cheng et.al. Proc Nat Acad Sci (USA) 1999; Falanga et.al Blood 1998

33 Occurrence of thrombo.c events in acute promyelocy.c leukemia correlates with consistent immunophenotypic and molecular features. Breccia M et al. Leukemia APL pa.ents treated with the all trans re.noic acid and idarubicin protocol: Comparison of clinico biologic characteris.cs of 11 pa.ents who developed thrombosis with those of 113 pa.ents who had no thrombosis. Pa.ents with thrombosis (as compared to those without) had: higher median white blood cell (WBC) count (17 x 10(9)/l, range , P=0.002), prevalence of the bcr3 transcript type (72 vs 48%, P=0.01), of FLT3 ITD (64 vs 28%, P=0.02), CD2 (P=0.0001) and CD15 (P=0.01) expression. No correla.on was found with sex, age, French American Bri.sh subtype, all transre.noic acid syndrome or with thrombophilic state that was inves.gated in 5/11 pa.ents. The findings suggest that, in APL pa.ents biologic features of leukemia cells may predict increased risk of developing thrombosis.

34 Cancer and Thrombosis: Year 2009 State-of-the-Science Update Key Questions 1. Does ac.va.on of blood coagula.on affect the biology of cancer posi.vely or nega.vely? 2. Can we treat tumors more effec.vely using coagula.on protein targets? 3. Can an.coagula.on alter the biology of cancer?

35 Cancer and Thrombosis: Year 2009 State-ofthe-Science Update Tentative Answers 1. Epidemiologic evidence is suggesyve that VTE is a bad prognos.c sign in cancer 2. Experimental evidence is supporyve of the use of an. thrombo.c strategies for both preven.on of thrombosis and inhibi.on of tumor growth 3. Results of recent, randomized clinical trials of LMWH in cancer pa.ents indicate superiority in preven.ng recurrent VTE and suggest increased survival (not due to just preven.ng VTE) 4. Strong links between the ac.va.on of clohng (development of THS) and tumor growth suggest new therapeu.c targets

36 Preven.on and Treatment of THS in Hematologic Malignancies Recommenda.ons extrapolated from expert panel: Bleeding and thrombosis in acute leukemia: What does the future of therapy look like? F Rickles, A Falanga, P Montesinos, MA Sanz, B Brenner and T Barbui Thromb Res (2007) 120 Suppl. 2:S99

37 Preven.on Thrombosis LMWH works beter than oral an.coagulants in pa.ents with variety of solid and liquid tumors Fondaparinux no data? Newer an. Xa agents/dtis no data? Need RCTs

38 Preven.on Hemorrhage ATRA is an example of targeted, bifunc.onal therapy Treats the leukemia at molecular level Treats the consump.ve coagulopathy at molecular level S.ll need temporizing measures Suppor.ve measures Platelet transfusions Use of coagula.on factor concentrates?

39 PETHEMA LPA96 & LPA99 Studies Antifibrinolytic prophylaxis No LPA96 n = 175 Yes LPA99 n = 564 TOTAL n = 739 Lethal bleeding 9 (5%) 28 (5%) 37 (5%)

40 Management of Thrombohemorrhagic Syndromes in Hematologic Malignancies 1. Pathogenesis 2. Preven.on 3. Treatment

41 Treatment of Venous Thrombosis in Hematologic Malignancies No ad hoc studies or guidelines are available Guidelines for pa.ents with solid tumors: Ini.al treatment: LMWH full dose (100 U/Kg x 2/d or 200 U/Kg/d) for 1 month Long term treatment: 70 80% of the ini.al dose for at least 5 months Adapted to Hematologic Malignancies: Reduce the ini.al dose to 70 80% if platelets 70 X X 10 9 /L Reduce the ini.al dose to 50% if platelets 50 X X 10 9 /L Stop therapy if platelets 2 20 X 10 9 /L

42 Treatment of VTE (cont d) Venous Thromboembolism LMWH x 6 months = minimum Dose adjustments vs. platelet count, as on previous slide Frequent measurement of an. Xa levels Role of fondaparinux, idraparinux, DTIs and new oral an. Xa inhibitors unknown Bleeding complica.ons may be responsive to rviia CVC related thrombosis may not always require Rx; Role of IVC filters? Removable filters in select pa.ents (e.g. platelet count 30 x 10 9 ) for short term use

43 Treatment Hemorrhage Platelet Support? TPO like drugs? Coagula.on factor concentrates (e.g. rviia for severe bleeding anecdotal evidence)

44 Management of acute promyelocy.c leukemia: recommenda.ons from an expert panel on behalf of the European LeukemiaNet Sanz et al, Blood 2009 Poiché una quota significa.va di pazien. con LAP muore prima dell inizio della terapia o durante l induzione per emorragie (correlate alla DIC), si raccomanda: Inizio immediato di ATRA anche prima della conferma diagnos.ca di LAP Poli.ca trasfusionale aggressiva (plasma, concentra. piastrinici, fibrinogeno) in modo mantenere: Plt > Fibrinogeno > 150 mg/dl Sopratuto in pz anziani, con iperleucocitosi, DIC molto evidente, e aumentata crea.nina Dubbia l u.lità di acido tranexamico, eparina

45 Summary No RCTs or guidelines available to guide decisions regarding prophylaxis or treatment of THS in hematological malignancies. Pa.ents with acute leukemias or other hematological malignancies carry a high risk of hemorrhage. This risk is aggravated by prolonged thrombocytopenia secondary to intensive chemotherapy regimens.