Rischio emorragico e trombotico nella TE e PV

Transcription

1 Convegno Interregionale SIE Delegazione Triveneto Approfondimento sulle sindromi mielodisplastiche e mieloproliferative Sessione: Sindromi Mieloproliferative Croniche Rischio emorragico e trombotico nella TE e PV Marco Ruggeri Hematology Department, San Bortolo Hospital Vicenza, Italy

2 Major complications in Polycythemia Vera (PV) and Essential Thrombocythemia (ET) (PVSG and WHO 2001) Chronic disorders with a long survival (> 15 years) Low rate of transformation into acute leukemia or overt myelofibrosis (~10-15% at 15 years) Increased rate of venous and arterial thrombosis Increased rate of hemorrhage Major contributors to morbidity and mortality Elliott M and Tefferi A Br J Haematol; 2005

3 Essential Thrombocythemia (ET) MPN (WHO 2008) with a long survival: survival rate at 10 y: 89% survival rate at 15 y: 80% Low rate of transformation into acute leukemia or overt myelofibrosis: Leukemic transformation rate at 10 y: 0.7%; at 15 y: 2.1% Rate of progression to myelofibrosis at 10 y: 0.8%; at 15 y : 9.3% Barbui T et al. JCO ; 2011

4 Rough percentage of major thrombosis and hemorrhage from different series Thrombosis Hemorrhage* Ratio H/T^ PV ET Presentation: range average Follow up: average range Presentation: range average Follow up: average range *Including minor hemorrhages in some series ^ratio H/T calculated only using the series reporting both H and T events

5 Randomised trials in polycythaemia vera with rates of important end-points for each of the treatment arms Mc Mullin M et al, Br J Haematol; 2005

6 RCT in ET Study Cortelazzo NEJM 1995 Harrison NEJM 2005 Therapy None HU HU + ANA + (ASA 69%) (ASA 70%) ASA(100%) ASA (100%) 300 mg mg mg Rate of thrombosis (2 years) 24% 4% 4% 8%

7 Aim of cytoreductive treatment To reduce the rate of cardiovascular events Some concerns about an increase rate of leukemic transformation with cytoreductive agents

8 Risk of AML/MDS without treatment PV F.U.(y) A.L/pts (%) Berk et al, 1981 phlebotomy 8.6 2/134 (1.5) (PVSG-01) Finazzi et al, 2005 phleb or INF 8.4 5/669 (0.7) (ECLAP) times higher than in the general population ET F.U.(y) A.L./pts Murphy et al, 1997 no therapy 7.3 1/7 (PVSG-12) Sterkers et al, 1998 no therapy 8 0/31 (retrospective) Finazzi et al, 2000 no therapy 6 0/20 (HU vs no therapy) Rare event (= in the general population?) in untreated patients (often without karyotype analysis at diagnosis: CML )

9 Risk of AML/MDS in PV with treatment Study Therapy N patients FU (y.median) AML % Annual inc. RCT Berk 81 Chloramb P Haanen 82 P Busulph Najean 97 P (max) P32+HU (max) Najean 97 HU (max) Pipobrom. 142 similar Obs.Prospect. Donovan 84 HU Tarstarky 97 HU Passamonti00 Pipobrom Kiladjian 03 Pipobrom ECLAP 05 Ph-HU-P Obs.Retrospect. GISP 95 Ph-HU-BU Brodman 00 Ph-HU-BU Gangat 07 No drugs/ ANA/INF HU Other Others mo 67mo 72mo 161mo

10 Risk of AML/MDS in ET with treatment Study Therapy N patients FU (median) AML % RCT Finazzi 00 HU 77 6y HU+BUS 15 6y 5 33 Harrison 05 HU m Ana* m *30% previous HU Prosp. Obs. Murphy 97 HU y BUS y HU + BUS y Retros. Obs. Sterkers 98 P y 2 7 P32 + CHT 11 8y 1 9 BUS 35 8y 1 3 BUS + CHT 6 8y 1 17 HU 201 8y HU + CHT 50 8y 7 14 Pipobro 12 8y 0 0 Pipo + CHT 31 8y 5 16

11 Blood 2011

12 Blood 2011

13 JCO 2011

14 Treatment according to individual risk factors Reduction of the rate of cardiovascular events is at the cost of an increased risk of AL/MDS evolution (myelofibrotic evolution?) Rationale for risk stratification according to thrombotic risk, to select for CHT only high-risk patients

15 Established thrombotic risk factors for PV and ET 1. Age 2. Previous thrombosis

16 PV Thrombotic risk factors in PV and ET Age PVSG-01, Sem.Hematol 1986; 431 PV, RCT Advanced age is associated with a statistical significant increased risk of thrombosis GISP Ann Internal Med 1995; 1213 PV, retrospective Age < events/100 pts/y Age > events/100 pts/y ECLAP, J Clin Oncol 2005: 1638 PV, prospective, F.U.: 3 y Vascular complications in patients age > 65 y: 5% patient-year; HR 2 (CI ; p < 0.006) vs age < 65 y ET Cortelazzo et al, J Clin Oncol 1990, retrospective, 100 pts Incidence rate: 1.7 p/y age < 40 y; 6.3 p/y age y; 15.1 p/y age > 60 y (OR age > 60: 10,1; CI ) Besses et al, Leukemia 1999, retrospective, 148 pts Cumulative rate (6 y F.U.): 35.6% > 60 y vs 21.4% < 60 y Wolanskyj et al, Mayo Clin Proc 2006, retrospective, 322 pts, F.U.: 13.6 y RR age > 60 y: 1.51 (CI , p= 0.03), multivariable analysis Carobbio et al, Blood 2007, retrospective, 439 pts, F.U.: 6.2 y HR age * > 60 y: 2.3 (CI , p= 0.04) * and or history of thrombosis

17 Thrombotic risk factors for PV and ET Previous thrombosis PV GISP Ann Internal Med 1995: 1213 PV, retrospective. 24.6% thrombosis in patients with prior thrombosis vs 17.3% with no prior thrombosis; p= ECLAP, J Clin Oncol 2005: 1638 PV, prospective, F.U.: 3 y Incidence of vascular complications in patients with a previous thrombotic events: 4.93% patientsyear, HR: 1.95, CI , p = ET Cortelazzo et al, J Clin Oncol 1990, retrospective, 100 pts Incidence rate: 31.4 p/y with previous thrombosis vs 3.4 p/y with no previous thrombosis, OR 13 (4-41.5) Besses et al, Leukemia 1999, retrospective, 148 pts HR for previous vascular complications: 3 (1.5-6; p=0.001) Wolanskyj et al, Mayo Clin Proc 2006, retrospective, 322 pts, F.U y RR for previous vascular complications: 1.73 ( ; p=0.03) Carobbio et al, Blood 2007, retrospective, 439 pts, F.U. 6.2 y HR age * > 60 y: 2.3 (CI , p= 0.04) * and or history of thrombosis

18 ? Age and previous thrombosis are patientrelated risk factors; not disease-specific Age and previous thrombosis are not modified risk-factors Age is a continuous variable : a different effect changing stratification? Concept of dynamic risk profile

19 Other (target ) thrombotic risk factors in PV and ET? 1. Platelet count 2. Hematocrit (PV) 3. Fibrosis 4. Leukocytosis 5. JAK2 V617F

20 Thrombotic risk factors in PV and ET Platelet count PV PVSG 01 (PVSG-01, Semin Hematol, 1986) platelet count (either baseline or near the event) did not predict thrombosis ECLAP, Blood 2007, prospective, 1638 pts Rate of thrombosis Plt > 400 x 10 9 /L: 8.3% HR: 0.96, CI , p=0.81 Plt < 400 x 10 9 /L: 9.3% ET Cortelazzo et al, J Clin Oncol 1990, retrospective, 100 pts No association between platelet count and rate of thrombosis Besses et al, Leukemia 1999, retrospective, 148 pts No association between platelet count and rate of thrombosis Carobbio et al, Blood 2007, retrospective, 439 pts, F.U. 6.2 y HR for plt count > 700 x 10 9 /L : 0.7 (CI ) p=0.1 No significant correlation between platelet count and thrombosis

21

22 Blood, 2010

23 Univariate and multivariate analysis for risk factors predicting thrombotic events in follow-up (events, n 27) Blood, 2010

24

25 Thrombotic risk factors in PV Hematocrit Pearson et al, Lancet 1978 Direct association between Htc > 0.45 and rate of thrombosis Implication for treatment: 0.45: target value for venosection

26 Thrombotic risk factors in PV Hematocrit: ECLAP cohort HR in Htc 45% vs > 45-50% for: Death: 0.85, CI Major thrombosis: 0.94, CI Total thrombosis: 0.97, CI CYTO-PV: ongoing RCT evaluating % thrombosis in Htc > 45% vs < 45%

27 Thrombotic risk factors in PV White blood cell Petti et al, Leukemia, 1998; retrospective, 390 pts, F.U.: 9 months WBC > 20K vs < 12K = 5.2 HR (CI p=0.002) for death Gangat el al, Br J Haematol 2007; retrospective, 459 pts, F.U.: 64 months WBC > 15K vs < 15K : p < for VTE

28 Thrombotic risk factors in PV White blood cell ECLAP, Blood 2007; prospective, pts, F.U 3 y Analysis: WBC > 15k vs < 10k baseline; HR adjusted for CHT and ASA Major thrombosis (169) HR 1.71 ( ) p=0.017 AT (121) HR 1.67 ( ) p ns VTE (51) HR 1.81 ( ) p ns AMI (41) HR 2.84 ( ) p=0.013 Stroke/TIA (54) HR 0.93 ( ) p ns PAT (21) HR 1.72 ( ) p ns

29 Thrombotic risk factors in ET :White blood cell

30 Thrombotic risk factors in ET White blood cell PT1 study, N Engl J Med 2005 Intervention HU (404) ANA (405) OR p Primary EP ( ) 0.03 AT ( ) 0.04 VTE ( ) Hemorrhage ( ) Death ns Myelofibrosis ( ) 0.01

31 Thrombotic risk factors in ET White blood cell PT1 study N Engl J Med 2005 Similar control of platelet count but no effect of ANA on WBC level WBC > ANA vs HU, p< 0.001

32 Thrombotic risk factors in ET White blood cell But what about the absolute risk in study-cohort (Carobbio et al, Blood 2007)? 67 events in 439 pts in 6 y: 15% (2.5% per y) High WBC Low WBC Total Thrombosis No thrombosis Total Absolute risk in high WBC = 43/221: 19%; in low WBC= 24/218: 11% Thrombosis rate per 100 p/y : 3.2 (high) vs 1.8 (low) Prospective, validation study possible only enrolling a very high number of patients!

33 JAK2 V617F mutation and thrombosis Early 2005: five groups reported the presence of an acquired point mutation, G1849T in Jak2 gene in patients with Ph-negative MPD (detected in 95% of PV and 50%-60% of ET patients) G1849T results in V to F substitution in JAK2 molecule (JAK2 V617F ) within its auto-inhibitory pseudo kinase domain Cytokine independent activation Unregolated cell proliferation

34 Studies addressing the association between JAK2 V617F and thrombosis in ET Study Pt JAK2 V617F Association? Confounding factors Cheung yes NR Heller yes Age, Hb Finazzi yes Hb, WBC Ohyashiki yes Hb, WBC Carobbio no Hb, WBC Kittur yes Age, Hb, WBC Alvarez no Hb Vannucchi yes Age, Htc Hsiao yes Hb, WBC

35 Association between JAK2 V617F and thrombosis in ET: systematic review OR thrombosis OR AT OR VTE Ziakas, Haematologica patients CI CI Dahabreh et al Thromb Res patients Lussana et al, Thromb Res patients CI CI CI

36 Thrombotic risk and JAK2V617F allele burden in PV Vannucchi et al, Leukemia 2007: prospective evaluation, 173 pts, F.U.: 24 months (median) Analysis: > 75% vs < 25% mutant allele Splenomegaly : RR 4.7, p < Pruritus : RR 3.1, p < CV events : RR 7.1, p = Correlation not confirmed in another study (Tefferi et al, Leukemia 2007)

37 Fibrosis and thrombosis in ET JCO 2011

38 Fibrosis and thrombosis in PV

39 Enrollment: 105 PV and 150 ET consecutive patients diagnosed from January 1985 to June 2005 with at least one surgical procedure from diagnosis to June 2005 (311 procedures). Data collection: patients characteristics and clinical events before and after surgery (3 months of follow-up), specific therapy for PV and ET, antithrombotic and anti-hemorrhagic prophylaxis

40 Thrombotic and hemorrhagic risk after surgery in PV and ET End-points Major thrombotic events defined as in ECLAP Study (NEJM 2004) Major hemorrhages included intracranial, ocular, joint, or retroperitoneal bleeding; episodes requiring surgery or angiographic intervention and any bleeding causing a hemoglobin loss of 2 gr/dl at least and/or requiring 2 or more blood units transfusions

41 Thrombotic and hemorrhagic risk after surgery in PV and ET Type of intervention Variable PV ET P Emergency procedures 11/128 (8.1%) 15/183 (8%) 0.91 Abdominal surgery laparoscopy/laparotomy 6/33 (18.1%) 15/58 (25.8%) Major surgery 65/128 (50%) 91/183 (49%) 0.87 General anaesthesia 74/128 (58%) 120/183 (65%) 0.529

42 Thrombotic and hemorrhagic risk after surgery in PV and ET Antithrombotic prophylaxis Data available in 292/311, 93.8%, surgeries 126/292 (43.2%) LMWH 38/292 (13%) UH 5/292 (1.7%) warfarin 123/292 (42.1%) no prophylaxis; in 45/123 (36.6%) ASA was administered peri-intervention 189/255 (74%) ongoing cytoreductive treatment; in 9 case a short cycle was administered

43 Thrombotic and hemorrhagic risk after surgery in PV and ET Post-surgery outcomes (3 months follow-up) 259/311 (83.2%) no events 24 thrombosis (7.3%, 12 AT, 12 VTE) 23 major hemorrhages (7.3%) 7 minor hemorrhages 5 deaths (surgery-related, within 3 months) VTE more frequent in PV than in ET (7.7% vs 1.0%, P=0.002)

44 Thrombotic and hemorrhagic risk after surgery in PV and ET Strong risk gradient for AT with the presence of one or more CV risk factors (OR for 4 or more risk factors: 40.9: p= 0.003) Platelet count and hematocrit at surgery (median 477 x 109/L and 42.6%) not associated with AT nor with VTE No correlation between bleeding episodes and type of cmpd, use of antithrombotic prophylaxis and type of surgery

45 Pregnancy, JAK2 V617F and thrombosis 103 pregnancies occurred in 62 women with ET; half of the studied women carried the JAK2 V617VF mutation Fetal loss in women with ET was higher (OR 3.4, CI 3-3.9, p < 0.001) than in the general population; a relationship was found between JAK2 V617F and fetal loss (p>0.05) JAK2 V617F patients had an odds ratio of 2.02 (95% CI: ) of developing complications in comparison with JAK2WT

46 Prognostic classification in terms of thrombotic risk in PV and ET Established risk factors Potential novel risk factors* Age > 60 years Leukocytosis Previous thrombosis JAK2 V617F Surgery Pregnancy * validation in large, prospective clinical trials required

47 Thrombosis risk oriented management in PV and ET Risk Category PV ET Low High Phlebotomy + ASA Myelosuppression +/- Phlebotomy + ASA No therapy or ASA Myelosuppresion + ASA

48

49 ?? Current risk stratification is designed to estimate the likelihood of thrombotic complications Different stratification and management strategies in case of other therapeutic target (survival, leukemic/myelodisplatic evolutions, myelofibrotic transformation?

50 JCO 2011

51

52 Risk factors for hemorrhage Platelet count > million/µl Previous bleeding (ECLAP entire cohort, Marchioli et al 2005) AVWS (reviewed by Michiels, 2004) Surgery (Ruggeri et al, Blood 2008) Anagrelide (?): (UK PT-1 Study, Harrison et al 2005) Antithrombotic prophylaxis

53 Prevention and treatment of thrombotic complications in ET: efficacy and safety of aspirin PJJ van Genderen et al, Br J Haematol 1997 Incidence of thrombotic and bleeding complications in 68 ET patients Treatment FU Thrombosis Bleeding (p/y) (x 100/p/y) (x 100/p/y) Careful observation Aspirin Cytoreduction Aspirin + cytoreduction

54 Blood, 2010

55

56

57

58

59 Primary prevention with low dose aspirin Low dose aspirin is effective in reducing the risk of arterial thrombosis The net benefit of aspirin as a form of primary prophylaxis becomes manifest when the individual risk of thrombosis is > 3 events per 100 pts/year

60 Implications of primary prevention trial results for PV and ET Even assuming a basal risk and an absolute increase of bleeding due to treatment similar to that of general population, any advantage of aspirin in PV and ET is expected only when the basal treatment risk is 3-4/100/yr The basal thrombotic risk in pts ET is not available since all series include pts treated with aspirin (for PV data from ECLAP study, placebo arm)

61

62

63

64

65 Clinical vignette -January 2010: male patient; age 70 years; ET diagnosis (PLT 733 x 10 9 /L; BM biopsy; JAK2 WT) *diabetes mellitus * dual antiplatelet (ASA + clopidogrel) from september 2009 for carotid bare- metal stent (asymptomatic stenosis) -January 2011: PLT 700 x 10 9 /L: ASA + clopidogrel -August 2011: PLT 642 x 10 9 /L: ASA + clopidogrel -November 2011: PLT 757 x 10 9 /L: ASA + clopidogrel

66 February 2012: death for cerebellar hemorrhage PLT 619 x 10 9 /L

67 Pts Sex Age (y) Diagnosis Therapy Setting Since: PFG M 80 ET Dual DES Nov 11 EE M 73 PV Dual DES Mar 12 MI M 80 PV Dual DES Sep 10 FP M 50 ET Dual DES Nov 06 DMR M 78 ET Dual Peripheral Stent Dic 11 SF M 56 PV TAO FA Dic 10 ASA Ictus RM M 87 ET TAO IMA Sep 11 ASA (2) GE M 80 ET Dual DES Feb 12 CB F 75 PV TAO ASA DAG F 79 PV TAO ASA ICTUS TIA EP TIA Oct 09 Jun 06

68 Dual or Mono Antiplatelet Therapy for Patients With Acute Ischemic Stroke or Transient Ischemic Attack: Systematic Review and Meta-Analysis of Randomized Controlled Trials Stroke RCT, 3766 patients mono antiplatelet dual therapy RR Stroke recurrence 5% ( ) Composite vascular event 6% 4.4% 0.75( ) Combination vascular event + death 9.1% 1.7% 0.71( ) Major bleeding 0.4% 0.9% 2.09( )

69 Twenty-seven major bleeds were recorded, with an incidence of 0.9% patient-years The incidence of major bleeding in per cent patient-years was: -0.8 antiplatelet agents -0.9 vitamin K antagonists -2.8 antiplatelet agents plus vitamin K antagonists Haematologica 2008

70 ??? Is dual antiaplatelet therapy or antiplatelet + warfarin) safe in ET and PV patients?