1. Prognostic factors for thrombosis and survival in PV, revisited
Tiziano Barbui
Hematology and Research Foundation Ospedale Papa Giovanni XXIII Bergamo, Italy
2-4 May 2014, Prague,Czech Republic.

2. Survival risk factors in PV

3. Life expectancy in 9,000 MPN patients compared to general population by subtype 2001-2008

4. Survival in 1545 patients with PV (23% followed to death); median survival 18.9 years) compared with expected survival based on individuals of the same age and gender from the US total population.
Tefferi et al, Leukemia 2013

5. Survival in 337 Mayo Clinic patients with PV (44% followed to death; median survival 14.1 years) compared with expected survival based on individuals of the same age and gender from the US total population.
Tefferi et al, Leukemia 2013

6. Prediction of Survival in 1,545 patients with WHO-PV (IWG-MRT study)
Risk factors
Age > 67 years
5 points
Age years
2 points
Leukocyte count 15  109/l
1 point
Venous thrombosis
Risk Categories/score
Low
Intermediate
1-2
High
 3
Survival
N=503
27.8 years
N=474
18.9 years
N=568
10.9 years
Years
Tefferi A, et al. Leukemia 2013 June 6. doi: /leu [Epub ahead of print].

7. Thrombosis risk factors in PV

8. for Thrombosis in ECLAP-study
Risk Factors
for Thrombosis in ECLAP-study
(PVSG-PV diagnosis)
Low-risk
Events/100 persons/yr HR
2.5 1 
Intermediate-risk
Events/100 persons/yr HR
5.0
4.9
2.00
1.96
ECLAP cohort 1,638
High-risk
Events/100 persons/yr HR
10.9
4.35
Marchioli et al, 23: , 2005 8

9. Prognostic studies may change over time
WHO diagnosis,
New biomarkers

10. in 526 strictly defined WHO-PV
THROMBOSIS
in 526 strictly defined WHO-PV
(Events n = 80)
Risk factor HR p-value
Previous thrombosis
WBC>10.1 x109/L
Multivariate model adjusted for: sex, age, Hb, HCT, plt count, active smoking, JAK2V617 allele burden, Hydroxyurea therapy, aspirin prophylaxis
Barbui et al, in preparation 2014

11. in 526 strictly defined WHO-PV
THROMBOSIS
in 526 strictly defined WHO-PV
(Events n = 80)
Low-risk……………... no risk factors
Intermediate risk…… previous thrombosis or WBC >10.1 x109/L
High-risk ……………. previous thrombosis and WBC >10.1 x109/L
Barbui et al, in preparation 2014

12. Different thrombosis rate and thrombosis-free survival in the three groups (n= 526) with WHO-PV
0 risk factors Rate: 1.88% pts/yr
1 risk factor Rate: 3.06% pts/yr
2 risk factors Rate: 6.53% pts/yr
Model 0
Model 1
Model 2
p=0.0004
Barbui et al, in preparation 2014

13. Prognostic model for thrombosis-free survival
0.00
0.25
0.50
0.75
Prognostic model for thrombosis-free survival
Internal validation : 316 patients
1.00
Low-risk
Intermediate-risk
High-risk
P=0.0079
Low-risk N=48 (15%) Rate: 1.24% pts/yr
Intermediate-risk N=210 (66%) Rate: 2.21% pts/yr
High-risk N=58 (18%) Rate: 5.19% pts/yr 5 10 15 20
Years from diagnosis
Barbui et al, in preparation 2014

14. Low-risk
Intermediate-risk
High-risk
P=0.0001
Low-risk N=33 (16%) Rate: 0.41% pts/yr
Intermediate-risk N=137 (65%) Rate: 2.29% pts/yr
High-risk N=41 (19%) Rate: 7.23% pts/yr
Barbui et al, in preparation 2014

15. Proposal: Hb/Hct values should be lowered in JAK2 mutated patients for the diagnosis of PV

16. Among 397 patients JAK2 mutated and with bone marrow morphology consistent with WHO-PV
257 (65%) met the full WHO-2008 criteria.
140 (35%) were classified and treated as PV, although they did not meet the hemoglobin level threshold that is required for the diagnosis of WHO-defined PV. These patients were operationally defined as «masked PV».

17. Thrombosis-free survival in masked and overt PV
Barbui et al, AJH 89:52-54,2013

18. Prognostic studies may change over time
WHO diagnosis
New biomarkers

19. New prognostic factors for thrombosis: JAK2V617F
JAK2 mutational status and thrombosis
Meta-analysis (17 studies) 2,905 ET patients, 778 patients with thrombosis
JAK2 V617F patients have a two-fold higher risk of developing thrombosis
In PV, the JAK2 mutation does not predict thrombosis or leukemia, but an allele burden higher than 75% may predict thrombosis and > 50% an higher risk of evolution to MF
Ziakas Haematologica 2008; 93:1412-4; Vannucchi et al, Blood 2008; Passamonti et al, Leukemia Sep;24(9):

20. Time-dependent multivariate analysis on the relative risk of major thrombosis among men and women with Polycythemia Vera (N = 1,638)*
*Model adjusted for: age, gender, time from PV diagnosis to recruitment, thrombotic or hemorrhagic events prior to recruitment, smoking, history of diabetes, hypertension, claudicatio intermittens, erythromelalgia, splenomegaly, circulating immature cells, leukocyte count, total blood cholesterol, phlebotomy use, interferon use, hydroxyurea use, antiplatelets use, anticoagulants use, 32P use, busulfan use, chlorambucil use, and pipobroman use
Landolfi et al., Blood 2006

21. New prognostic factors for thrombosis: Leukocyte count
Leukocytosis and thrombosis in ET
657 ET
The cumulative probability to develop thrombosis in LR patients with high WBC count was similar to that of HR patients
The value of WBC count with highest specificity and sensitivity was 9.4 x109/L
Leukocyte count >15 x109/L in PV
Higher risk of myocardial infarction (vs. leukocyte counts <10 x109/L)
Landolfi et al. N Engl J Med. 2004;350(2): Carobbio et al. J Clin Oncol Jun 1;26(16): Epub 2008 Apr 28.

22. Sub group analysis of CYTO-PV trial supports the correlation between leukocytosis and thrombosis

23. Standard arm (A) HCT< 45% Experimental arm (B) HCT 45-50%
Eligible Patients
WHO-2008 diagnosis
All comers: newly diagnosed and previously treated
Standard arm (A)
HCT< 45%
Experimental arm (B)
HCT 45-50%
1:1
Median follow-up 31 months ( range )

24. Cyto-PV is a pragmatic clinical trial
The choice of the best therapeutic approach (phlebotomy, cytotoxic drugs or both) to maintain the assigned HCT level was left to the investigator decision, although a recommendation was made to use hydroxyurea in high risk patients or in those with progressive disease

26. HEMATOCRIT LEVEL DURING THE STUDY

27. WHITE-CELL COUNT DURING THE STUDY
P=0.001

28. PLATELET COUNT DURING THE STUDY
P=n.s.

29. White Blood Cells count influence the prognosis of Polycythemia Vera patients: a sub-analysis of the CYTO-PV study.  
WBC
(109/L)
Events/Pts
(%)
HR (95% CI)
P-Value
< 6.0
2/54 (3.7) 1
(reference)
6.0-12
15/237 (6.3)
2.39
( )
0.26
>12
11/74 ( 14.9)
4.89
( )
0.04
Barbui et al, ASH 2013

30. Ignore Value, Repeat Test in 3 weeks
Inflammatory markers and thrombosis High sensitivity-CRP is a strong predictor of CV disease
1 mg/L
3 mg/L
10 mg/L
>100 mg/L
Low
Risk
Moderate
Risk
High
Risk
Acute Phase Response
Ignore Value, Repeat Test in 3 weeks
Ridker PM. Circulation 2003;107:363-9

31. Unadjusted and sequentially multivariable adjusted risk of thrombosis associated to different hs-CRP levels
*Reference category: hs-CRP < 1.0 mg/L
Barbui et al, Haematologica 2011

32. CONCLUSION Prognostic factors in MPN, revisited
Improvements in diagnostic tests, biomarker measurement, or treatments may change the prognosis of patients.
Changes over time may even lead to the situation that prior prognostic models are no longer used to estimate outcome risks and to influence patient management.