1. If platelets are not a prognostic factor
in ET, what is?
Carles Besses
Hospital del Mar–IMIM, Barcelona

2. Factors associated with risk of vascular complications in ET patients
Host factors
Advanced age
History of thrombosis
Cardiovascular risk factors
ET-specific factors
Thrombocytosis
Leukocytosis
Mutations (JAK2 V617F, CALR)
MPN-associated prothrombotic state

3. Main points Thrombocytosis as a risk factor for vascular complications
Other factors associated with thrombotic risk
Clinical assessment of thrombotic risk
How to deal with thrombocytosis in ET patients

4. Thrombocytosis and risk of vascular complications in ET
An unpredictable connection?
What the studies say?

5. Extreme thrombocytosis is associated with bleeding diathesis
Study
Patients no.
Risk factor for bleeding
Platelet count at diagnosis P
Fenaux et al.1
147
>2000x109/L
<0.02
Bellucci et al.2 94
>1000x109/L
<0.01
Alvarez-Larrán et al.3 #
300
>800x109/L
Palandri 4
565
0.003
#patients <60 years
1 Cancer 1990;66:549
2 Cancer 1986;58:2440
3 Blood 2010;116:1205
4 Br J Haematol 2012;156:281
van Genderen & Michiels, Presse Med 1994;23:73

6. The level of the platelet count per se does not correlate with thrombotic incidence or symptoms at diagnosis
Lengfelder et al, Br J Haematol 1998;100:15

7. Thrombocytosis at diagnosis is not a predictive factor for thrombosis
Patients no.
Risk factors for thrombosis (RR or P)
Age >60
Previous thrombosis
Platelet count
Leukocytosis
CRF
Cortelazzo et al. (1990)
100
10.3 ( )
13 ( ) NS ─
Colombi et al. (1991)
103
P<0.001
Besses et al. (1999)
148
3.3 ( )
3.0 ( )
4.7 ( )
Bazzan et al. (1999)
187
NS (>55)
Jantunen et al. (2001)
132
P=0.01
Wolanskyj et al. (2006)
322
1.51 ( )
2.3 ( )1
1.74 ( )2
Carobbio et al. (2007)
439
2.3 ( )3
2.3 ( )4
Passamonti et al. (2008)
605
P=0.03
Carobbio et al. (2008)
657
2.1 ( )3
3.0 ( )5
Girodon et al. (2010)
311
P<0.05
Palandri et al. (2011)
532
2.2 ( )3
1.76 ( )6
Campbell (2012)
776
Montanaro et al. (2014)
1144
2.36 ( )
2.98 ( )
CRF: cardiovascular risk factors; 1arterial only; 2WBC ≥15x109/L; 3age >60 and previous thrombosis evaluated together; 4WBC ≥8.7x109/L; 5WBC ≥10.4x109/L; 6WBC ≥11x109/L;

8. Thrombocytosis at diagnosis is not a predictive factor for thrombosis
Patients no.
Risk factors for thrombosis (RR or P)
Age >60
Previous thrombosis
Platelet count
Leukocytosis
CRF
Cortelazzo et al. (1990)
100
10.3 ( )
13 ( ) NS ─
Colombi et al. (1991)
103
P<0.001
Besses et al. (1999)
148
3.3 ( )
3.0 ( )
4.7 ( )
Bazzan et al. (1999)
187
NS (>55)
Jantunen et al. (2001)
132
P=0.01
Wolanskyj et al. (2006)
322
1.51 ( )
2.3 ( )1
1.74 ( )2
Carobbio et al. (2007)
439
2.3 ( )3
2.3 ( )4
Passamonti et al. (2008)
605
P=0.03
Carobbio et al. (2008)
657
2.1 ( )3
3.0 ( )5
Girodon et al. (2010)
311
P<0.05
Palandri et al. (2011)
532
2.2 ( )3
1.76 ( )6
Campbell (2012)
776
Montanaro et al. (2014)
1144
2.36 ( )
2.98 ( )
CRF: cardiovascular risk factors; 1arterial only; 2WBC ≥15x109/L; 3age >60 and previous thrombosis evaluated together; 4WBC ≥8.7x109/L; 5WBC ≥10.4x109/L; 6WBC ≥11x109/L;

9. Correlation of thrombocytosis and leukocytosis with
vascular complications during cytoreductive treatment in ET patients
Author
Patient no.
Cytoreductive drug
Thrombosis
Bleeding
Cortelazzo et al.1
100
Busulfan
Platelet count <600x109/L
for <70% of follow-up (P<0.025)
Carobbio et al.2
416
HU ± ASA
Platelet count <400x109/L (P=0.95)
WBC >10x109/L (P<0.015)
Hernández-Boluda et al.3
166
Patients in mantained CR according ELN criteria (2009) (P=0.8)*
Campbell et al.4
776
HU + ASA
AG + ASA
Platelet count >450x109/L (P=0.4)
High WBC (P=0.03)
Platelet count >450x109/L (P=0.001)
High WBC (P=0.01)
Hernández-Boluda et al.5
154
AG ± ASA
Patients in mantained CR according ELN criteria (2009) (P=0.59)#
Patients in mantained CR according ELN criteria (2009) (P=0.23)Δ
1J Clin Oncol 1990;8:556; 2Blood 2010;116:1051; 3Br J Haematol 2011;152:81; 4Blood 2012;120:1409; 5Ann Hematol 2013;92:771
*cumulative incidence of thrombosis, #incidence rate of major thrombosis, Δincidence rate of major bleeding
HU: hydroxyurea, AG: anagrelide, ASA: acetylsalycilic acid

10. Risk of major bleeding in the PT-1 cohort according to platelet counts during follow-up
Campbell et al, Blood 2012;120:1409

11. Main points Thrombocytosis as a risk factor for vascular complications
Other factors associated with thrombotic risk
Clinical assessment of thrombotic risk
How to deal with thrombocytosis in ET patients

12. Leukocytosis at diagnosis: controversial results
Patients no.
Risk factors for thrombosis (RR or P)
Age >60
Previous thrombosis
Platelet count
Leukocytosis
CRF
Cortelazzo et al. (1990)
100
10.3 ( )
13 ( ) NS ─
Colombi et al. (1991)
103
P<0.001
Besses et al. (1999)
148
3.3 ( )
3.0 ( )
4.7 ( )
Bazzan et al. (1999)
187
NS (>55)
Jantunen et al. (2001)
132
P=0.01
Wolanskyj et al. (2006)
322
1.51 ( )
2.3 ( )1
1.74 ( )2
Carobbio et al. (2007)
439
2.3 ( )3
2.3 ( )4
Passamonti et al. (2008)
605
P=0.03
Carobbio et al. (2008)
657
2.1 ( )3
3.0 ( )5
Girodon et al. (2010)
311
P<0.05
Palandri et al. (2011)
532
2.2 ( )3
1.76 ( )6
Campbell (2012)
776
Montanaro et al. (2014)
1144
2.36 ( )
2.98 ( )
CRF: cardiovascular risk factors; 1arterial only; 2WBC ≥15x109/L; 3age >60 and previous thrombosis evaluated together; 4WBC ≥8.7x109/L; 5WBC ≥10.4x109/L; 6WBC ≥11x109/L;

13. Leucocytosis and thrombocytosis at diagnosis as risk factors for vascular complications in 891 WHO-defined ET patients
Bleeding
Arterial thrombosis
Venous thrombosis
Finazzi et al 1*
Higher risk
WBC ≥11x109/L
HR: 1.74 ( )
P=0.04
No increased risk
PLT ≥800, ≥1000,
≥1200, ≥1500,
≥2000x109/L
Carobbio et al 2
WBC ≥11x109/LΔ
HR: 1.66 ( )
P=0.044
Lower risk
PLT>1000x109/L#
HR: 0.42 ( )
P=0.007
Male sex
HR: 1.99 ( )
P=0.039)
1Leukemia 2012;26:716; 2Blood 2011;117:5857
*Including early-PMF patients; #in the entire study population and in JAK2V617F-positive patients; Δnot significant when retricted to JAK2V617F-positive patiens

14. Hematologic and clinical features at diagnosis of 214 ET patients
Age, years,
median (range)
64 (9-93)
Sex (male/female)
57/157
Splenomegaly, no. (%)
15 (7)
Cardiovascular risk
factors, no. (%)
116 (54.5)
Hemoglobin, g/L,
140 (82-167)
WBC count, x109/L,
>10x109/L, no. (%)
8.6 ( )
63 (29.9)
Platelet count, x109/L,
≥1000x109/L, no. (%)
≥1500x109/L, no. (%)
691 ( )
36 (16.8)
7 (3.3)
Angona et al, Med Clin (Barc) (in press)

15. Thrombosis-free survival of 214 ET patients according to initial WBC count
62% at 10 years
86% at 10 years
WBC  10x109/L
WBC > 10x109/L
Median follow-up 6.9 years (0-27)
Angona et al, Med Clin (Barc) (in press)

16. JAK2 V617F mutation and clinical outcomes in ET patients
Author
Patients no.
Overall risk of thrombosis
Arterial thrombosis
Venous thrombosis
Thrombosis at presentation
Evolution
to PV
Ziakas1
2905
1.84
( )
1.96
( )
2.09
( )
1.88
( ) ─
Dahabreh et al 2
2436
1.83
( )
1.68
( )
2.50
( )
2.05
( )
7.67
( )
Lussana et al 3
3150
1.92
( )
1.77
( )
2.49
( )
1Haematologica 2008;93:1412; 2Leuk Res 2009;33:67; 3Thromb Res 2009;124:409
Results are expressed in Odds Ratios and 95% CI

17. Chao & Gotlib, Blood 2014;123:1438
Professional illustration by Debra T, Dartez

18. CALR-mutated ET A distinct disease entity from JAK2V617F-mutated ET
CALR-mutated vs JAK2V617F-mutated
Younger age
Higher number of male patients
Higher platelet count
Lower risk of thrombosis
Lower hemoglobin level
Lower WBC count
Higher serum erythropoietin level
No difference in major bleeding
No polycythemic transformation
Higher mutant allele burden
No difference in the risk of MF transformation
No difference in the risk of AL transformation
Higher number of patients in low-risk
group (classical and IPSET)
No difference in overall survival*
Clinical/Biological Phenotype
Clinical Outcomes
Rumi et al, Blood 2014;123:1544
Rotunno et al, Blood 2014;123:1552
* Longer overall survival according to Klampfl et al,
N Engl J Med 2013;369:2379

19. ET CALR-pos: 10 cases per 1000 person - years
Cumulative incidence of thrombotic events in patients with CALR mutated ET, JAK2 mutated ET and PV
ET CALR-pos: 10 cases per 1000 person - years
ET JAK2-pos: cases per 1000 person - years
PV: cases per 1000 person - years
P=0.001
P=0.314
Rumi et al, Blood 2014;123:1544

20. Vannucchi & Guglielmelli, Semin Thromb Hemost 2013;39:496

21. Main points Thrombocytosis as a risk factor for vascular complications
Other factors associated with thrombotic risk
Clinical assessment of thrombotic risk
How to deal with thrombocytosis in ET patients

22. Risk factors for thrombosis (RR or P)
Advanced age and previous thrombosis at diagnosis as predictive factors for thrombosis
Patients no.
Risk factors for thrombosis (RR or P)
Age >60
Previous thrombosis
Platelet count
Leukocytosis
CRF
Cortelazzo et al. (1990)
100
10.3 ( )
13 ( ) NS ─
Colombi et al. (1991)
103
P<0.001
Besses et al. (1999)
148
3.3 ( )
3.0 ( )
4.7 ( )
Bazzan et al. (1999)
187
NS (>55)
Jantunen et al. (2001)
132
P=0.01
Wolanskyj et al. (2006)
322
1.51 ( )
2.3 ( )1
1.74 ( )2
Carobbio et al. (2007)
439
2.3 ( )3
2.3 ( )4
Passamonti et al. (2008)
605
P=0.03
Carobbio et al. (2008)
657
2.1 ( )3
3.0 ( )5
Girodon et al. (2010)
311
P<0.05
Palandri et al. (2011)
532
2.2 ( )3
1.76 ( )6
Campbell (2012)
776
Montanaro et al. (2014)
1144
2.36 ( )
2.98 ( )
CRF: cardiovascular risk factors; 1arterial only; 2WBC ≥15x109/L; 3age >60 and previous thrombosis evaluated together; 4WBC ≥8.7x109/L; 5WBC ≥10.4x109/L; 6WBC ≥11x109/L;

23. Conventional risk stratification in ET patients
Low-risk
Age 60 years
No history of thrombosis
Platelet count <1500x109/L
High-risk
Age >60 years*
History of thrombosis*
Platelet count 1500x109/L†
* High-risk of thrombosis; † High-risk of bleeding
modified from Cervantes, Hematology Am Soc Hematol Educ Program 2011:215

24. International Prognostic Score for ET
IPSET
IPSET-survival*
Age ≥60 years
Leukocyte count ≥11x109/L
History of thrombosis
: 2 points
: 1 point
IPSET-thrombosis*
Age >60 years
History of thrombosis
Cardiovascular risk factors
JAK2V617F
: 1 point
: 2 points
Score
Median survival
Low-risk
Intermediate
High-risk
1-2 ≥3
not reached
24.5 years
13.8 years
Score
Thrombosis risk (patients/year)
Low-risk
Intermediate
High-risk
<2 2
>2
1.03%
2.35%
3.56%
* based on 867 WHO-defined ET patients
* based on 891 WHO-defined ET patients
Passamonti et al, Blood 2012;120:1197
Barbui et al, Blood 2012;120:5128

25. International Prognostic Score for ET
IPSET
IPSET-survival*
Age ≥60 years
Leukocyte count ≥11x109/L
History of thrombosis
: 2 points
: 1 point
IPSET-thrombosis*
Age >60 years
History of thrombosis
Cardiovascular risk factors
JAK2V617F
: 1 point
: 2 points
Score
Median survival
Low-risk
Intermediate
High-risk
1-2 ≥3
not reached
24.5 years
13.8 years
Score
Thrombosis risk (patients/year)
Low-risk
Intermediate
High-risk
<2 2
>2
1.03%
2.35%
3.56%
* based on 867 WHO-defined ET patients
* based on 891 WHO-defined ET patients
Passamonti et al, Blood 2012;120:1197
Barbui et al, Blood 2012;120:5128

26. Main points Thrombocytosis as a risk factor for vascular complications
Other factors associated with thrombotic risk
Clinical assessment of thrombotic risk
How to deal with thrombocytosis in ET patients

27. Treatment targets of cytoreductive therapy in ET
Clinical setting
Platelet count <400x109/L
<600x109/L
History of thrombosis and/or major bleeding
Intolerance to cytoreductive drugs
Leukocyte count (normal)
No consensus
Leukocytosis in the setting of thrombosis?
bleeding?

28. Control of cardiovascular risk factors (CRF)
Management of ET
HIGH RISK
LOW RISK
Age ≥60 years
History of thrombosis/
serious hemorrhage Thrombocytosis >1500x109/L
Age <60 years
No history of thrombosis/ serious hemorrhage
Control of cardiovascular risk factors (CRF)
JAK2V617F-negative AND no CRF
JAK2V617F-positive OR CRF
First-line therapy
Second-line therapy
Resistance
Thrombosis2 Hemorrhage3
MD not responding
to ASA
Hydroxyurea1 +
Low-dose ASA
Watch & Wait
Low-dose ASA
Anagrelide Interferon alfa-2
Intolerance
Microvascular disturbances (MD)
Special situations
Pregnancy  Interferon alfa-2
Very elderly  Busulphan
1 use with caution if <40 years
2 oral anticoagulation in venous thrombosis
3 ASA contraindicated

29. General recommendations in the treatment of ET patients
Follow the policy of risk-adapted therapy
Preferentially use non-leukemogenic drugs as first-line therapy in high-risk young patients
Avoid alkylating agents after hydroxyurea exposure
Use acetylsalycilic acid on an individual basis
Do not treat pediatric patients with cytoreductive drugs unless it is absolutely necessary
Include patients in clinical trials

30. Take-home messages
In most ET patients the degree of thrombocytosis per se should not be the only criterion to start cytoreductive therapy
Risk stratification is the best strategy to decide when to treat or not a patient
WHO-defined ET diagnosis is essential to assess risk of vascular complications and survival
The role of CALR mutations in the current treatment approach of ET patients has to be defined