1. Algoritmo di trattamento nei pazienti con Policitemia Vera
Tiziano Barbui MD
Hematology and Foundation for Clinical Research ,
Hospital Papa Giovanni XXIII
Bergamo, Italy

2. Polycythemia Vera A chronic MPN, primarily characterized by …
Erythrocytosis, and often leukocytosis and/or thrombocytosis
A chronic MPN, primarily characterized by …
JAK2-V617F mutations in 96%
Exon 12 JAK2 mutations in ~3% of patients with PV
Thrombotic events, progression to post-PV MF or sAML
↑ risk of mortality mainly caused by …
Kralovics R et al. N Engl J Med. 2005;352: Levine RL et al. Cancer Cell. 2005;7: Passamonti F et al. Am J Med. 2004;117: Tefferi A et al. Leukemia. 2013;27:

3. The Disease Burden Thrombosis Disease transformation
Myelofibrosis
AML
Thrombosis
Micro/macrovascular
Arterial > venous
Unusual sites: age/gender
Typically second decade
Newly diagnosed
Symptoms (Independent From Risk)
Cytokine: fatigue, pruritus, constitutional symptoms, bone pain
Vascular: headache, dizziness, numbness, decreased concentration, low mood, sexuality problems
Disease evolution: splenomegaly, constitutional symptoms
1. Mesa RA et al. Cancer. 2007;109: Scherber R et al. Blood. 2011;118: Geyer HL et al. Blood. 2014;123:

4. Thrombotic Risk Stratification in PV
Risk Category
Age >60 Years or
Prior Thrombosis
Low No
High
Yes
Low-risk
Phlebotomy
Aspirin
High-risk
PHL/ASA and Cytoreductive therapy
Goals of treatment
Reduce thrombosis rate
Delay disease transformation
a Diabetes, hypertension, dyslipidemia, tobacco use. 1. Marchioli R et al. J Clin Oncol. 2005;23: Barbui T et al. J Clin Oncol. 2011;29:

5. Incidence of thrombosis in contemporary
patients with PV (n=1,545)
Age < 60 years and no previous thrombosis
n=604 (40%)
Age ≥ 60 years and/or previous thrombosis
N=941 (60%)
International IWG-MRT
Annual Rate 2.08 %
Stroke/TIA: 40 (32%)
IMA: 13 (10%)
PAT: 13 (10%)
DVT/PE: 28 (22%)
Splanchnic: 16 (13%)
Other/Unk: 16 (13%)
Annual Rate 3.14%
Stroke/TIA: 64 (33%)
IMA: 22 (11%)
PAT: 21 (11%)
DVT/PE: 60 (31%)
Splanchnic: 11 (6%)
Other/Unk: 17 (9%)
Barbui T et al, Blood Nov 6;124(19):

6. Annual rate of thrombosis in MPN and general population (%) patients)
General population without risk factors*
0.6%
General population with multiple CV risk factors**
0.90 %
PV patients (n=1,545) §§
Low-risk……………………………………………………….
Highrisk………………………………………………………
2.08%
3.14%
* Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual partecipant data from randomized trials, Lancet 2009; 373: Yusef S et al Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease NEJM 2016
**The Risk and Prevention Study Collaborative Group. N−3 Fatty Acids in Patients with Multiple Cardiovascular Risk Factors. N Engl J Med 2013;368:
§ Barbui T, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer Journal. In press
§§ Barbui T, et al. In contemporary patients with polycythemia vera, rates of thrombosis and risk factors delineate a new clinical epidemiology. Blood :

7. How to improve the incidence of fatal and non fatal thrombosis in PV

8. Potentially modifiable risk factors
Cardiovascular risk factors
Obesity Diabetes Hypertension Hyperlipidemia
Smoking, Unhealthy diet, Lack of physical activity
Thrombosis
THROMBOSIS
Disease related abnormalities Hyperviscosity, Leukocyte and platelet abnormalities
Inflammation, Mutational status

9. Arterial hypertension and Thrombosis-free survival in low-risk PV-
N (%) IR %pts/yr HR p
750 (45) (ref) -
638 (20) <.0001
Barbui T et al, AJH 2017; Blood 2017

10. Additional effect of hypertension (HTN)
in Low and High risk PV cases enrolled in ECLAP trial

11. Potentially modifiable risk factors
Cardiovascular risk factors
Obesity Diabetes Hypertension Hyperlipidemia
Smoking, Unhealthy diet, Lack of physical activity
Thrombosis
THROMBOSIS
Disease related abnormalities Hyperviscosity, Leukocyte and platelet abnormalities
Inflammation, Mutational status

12. Stringent Hematocrit Control reduces the rate of major thrombosis
Probability
In patients with hematocrit levels ≥45%, the risk of CV-related death or major thrombosis was increased approximately 4 times (P = 0.007) versus patients with hematocrit <45%1
1. Marchioli R et al. N Engl J Med. 2013;368:22-33.

13. The role of leukocyte number Time-Dependent Multivariable Analysis on Risk of Major Thrombosis in CYTO-PV
WBC Class (x 109/L)
Events/ Patients (%)
HR (95% CI) P
<7.0
4/100 (4.0)
1.00
4/84 (4.8)
1.58 ( )
.52
8/88 (9.1)
2.69 ( )
.11
≥11.0
12/93 (12.9)
3.90 ( )
.02
Subanalysis of CYTO-PV study (N = 365)
WBC categorized into approximate quartiles and recorded in last clinical visit before the thrombotic event
a Adjusted for age, gender,
CV risk factors, previous thrombosis, and
hematocrit levels.
Barbui T et al. Blood. 2015;126:

14. Inflammation and thrombosis in MPN. Role of leukocytes and platelets
Barbui et al, Haematologica 2011; Landolfi et al haematologica 2011

15. High risk PV. Hydroxyurea is First-Line Therapy
Rate of
Thrombosis
Leukemia
9.8% 6%
32.8%
1.5%
PVSG-08
Prospective
cohort
N = 51
Hydroxyurea
P .009
P = .18
Historical
control
N =134
Therapeutic phlebotomy only
PVSG-01
1. Fruchtman SM et al. Semin Hematol. 1997;34:17-23.

16. Stratified Wilcoxon test
In comparison with phlebotomy ( n=700) HU (n 342) reduces the incidence of thrombosis only in high risk patients with PV (n=700). Propensity score matching analysis from ECLAP
Stratified Wilcoxon test
0.017
LR: low-risk; HR: high risk
Barbui T et al. Am J Hematol 2017 [Epub ahead of print]

17. Not fully respondent patients Hematologic toxicities
A proportion of patients with PV are resistant and intolerant to Hydroxyurea
Not fully respondent patients
Resistant or intolerant to hydroxyurea
% refers to Patients on hydroxyurea therapyPatients on hydroxyurea therapy
% refers to Patients on hydroxyurea therapyPatients on hydroxyurea therapyPatients on hydroxyurea therapy
11%
13%
INTOLERANT PATIENTS
Non hematologic toxicities
Leg ulcers or
other unacceptable HU-related non- hematological toxicities, gastrointestinal symptoms, pneumonitis or fever at any dose of hydroxycarbamide
Hematologic toxicities
Neutrophil count <1,000/mL
platelet count <100,000/mL
Hb <10 g/dL
RESISTANT PATIENTS
Resistance is defined after 3 months HU ≥ 2 g/day by:
the inability of patients optimally treated with HU to adequately control blood counts without phlebotomies or symptoms:
Need for phlebotomy to keep Ht <45%
Uncontrolled myeloproliferation:
platelet count >400,000/mL
blood cell count >10,000/mL
Failure to reduce massive splenomegaly by more than 50% as measured by palpation OR Failure to relieve symptoms related to splenomegaly2
Some patients can be both
Intolerant & Resistant
Álvarez-Larrán et al, Blood 2012;119(6):1363-9

18. Development of resistance or intolerance to HU in a real life setting represents a therapeutic challenge
Cytoreductive agents
Busulfan
Potentially leukemogenic in long term treatment
Pipobroman
Potentially leukemogenic in long term treatment; withdrawn from the market
Radiophosphorus
Not recommended
IFN-α
Off label
High discontinuation rates
JAK2-Inhibitors
Ruxolitinib is now approved
Finazzi et all 2005; Mesa et al 2015

19. Conclusione Algoritmo di trattamento nei pazienti con Policitemia Vera Risk Adapted Management
Risk Status
High
Low
Second-line cytoreductive therapy for PV
IFN-α
Ruxolitinib (approved in HU-refractory PV)
First-line cytoreductive therapy for PV
Hydroxyurea
IFN-α
Busulfan
Therapeutic phlebotomy for PV: Goal Hct <45%
ASA 100 mg daily for PV
Address CV modifiable risk factors