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.

Survival risk factors in PV

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

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

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

Prediction of Survival in 1,545 patients with WHO-PV (IWG-MRT study) Risk factors Age > 67 years 5 points Age 57-66 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:10.1038/leu.2013.163 [Epub ahead of print].

Thrombosis risk factors in PV

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, 23:2224-2232, 2005 8

Prognostic studies may change over time WHO- 2008 diagnosis, New biomarkers

in 526 strictly defined WHO-PV THROMBOSIS in 526 strictly defined WHO-PV (Events n = 80) Risk factor HR p-value Previous thrombosis 2.22 0.004 WBC>10.1 x109/L 1.51 0.036 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

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

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

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

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

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

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».

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

Prognostic studies may change over time WHO- 2008 diagnosis New biomarkers

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):1574-9.

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

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):114-124. Carobbio et al. J Clin Oncol. 2008 Jun 1;26(16):2732-6. Epub 2008 Apr 28.

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

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 1.5-48)

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

HEMATOCRIT LEVEL DURING THE STUDY

WHITE-CELL COUNT DURING THE STUDY P=0.001

PLATELET COUNT DURING THE STUDY P=n.s.

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 (0.5-10.8) 0.26 >12 11/74 ( 14.9) 4.89 (1.1-22.7) 0.04 Barbui et al, ASH 2013

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

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

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.