Algoritmo di trattamento nei pazienti con Policitemia Vera Tiziano Barbui MD (tbarbui@asst-pg23.it Hematology and Foundation for Clinical Research , Hospital Papa Giovanni XXIII Bergamo, Italy  

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;352:1779-1790. 2. Levine RL et al. Cancer Cell. 2005;7:387-397. 3. Passamonti F et al. Am J Med. 2004;117:755-761. 4.Tefferi A et al. Leukemia. 2013;27:1874-1881.

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;109:68-76. 2.Scherber R et al. Blood. 2011;118:401-408. 3. Geyer HL et al. Blood. 2014;123:3803-3810.

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;23:2224-2232. 2. Barbui T et al. J Clin Oncol. 2011;29:761-770.

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. 2014 Nov 6;124(19):3021-3.

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; 373:1849-1860.. 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;368:1800-8. § 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 2014 124: 3021-3023

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

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

Arterial hypertension and Thrombosis-free survival in low-risk PV- N (%) IR %pts/yr HR p 750 (45) 1.30 1 (ref) - 638 (20) 2.15 1.66 <.0001 Barbui T et al, AJH 2017; Blood 2017

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

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

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.

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 7.0-8.4 4/84 (4.8) 1.58 (0.39-6.43) .52 8.5-11.0 8/88 (9.1) 2.69 (0.80-9.05) .11 ≥11.0 12/93 (12.9) 3.90 (1.24-12.3) .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;126:560-561.

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

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.

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]

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

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

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