Essential thrombocythemia

Seong Hyun Jeong, MD.

Department of Hematology-Oncology Ajou University School of Medicine Contents

• Introduction • Clinical features • Pathogenesis • Diagnosis • Management

Q1. ET가 의심되는 Thrombocytosis환자에서 골수검사를 시행해야 하는 경우는?

1. JAK2 mutation test가 음성일 경우 2. JAK2 mutation과 상관 없이 모든환자에서 3. 다른 myeloid neoplasm을 의심할 수 있는 (splenomegaly, anemia, PB이상)소견이 있을때 4. 시행하지 않는다.

Q2. Thombosis 과거력이 없는 60세 미만의 ET 환자에서 cytoreductive therapy를 시작해야 하는 경우는?

1. 혈소판이 정상수치 이상인 경우 2. Platelet > 1,000 x 109/L 3. Platelet > 1,500 x 109/L 4. 무증상이면 경과관찰 한다.

Q3. 임신한 고위험군의 ET환자에서 처방이 가능한 약제는?

a. Low dose aspirin b. Interferon-α c. Anagrelide d. Hydroxyurea

1. a 2. a, b 3. a, b, c 4. a, b, c, d 5. 모두 가능하지 않음 History

• First recognized as a specific disease entity in 1934 under the term hemorrhagic thrombocythemia. - Characterized by thrombocytosis with bone marrow megakaryocytic hyperplasia and a tendency to develop vascular complications. • Placed within myeloproliferative disorders in 1951 by Dameshek. • Shown to be a clonal disorder in 1981. • Discovery of an acquired mutation in the JAK2 gene in 2005.

William Damshek (1900-1969) WHO (2008) classification of the MPNs

Myeloproliferative neoplasms (MPN) Chronic myelogenous leukemia, BCR-ABL1-positive Chronic neutrophilic leukemia Polycythemia vera Primary myelofibrosis Essential thrombocythemia Chronic eosinophilic leukemia, not otherwise specified Mastocytosis Myeloproliferative neoplasms, unclassifiable

Vardiman et al. Blood. 2009;114:937-51 Clinical features

• ET is the most common of the Philadelphia chromosome negative MPN. • The annual incidence 1-2.5/100,000 with female predominance. • May present at any age, peak incidence between age of 50 and 70 years. • No survival difference compared to the general population. Survival of patients with ET

N : 435 F/U : 9.3y OS : 22.6

Passamonti et al. Am J Med. 2004;117:755-61 Clinical features

• Thrombosis - 12 to 30% of patients - predominantly arterial

• Bleeding - less frequent - usually associated with marked thrombocytosis (acquired vWD)

• Microvascular occlusion - more frequent manifestation - includes erythromelalgia, peripheral, neurological and visual disturbances Clinical features

• Evolution to myelofibrosis - 4 to 8% at 10 years - different frequency on treatment? - prognosis seems similar to that of PMF

• Leukemic transformation - 1-4% with poor prognosis - usually associated with use of cytoreductive drugs (alkylator, radioactive phophorus…) - frequency increases with use of ≥2 cytoreductive drugs - could develop without exposure to cytoreductive therapy - Hydroxyurea?

What makes ET?

• JAK2 mutation (50-60%)

Alessandro M. et al. Hematologica 2008;93:972-5

• TPO receptor gene (MPL gene) mutation (3-5%)

JAK2 mutation

Campbell et al. N Engl J Med. 2006;355:2452-66 Q. Why the same molecular lesion produces three different phenotypes?

• Gene-dosage hypothesis - Higher JAK2 mutated allele burden is found in PV and PMF - Homozygosity for the JAK2 mutation is frequent in PV and PMF - Mouse model over expression of JAK2 V617F  mimicking PV without thrombocytosis low JAK2 V617F expression  ET-like disease without erythrocytosis • Pre-JAK2 mutation events • Host genetic factors

Alessandro M. et al. Hematologica 2008;93:972-5 How to diagnose ET?

 Diagnosis of ET remains one of exclusion

Tefferi A. et al. Blood 2007;110:1092-7

Causes of thrombocytosis

Clonal thrombocytosis Reactive thrombocytosis Spurious thrombocytosis

Essential thrombocytosis Infection Micospherocyte Polycythemia vera Inflammation Cryoglobulinemia Primary myelofibrosis Tissue damage Neoplastic cell fragments MDS with del(5q) Hyposplenism Schistocyte RARS with thrombocytosis Post-operative Bacteria CML Hemorrhage Pappenheimer body CMML Iron deficiency Atypical CML Hemolysis MDS/MPN-U Malignancy Drug (e.g. corticosteroid; adrenaline) Cytokine (thrombopoietin) Rebound after chemotherpy Differential diagnosis of thrombocytosis

Harrison et al. Br J Hematol .2010;149:352-75 Goal of therapy in ET

• To avoid thrombosis and bleeding

• To treat thrombotic and bleeding complications

• To treat symptoms of microvascular complications

• To manage risk situations ( pregnancy, operation…)

• To minimize risk of acute leukemia, MDS and MF

Barbul. et al. J Clin Oncol 2011;29:761-70 Proper management

• Risk stratification for - thrombosis - bleeding

• Proper choice of drugs - thrombosis prophylaxis - cytoreduction Risk stratification of patients with ET

Low-risk High-risk Age ≤ 60 years Age > 60 years* No history of thrombosis History of thrombosis* Platelet count < 1,500 x 109/L Platelet count > 1,500 x 109/L† *High risk of thrombosis. †High risk of bleeding.

Barbui et al. JCO 2011;29:761-70

Risk factors for thrombosis

Host factors ET-specific factors Advanced age Thrombocytosis History of thrombosis Platelet biochemical and functional abnormalities Cardiovascular risk factors Coagulation and endothelial activation Thrombophilia Higher leukocyte counts Leukocyte and platelet activation Leukocyte-platelet interaction JAK2V617F mutation and higher allele burden Antiplatelet therapy in Low-risk ET

Observation Antiplatelet (n=102) (n=198) P Follow-up (pt-yr) 848 802 Thrombosis (IR) 17.7 21.2 0.6 Bleeding (IR) 6 12.6 0.09

• JAK2 V617F patients not receiving antiplatelet therapy had higher risk of venous thrombosis (p=0.02)

• Patients with CV risk factors not receiving antiplatelet therapy had higher risk of arterial thrombosis (p=0.047)

• Patients with platelets >1000 x 109/L had higher risk of major bleeding under antiplatelet therapy (p=0.004)

Alverez-Larran A et al. Blood 2010;116:1205-10

Hydroxyurea in high-risk ET

Cortelazzo et al. NEJM 1995;332:1132-6

Hydroxyuria and Anagrelide

Hydroxyurea Anagrelide Mechanism of action Direct Inhibition of Inhibition of platelet platelet production maturation from (Ribonucletide reductase megakaryocytes inhibition) (Phosphodiesterase inhibition) Side effect drowsiness/dizziness headache/dizziness nausea/vomiting weakness/fatigue diarrhea/constipation palpitation/arrhythmia mucositis/stomatitis fluid retention anemia/leukopenia heart failure skin change nausea fever diarrhea liver/kidney/lung toxicity hair loss *Leukemogenic risk? anemia Tolerance generally well tolerated discontinuation up to 1/3 Hydroxyurea vs. Anagrelide

ANAHYDRET Trial PT-1 Trial Diagnosis WHO criteria (2001) PVSG criteria Central review of Diagnosis by treating histology physician Patients High risk High risk Treatment naive Treated or untreated Median age: AN/HU 58/56 61/62 Patient number: AN/HU 122/136 405/404 Followup 539 patient-years 2,653 patient-years Total events Arterial thrombosis 10 54 Venous thrombosis 7 17 Hemorrhage 6 30 Transformation to MF 0 21 PT-1 trial

Harrison et al. N Engl J Med 2005;353:33-45 Definition of treatment response (ELN)

Definition of Response Complete response 1. Platelet count ≤ 400 x 109/L, AND 2. No disease-related symptoms,* AND 3. Normal spleen size on imaging, AND 4. WBC count ≤ 10 x 109/L Partial response In patients who do not fulfill the criteria for complete response: platelet count ≤ 600 X 109/L OR decrease of 50% from baseline No response Any response that does not satisfy partial response *Disease related symptoms include microvascular disturbances, pruritus, and headache

Barosi G et al. Blood 2009;113:4829-33

Management of low/high risk patients

Low risk patients High risk patients Thrombosis Low dose aspirin except Low dose aspirin except prophylaxis - aspirin contraindicated or - aspirin contraindicated or - Platelet > 1,000 x 109/L - Platelet > 1,500 x 109/L

Cytoreduction Not indicated Hydroxyurea as first choice Anagrelide for hydroxyurea refractory/intolerance Other agents

Busulfan Interferon-α Pipobroman Radioactive phosphorus High-risk pregnancy Leukemogenic potential Patients < 40 years Restricted to elderly patients With hydroxyurea intolerance/resistance Pregnancy

• ET-associated risks - miscarriage - preeclampsia - Placental abruption - intrauterine death or still birth - intrauterine growth retardation - venous thrombosis

• Available agents - Aspirin - Interferon - Hydroxyurea (?) - Anagrelide (?)

Risk stratification of pregnant ET patients

Low-risk pregnancy High-risk pregnancy Low risk ET High risk ET or Plt. >1,500 x 109/L No bleeding related to ET Problems in previous pregnancies First pregnancy or no problems in History of abortion or feral problems previous pregnancies Severe obstetric complication Management of pregnant ET patients

Low-risk pregnancy High-risk pregnancy Low-dose aspirin throughout IFN-α to normalize platelet count pregnancy Prophylactic LMWH after delivery for Aspirin and LMWH as in low-risk 6 weeks pregnancy Consider LMWH during pregnancy if history of severe pregnancy problems Proposed management algorithm

Cervantes Hematology Am Soc Hematol Educ Program. 2011;2011:215-21 Investigational Drugs

• Pegylated IFNα2a • JAK2 inhibitors • HDACi • Telomerase inhibitors Pegylated-IFN

MD Anderson study French study (N=39) (N=59) Median dose 90 μg 88 μg Median F/U 21 (2-45) 16 (1-45) Hematologic response 81% 83% CHR 76% 76% Molecular response 13% NA > 50% reduction 9% Complete 6% Discontinuation 10% 19%

Quinats-Cardama et al. JCO 2009;27:5410-24 Roy et al. ASH meeting 2010;116:abst. 461

* Randomized phase 3 study is ongoing (MPD-Research Consortium) JAK2 inhibitors

Ruxolitinib in High-risk ET ET Patients no. 39 Median F/U, mo 15 CHR 49% Median duration CHR 3.5y Discontinuation 23% V617F decrease >60% 12%

Verstovsek et al. ASH meeting 2010;116:313C Summary I

• ET affects more QOL of life than survival.

• Diagnosis of ET remains one of exclusion.

• Treatment of ET should be guided by the risk of thrombosis and bleeding complications.

Summary II

• Low dose aspirin is recommended for all patients with ET except high risk for bleeding.

• Cytoreductive therapy is recommended for high- risk ET patients with Hydroxyurea as first choice.

• Interferon could be considered in high-risk pregnancy.

• New drugs are under investigation (ex. JAK2 inhibitors, Peg-IFN..).