Essential thrombocythemia

Essential thrombocythemia

Department of Hematology-Oncology Ajou University School of Medicine

Seong Hyun Jeong, MD.

Contents

•

Introduction

•

Clinical features

•

Pathogenesis

•

Diagnosis

•

Management

Q1. ET가 의심되는

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

시작해야 하는 경우는?

1. 혈소판이 정상수치 이상인 경우 2. Platelet > 1,000 x 10

⁹

3. Platelet > 1,500 x 10

⁹

4. 무증상이면 경과관찰 한다.

Q3. 임신한 고위험군의 ET환자에서 처방이

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

Passamonti et al. Am J Med. 2004;117:755-61 N : 435

F/U : 9.3y OS : 22.6

Clinical features

• Thrombosis

• 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

- 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%)

• TPO receptor gene (MPL gene) mutation

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

(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

•

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

- bleeding

•

Proper choice of drugs

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 (n=102)

Antiplatelet

(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 platelet production (Ribonucletide reductase inhibition)

Inhibition of platelet maturation from

megakaryocytes (Phosphodiesterase inhibition)

Side effect drowsiness/dizziness nausea/vomiting

diarrhea/constipation mucositis/stomatitis anemia/leukopenia skin change

fever

liver/kidney/lung toxicity

*Leukemogenic risk?

headache/dizziness weakness/fatigue

palpitation/arrhythmia fluid retention

heart failure nausea

diarrhea hair loss anemia

Tolerance generally well tolerated discontinuation up to 1/3

Hydroxyurea vs. Anagrelide

ANAHYDRET Trial PT-1 Trial Diagnosis WHO criteria (2001)

Central review of histology

PVSG criteria

Diagnosis by treating physician

Patients High risk

Treatment naive

High risk

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 Venous thrombosis Hemorrhage

Transformation to MF

10 7 6

0 54

17 30 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 10^9/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

prophylaxis

Low dose aspirin except - aspirin contraindicated or - Platelet > 1,000 x 10⁹/L

Low dose aspirin except - aspirin contraindicated or - Platelet > 1,500 x 10⁹/L Cytoreduction Not indicated Hydroxyurea

as first choice

Anagrelide for hydroxyurea refractory/intolerance

Other agents

Interferon- α ^Busulfan 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

previous pregnancies

History of abortion or feral problems Severe obstetric complication

Management of pregnant ET patients

Low-risk pregnancy High-risk pregnancy

Low-dose aspirin throughout

pregnancy IFN-α to normalize platelet count Prophylactic LMWH after delivery for

6 weeks Aspirin and LMWH as in low-risk

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 IFN

α

• JAK2 inhibitors

• HDACi

• Telomerase inhibitors

Pegylated-IFN

MD Anderson study

(N=39) French study (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 > 50% reduction Complete

13%

9%

6%

NA

Discontinuation 10% 19%

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

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

JAK2 inhibitors

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

Ruxolitinib in High-risk ET

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..).