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Expert Update: What’s New in Essential Thrombocythemia

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Clinical Features of Essential Thrombocythemia (ET)

• Overproduction of platelets (thrombocythemia)1,2

─ Elevation in platelet count ≥450 x 109/L

• Cardiovascular complications due to bleeding and thrombosis

• Symptoms are variable and may be due to:3

– Microvascular complications (e.g., headache, dizziness, paresthesia, erythromelagia, blurred vision)

– Macrovascular complications (e.g., myocardial infarction, stroke, pulmonary embolus)

– Constitutional symptoms (e.g., fatigue, night sweats, itching [pruritus], weight loss)

– Splenomegaly and associated symptoms

1. Vardiman JW, et al. Blood. 2009;114:937-951; 2. Vannucchi AM, et al. CA Cancer J Clin. 2009;59:171-191; 3. Gowin K, Mesa R. F1000Res 2014;3:227-237.

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6

Myeloproliferative Neoplasms (MPN) Continuum: Shared Clinical Features

MPN Blast-phase; Acute myeloid leukemia

Polycythemia vera (PV)

Essential

thrombocythemia (ET)

Primary myelofibrosis (MF);Post-PV/ET MF

1. Tefferi A. Am J Hematol. 2008;83:491-497; 2. Rampal R, Mascarenhas J. Curr Opin Hematol. 2014;21:65-71.

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MPN Shared Biology:Hyperactive JAK-STAT Signaling

• A well characterized signaling pathway involved in normal hematopoiesis (blood making), inflammation, and immune function

• Four members of JAK family

– JAK1, JAK2, JAK3 and Tyk2

– Promiscuous signaling (!)

• JAK2 specifically mediates cytokine signaling for red blood cells and platelets (its inhibition causes anemia and low platelets)

• JAK-STAT is hyperactive in MPN due

to different mutations ( )Shuai, K. & Liu,B. (2003) Nature Reviews Immunology 3:900

blood

cell

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Phenotypic Driver Mutations (Activate JAK-STAT Pathway) in MPN

PV ET MF

JAK2 V617F

JAK2 Exon12

Others (SH2B3)

MPL (W515x)

CALR mut

Unknown (Triple Negative)

96% 60% 60%

3%

1%

3-5% 5-8%20-25% 20-25%

10-15% 10-15%

Type1/Type1-like

Type2/Type2-like

Klampfl T, et al. NEJM 2013;369(25):2379-90; Nangalia J, et al. NEJM 2013;369(25):2391-405.

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Most Common, Non-Driver, Mutations in MPN

Gene ET(%)

PV(%)

MF(%)

Blastphase (%)

TET2 4-5 10-16 7-17 17-32

IDH1/2 1 2 4 9-22

DNMT3A <1 3-7 2-15 14-17

EZH2 <1 3 7-13 ---

ASXL1 0-3 2-7 13-32 18-33

SRSF2 --- --- ≈15% ≈20%

SF3B1 --- --- 7% ---

CBL rare rare 6% ---

TP53 --- --- 4% 27%

U2AF1 --- --- 16% ---

• Also found in other malignancies (MDS, AML)• Therefore, they are of no specific diagnostic va lue but indicate a myeloid malignancy

Vainchenker W et al, Blood. 2011; 18;118(7):1723-35; Vannucchi AM et al, Leukemia 2013; 27:1861-9.

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Functional Classification of Somatically Acquired Mutations in MPN

Signalling Epigenetics mRNA Splicing Transcription

• JAK2 V617F• JAK2 exon12• MPL• CALR• CBL• LNK• SOCS• CSF3R• SETBP1• KIT• NF1• TK fusions

• TET2• ASXL1• EZH2• DNMT3A• IDH1/2

• SF3B1• SRSF2• U2AF1• ZSRS2

• CUX1• RUNX1• P53

*Not exhaustive; Includes those at >1% frequency.

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Mutations in ET/MPN: Conclusion

• JAK2V617F mutation is not a cause for the disease in humans, but main contributor to clinical phenotype

• Other mutations identified (> 20 so far) affecting clinical presentation; clonal hierarchy → “oligoclonal” state

• JAK-STAT pathway dysregulation, regardless of JAK2 mutational status, is a key pathologic feature of MPNs

Quintás-Cardama A, Nat Rev Drug Discov ;10(2):127-40.. Anand S, Blood 2011;118(6): 1610-21

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• The 3 phenotypic driver mutations should be searched in any subjects suspected to have MPN

Why Test for Different Mutations? Diagnostic Purposes

JAK2 V617F

JAK2 exon 12

LNK

JAK2 V617F JAK2 V617F

CALR CALR

MPL MPL

1st

2nd

3rd

Polycythemia Vera Essential Thrombocythemia Myelofibrosis

In the suspicion of

If negative,

If negative,

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WHO Criteria for Diagnosis of Essential Thrombocythemia (ET)

• WHO Diagnosis of ET requires:

– Presence of ALL 4 major criteria or the first 3 major criteria and the minor criterion

Major Criteria

1. Sustained platelet count ≥450 x 109/L

2. BM biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers

3. Not meeting WHO criteria for BCR-ABL-positive CML, PV, PMF, myelodysplasticsyndromes, or other myeloid neoplasms

4. Presence of JAK2V617F or CALR or MPL mutation

MINOR CRITERION: presence of clonal marker or absence of evidence for reactive thrombocytosis

Arber et al., Blood (2016) 127:2391-2405

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• WHO Diagnosis of prefibrotic/early MF requires:– ALL 3 major criteria plus 1 minor criteria

WHO Criteria for Diagnosis of Prefibrotic/Early Primary Myelofibrosis

Major Criteria

1. Megakaryocytic proliferation and atypia, without reticulin fibrosis > grade 1*, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation and often decreased erythropoiesis

2. Not meeting WHO criteria for ET, PV, CML, MDS, or other myeloid neoplasm

3. Presence of JAK2, CALR or MPL mutation or in the absence of these mutations, presence of another clonal marker or absence of reactive myelofibrosis

Minor Criteria

1. Anemia not attributed to a comorbid condition

2. Leukocytosis >11 x 109/L3. Palpable splenomegaly4. LDH increased to above upper

normal limit of institutional reference range

Arber et al., Blood (2016) 127:2391-2405

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ET prePMF(prefibrotic/early)

▪ no or only slight increase in age-matched cellularity

▪ marked increase in age-matched cellularity

▪ no significant increase in granulo- and erythropoiesis

▪ pronounced proliferation of granulopoiesis and reduction of erythroid precursors

▪ prominent large to giant mature megakaryocytes with hyperlobulated or deeply folded nuclei, dispersed or loosely clustered in the marrow space

▪ dense or loose clustering and frequent endostealtranslocation of medium sized to giant megakaryocytes showing hyperchromatic, hypolobulated, bulbous, or irregularly folded nuclei and an aberrant nuclear/cytoplasmic ratio

▪ no or very rarely minor increase in reticulinfibers

▪ no or no significant increase in reticulin fibers

Reprinted with permission: Thiele J, et al., Blood 2011, 117, 5710-5718

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0.2%0.8%

9.3%

2.3%

12.3%

16.9%

0.0%

5.0%

10.0%

15.0%

20.0%

5-year CI 10-year CI 15-year CI

ET

PMF

Incidence of MF

0.2%0.7%

2.1%1.5%

5.8%

11.7%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%


ET

PMF

Incidence of AML

Clinical Impact of WHO-Defined ET vs Early PMF

3.0%

14.8%

24.6%

8.6%

24.4%

56.1%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%


ET

PMF

Overall Survival

KEY AREA OF CONCERN IS REPRODUCIBILITY AND LOW DEGREEOF CONCORDANCE AMONG HEMATOPATHOLOGIST

N=1104

Barbui et al, J Clin Oncol. 2011 Aug 10;29(23):3179-84

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Diagnostic Criteria for Post-ET Myelofibrosis

Required criteria

• of previous diagnosis or ET as defined by WHO criteria• Grade 2 or 3 bone marrow fibrosis (0-3 scale) or grade 3 or 4 bone

marrow fibrosis (0-4 scale)

Additional criteria (2 required)

• Anemia and decrease of ≥2 mg/mL from baseline hemoglobin level• Leukoerythroblastosis• ≥5 cm increase in palpable splenomegaly or new splenomegaly• Increased serum LDH level• Development of ≥1 of 3 constitutional symptoms (low grade fevers,

weight loss, night sweating)

ET, essential thrombocy themia; LDH, lactate dehy drogenase

Barosi G, et al. Leukemia. 2008(2);22:437-438.

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Modern Natural History of ET435 patients followed for a median of 9.5 years

•Median survival 22.6 years•Survival same as controls•15-year leukemia risk = 2% •15-year myelofibrosis risk = 4%•15-year thrombosis risk = 17%•Leukemia risk not influenced byhydroxyurea

Reprinted with permission: Passamonti et al. Am J Med 2004; 117: 755-761

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Additional CV risk factors include:• Congestive heart failure• Smoking• Hyperlipidemia• Diabetes mellitus• Obesity

Essential Thrombocythemia Thrombosis Risk Stratification

Category Characteristics

Low risk Age < 60 years and no history of thrombosis

High risk Age ≥ 60 years or history of thrombosis

Risk Categories in PV

Platelet number is not a risk factor for thrombosis

Barbui T, et al. J Clin Oncol. 2011;29:761-70

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HR 95% CI

JAK2 mut 1.78 1.06-3.18

MPL mut 1.65 1.70-3.92

CALR mut 0.74 0.33-1.00

P= 0.008

1.0

0.8

0.6

0.4

0.2

0.0

0 100 200 300 400

Time (months)

Thro

mbo

sis

Free

-Sur

viva

l

Patients with CALR-mutated ET Have Lower Rate of Thrombosis

• The effect of the CALR mutation may be particularly evident in younger patients4

• Triple-negative (WT) patients may a lso have a low risk of thrombosis

HR-Hazard ratioN.B. Wild type patients were taken as a reference population

Thrombosis risk at 10 years1

CALR vs JAK2-V617F11% vs 21%

Reprinted with permission from Rotunno G, et al. Blood. 2014;123:1552-5.

JAK2

MPL+

WT CALR+

1. Klampfi T, et al. N Engl J Med. 2013;369:2379-90; 2. Reprinted with permission: Rotunno G, et al. Blood. 2014;123:1552-5; 3. Rumi E, et al. Blood. 2014;123:1544-51; 4. Gangat N, et al. Eur J Haemtol. 2015;94:31-6.

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21

IPSET-Thrombosis: A new Model to Better Predict Thrombosis in Patients with ET

• Age > 60: 1 point

• History of thrombosis: 2 points

• Cardiovascular Risk factors: 1 point

• Presence of JAK2 V617F: 2 points

Low Risk:< 2 points1% pt-yrs

Intermediate Risk:2 points

2.4% pt-yrs

High Risk:> 2 points

3.6% pt-yrs

NCCN guidelines for management of ET are coming!!!!

Barbui T, et al. Blood. 2012;120:5128-33.

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Current Treatment Continuum in ET

On Drug Treatment70%

No Active Treatment30%

Current ET patients

Hydroxyurea~75-95% of treated

1st-Line

~25% of HU patients have suboptimal response/do not tolerate HU

Anagrelide Ruxolitinib?Interferon/

Peg-Interferon

2nd-Line

Alkylating Agent Other or no Rx

Interferon/Peg-Interferon~5-25% of treated

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Key Issues in ET Management

• Normalization of platelet count (cytoreduction) to decrease thrombotic risk in high-risk patients

– Stroke and heart attack are the main concerns

• Correction of other CV risk factors

– Weight reduction, blood pressure control, glucose control in diabetic patients, smoking cessation

• Improvement in disease-related symptoms

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ET (N=775)

PV (N=654)

MF (N=423)

Q1 – 30% Q2 – 26% Q3 – 24% Q4 – 20%

Q1 – 17% Q2 – 21% Q3 – 26% Q4 – 36%

Q1 – 25% Q2 – 23% Q3 – 26% Q4 – 26%

Parameter P value of Comparison

Age 0.24

Gender F>M <0.001

MPN Diagnosis <0.001

Subtype of MF 0.86

IPSET (ET Risk) 0.18

PV Risk (PV) 0.30

DIPSS (MF Risk) <0.001

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• ET Patients (N = 843)

Current ET Therapies Seem to Have Minimal Impact on Symptom Burden

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5 Current HU HU Control

Current Anagrelide Anagrelide Control

Geyer HL, et al. Presented at ASH 2015. December 5-8, 2015. Orlando, Florida. Abstract 4080.

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Pegylated Interferon-α2a is an Acceptable Alternative to HU in ET

Phase II studies in ET and PV: Treatment with PEG-IFN- α2a resulted in high rates of complete hematologic and molecular response, and low rates of thrombosis. 1,2

*Complete response included absence of thrombosis

IFN α2a (n=39)1*

76

5

19

0

20

40

60

80

100

ET

Pro

po

rtio

n o

f Re

spo

nde

rs (%

)

Complete

Partial

No response

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

23 20.416.4 15.5

1314.7

1210 11.6

5.6

20.3

% J

AK

V6

17

FM

uta

nt

All

ele

Time (months)

Essential thrombocythemia2

No. Patients 18 13 14 13 13 13 10 9 7 4 3

1. Reprinted with permission: Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24; 2. Reprinted with permission: Quintas-Cardama A et al. Blood 2013;122:893-901.

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Interim Analysis of the Myeloproliferative Disorders Research Consortium (MPD-RC) 112

Global Phase III Trial of Front Line Pegylated Interferon Alpha-2a vs. Hydroxyurea in High Risk

Polycythemia Vera and Essential Thrombocythemia

(NCT01258856)

ASH 2016

Abstract 479

Mascarenhas JO, et al. Presented at ASH 2015. December 3-6, 2016. San Diego, CA. Abstract 479.

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Overall Response Rates at 12 Months by Treatment Arm

HU

(n = 39)

PEG

(n = 36)

P

value

PR

n (%)

CR

n (%)

ORR

n (%)

PR

n (%)

CR

n (%)

ORR

n (%)

Entire cohort

(n=75)

14

(36)

13

(33)

27

(69)

19

(53)

10

(28)

29

(81)

.6*

ET

(n=31)

4/16

(25)

7/16

(44)

11/16

(69)

6/15

(40)

6/15

(40)

12/15

(80)

.8

PV

(n=44)

10/23

(44)

6/23

(26)

16/23

(70)

13/21

(62)

4/21

(19)

17/21

(81)

.6

*CR comparison based on z-test; did not cross stopping boundary

PR, partial response; ORR, overall response rate

Mascarenhas JO, et al. Presented at ASH 2015. December 3-6, 2016. San Diego, CA. Abstract 479.

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Number of Patients With Any Grade Adverse Events (AEs) Regardless of Attribution Occurring in ≥15% of

Patients in Either ArmAdverse event HU (n =

36)

PEG (n = 36) P value*

Abdominal pain 2 (6%) 7 (19%) .07Anemia 6 (17%) 7 (19%) .76Depression - 10 (28%) <.001Diarrhea 5 (14%) 7 (19%) .53Dyspnea 1 (3%) 7 (19%) .02Fatigue 10 (28%) 18 (50%) .05Flu-like symptoms 1 (3%) 12 (33%) <.001Headache 4 (11%) 7 (19%) .33Injection site reaction - 9 (25%) .001

Leukopenia 3 (8%) 8 (22%) .10Nausea 7 (19%) 7 (19%) .99Pain 9 (25%) 11 (31%) .60Pruritus 3 (8%) 10 (28%) .03Thrombocytopenia 7 (19%) 6 (17%) .76Overall (grade 1+) 32 (89%) 36 (100%) .04Overall (grade 3+) 5 (14%) 17 (47%) .002

*Based on z-test for all AEsMascarenhas JO, et al. Presented at ASH 2015. December 3-6, 2016. San Diego, CA. Abstract 479.

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The Implication of HU-resistance in ET

166 ET patients with a median follow-up of 4.5 yrs

• Resistance to HU was associated with a 6.2 fold increase in the risk of death

• Death occurred in 11/15 patients with HU-resistant ET and in 27/151 with non-resistant ET

• 10-year survival probability was 26% in HU-resistant ET and 79% in non-resistant ET

ern nde oluda et al 2 1 52 1–

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Long-Term Results from a Phase II Open-Label Study of Ruxolitinib in Patients

with Essential ThrombocythemiaRefractory to or Intolerant of

Hydroxyurea

A 1

Abstract 1

Verstovsek et al. Presented at ASH 2014. December 6–9, 2014; San Francisco, CA. Abstract 1847

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Overview of Academic ET Trials with Ruxolitinib

PI Trial Phase ET Population Sample size

Prof C. HarrisonUK

MAJICII

Ruxolitinib vs BAT

High Risk ETResistant/intolerant

to HUN=116

Prof. S. KoschmiederGermany

RuxoBEATIII (IIb)

Ruxolitinib vs BAT 1:1High Risk ET N=190

Prof. S. GiraudierFrance

RuxBETAIII (IIb)

Ruxolitinib vs BAT (Anagrelide or

Interferon/Peg Interferon) 1:1

High risk ET Resistant/Intolerant

to HU

N=280

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Systemic Therapy for ET

• In low-risk asymptomatic ET, observation is appropriate– Daily low-dose aspirin is standard practice for most patients, if not

contraindicated*• Due to high risk of bleeding in patients with platelet counts

>1500 x 109/L, cytoreduction may be considered prior to aspirin initiation

• High-risk ET– Cytoreductive therapy

• Hydroxyurea (HU) is the first-line treatment of choice• Anagrelide is generally considered 2nd-line therapy if

resistant or intolerant to HU• IFN-alpha is used for young patients, pregnant women, or

patients who are refractory/intolerant to HU• Consider clinical trials for patients who are intolerant to or

have progressed on all 3 agents

*Aspirin is not univ ersally recommended - ty pically for those with JAK2 positiv e ET, CV risk f actors, or

microv ascular sy mptoms.

Gowin K, Mesa R. F1000Res 2014;3:227-237.

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