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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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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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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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%
5-year CI 10-year CI 15-year CI
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%
5-year CI 10-year CI 15-year CI
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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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
• 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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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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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Verstovsek et al. Presented at ASH 2014. December 6–9, 2014; San Francisco, CA. Abstract 1847
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Verstovsek et al. Presented at ASH 2014. December 6–9, 2014; San Francisco, CA. Abstract 1847
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Expert Update: What’s New in Essential Thrombocythemia
© 2017 Vindico Medical Education
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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