ET vs. Prefibrotic myelofibrosis: Why does it matter

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ET vs. Prefibrotic myelofibrosis Why does it
matter

• 
  
• 
  Tiziano BARBUI,MD
• Hematology and Research Foundation,
  Papa Giovanni XXIII Hospital
• Bergamo, Italy
• European Focus on Myeloproliferative Neoplasms
  and Myelodysplastic Syndromes
  5-7 April 2013, Madrid, Spain

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WHO Classification
Distinguishing ET from PMF
ET

3

• Three important components to the process of
  developing classification of Hema Malignancies
• First, use morphology, immunophenotype, genetic
  features, and clinical features to define
  diseases.
• Second principle is that classification relies on
  building a consensus among as many experts as
  possible on the definition and nomenclature of
  the disease.
• Third, while pathologists must take primary
  responsibility for developing a primary
  classification, involvement of clinicians is
  essential to ensure its usefulness and acceptance
  in daily practice.

4
Morphology in true ET and in prefibrotic
myelofibrosis
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ET and early PMF
different biology?

• The molecular mechanisms underlying the
  development of histological features such as
  megakaryocyte clustering, are unclear.
• The cellularity factor, correlates with whether
  the patient has the JAK2 V617 mutation (Wilkins
  et al Blood 200811160-70)
• JAK2V617F allele burden discriminates ET from
  early PMF (Hussein K et al.,Exp.Hematology
  37,1186,2009)
• About the molecular regulation of megakaryocyte
  location and clustering, it may be relevant that
  megakaryocyte clusters are observed in mice
  treated with SDF-1, the ligand for the CXCR4
  receptor. (Avecill et al. Nat Med. 20041064-71)
• Patients with pre-fibrotic PMF have a pattern of
  proplatelet formation similar to fibrotic PMF and
  different from that of true ET (Balduini
  A,PLoSOne, 2011)

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Different presentation and outcomes?
Seven international centers Inclusion criteria
local ET diagnosis (from 1975 to 2008) and
pre-treatment Bone Marrow biopsy obtained at time
of diagnosis (or within 1 year of diagnosis in
untreated patients)
1,104 ET patients WHO 2008 review by WHO author
(JT) completely blinded to outcome data
Barbui et al, J Clin Oncol. 2011 Aug
1029(23)3179-84
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Main characteristics at diagnosis
ET (n891) PMF (n180) P value
Age, years, median (range) 56 (13-91) 57 (21-88) 0.66
Male/Female 370/521 74/106 0.92
Follow-up, years 6.2 (0-27) 7.0 (0-27.2) 0.30
WBC, x 109/L, median (range) 8.6 (2.5-53.4) 9.7 (4.8-24.2) lt 0.001
Hb, g/dL, median (range) 14.1 (6.9-18.0) 13.8 (6.9-16.7) 0.01
PLT, x 109/L, median (range) 774 (291-3920) 902 (462-3401) 0.002
LDH (n519), mU/mL median (range) 298 (113-1070) 429 (70-1517) lt 0.001
CD34 (N246) /mcL, median (range) 2 (0-15.2) 4.7 (0-60) 0.03
JAK2 (V617F)-pos (n805) 422 (61) 67 (58) 0.56
Fibrosis (n968) 23 (3) 38 (22) lt 0.001
Splenomegaly 146 (16) 41 (23) 0.04
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Disease complications during follow-up WHO ET
6.2 yrs (range 0-27) WHO early prefibrotic PMF
7 yrs (range 0-27)
Events
Thrombosis
Myelofibrosis
Acute leukemia
Survival
Barbui et al, JCO 2011
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Thrombosis-free survival
Barbui et al, JCO 2011
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Does it matter to predict hematologic
transformations?
Survival, Leukemic Transformation and Fibrotic
Progression in Essential Thrombocythemia are
significantly influenced by Accurate Morphologic
Diagnosis
OS
Barbui et al, J Clin Oncol. 2011 Aug
1029(23)3179-84
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EUROSTAT 2008 (crude death rates, all causes of
death, EU 27 countries)
Barbui et al, JCO 2011
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Survival in patients categorized by
different stages of primary myelofibrosis
Barosi et al, PlosOne 2012,7,4.
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• Three important components to the process of
  developing classification of Hema Malignancies
• First, recognising that the underlying causes of
  the neoplasm are often unknown and may vary. So,
  we use morphology, immunophenotype, genetic
  features, and clinical features to define
  diseases.
• Second principle is that classification relies on
  building a consensus among as many experts as
  possible on the definition and nomenclature of
  the disease.
• Third, while pathologists must take primary
  responsibility for developing a primary
  classification, involvement of clinicians is
  essential to ensure its usefulness and acceptance
  in daily practice.

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• Criticism to histopathology in early stage PMF
  and ET
• Poor reproducibility and debate on the
  nomenclature
• Morphological criteria are impaired by
  subjectivity their value in predicting clinical
  outcome is not yet consistently proven
• In pathology, the typing and subtyping of most
  diseases should have a high degree of
  interobserver reliability and may be inadequate
  for routine clinical use
• Classifications which cannot guarantee this
  reliability must be reconsidered.

Wilkins et al., Blood 2008 Brousseau et al
Histopathology 2010 Buhr et al, Haematologica
2012 Koopman et al,Am J Clin Pathol. 2011
15

• Three important components to the process of
  developing classification of Hema Malignancies
• First, recognising that the underlying causes of
  the neoplasm are often unknown and may vary. So,
  we use morphology, immunophenotype, genetic
  features, and clinical features to define
  diseases.
• Second principle is that classification relies on
  building a consensus among as many experts as
  possible on the definition and nomenclature of
  the disease.
• Third, while pathologists must take primary
  responsibility for developing a primary
  classification, involvement of clinicians is
  essential to ensure its usefulness and acceptance
  in daily practice.

16
Risk factors for thrombosis in ET (PVSG
diagnosis) Cox Multivariable Analysis
HB
HCT
PLT
WBC
Reference categories Bergamo centre Females
Low risk factors HB lt 13 g/dL HCT lt 39.5 PLT
lt 650 (x109/L) WBC lt7.2 (x109/L) Absence of
JAK2V617F
Carobbio A et al., Blood 2007 JCO 2008 Barbui T
et al,Blood 20010
Carobbio et al, JCO 2008 Carobbio et al, Blodd
2008, Barbui et al, Blood 2009
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PT-1 randomized clinical
trial in high risk ET (Hydroxyureaasa ) WCC
major hemorrhage p0.01WCC
thrombosis p0.05Plts major
hemorrhage p 0.0005Plts thrombosis
p 0.4 (not significant)
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RISK FACTORS FOR THROMBOSIS in WHO-ET (n891)
(inception cohort)
Risk factor HR scores Age gt
60 1.50 1 CV risk
factors 1.56 1 Previous
thrombosis 1.93 2 JAK2 V617F
2.04 2
Multivariate model adjusted for sex,
hemoglobin ,leukocyte and platelet counts,
Hydroxyurea and aspirin use.
Score 0 low-risk Score 1-2
intermediate risk Score gt 3 high
risk
Barbui et al, J Clin Oncol. 2011 Aug
1029(23)3179-84 Barbui et al,Blood
2012. Carobbio et al, Blood. 2011 Jun
2117(22)5857-9. Epub 2011 Apr 13.
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The IPSET thrombosis model in WHO-ET
Barbui et al, Blood 2012
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Early prefibrotic PMF Multivariate analysis
(metric variables) for risk factors predicting
fatal and nonfatal thrombotic events in the
follow-up of 264 patients
Major thrombosis
AT DVT
HR (95 CI) p HR (95
CI) p HR (95 CI) p Female
gender 1.0 (0.48-2.19) 0.94 1.7
(0.69-4.21) 0.25 0.3 (0.07-1.42)
0.13 Age 1.0
(0.99-1.05) 0.20 1.0 (0.99-1.06) 0.11
1.0 (0.91-1.03) 0.28 Prev. thrombosis
1.8 (0.79-4.20) 0.16 1.6 (0.66-4.05)
0.29 1.9 (0.28-12.8) 0.51 Hb (higher)
0.9 (0.69-1.09) 0.22 1.0
(0.78-1.32) 0.9 0.6 (0.40-0.86)
0.01 Plt count (higher) 1.0 (1.00-1.00)
0.06 1.0 (0.99-1.00) 0.04 1.0
(1.00-1.00) 0.15 WBC (higher)
1.2 (1.04-1.26) 0.01 1.1 (1.00-1.25)
0.047 1.2 (0.97-1.40) 0.09 JAK2 V617F
1.5 (0.52-4.12) 0.46 2.0
(0.60-6.97) 0.25 0.9 (0.16-5.06)
0.89 CV risk factors 0.6
(0.23-1.54) 0.28 0.7 (0.25-1.91) 0.47
1.1 (0.20-6.27) 0.91
Buxhofer et al., AJH ,2012
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Hazard ratio (HR) for disease complications in
patients treated with Anagrelide ( asa) vs
Hydroxyurea (asa) in PT1 trial
Bone marrow in PT1 trial
Fiber grade 0-1 135
Fiber grade 2 146
Fiber grade 3-4 80
Venous thromboembolism occurred less frequently
in Anagrelide group (HR 0.27)
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ANAHYDRET-Study vs. PT1-Trial Difference in the
patient cohorts may explain the difference in
study-results
ANAHYDRET-Study PT1-Trial
PVSG-ET e.g. prefibrotic PMF and PMF1
true-ET
Gisslinger et al, Blood 2013 Harrison et al,
NEJM 1995
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Bleeding is more frequent in early PMF and
suggests caution on the use of aspirin in
primary prophylaxis of thrombosis
ET (n891) PMF (n180) P value
Aspirin () 602 (68) 131 (73) 0.20
Bleeding in the follow-up, n () 55 (6) 21 (12) 0.009
Rate of bleeding ( pts/year) 0.79 1.39
Incidence Rate Ratio 1 (ref.) 1.76 0.039
Finazzi G, et al, Leukemia 2011
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Multivariate analysis of risk factors for bleeding
HR (95 CI) p-value
early/prefibrotic PMF 1.74 (1.00-3.06) 0.050
WBC 11 x109/L 1.74 (1.02-2.97) 0.041
Previous bleeding 2.35 (1.11-4.98) 0.025
Aspirin use 3.16 (1.63-6.08) 0.001
Finazzi et al,Leukemia 2011
25
PT-1 randomized clinical
trial in high risk ET (Hydroxyureaasa ) WCC
major hemorrhage p0.01WCC
thrombosis p0.05Plts major
hemorrhage p 0.0005Plts thrombosis
p 0.4 (not significant)
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WHO-ET vs. EARLY- PMF
Way does this distinction matter

• Different clinico-hematological presentation
• Different overall survival
• Different myelofibrosis-free survival
• Different leukemia-free survival
• No difference in thrombosis-free survival,
• but different risk factors for total
  thrombosis
• Different risk of bleeding
• There is a difference in the risk for thrombosis
  and bleeding

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• CONCLUSION The limited reproducibility of this
  distinction precludes its use in clinical
  practice
• Proposed solution a scientific project,
  including the pathologists and hematologists
• Aim
• to select a small set of robust diagnostic
  criteria
• to assess the reproducibility
• to evaluate the corresponding clinical outcomes

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ACKNOWLEDGEMENT