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
ET
WHO Classification
Distinguishing ET from PMF
“True ET” “Prefibrotic PMF”
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.
Morphology in «true ET» and in prefibrotic myelofibrosis
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 2008;111:60-70)
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. 2004;10:64-71)
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)
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
True ET PMF
Barbui et al, J Clin Oncol. 2011 Aug 10;29(23):3179-84
Main characteristics at diagnosisET (n=891) PMF (n=180) 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) < 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 (n=519), mU/mL median (range)
298 (113-1070) 429 (70-1517) < 0.001
CD34+ (N=246) /mcL, median (range)
2 (0-15.2) 4.7 (0-60) 0.03
JAK2 (V617F)-pos (n=805) 422 (61%) 67 (58%) 0.56
Fibrosis (n=968) 23 (3%) 38 (22%) < 0.001
Splenomegaly 146 (16%) 41 (23%) 0.04
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
Thrombosis-free survival
0.00
0.25
0.50
0.75
1.00
0 5 10 15 20Years from diagnosis
ET vs PMF
ETPMF
P-value = 0.69
Events 73 39 13 10At risk 585 278 129 45
Barbui et al, JCO 2011
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
OS
Barbui et al, J Clin Oncol. 2011 Aug 10;29(23):3179-84
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
Survival, Leukemic Transformation and Fibrotic Progression in Essential Thrombocythemia are significantly influenced by Accurate Morphologic Diagnosis
Does it matter to predict hematologic transformations?
ET and pre-fibrotic MF vs Europe*Age- and sex-adjusted actuarial survival curves
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Years
Su
rviv
al
Europe
ET
Pre-fibrotic MF
*EUROSTAT 2008 (crude death rates, all causes of death, EU 27 countries) Barbui et al, JCO 2011
Barosi et al, PlosOne 2012,7,4.
Survival in patients categorized by different stages of primary myelofibrosis
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.
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
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.
Risk factors for thrombosis in ET (PVSG diagnosis)Cox Multivariable Analysis
1,7 1,5 1,4
0,6 0,7 0,61,2
1,51,8
3,02,72,42,1
0,80,90,9
1,01,1
0
1
2
3
4
5
6
7
8
HR
* Reference categories: Bergamo centre; Females; Low risk factors; HB < 13 g/dL; HCT < 39.5 %; PLT < 650 (x109/L); WBC <7.2 (x109/L); Absence of JAK2V617F
HB HCT PLT WBC
Carobbio A et al., Blood 2007; JCO 2008 Barbui T et al,Blood 20010Carobbio et al, JCO 2008; Carobbio et al, Blodd 2008, Barbui et al, Blood 2009
PT-1 randomized clinical trial in high risk ET (Hydroxyurea+asa ) WCC & major hemorrhage p=0.01WCC & thrombosis p=0.05
Plts & major hemorrhage p =0.0005Plts & thrombosis p= 0.4 (not significant)
RISK FACTORS FOR THROMBOSIS in WHO-ET (n=891) (inception cohort)
Score: 0 low-risk Score: 1-2 intermediate risk Score => 3 high risk
Risk factor HR scores
Age > 60 1.50 1
CV risk factors 1.56 1
Previous thrombosis 1.93 2
JAK2 V617F 2.04 2
Barbui et al, J Clin Oncol. 2011 Aug 10;29(23):3179-84; Barbui et al,Blood 2012.Carobbio et al, Blood. 2011 Jun 2;117(22):5857-9. Epub 2011 Apr 13.
* Multivariate model adjusted for: sex, hemoglobin ,leukocyte and platelet counts, Hydroxyurea and aspirin use.
0.5
00
.60
0.7
00
.80
0.9
01
.00
0 5 10 15
.
N=535 PATIENTSTRAINING SET
LOW
INTERMEDIATE
HIGH
p=0.0001
Barbui et al, Blood 2012
The IPSET thrombosis model in WHO-ET
Buxhofer et al., AJH ,2012
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) pHR (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
Hazard ratio (HR) for disease complications in patients treated with Anagrelide (+ asa) vs Hydroxyurea (+asa) in PT1 trial
Venous thromboembolism occurred less frequently in Anagrelide group (HR 0.27)
Fiber grade 0-1 135
Fiber grade 2 146
Fiber grade 3-4 80
Bone marrow in PT1 trial
ANAHYDRET-Study vs. PT1-TrialDifference in the patient cohorts may explain the
difference in study-results
ET R
elated
Eve
nts F
ree S
urviv
al
Time [Months]
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Anagrelide
Hydroxy
1st Year 2nd Year 3rd Year
ANAHYDRET-Study PT1-Trial
PVSG-ET e.g. prefibrotic PMF and PMF1„true-ET“
Gisslinger et al, Blood 2013 Harrison et al, NEJM 1995
ET (n=891) PMF (n=180) 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
Bleeding is more frequent in early PMF and suggests caution on the use of aspirin in primary prophylaxis of
thrombosis
HR (95% CI)HR (95% CI) p-valuep-value
early/prefibrotic PMFearly/prefibrotic PMF 1.74 (1.00-3.06)1.74 (1.00-3.06) 0.0500.050
WBC ≥11 x10WBC ≥11 x1099/L/L 1.74 (1.02-2.97)1.74 (1.02-2.97) 0.0410.041
Previous bleedingPrevious bleeding 2.35 (1.11-4.98)2.35 (1.11-4.98) 0.0250.025
Aspirin useAspirin use 3.16 (1.63-6.08)3.16 (1.63-6.08) 0.0010.001
Multivariate analysis of risk factors for bleedingMultivariate analysis of risk factors for bleeding
Finazzi et al,Leukemia 2011Finazzi et al,Leukemia 2011
PT-1 randomized clinical trial in high risk ET (Hydroxyurea+asa ) WCC & major hemorrhage p=0.01WCC & thrombosis p=0.05
Plts & major hemorrhage p =0.0005Plts & thrombosis p= 0.4 (not significant)
Different clinico-hematological presentationDifferent overall survivalDifferent myelofibrosis-free survivalDifferent leukemia-free survivalNo difference in thrombosis-free survival,
but different risk factors for total thrombosisDifferent risk of bleeding
There is a difference in the risk for thrombosis and bleeding
WHO-ET vs. EARLY- PMF Way does this distinction matter
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
ACKNOWLEDGEMENT