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