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MYELOFIBROSISMYELOFIBROSIS THE ITALIAN EXPERIENCE
Giovanni Barosi IRCCS Policlinico S. Matteo. Pavia. Italy
Angers, 1-3 October 2004
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Myelofibrosis in the eightiesMyelofibrosis in the eighties
• A poorly characterized biological syndrome
• Heterogeneity of clinical presentations
• No effective therapies• No effective therapies
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Erythrokinetic Classification of Myelofibrosis (G. Barosi et al, BJH 1981, 26 cases from our(G. Barosi et al, BJH 1981, 26 cases from our
Institution)Class I (42%)( )• Highly expanded erythropoiesis• Centrifugal active marrow displacement• Red cell mass normal or increasedRed cell mass normal or increased• Ineffective erythropoiesis
l ( )Class II (46%)• Slightly increased erythropoiesis• Axial erythropoiesis• Red cell mass normal or decreased• Peripheral hemolysis
Class III (12%)• Erythroid failure• Decreased red cell volume• Decreased red cell volume
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Prognostic Classification of Myelofibrosis (GPrognostic Classification of Myelofibrosis (G. Barosi et al, BJH 1988; 137 cases from our
Institution))
137Age >45
31 106Hb <13
IMC>24%
Hb <13
87IMC>24%
87
27 4 19 46 41
Low Intermediate High
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Anatomo-clinical Classification of Myelofibrosisy
Hyperplastic type (20%)yp p yp ( )• Young age (<50)• High expansion of erythropoiesis• Mild or no anemiaMild or no anemia• Possibly post-polycythemia• Good prognosis
Dysplastic type (50%)• Megacaryocytic dysplasia• Mild anemia• Mild anemia• Intermediate prognosis
Aplastic type (30%)Aplastic type (30%)• Erythroid failure• Severe anemia• Bad prognosis• Bad prognosis
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Myelofibrosis: a difficult disease for research
•The disease is rare
•The cases are dispersed•The cases are dispersed
•The disease is undefined
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The Italian Consensus Conference for the Diagnostic Criteria of MMM (Barosi et al. BJH, 1998)Diagnostic Criteria of MMM (Barosi et al. BJH, 1998)
NECESSARY CRITERIAA. Diffuse bone marrow fibrosis
OPTIONAL CRITERIA
B. Absence of Philadelphia chromosome or BCR-ABL rearrangement in peripheral blood cells
OPTIONAL CRITERIA1. Splenomegaly of any grade2. Anisopoikilocytosis with tear-drop erythrocytes3. Presence of circulating immature myeloid cells4. Presence of circulating erythroblasts5. Presence of clusters of megakaryoblasts and anomalous g y
megakaryocytes in bone marrow sections6. Myeloid metaplasia
DIAGNOSIS OF MMM IS ACCEPTABLE IF THE FOLLOWING COMBINATIONS ARE PRESENTThe two necessary criteria plus any other two optional criteria when splenomegaly is present, or plus any other four when splenomegaly is absent
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RIMM- An Italian Research Registry forRIMM An Italian Research Registry for Myelofibrosis with Myeloid Metaplasia
(1999-…..)
A permanent organizational structure that maintains a data file for patients who have a specific disease collected within a geographical region with different research objectives
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RIMM-Objectives
• Nationwide epidemiology of the disease di i h d di d di i i i
RIMM-Objectives
according with standardized diagnostic criteria
• Process of care of patients with MMM in Italy• Process of care of patients with MMM in Italy
• Population-based natural history of the diseasep y
• Population-based outcome of the disease
• New treatment approaches (population-adjusted clinical trials)adjusted clinical trials)
• Biology of the disease gy
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RIMM – The Model
DATA
AGENTS
APPLICATIONS
AGENTS
POLICIES
COMMUNICATION INFRASTRUCTURE
POLICIES
COMMUNICATION INFRASTRUCTURE
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1 i i i i f (I
RIMM – The Model
1st tier: communication infrastructure (Internet-based applications, prepaid transport and mailing services);
2nd tier: collaborative policies (ownership, liability, intellectual property, confidentiality, security);p p y, y, y);
3rd tier: agents (coordinating team and participants);
4th tier: applications (research programs and clinical trials implemented in the registry);
5th tier: data (a web-accessible data base for data of all consecutive cases of MMM).
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RIMM- Expected-Observed New Cases
• Based on the incidence rates reported in the literature, we expected from 175 to 800 new cases per yearwe expected from 175 to 800 new cases per year
• 1005 patients were registered from June 1999 to September 2004
h f ll f d d– 954 with fully verified diagnostic criteria– 51 without the criteria
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MMM- Age at diagnosis
35%
40%
20%
25%
30%
10%
15%
20%
0%
5%
<45 45-55 55-65 65-75 75-85 >85<45 45-55 55-65 65-75 75-85 >85
Age, years
Range = 25-96 yrRange = 25-96 yrMedian = 72 yrMean = 70 yr
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RIMM- Characteristics of the Patients
From From internistsFrom hematologists
From internists
Median age 69 76Median age (yrs)
69 76
Previous PV/TE 15% 18%Previous PV/TE 15% 18%
Spleen > 10 cm f th CM
19% 25%from the CMLeukocytosis (>30)
6% 11%(>30)Severe anemia (Hb < 10g/dL)
14% 21%(Hb < 10g/dL)
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Performance of Italian Diagnostic CriteriaPerformance of Italian Diagnostic Criteria475 Reported cases (Italian Registry of MMM)
461
Not fulfilling the Italian diagnostic criteria
Fulfilling the Italian diagnostic criteria 14 (2 9%)461criteria 14 (2.9%)
Ad hoc Committee
Alternative diagnosis Confirmed MMM (false
4 10 (2.1%)
Alternative diagnosisAtypical CML Mixed myeloproliferative myelodysplastic syndrome
Confirmed MMM (false negative)
MDS with bone marrow fibrosis
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Georgii/Thiele Vision of MyelofibrosisGeorgii/Thiele Vision of Myelofibrosis
MyelofibrosisMyelofibrosis
Initial prefibrotic stage of the disease: Chronic MegakaryocyticMegakaryocytic-Granulocytic Myelosis
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Di ti C it i f MMM C l iDiagnostic Criteria for MMM - Conclusion
• The nominalistic approach to the ppdiagnosis is not able today to identify all cases of MMM
• Need of revision of diagnostic criteria
• Need of a better disease stratification• Need of a better disease stratification
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St i MMMStaging MMM
- To stratify the disease according to survival
- To stratify the disease according toTo stratify the disease according to intermediate outcomes (provide a correspondence between treatment requirements and available therapeutic resources)and available therapeutic resources)
- To identify unusual disease presentationsthat may prove to be clinically relevanty p y
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L i l f ti t ithLearning sample of patients with Idiopathic Myelofibrosis
• 100 consecutive patients with IMF (post-ET and100 consecutive patients with IMF (post ET and post-PV excluded) followed at IRCCS Policlinico S. Matteo in Pavia and diagnosed from 1980 to 2000
• M/F =63/37
• Median age = 61.5 yrs (range 16-81 yrs)
• Median follow-up = 48 months (range 16-268 months)
S l i d 123 (12%)• Splenectomized = 123 (12%)
• Dead = 24 (24%)
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Outcome Prediction of Hb >12 g/dL (at Diagnosis)-RIMM cases
1 0 1 0
ANEMIA SPLENOMEGALY
0 7
0,8
0,9
1,0
/=10
g/d
L Log rank test P=0.002
0,7
0,8
0,9
1,0
<10
cm
fro
m Log rank test= NS
0 4
0,5
0,6
0,7
on w
ith
Hb
>/
Hb>=12 g/dL
0,4
0,5
0,6
n w
ith
spl
een
<LC
M
Hb>=12 g/dL
0,1
0,2
0,3
0,4
Pro
port
io
Hb< 12 g/dL
0 50 100 150 200 250 3000,0
0,1
0,2
0,3
Pro
port
ion
Hb< 12 g/dL
0 50 100 150 200 250 300
Time from diagnosis (months)
0,1 0 50 100 150 200 250 300
Time from diagnosis (months)
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Outcome Prediction of WBC >10x109/L (at Diagnosis)(at Diagnosis)
ANEMIA SPLENOMEGALY
0,7
0,8
0,9
1,0
10 c
m f
rom
0 8
0,9
1,0
10 g
/dL Log rank test =
NS
Log rank test P=0.003
0,4
0,5
0,6
,
th S
plee
n <
1LC
M
0,6
0,7
0,8
n w
ith
Hb
> 1
WBC <10x109/L
0,0
0,1
0,2
0,3
Pro
port
ion
wit
0,4
0,5
Pro
port
io
WBC <10x109/L
WBC > 10 109/LWBC >=10x109/L
0 50 100 150 200 250 300
Time from diagnosis (months)
-0,1
0,0P0 50 100 150 200 250 300
Time from diagnosis (months)
0,3WBC >=10x109/L
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Outcome Prediction of Spleen Volume (at Diagnosis)
1 0
ANEMIA SPLENOMEGALY
0,8
0,9
1,0
>10
g/d
L
Log rank test P=0.009
0,7
0,8
0,9
1,0
> 1
0 cm
fro
m Log rank test P=0.0002
Spleen grade 0-1
0,5
0,6
0,7
ion
wit
h H
b >
0 3
0,4
0,5
0,6
ith
a sp
leen
>LC
M
Spleen grade 0-1Spleen grade 0 1
0,3
0,4
Pro
port
i
0,0
0,1
0,2
0,3
Pro
port
ion
wi
Spleen grade 2-4Spleen grade 2-4
0 50 100 150 200 250 300
Time from diagnosis (months)
0,20 50 100 150 200 250 300
Time from diagnosis (months)
-0,1
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Outcome Prediction of Bone Marrow Fibrosis (at Diagnosis)
ANEMIA SPLENOMEGALY
1,0
cm
Log rank test P=0.009
0,9
1,0
L
Log rank test P=0.002
0,6
0,8
a sp
leen
<10
LC
M
0,6
0,7
0,8
,
h H
b >
10 g
/dL
BM fibrosis absent or modest
0,2
0,4
port
ion
wit
h a
from
0,3
0,4
0,5
,
ropo
rtio
n w
ith
BM fibrosis absent or modest
BM fibrosis intense BM fib i
0 50 100 150 200 250 300
Time from diagnosis (months)
0,0Pro
p
0 50 100 150 200 250 300
Time from diagnosis (months)
0,1
0,2
Pr intense BM fibrosis
intense
g ( )
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Outcome Prediction of CD34+ Cells >20 x106/L (at Diagnosis)(at Diagnosis)
ANEMIA SPLENOMEGALY
0,8
0,9
1,0
cm f
rom
th
e
Log rank test P=<0.05
0 7
0,8
0,9
1,0
0 g/
dL
CD34+ <20x106/L
Log rank test P=<0.04
0,5
0,6
0,7
a Sp
leen
<10
LC
M
0,4
0,5
0,6
0,7
n w
ith
Hb
>10
/
0,2
0,3
0,4
opor
tion
wit
h a
CD34+ <20x106/L
CD34+ >20x106/L0 0
0,1
0,2
0,3
Pro
port
ion
CD34+ >20x106/L
0 50 100 150 200 250 300
Time from diagnosis (months)
0,1Pro
0 50 100 150 200 250 300
Time from diagnosis (months)
-0,1
0,0
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OUTCOME PREDICTION IN MMMOUTCOME PREDICTION IN MMM
• Hb, spleen volume, bone marrow fibrosis and CD34+ cells at diagnosis predict the development of anemiadevelopment of anemia
• WBC, spleen volume, CD34+ cells and bone marrow fibrosis at diagnosis predict the g pdevelopment of splenomegaly
• They may be used for staging the disease
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Multivariate Prediction (by Regression CoxMultivariate Prediction (by Regression Cox Model)
• Hb >12 g/dL, and
• WBC <10 x109/l and >5 x109/L, and
• CD34+ cells in peripheral blood <20 x109/L
yes no
Neither development of anemia nor splenomegaly
Development of anemia or splenomegaly p g y
(Early stage IMF)p g y
(Advanced stages of IMF)
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Predictive Power of Early Stage IMF
0,9
1,0
L
1,0
m f
romEarly Stage IMF Early Stage IMF
ANEMIA SPLENOMEGALY
0 5
0,6
0,7
0,8
0,9
wit
h H
b >
10 g
/dL
0,4
0,6
0,8
h sp
leen
< 1
0 cm
LCM
0,2
0,3
0,4
0,5
Pro
port
ion
w
0,0
0,2
,
Pro
port
ion
wit
h
Advanced stages IMFAdvanced stages IMF
0 50 100 150 200 250 300
Time from diagnosis (months)
0,10 50 100 150 200 250
Time from diagnosis (months)
1,0
g
E l S IMF
0,6
0,7
0,8
0,9
port
ion
Surv
ivin
SURVIVAL
Early Stage IMF
0,2
0,3
0,4
0,5
Cum
ulat
ive
ProSURVIVAL
Advanced stages IMF
0 50 100 150 200 250 300
Time from diagnosis (months)
0,1
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Early Stage IMF Advanced stages (Indolent Myelofibrosis)
• N= 13 (13%)
IMF• N= 87 (87%)
• Age = 34.5 years (16-72)• M/F = 8/5
S l l b t 3/13
• Age = 65 years (19-81)• M/F = 58/29
S l l b t 10/87• Splenomegaly absent = 3/13 (23%)• Hb = 13.4 (12-16,4)
• Splenomegaly absent = 10/87 (11.4%)• Hb = 12 (6.2-18)
• WBC = 7.5 (5.2-10)• Ptl count = 465 x109/L (255-1 100)
• WBC = 9.1 (2.1-35)• Ptl count = 327 x109/L (43-1 196)1,100)
• Bone marrow fibrosis absent = 2/13 (15.3%)
1,196)-• Bone marrow fibrosis absent = 3/87 (3.4%)
• LDH = 679 (336-1146)• CD34=11.4 (range 2.7-20)
• LDH = 784 (191-2455)• CD34=26.4 (range 1.2-375)
• Splanchnic vein thrombosis at diagnosis =4/13 (31%)
• Splanchnic vein thrombosis at diagnosis = 2/87 (2.3%)
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Early Stage IMF (Indolent Myelofibrosis): Possibly Corresponding
Syndromes
An atypical myeloproliferative disorder ith hi h th b ti i k d l di
Syndromes
with high thrombotic risk and slow disease progression (Barosi et al, Cancer, 1991)
• Young age
• No myeloproliferative evolution
• High tendency to develop thrombosis in atypical itsites
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Early Stage IMF (Indolent Myelofibrosis): Possibly Corresponding
Syndromes
Formes frustes in myeloproliferative di d (R id t l L t 1982)
Syndromes
disorders (Reid et al, Lancet, 1982)
• Peripheral vascular disease
l h l l d l l• Slightly elevated platelet count
• Endogenous erythroid colonies
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Early Stage of IdiopathicEarly Stage of Idiopathic Myelofibrosis
• An early stage of IMF exists
• This has been probably overlooked (misdiagnosis, no symptoms)
• It does not completely correspond to the “prefibrotic” picture of the disease
In some case it takes the form of a very indolent• In some case it takes the form of a very indolent disease (more than 10 years without evolution)
• Diagnostic criteria?Diagnostic criteria?
• Biology?
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Angiogenesis in MMM
• Marrow vascularity in patients with MMM is substantially increased compared with normals andsubstantially increased compared with normals and patients with PV and ET
Visual MVD grade
MMM (N=114)
Normals (N= 44)
PV (N=15)
ET (N=17)
g
1 (Normal)
1.8% 77.3% 26.7% 23.5%
2 28% 22.7% 40% 64.7%
3 37.7% 0% 33% 12%
4 32.5% 0% 0% 0%
Mesa et al, Blood 2000;96:3374
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Angiogenesis in MMM
• Capillary microvessel density in the spleen of patients with MMM correlates with spleen size
200000
ity
rea
120000
160000
ar d
ensi
copi
c a
80000
120000
vasc
ula
/mic
rosc
40000
apill
ary
vic
ron2 )/
300 400 500 600 700 800 900
2
0
Ca
(mi
Barosi et al. BJH Spleen index (cm 2) 2004
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Angiogenesis in MMM
• Capillary microvessel density of the spleen of patients with MMM correlates with the extent of
180000
amyeloid metaplasia
140000
dens
ityop
ic a
rea
100000scul
ar d
icro
sco
60000llary
vas
on2 )/m
i
20000
Cap
il(m
icr
Barosi et al. BJH 0 2 4 6 8 10 12 14 16
Spleen CD34+ Cells (%)2004
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Pro-angiogenic Factors inPro-angiogenic Factors in Myelofibrosis
• Elevated expression of plasma and BM• Elevated expression of plasma and BM VEFG, b-FGF and TGF-β is consistently documented in MMMdocumented in MMM
• Poor evidence of their pathogenetic role in angiogenesis of MMMangiogenesis of MMM
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Angiogenesis – cellularAngiogenesis – cellular mechanism
• During development, new vessels are formed by differentiation of progenitor cells (endothelialby differentiation of progenitor cells (endothelial progenitor cells or angioblasts)
• In adult life endothelial progenitor cells• In adult life, endothelial progenitor cells circulate in normal subjects and are increased in patients with vascular injury (trauma, myocardial p j y ( , yinfarction, angina..)
• In some tumors mature endothelial cells may• In some tumors, mature endothelial cells may bear the same cytogenetic aberration of hematopoietic progenitor cells (CML, lymphoma)
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Endothelial Progenitor Cells (EPC) in Myelofibrosis
• The phenotypically characterized circulating EPC• The phenotypically characterized circulating EPC are consistently elevated in a significant proportion of MMM patients p p p
40︵%
︶
25
30
35
R-2
+ C
ells
10
15
20
33+V
EG
FR
Rosti ASH 20030
5
10
0 1 2 3 4D34
+C
D13
MMM Ph1-CMPDs Normals0 1 2 3 4C
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120Endothelial Progenitor Cells
100
120
Analysis of chromosomal
(EPC) in Myelofibrosis
80
100aberration documents that CFU-End of patients with MMM derive from a l l ll
60
clonal progenitor cell
40
20
0
MMM Ph1-CMPDs Normals
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Endothelial Progenitor Cells (EPC) in Myelofibrosis - Conclusions
• Increased number of EPCs (immunophenotype and endothelial cell colture) is a distinctiveand endothelial cell colture) is a distinctive characteristic of MMM
• Circulating EPCs belong to the malignant clone• Circulating EPCs belong to the malignant clone
• New mechanisms for angiogenesis may be hypothesizedhypothesized