Transcript Nuove acquisizioni nel campo della mielofibrosi primaria

Prognostication in MF: From CBC
to cytogenetics to molecular markers
Alessandro M. Vannucchi
University of Florence, Italy
Survival is Significantly Shortened in PMF
Whole series: actuarial survival (± 95% CI)
according to period of diagnosis
1.0
p < 0.0001
Probability
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12 14
Years
1980 - 1995
16
18
20
22
24
26
1996 - 2007
Median survival: 4.6 versus 6.5 y
Cervantes F et al. JCO 2012; 24:2891-7.
Why do we Need Accurate Prognostic Scores?
• Long term remissions with the potential of being cured have been
described only in patients undergoing allogeneic HSCT
• However, HSCT approach to MF has several limitations, currently:
Disease related
Procedure related
• Median age is 65 y (but
changing…)
• Donor availability
• Age-related comorbidities
• Only one prospective trial (+1 not
yet fully reported)
• Fragile patients (splenomegaly,
cytopenias, previous therapies…)
• High, and highly variable, TRM
• Rapid evolution to AML
• Choice of fully ablative versus RIC
• Uncertainties about whom and
when
• Poor information about long-term
effects
Risk Stratification in PMF
Variable
IPSS
DIPSS
Age >65 y


Constitutional symptoms


Hemoglobin <10 g/dL


Leukocyte count >25x109/L


Circulating blasts > 1%


Platelet count <100x109/L
RBC transfusion need
Unfavorable karyotype
+8,-7/7q-,i(17q),inv(3), -5/5q-,12p-, 11q23 rearr.
Cervantes et al, Blood 2009;113:2895-901
Passamonti et al, Blood 2010; 115:1703-8
Gangat N et al, J Clin Oncol 2011; 29:392-7
International Prognostic Scoring System-IPSS
Points
Median
survival
(mo)
Low
0
135
Int-1
1
95
Int-2
2
48
High
>3
27
Low
High
Int-2
Int-1
Cervantes F et al. Blood 2009;113:2895-901
Impact of Anemia on Disease Progression
• Disease-related anemia* has been associated with worse prognosis in all
risk scoring systems (Lille, IPSS and derivatives)
• RBC transfusional dependency is included in the DIPSS-plus score
* NOT treatment-related
Passamonti F.et al, Blood 2010; 115:1703-8
Dynamic IPSS (DIPSS)
Points
Median
survival
(mo)
Low
0
Not reach.
Int-1
1-2
170
Int-2
3-4
48
High
5-6
18
Passamonti F et al. Blood 2010;115:1703-8
Survival by Cytogenetic Category in PMF
At diagnosis
Beyond initial diagnosis
CPX= complex (>3 abnormalities)
Tam C S et al. Blood 2009;113:4171-4178
"Unfavorable" Karyotype in PMF: Effect on OS
Unfavorable Karyo
M 2.0 yr
5-yr survival: 8%
UNFAVORABLE KARYO:
- Complex karyo,
- Sole or 2 abnormalities including:
• Trisomy 8
• -7/del(7q)
• Del(5q)
• Inv(3)
• isochromosome 17q/17p• 12p• 11q23 abnormality
Favorable Karyo
M 5.2 yr
5-yr survival: 51%
Caramazza D et al. Leukemia 2011; 25:82-88
"Unfavorable" Karyotype in PMF: Effect on LFS
Favorable Karyo
5-yr AML transformation rate: 7%
Unfavorable Karyo
5-yr AML transformation rate: 46%
Caramazza D et al. Leukemia 2011; 25:82-88
Risk Stratification in PMF
Variable
IPSS
DIPSS
DIPSS-plus
Age >65 y



Constitutional symptoms



Hemoglobin <10 g/dL



Leukocyte count >25x109/L



Circulating blasts > 1%



Platelet count <100x109/L

RBC transfusion need

Unfavorable karyotype

+8,-7/7q-,i(17q),inv(3), -5/5q-,12p-, 11q23 rearr.
Cervantes et al, Blood 2009;113:2895-901
Passamonti et al, Blood 2010; 115:1703-8
Gangat N et al, J Clin Oncol 2011; 29:392-7
Dynamic IPSS-plus (DIPSS-plus)
∆ Low risk (0 adverse points)
n=66; median survival ~ 185 months
▲ Intermediate-1 risk (1 adverse point)
n=174; median survival ~ 78 months
1
○
High risk (4 or more adverse points)
n=193; median survival ~ 16 months
.8
Survival
Intermediate-2 risk (2 or 3 adverse points)
n=360; median survival ~ 35 months
.6
Low risk (0 variable)
M 185 mo
.4
Int-1 risk (1 variable)
M 78 mo
.2
0
High risk
(>4 variables)
M 16 mo
0
50
Int-2 risk (2-3 variables)
M 35 mo
100
150
200
250
300
350
400
Months
Gangat et al. J Clin Oncol 2011;29:392-7
Adverse Impact of Monosomal Karyotype
Normal karyo
M 50 mo
Sole +8
M 20 mo
Complex karyo
No monosomal
M 24 mo
Monosomal
karyo
M 6 mo
Vaidya R et al. Blood 2011;117:5612-15
“Very-High Risk” Patients: >80% Mortality
At 2 Years
Very-High risk variables
•
monosomal karyotype
•
inv(3)/i(17q)
or any 2 of the following:
•
PB blasts >9%
•
WBC >40x109/L
•
other unfavorable karyotype
Low (3%)
Int-1 (11%)
High (53%)
Int-2 (26%)
Very High (82%)
Tefferi A et al. Blood 2011; 118:4595-8
Novel Prognostic Variables
• Somatic Mutations
• Germline Characteristics
• Cytokines
• Other biomarkers (FLC, hepcidin & ferritin
levels)
JAK2 V617F Mutation and Prognosis in PMF
P=0.198
JAK2 V617F
JAK2 wt
89 (31.1%)
68 (34.5%)
103.4 mo
(77.5-129.3)
137.6 mo
(48.5-226.8)
WT
V617F
N=483
Guglielmelli P et al, ASH2012
No Impact of JAK2V617F on Leukemia Risk
P=0.839
HR: 1.05 (95% CI, 0.7-1.7)
WT
V617F
(Competitive risk analysis)
Guglielmelli P et al, ASH2012
Blast transformation: Kaplan-Meier analysis
Kaplan Meier estimates for JAK2
Event=Leukemia-transformation
1.00
jak2=homoz
0.75
jak2=wt
0.50
jak2=heteroz
0.25
0.00
0
36
72
108
144
Number at risk
jak2=wt 225
130
jak2=heteroz 223
118
jak2=homoz 145
101
83
56
58
60
36
37
42
19
23
180 216
Months
27
13
15
19
9
12
252
288
324
360
9
6
6
5
4
1
2
4
1
0
2
0
IPSS prognostic score
4.33 (1.5-12.6)
0.007
JAK2 V617F wt or Homo vs.
Hetero
2.43 (1.44-4)
0.02
Barosi et al. PlosOne 2013, In press
Mutation Complexity in PMF
 382 (79.1%) of patients presented at least one somatic mutation
• 154 pts (32.5%) had >2 mutations
• 31 pts (6.4%) had >3 mutations
Guglielmelli P et al, ASH2012
Mutations Associated with Reduced Overall Survival
in Multivariate Analysis
EZH2
ASXL1
WT
WT
Mut
P= 0.0008
P< 0.0001
SRSF2
WT
P< 0.0001
Mut
Mut
Hazard Risk
(95% CI range)
P
EZH2
1.91 (1.08-3.36)
0.025
ASXL1
2.21 (1.57-3.11)
<0.0001
SRSF2
2.60 (1.63-41.6)
<0.0001
Guglielmelli P et al, ASH2012
Mutations Associated with Leukemia
in Multivariate Analysis
EZH2
WT
Mut
ASXL1
Mut
WT
P=.003
HR=1.98 (95%CI: 0.88-4.46)
SRSF2
P<.0001
HR=2.5 (95%CI: 1.51-4.13)
IDH1/2
Mut
Mut
WT
WT
P=.007
HR= 2.73 (95%CI: 1.34-5.55)
* Competitive Risk Analysis
P<.0001
HR= 2.66(95%CI: 1.10-6.47)
Guglielmelli P et al, ASH2012
A "Molecularly High-Risk" Status Associates with
Reduced Overall Survival
P<0.0001
•
•
•
•
EZH2
ASXL1
SRSF2
IDH1/2
Low Risk
High Risk
HR= 2.29 (95%CI: 1.65-3.19)
•
In the “molecularly high-risk” category, overall survival was 81 months (range: 61.9-99.5)
compared with 148 months (range: 52.5-243.2) in the “molecularly low-risk” category
(P<0.0001). Mutivariate analysis.
Guglielmelli P et al, ASH2012
A "Molecularly High-Risk" Status Associates With
Leukemia Transformation
•
•
•
•
EZH2
ASXL1
SRSF2
IDH1/2
High Risk
Low Risk
P<0.0001
HR 2.96 (95%CI:1.85-4.76)
•
In the “molecularly high-risk” category, leukemia-free survival was 129 months (range: 90-168)
compared with 323 months (range: 194-452) in the “molecularly low-risk” category (P<0.0001) –
Competitive risk analysis
Guglielmelli P et al, ASH2012
The "Molecularly High-Risk" Status Contributes to
Refined IPSS Categorization
IPSS (LOW-INT1)
IPSS (INT2-HIGH)
P= 0.017
P= 0.002
Low Risk
Low Risk
High Risk
High Risk
Molecular Risk
category
Median Overal Survival,
months (range)
Molecular Risk
category
Median Overal Survival,
months (range)
LOW
264.2
(184.7-343.6)
LOW
71.5
(59.2-23.7)
HIGH
125.6
(77.4-173.8)
HIGH
32.4
(26.6-38.3)
Guglielmelli P et al, ASH2012
The "Molecularly High-Risk" Status Predicts for
Leukemia Risk within IPSS Categories
IPSS (LOW-INT1)
IPSS (INT2-HIGH)
P= 0.001
P= 0.01
High Risk’
High Risk
Low Risk
Low Risk
IPSS category
Hazard Risk (95%CI,range)
LOW-INT1
2.28 (1.20-4.36)
INT2-HIGH
3.22 (1.52-6.83)
Guglielmelli P et al, ASH2012
ABSTRACT #430
Prognostic Interactions Between SRSF2, ASXL1, and IDH Mutations
in Primary Myelofibrosis and Determination of Added Value to
Cytogenetic Risk Stratification and DIPSS-Plus
Terra L Lasho, MT, (ASCP)1*, Naseema Gangat, MD1*, Christy Finke, BS1*, Rebecca R.
Laborde, PhD1*, Curtis A Hanson, MD2*, Rhett P Ketterling, MD3*, Ryan A Knudson3*,
Animesh Pardanani, MBBS, PhD1 and Ayalew Tefferi, MD1
The A3669G Polymorhism of Glucocorticoid Receptor
Contributes to Blast Transformation in PMF
• The A3669G allele is a susceptibility allele for PMF (HR 1.6-1.8)
• The G/G allele associated with a «more-myeloproliferative» phenotype
OS*
BT*
0.47 per 100 pt-yr
N=274
N=21
77.6mo vs 298mo; P=0.049
*, restricted to JAK2V617Fpos pts, n=295
13.6 per 100 pt-yr
76.7mo vs 261mo; P=0.018
remained significant in multivariate
Barosi G et al, Blood 2012; 120:3112-7
Abnormally Increased IL-8 and IL2R Plasma
Levels Are Prognostically Detrimental
All (n=127)
Int-1 (n=27)
Int-2 (n=70)
Treatment naive
(n=90)
Tefferi A et al. JCO 2011;29:1356-1363
Plasma Free Light Chain (FLC) Levels Predict
Survival in PMF
FCL
FCL +/- IL-8 and/or IL-2R
< 3.78 mg/dL
Both normal
Both
> 3.78
abnormal
mg/dL
Either abnormal
Both abnormal
Levels above or below the ROC cutoff (3.78 mg/dL)
Pardanani A et al. JCO 2012;30:1087-94
Conclusions
• Prognostic scores in OMF are needed for therapeutic
choices
• At present, they are mainly reserved for HSCT decision
• Most used scores are based on clinical and hematologic
variables
• Cytogenetics has been show to add to clinical scores
• Molecular characterization may help refine clinical
scores, be cost-effective and overcome technical
limitations of conventional cytogenetics
Acknowledgments
Section of Hematology,
University of Florence
Paola Guglielmelli
Flavia Biamonte
Tiziana Fanelli
Ambra Spolverini
Maria Chiara Susini
Giada Rotunno
Alessandro Pancrazzi
Lisa Pieri
Contributors
Mario Cazzola - Pavia
Gianni Barosi - Pavia
Francisco Cervantes - Barcelona
Andrea Reiter - Mannheim
Andrew Duncombe - Southampton
Katerine Zoe - Athens
Nick Cross - Salisbury