A Practical Approach to Risk Stratification
for PMF: from IPSS to DIPSS-plus
Francisco Cervantes
Lisbon, May 2012
Hematology Department, Hospital Clínic, Barcelona, Spain
Primary Myelofibrosis:Age Distribution (n= 180)
50
20
30
40 Median: 64 years (17-89)
Years
0
10
10 20 30 40 50 60 70 80 90
Clinical Manifestations and Laboratory Features of Myelofibrosis
SymptomsPhysical findings
Hematologic abnormalities
Bone marrowfeatures
Molecularabnormalities
- Anemic symp.
- Splenomegaly
- ConstitutionalSplenomegaly
(+ hepatomegaly)
AnemiaLeukocytosisLeukopenia
ThrombocytosisThrombocytopenia
Abnormal megak.Cytogenetic abn.
FibrosisOsteosclerosis
JAK2 V617FC-MPL
Relative Survival in PMF
Cervantes et al., Blood 2009; 113:2895-901
Survival in PMF
No. patients: 1,054
Median Srv (95% CI): 69 (61 - 76)
Deaths: 517 (49 %)
Cervantes et al., Blood 2009; 113:2895-901
1.0
Survival of PMF Patients < 55 years(n= 121)
0.2
0.4
0.6
0.8
Pro
bab
ility
Median: 10.6 years
0 4 8 12 16 20 24 28
0.0
0.2
Years
Cervantes et al., Br J Haematol 1998; 102:884-90
Causes of Death in PMF
4%
13%
14%
10%
5%
4%
4%
Cervantes et al., Blood 2009;113:2895‐901
31%
19%
Prognostic Scoring Systems of PMF
Author (year) Prognostic factors Risk groups Median srv *
Visani (1990) Hb < 10 g/dL
Blood myeloid precursors > 10%3 81, 39, 31
Dupriez (1996) Hb < 10 g/dL
WBC < 4 or > 30 x109/L
3 93, 26, 13
Cervantes (1997) Hb < 10 g/dL
Constitutional symptoms
Blood blasts > 1%
2 99, 21
Reilly (1997) Hb < 10 g/dLAge > 68 yrs 2 108 16
Studies not including “prefibrotic” PMF; * months
Platelets < 100 x109/L
Monocytes > 1 x109/L
Age > 68 yrs Abnormal karyotype
2 108, 16
Tefferi (2007) Hb < 10 g/dLWBC < 4 or > 30 x109/L 3 134, 50, 29
Dupriez´s Prognostic Score
• Hb < 10 g/dL
Adverse factors
• Hb < 10 g/dL
• WBC < 4 or > 30 x 109/L
• Low risk: 0 factors
Prognostic groups
93 months
Median survival
• Intermediate risk: 1 factor
• High risk: 2 factors
26 months
13 months
Dupriez et al., Blood 1996; 88:113-18
Prognostic factors
A > 65 9
1
Survival by PMF-PS
IPSS: Risk Classification of PMFat Presentation
• Age > 65 years
• Constitutional symptoms
• Hb < 10 g/dL
• Leukocytes > 25 x 109/L
• Blood blasts > 1%
.1
.2
.3
.4
.5
.6
.7
.8
.9
Pro
babi
lity
Risk gro ps0
0 24 48 72 96 120 144 168 192 216 240 264 288Months
95% CI 95% CI 95% CI 95% CIPMF-PS = 0 PMF-PS = 1 PMF-PS = 2 PMF-PS = 3
Risk groups
• Low 0
• Intermediate-1 1
• Intermediate-2 2
• High > 3
Cervantes et al., Blood 2009;113:2895-901
PMF- IPSS Risk Groups
Risk No Median SrvRisk
Group
No.
factorsPatient %
Median Srv
(95% CI)% Deaths
Low 0 22 % 135 (117 - 181) 32 %
Interm. 1 1 29 % 95 (79 - 114) 50 %
I t 2 2 28 % 48 (43 59) 71 %Interm. 2 2 28 % 48 (43 - 59) 71 %
High ≥ 3 21 % 27 (23 - 31) 73 %
Cervantes et al., Blood 2009; 113:2895-901
0.8
0 6
1.0
0.8
0 6
1.0
IPSS of PMF: Relative Survival by Risk Group
Low Intermediate ‐1
0.6
0.4
0.2
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 1
0.6
0.4
0.2
0.0
0 2 3 4 5 6 7 8 9 10 11 12
1.0 1.0
Observed
Population
Relative
Probability
HighIntermediate ‐2
Cervantes et al., Blood 2009; 113:2895-90112
0.8
0.6
0.4
0.2
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12
0.8
0.6
0.4
0.2
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12
Years
Dynamic IPSS (DIPSS) of PMF:Weight of Variables and Risk Groups
Passamonti et al., Blood 2010; 115:1703-08
DIPSS: Time of Appearance of Risk Factors
Passamonti et al., Blood 2010; 115:1703-08
DIPSS of PMF: Survival by Risk GroupOverall Series
Passamonti et al., Blood 2010; 115:1703-08
DIPSS in Patients < 65 years:Weight of Variables and Risk Groups
Passamonti et al., Blood 2010; 115:1703-08
Survival by DIPSS Risk Groups for Patients < 65 years
Passamonti et al., Blood 2010; 115:1703-08
Cytogenetic Abnormalities in PMF
More frequent abnormalities
Others
• del 20q
• del 13q
• Trisomy 8
• Trisomy 9
• del 7 / 7q-
• del 5 / 5q-
• t (1;7)
• del 12p
d l 17 / i 17• Trisomy 1q • del 17 / iso 17q
• Rearr. 11q23
• Inv (3)
• t (1;6)
Karyotype and Prognosis in PMF
Favorable:• 13q-, 20q-, +9
• Normal diploid
Unfavorable:• Abnormal 5, 7 or 17
Tam et al., Blood 2009
,
• Complex
Karyotype and Prognosis in PMF
• Favorable:13q-, 20q-, +9
• Unfavorable:Complex, +8
• Normal diploid
Hussein et al., Blood 2010
• Others
DIPSS-Plus for Primary Myelofibrosis
Gangat et al., JCO 2011; 29:392-397
*** Complex karyotype or +8, -5/-5q-, -7/-7q, i(17q), 12p-, inv(3), 11q23 rearr.
DIPSS-Plus for Primary Myelofibrosis
Gangat et al., JCO 2011; 29:392-397
Summary of Current Prognostic Models for PMF
Cervantes et al., Blood 2009; 113:2895-901Passamonti et al., Blood 2010; 115:1703-08Gangat et al., JCO 2011; 29:392-397
“Very‐High Risk” PMF Patients:> 80% Mortality at 2 Years
Very‐High risk variables
• monosomal karyotype
Low (3%)
• inv(3)/i(17q)
or any 2 of the following:
• PB blasts >9%
• WBC >40x109/L
• other unfavorable karyotype
Tefferi et al., Blood 2011; 118:4595‐8
Int‐1 (11%)
Int‐2 (26%)High (53%)
Very High (82%)
Mutation JAK2 V617F in the MPNs
V617F
FERM JH2SH2Amino-terminal
Carboxy-terminal JH1
Frequency of the JAK2 mutation
PV
ET
PMF
90-95%
50-60%
60%
Prognostic Value of the JAK2 Mutation in PMF
Author No. of Prognostic(year) patients influence
Tefferi (2005) 157 No
Campbell (2006) 152 Yes
Barosi (2007) 174 Yes *
C (2009) 34 NCervantes (2009) 345 No
Guglielmelli (2009) 186 Yes **
* Higher leukemic transformation rate; ** shorter survival for lower burden
Other Mutations in PMF
Gene Chromosome location
Frequency
TET2
CBL
ASXL1
IDH
4q
11q
20q
2q
20%
6%
13- 23%
1- 4%
IKZF1
EZH2
7p
7q
0-4%
6-13%
Tefferi A,. Leukemia 2010; Guglielmelli et al., 2011
Newer Mutations and Prognosis of PMF: EZH2
• Mutations of EZH2 (catalytic component of Polycomb Repressive Complex‐2) are found in 6% of
PMF subjects
P< 0.001
EZH2WT
P= 0.028
EZH2WTOverallSurvival
kemia‐free Survival
Guglielmelli et al., Blood 2011; 118;19:5227‐34
• In multivariate analysis, EZH2mutated status was an IPSS‐independent variable significantly
associated with reduced OS (P=0.016)
EZH2WT
EZH2mut
EZH2WT
EZH2mut
O
Leu
Newer Mutations and Prognosis of PMF: IDH
Tefferi et al., Leukemia 2012; 26:475‐80
Treatment Options for Myelofibrosis
Wait & seeConventional
treatmentInvestigational
drugsAllo-HSCT
Symptom Type
Factors Driving Therapy Choice in Myelofibrosis
Prognostic GroupSymptom Type
& Burden
Poor Other
Therapy adjusted
to symptomsPrioritize curative
options (HSCT) or
investigational drugs
Proposed Algorithm for PMF Treatment
Low risk Intermediate-1risk
Intermediate-2 risk High risk
Conventional or
Wait & seeAllo-HSCT or
Investigational drugs
Wait & seeor Symptomatic
treatment *
* Check cytogenetics & transfusion dependency
Conventional or Investigational
Drugs / Allo-HSCT **
* Poor cytogenetics
Transfusion dependency,
No response to treatment
Thanks ¡¡
