1. IWG-PM: Prognostic Significance of MDS-Associated Somatic Gene Mutations Independent of IPSS-R
New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
IPSS-R, Revised International Prognostic Scoring System; IWG-PM, International Working Group for Prognosis in MDS; MDS, myelodysplastic syndrome.
This program is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, Seattle Genetics, and Takeda Oncology.

2. IWG-PM: Background
IPSS-R for MDS Risk Assessment Calculator does not include somatic mutations in its algorithm
Several common MDS-associated somatic mutations have prognostic significance
As yet, independent of IPSS-R
Clinical guidance may benefit from known prognostic impact of specific gene mutations
Current study developed multivariable survival model to investigate influence of MDS-associated somatic mutations on patient prognosis
IPSS-R, Revised International Prognostic Scoring System; IWG-PM, International Working Group for Prognosis in MDS; MDS, myelodysplastic syndrome.
Slide credit: clinicaloptions.com
Bejar R, et al. ASH Abstract 907.

3. IWG-PM: Study Design MDS data compiled from 18 international centers
United States, Europe, Asia
Data collected for analysis
Clinical features: age, sex, percentage of blasts, karyotype, hemoglobin, platelet count, neutrophil count
OS data (N = 3359): 3.6 yrs of follow-up; 1780 deaths; median OS: 2.65 yrs
Patient treatment status
Gene mutations
IWG-PM, International Working Group for Prognosis in MDS; MDS, myelodysplastic syndrome.
Slide credit: clinicaloptions.com
Bejar R, et al. ASH Abstract 907.

4. IWG-PM: Patient Characteristics
Primarily male pts between 60 and 79 yrs of age with low blast percentages and fairly even distribution among IPSS-R risk groups 2% 2%
0.45%
< ≥ 90 Unknown 5%
38%
Male
12%
13%
62%
Female
36%
30%
Sex 1%
Age, Yrs 6%
Very Low Low Intermediate High Very High Unknown
< 5%
5% to 10%
11% to 20%
21% to 30%
Unknown
IPSS-R, Revised International Prognostic Scoring System; IWG-PM, International Working Group for Prognosis in MDS.
16%
22%
10%
55%
22%
11%
24%
14%
19%
Bone Marrow Blasts, %
IPSS-R Risk Group
Slide credit: clinicaloptions.com
Bejar R, et al. ASH Abstract 907. Reproduced with permission.

5. IWG-PM: OS by Number of Mutations
In 1996 pts with OS data:
17 genes sequenced
ASXL1, CBL, DNMT3A, ETV6, EZH2, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF1
Number of Mutated Genes
100
0 (n = 377)
1 (n = 595) 90
2 (n = 460) 80
3 (n = 210)
4 (n = 125) 70
5/6/7 (n = 22) 60
SF3B1 only (n = 207)
OS (%) 50 40 30 20
IWG-PM, International Working Group for Prognosis in MDS. 10 2 4 6 8 10 12 14
Yrs
Slide credit: clinicaloptions.com
Bejar R, et al. ASH Abstract 907. Reproduced with permission.

6. IWG-PM: OS by Gene Mutation10
HR of Death 1
Univariate HR (95% CI)
IPSS-R adjusted HR (95% CI)
IPSS-R, Revised International Prognostic Scoring System; IWG-PM, International Working Group for Prognosis in MDS.
0.1
TP53
PRPF8
RAD21
GATA2
PTPN11
NRAS
RUNX1
NF1
ATRX
IDH2
ETV6
KRAS
EZH2
ASXL1
STAG2
FLT3
CBL
U2AF1
SRSF2
SF3B1
Slide credit: clinicaloptions.com
Bejar R, et al. ASH Abstract 907. Reproduced with permission.

7. IWG-PM: IPSS-R Adjusted HR by Gene Mutation
RUNX1
TP53
EZH2
PRPF8
≥ 4.0
ASXL1
3.5
42%
3.0
SF3B1
CBL
2.5
NRAS
-log10 (P Value)
2.0
U2AF1
FLT3
IDH2
1.5
PTPN11
P = .05
NF1
ETV6
RAD21
1.0
IPSS-R, Revised International Prognostic Scoring System; IWG-PM, International Working Group for Prognosis in MDS.
SRSF2
0.5
DNMT3A
TET2
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4
2.6
2.8
3.0
3.2
3.4
HR After Adjustment for IPSS-R Risk Group
Slide credit: clinicaloptions.com
Bejar R, et al. ASH Abstract 907. Reproduced with permission.

8. IWG-PM: Final Multivariate Model
HR (95% CI)
Characteristic HR
P Value
IPSS-R risk group (vs very low)
Low
Intermediate
High
Very high
1.08
1.97
2.56
4.36
.542
< .0001
Mutated genes (vs unmutated)
TP53
RUNX1
EZH2
NRAS
SF3B1
CBL
U2AF1
ASXL1
TET2
IDH2
KRAS
NPM1
2.35
1.51
1.58
1.44
0.82
1.35
1.22
1.17
0.88
1.31
1.2
.0002
.0006
.019
.041
.056
.069
.090
.104
.111
.362
.546
0.1 1 10
IPSS-R, Revised International Prognostic Scoring System; IWG-PM, International Working Group for Prognosis in MDS.
Slide credit: clinicaloptions.com
Bejar R, et al. ASH Abstract 907. Reproduced with permission.

9. IWG-PM: Conclusions
MDS-associated somatic mutations carry prognostic significance, independent of IPSS-R
Adverse: TP53, RUNX1, EZH2, NRAS
Favorable: SF3B1
Prognostic value of individual genes may vary by clinical context and in different combinations of multiple mutations
Relevance may be better assessed by multistep model
Study investigators suggest standardized sequencing of a large clinical MDS cohort in additional genes with common nomenclature and determined allele frequencies
IPSS-R, Revised International Prognostic Scoring System; IWG-PM, International Working Group for Prognosis in MDS; MDS, myelodysplastic syndrome.
Slide credit: clinicaloptions.com
Bejar R, et al. ASH Abstract 907.

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