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.

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 2015. Abstract 907.

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 2015. Abstract 907.

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% < 40 40-49 50-59 60-69 70-79 80-89 ≥ 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 2015. Abstract 907. Reproduced with permission.

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 2015. Abstract 907. Reproduced with permission.

IWG-PM: OS by Gene Mutation 10 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 2015. Abstract 907. Reproduced with permission.

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 2015. Abstract 907. Reproduced with permission.

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 2015. Abstract 907. Reproduced with permission.

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 2015. Abstract 907.

Go Online for More CCO Coverage of ASH 2015! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Acute leukemias/chronic leukemias Myeloma/plasma cell disorders Lymphomas MDS and myeloproliferative neoplasms clinicaloptions.com/oncology