KIR Genes Associated With MDS Risk CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting* May 29 - June 2, 2015 *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. This program is supported by educational grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene Corporation, Genentech, Incyte, and Novartis.

Myelodysplastic Syndrome Spectrum of clonal hematopoetic disorders[1] Relatively rare In the US, only 4 new cases per 100,000 persons each yr Syndrome marked by ineffective hematopoiesis and dysplastic cytologic features Risk of development of secondary AML MDS mortality risk correlates to score on revised IPSS[2] AML, acute myeloid leukemia; IPSS, International Prognosis Scoring System; MDS, myelodysplastic syndrome. 1. Garcia-Manero G, et al. Am J Hematol. 2014;89:97-108. 2. Greenberg PL, et al. Blood. 2012;120:2454-2465.

Natural Killer Cells Cytotoxic blood lymphocytes important in tumor surveillance and infectious disease control[1] 5% to 15% of peripheral blood lymphocytes Do not require previous antigen sensitization Phenotype: CD3- CD56+ Large array of activating and inhibitory killer cell immunoglobulin-like receptors Inhibitory receptors: 2 or 3 extracellular domains, long cytoplasmic tail[2] Ligands: HLA class I Activating KIR receptors: 2 or 3 extracellular domains, short cytoplasmic tail[2] Ligands: tumor ligands MICA, MICB, ULBP 1. Terszowski G, et al. Swiss Med Wkly. 2012;142:w13668. 2. Kaur G, et al. Brain. 2013;136:2657-2676.

KIR Gene Complex Chromosome 19q13.4[1] Haplotype A: only 1 activating KIR gene Haplotype B: ≥ 1 of 6 activating KIR genes Pts with higher number of activating KIR genes associated with significant risk reduction in developing childhood ALL[2] Current study sought to determine if association exists between number of activating KIR genes and risk of MDS[3] ALL, acute lymphocytic leukemia; KIR, killer cell immunoglobulin-like receptors; MDS, myelodysplastic syndrome. 1. Moussa P, et al. Front Immunol. 2013;18:425. 2. Almalte Z, et al. Blood. 2011;8:1323-1328. 3. Daher M, et al. ASCO 2015. Abstract 7001.

KIR Gene Study in MDS: Study Design and Pt Characteristics Case control study MDS pts (n = 180) compared with healthy controls (n = 117) MDS pts both high risk (n = 60) and low risk (n = 120) by IPSS MDS Pt Characteristics Characteristic, % Low-Risk MDS (n = 120) High-Risk MDS (n = 60) Male sex 72 70 Age older than 60 yrs 88 87 AML transformation 12 22 Previously treated 29 34 AML, acute myeloid leukemia; IPSS, International Prognostic Scoring System; KIR, killer cell immunoglobulin-like receptors; MDS, myelodysplastic syndrome. Daher M, et al. ASCO 2015. Abstract 7001. Reprinted with permission.

KIR Gene Study in MDS: Analysis Pt DNA samples from Leukemia Biobank at M.D. Anderson Cancer Center Analysis of KIR genes by PCR Samples correlated for phenotypic, genotypic, and outcome data Logistic regression model used to study relationship of number of activating KIR genes and MDS risk category KIR, killer cell immunoglobulin-like receptors; MDS, myelodysplastic syndrome. Daher M, et al. ASCO 2015. Abstract 7001.

KIR Gene Study: Number of Activating KIR Genes Associated With Risk of MDS Each additional activating KIR gene conferred protective effect against development of high-risk MDS No independent survival benefit seen with higher number of activating KIR genes No association shown between number of activating KIR genes and AML transformation P = .00001 P = .009 P = .04 60 50 Number of activating KIRs 0 or 1 2 or 3 4 or more 40 Frequencies (%) 30 20 AML, acute myeloid leukemia; IPSS, International Prognostic Scoring System; KIR, killer cell immunoglobulin-like receptors; MDS, myelodysplastic syndrome. 10 High IPSS Low IPSS Healthy Control Daher M, et al. ASCO 2015. Abstract 7001. Reprinted with permission.

KIR Gene Study: Conclusions Inheritance of a lower number of activating KIR genes associated with increased risk of developing MDS Low number of activating KIR genes associated with a high- risk score (IPSS) in MDS pts Each additional activating KIR gene in pts appears to lower risk of high-risk MDS Future directions: development of immunotherapies for MDS using NK cells IPSS, International Prognostic Scoring System; KIR, killer cell immunoglobulin-like receptors; MDS, myelodysplastic syndrome; NK, natural killer. Daher M, et al. ASCO 2015. Abstract 7001.

Go Online for More CCO Coverage of ASCO 2015! Short slidesets of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Gastrointestinal cancer Genitourinary cancer Hematologic malignancies Immunotherapy Lung cancer clinicaloptions.com/oncology