Review of 54 th ASH Annual Meeting in 2012

1. Dec 28, 2012 Review of 54th ASH Annual Meetingin 2012 December 8 – 12, 2012 Georgia World Congress Center, Atlanta, GA Kim Hwan-Young

2. 학회 장소 Georgia World Congress Center, Atlanta, GA Atlanta • 미국 남동부의 최대도시 • 공업과 상업의 중심지 • 인구의 40% 정도가 흑인 • 1996년 7월 제26회 올림픽게임이 개최

3. 학회장 주변 CNN: 전 세계 212개국 2억 가구에 전파를 보내고 있는 세계 최고의 뉴스 브랜드이나 CNN studio tour는 전반적으로 특별하지 않았다. Tour프로그램 만들어 사업화했다는 점에서 미국자본주의의 한단면을 보는 듯 했다. World of Cocacola: 코카콜라라는 브랜드를 세세하게 기록하여 보여주어 코카콜라와코카콜라를 탄생시킨 Penberton의 가치를 높임으로써 회사의 이미지 제고에 활용하였다. 코카콜라는 친숙하게 그리고 그 조성에 대한 비밀은 신비스럽게 잘 기록해놓았다. 학회: 국내학회와는 비교를 할 수 없을 만큼 큰 규모에 광범위한 내용을 따라가기 어려웠다. 아는 만큼 보인다고 하는데 몰랐던 것이 많아서 못 본것은 아닐까 하는 생각이 남았다. 아쉬웠다. 공부하지 않으면 많이 얻어갈 수 없는 곳이라는 생각이 들었다. 미국: 우선 광활한 면적에 한번 놀라고 건물과 도로등이 계획적으로 만들어진 모습이 보기 좋았다. 도심을 제외하고는 자연환경도 잘 보존되어 있었고 다양한 기후와 인종, 그리고 획일화되지 않은 개성이 좋았다.

4. 2012 Annual Meeting of ASH • Education program: 30 subjects • Education Spotlight Session (ticket): 7 subjects • Scientific program: 17 subjects • Oral and Poster Sessions: 4,289 (972 & 3,317) • General Sessions: 10 subjects • Special-Interest Sessions: 15 subjects • Trainee Activities: 6 subjects • Scientific Forum: 4 subjects • How I Treat: Bridging Science to Clinical Delemmas: 23 subjects • Meet-the-expert(ticket): 12 subjects • Plenary scientific session: 6 abstracts

5. Sientific Programs • Bone Marrow Failure • Plasma Cell Neoplasia • Blood Disorders in Childhood • Hematopathology and Clinical Laboratory Hematology • Hematopoiesis • Hemostasis • Immunology and Host Defense • Iron and Heme • Lymphoid Neoplasia • Myeloid Biology • Myeloid Neoplasia • Platelets • Red Cell Biology • Stem Cells and Regenerative Medicine • Thrombosis and Vascular Biology • Transfusion Medicine • Transplantation Biology

6. Myeloid Biology • -Role of HOX genes in Normal and Malignant Hematopoiesis • Lymphoid Neoplasia • - B-cell Receptor Signaling inthe Pathogenesis and Treatment of • Lymphoid Malignancy • Hematopoiesis • - RNA Splicing in Normal and Malignant Hematopoiesis • Myeloid Neoplasia • - Personalized Diagnostics in Acute Myeloid Leukemia and Myelodyspalsia

7. Homeobox gene •Homeobox is a DNA sequence found within genes that are involved in the regulation of development (morphogenesis) of animals, fungi and plants. Genes that have a homeobox are called homeobox genes and form the homeobox gene family • Homeobox is about 180 base pairs long; it encodes a protein domain (the homeodomain) which can bind DNA • One of a group of genes with a shared nucleotide segment that are involved in the formation of bodily segmentation during embryologic development

8. Anterior Hox proteins (Hoxa1-4) are expressed predominantly in hematopoietic stem cells and posterior HOX proteins (Hoxa7-11) are expressed in committed progenitors. • Moreover, Hox genes are critical for the pathogenesis of myeloid malignancies and are the target of some of the genetic lesions that drive leukemogenesis. • Hoxa9, which is overexpressed in more than half of acute myeloid leukemias, modulates the activity of lineage-specific enhancers controlling a network of proleukemogenic target genes.

9. PLENARY SCIENTIFIC SESSION • The Effect of a No-Prophylactic Versus Prophylactic Platelet Transfusion Strategy On Bleeding in Patients with Hematological Malignancies and Severe Thrombocytopenia (TOPPS trial). A Randomized Controlled, Non-Inferiority Trial • Somatic Mutations in Schinzel-Giedion Syndrome Gene SETBP1 Determine Progression in Myeloid Malignancies • RAD52-Dependent Synthetic Lethality Eradicates Leukemia Stem Cells • A Large-Scale Trial Testing the Intensity of Cytoreductive Therapy to Prevent Cardiovascular Events in Patients with Polycythemia Vera (CYTO-PV trial) • The Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia • ATRA and Arsenic Trioxide (ATO) Versus ATRA and Idarubicin (AIDA) for Newly Diagnosed, Non High-Risk Acute Promyelocytic Leukemia (APL): Results of the Phase III, Prospective, Randomized, Intergroup APL0406 Study by the Italian-German Cooperative Groups Gimema-SAL-AMLSG

10. #5 The Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemiareported from Yale Cancer Center • The impact of clonal heterogeneity on cancer progression in chronic lymphocytic leukemia (CLL) is not well understood. • We hypothesized that the evolutionary dynamics of subclonal mutations contribute to the variations in disease tempo and response to therapy that characterize CLL. • We therefore carried out a large-scale analysis of subclonal and clonal point mutations and copy-number alterations in 149 CLLs, detected by whole exome sequencing (WES) and SNP arrays. • Subclonal mutations were detected in 146/149 CLLs and were enriched with putative cancer driver events (P=0.001).  • Furthermore, higher numbers of subclonal mutations were associated with prior anti-leukemia therapy (P=0.017).  • Together, these results suggest that a strong extrinsic selection pressure, such as cytotoxic treatment, promotes the expansion of fitter subclones, driving them to above our detection threshold (CCF of ~0.10). • The order of mutation acquisition may be inferred from the aggregate frequencies at which driver events are clonal or subclonal, as clonal mutations represent earlier events and subclonal later events.  • Of the 149 samples, we found 3 drivers (MYD88, trisomy 12, and del(13q)) that were clonal in 80-100% of samples harboring these alterations --significantly higher than other driver events (q<0.1), suggesting that they arise earlier in typical CLL development. • Other drivers (e.g., ATM, TP53 and SF3B1) were often observed at subclonal frequencies, indicating that they often arise later in leukemic development. • We directly assessed the evolution of somatic mutations in 18 patients, in which data from two distant timepoints were available.  • Clonal evolution was observed in 11 of 18 patients (10 of 12 who received intervening treatment, but only 1 of 6 without intervening treatment, P=0.012) and confirmed that subclonal mutations (e.g., del(11q), SF3B1 and TP53) shifted towards clonality over time.  

11. Indeed, expanding subclonal mutations were enriched in putative drivers (P=0.021), suggesting that these mutations not only mark genetic evolution but also provide the fitness advantage driving it. Changes in the genetic composition of CLL cells with clonal evolution were associated with network level changes in gene expression. • If treatment-associated genetic evolution leads to expansion of a fitter subclone, we would predict a shorter time to relapse in these individuals. • Indeed, presence of a detectable subclonal driver mutation was associated with a shorter time to retreatment in these 18 samples (P=0.04), indicating that the presence of subclonal drivers adversely impacts clinical outcome.  • In the analysis of the full cohort of 149 samples, we observed that CLLs with subclonal driver mutations were associated with shorter times from diagnosis to first therapy (P=0.001) and between sample collection to treatment (P<0.001).  • Moreover, in the subset of 67 of 149 patients who were treated after sampling, presence of subclonal driver mutations evident in the pre-treatment sample was associated with earlier retreatment (P=0.003). Regression models adjusting for CLL prognostic factors (IGHV status, prior therapy and high risk cytogenetics) demonstrated that the presence of a subclonal driver was an independent risk factor for earlier retreatment (adjusted hazard ratio of 4.61 (CI 1.59-13.34), P=0.005).    • Thus, the detection of subclonaldrivers(indicative of an active evolutionary process) is associated with shorter duration of remission. • In conclusion, the analysis of clonal heterogeneity in CLL provides a glimpse into the past, present and future of a patient’s disease. Through the cross-sectional analysis of 149 samples, we derived the number and genetic composition of clonal and subclonal mutations and thus uncovered footprints of the past history of CLL. • Furthermore, we inferred a temporal order of genetic events implicated in CLL. Finally, our combined longitudinal and cross-sectional analyses revealed that knowledge of subclonal mutations anticipates the genetic composition of the future relapsing leukemia as well as the rapidity with which it will occur.  These data challenge us to therapeutically address not only genetic targets but also their dynamic evolutionary landscape.

12. It was a really good experience.

13. Education Programs • 3 P's In a Pod • Acute Myeloid Leukemia: Newly Discovered Genes, Screens (for • Minimal Residual Disease), and Therapeutic Means • Advances in the Pathogenesis and Treatment of Myelodysplastic • Syndromes • Chronic Lymphocytic Leukemia: Can New Prognostic Factors • Guide New Therapeutic Approaches? • Chronic Myeloid Leukemia: The Pristine Paradigm for Successful • Targeted Therapy • Dynamic Discoveries and Directions in Pediatric Leukemias • Everyday Bleeding Disorders

14. Education Programs • Evidence-Based Approaches to Cytopenias • Hematologic Diseases in Pregnancy • Hematopoietic Stem Cell Transplantation I: Exploiting Alternative • Donors • Hematopoietic Stem Cell Transplantation II: Towards Safer • Allogeneic Transplantation • Hemoglobinopathies: New Frontiers and Insights • Immune Dysregulation • Insights into Biology and Refinement of Treatment Strategies in • Hodgkin Lymphoma

15. Education Programs • Keeping Pace with Advances in Myeloma • Landscape Changes and Challenges In Hemophilia • New Insights into the Genetic Pathogenesis of Acute • Lymphocytic Leukemia and New Treatment Strategies • Non-Hodgkin Lymphoma I: Changing Therapeutic Strategies in • Aggressive Lymphomas • Non-Hodgkin Lymphoma II: Understanding the Indolent • Lymphomas • Not So “Benign” Hematologic Issues in Children • Pearls and Pitfalls in the Hematology Lab: Clotting and Bleeding • Pearls and Pitfalls in the Hematology Lab: Updates on Cellular • Diagnostics

16. Education Programs • Pediatric Issues in Platelet Transfusions • Perioperative Hematology: To Bleed or Not To Bleed • The New Era in Antithrombotic Therapy • The Spectrum of JAK2-Positive Myeloproliferative Neoplasms: • Complications and Therapeutic Advances • The Spectrum of Plasma Cell Dyscrasias • The Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic • Syndromes: New Insights and New Treatments • Thrombosis in Challenging Populations • Untangling Uncommon Lymphoproliferative Disorders