1. University of Bologna (UNIBO) Institute of Hematology and Medical Oncology “L. e A. Seragnoli” Bologna Italy Giovanni Martinelli as EHA representative ECCO-ESMO-ESTRO Congress Amsterdam 29th September Personalized medicine in hematological malignancies: a new horizon

2. Road map of my perspective The NGS-PTL project: “From patients genomes, in few days, to be able to set up a individualized target therapy” with information by snps array, transcriptome-GEP and NGS thus providing for each “hematological” patients an “avatar” with pharmaco-genomic information, and providing targets suitable to personalized THERAPY. The 'state of the art' in haematological personalized medicine research Why a need to support haematological research?

3. reads for each gene “Avatar” Diagnosis: es. BCR-ABL1 like ALL diagnosis relapse RNA/DNA Genome Analyzer II (Illumina/Solexa)/Roche 454 Old Classic therapy + ? (ex. Tki, Antibiotic, Vitamin,..) Individual new therapy Old therapy combined with new (eg.TKI) therapy 1 week work = “molecular make up” Individual New Target(s ) Extra Rapid (mins not months) Bioinformatics NGS analysis ( e.g. KNOME analysis) done by a medical doctor “Back to bed, soon” 1 day work The personalized “avatar” for each haematological patient to get right target therapy, in a correct dosage, (possible at home) CURE Simulation or Computer assisted decision, in vitro identification of new drugs, etc. Design and apply experimental “individual” and personalized clinical trial (need regulatory EMEA changes )

4. Title: "Next Generation Sequencing platform for targeted Personalized Therapy of Leukemia“ Acronym: NGS-PTL Grant agreement: n. 306242 Call identifier: FP7-HEALTH-2012-INNOVATION-1 Funding scheme: Collaborative project EC contribution: 5,870,815 € Duration: 3 years (starting date: 1-11-2012) The NGS-PTL project: Project details

5. University of Turin (UNITO) Italy University of Bologna (UNIBO) Italy SINAPTICA IT SRL Italy Katholieke Universiteit Leuven (KU Leuven) Belgium University of ULM (UULM) Germany Masarykova Univerzita (MU) Czech Republic FASTERIS SA Switzerland Personal Genomics SRL Italy Fundacion De Investigacion Del Cancer De La Universidad De Salamanca (FICUS) Spain Muenchner LeukaemiaLabor GmbH (MLL) Germany Partners 5 academic partners + 5 SMEs

6. 1.To develop a European Hematological/NGS network of physicians and scientists. 2.To discover novel insights into the mechanisms involved in leukemogenesis and to develop genetic models that accurately define novel leukemia subtypes based on the genomic profile of individual patients. 3.To develop biostatistic and bioinformatic tools for coupling genomic data with clinical/molecular ones. 4.To develop “leukemia diagnostic panels” to drive personalized treatments and tailor therapies: 1.To different stratified groups of leukemia patients. 2.To treat elderly and unfit patients 3.To provide out come therapies (home sweet home) Objectives

7. Overall Workflow

8. Work plan WP Number WP Title Lead beneficiary WP 1Management & CoordinationUNIBO WP 2 Constitution of a European Hematological/NGS Platform UNIBO WP 3 Creation of a biological biobank & clinical Data Warehouse SINAPTICA IT WP 4 Identification of novel mutations & molecular profiles by exome and/or transcriptome NGS Personal Genomics WP 5 Screening of point mutations in candidate gene targets by amplicon NGS & DNA enrichment approach MLL WP 6 Identification of bone marrow & circulating miRNA and their association with clinical outcome UNITO WP 7 Translation of NGS data on industry applications FASTERIS SA WP 8Dissemination & ExploitationUULM 8 Work Packages (WPs) spanning a temporal frame of 36 months √ √

9. “Cloud” based “avatar” patient information suitable for home care therapy

11. Work plan ( first 8 months reports) WP Number WP Title Lead beneficiary WP 1Management & CoordinationUNIBO WP 2 Constitution of a European Hematological/NGS Platform UNIBO WP 3 Creation of a biological biobank & clinical Data Warehouse SINAPTICA IT WP 4 Identification of novel mutations & molecular profiles by exome and/or transcriptome NGS Personal Genomics WP 5 Screening of point mutations in candidate gene targets by amplicon NGS & DNA enrichment approach MLL WP 6 Identification of bone marrow & circulating miRNA and their association with clinical outcome UNITO WP 7 Translation of NGS data on industry applications FASTERIS SA WP 8Dissemination & ExploitationUULM 8 Work Packages (WPs) spanning a temporal frame of 36 months √ √ √ 200 Acute Myeloid leukemia 150 Acute Lymphoblastic Leukemia 130 CLL >600 hema disease.. √

12. Expected results The described work plan is expected to ensure: new knowledge of the etiology of hematological diseases and of the causes of within patient cohorts’ variability in response to treatments identification of novel diagnostic and prognostic biomarkers and/or genome-wide signatures able to allow an early diagnosis identification of innovative tools for patients’ stratification to guide the adoption of the most suited treatment for each leukemia patient identification and tweak of innovative tools aimed at finally including personalized medicine into routine clinical practice

13. The 'state of the art' in haematological personalized medicine research Hematopathology has advanced in parallel with technological developments that have expanded our understanding of the phenotypic, genetic, and molecular characteristics of the hematological neoplasms.

14. Discovery Gene/s candidate Screening, follow-up, clonal evolution, drug-resistance, risk-assessment, etc….. Diagnostics The future: CIRCULAR DNA ON BLOOD

15. Next Generation Sequencing Next Generation Sequencing and identification of genetic defect and possible target for personalized therapy CML and Acute Lymphoblastic Leukemia TP53 NOTCH1 FBXW7 IKZF1 BCR-ABL IL7R CRLF2 Acute Myeloid Leukemia TP53 IDH1/IDH2 EZH2 DNMT3A CEBPA CBL KRAS TET2 RUNX1 BCOR PML-RAR alpha MDS EZH2 IDH1 IDH2 TET2 SF1 SF3A1 SF3B1 U2AF1 ASXL1 CBL NPM1 Myeloprolipherative Disease and Ph- TP53 EZH2 IDH1 IDH2 TET2 CBL KRAS TP53 NOTCH1 (PEST) SF3B1 (HEAT) FBXW7 MYD88 XPO1 Multiple Myeloma TP53 B-RAF Hairy Cell Leukemia B-Raf Landscape of Somatic Mutations in Hema Neoplasms CLL Leukemia