Acute Promielocytic Leukemia APL 0406 Study Acute Promyelocytic Leukemia Low/intermediate risk patients (WBC ≤10 x 109/L) R ATRA + ATO (No chemo!) ATRA + Chemotherapy Overall Survival 98.7% Overall survival probability 91.1% ATRA+ATO ATRA+Chemo p = 0.02 Months from diagnosis Next Generation Sequencing and identification of genetic defect and possible target for personalized therapy CLL Leukemia Multiple Mieloma TP53 NOTCH1 (PEST) SF3B1 (HEAT) FBXW7 MYD88 Hairy XPO1 TP53 B-RAF Cell Leukemia Next Generation Sequencing MDS EZH2 IDH1 IDH2 TET2 SF1 SF3A1 SF3B1 U2AF1 ASXL1 CBL NPM1 B-Raf Myeloprolipherative Disease and PhTP53 EZH2 IDH1 IDH2 TET2 CBL KRAS Acute Myeloid Leukemia CML or Acute Lymphoblastic Leukemia TP53 NOTCH1 FBXW7 IKZF1 BCR-ABL IL7R CRLF2 TP53 IDH1/IDH2 EZH2 DNMT3A CEBPA CBL KRAS TET2 RUNX1 BCOR PML-RAR alpha Imatinib Changed the Therapeutic Landscape for Patients With Ph+ CML Best available therapy Imatiniba IFN- or SCT plus 2nd-line imatinibb IFN- or SCTc IFN- Hydroxyurea Busulfan (All Ph+ CML Disease Phases) Survival Probability 1.0 0.9 2002-2008, imatiniba 0.8 0.7 5-year OS 2010 93% 71% 63% 53% 46% 38% 2000 1997-2008, IFN- or SCT plus 2nd-line imatinibb 0.6 1990 0.5 1995-2008, IFN- or SCTc 0.4 1980 0.3 1986-2003, IFN- 0.2 1983-1994, Hydroxyurea 0.1 1970 1983-1994, Busulfan 0.0 0 2 4 6 8 10 12 14 Years After Diagnosis 16 18 20 22 1960 aCML IV; bCML IIIA; cCML III. IFN-, interferon-alpha; OS, overall survival; SCT, stem cell transplant. Adapted from R. Hehlmann, German CML Study Group. 7 Landscape of Somatic Mutations in Lymphoid Neoplasms Acute Lymphoblastic Leukemia Acute Myeloid Leukemia CLL BCR-ABL like ALL Rossi et al. Blood 2012 Novel rearrangements, copy number alterations, and sequence mutations constitutively activating kinase signaling and dysregulating cytokine receptor signaling. New assessment risk based on genetic alterations New target for new therapy Genotype-based specific treatment in AML APL [t(15;17)] ATO + ATRA APL0406 GIMEMA/AMLSG/DSIL CBF-AML Dasatinib AMLSG 11-08 FLT3-ITD PKC412 AMLSG 16-10 NPM1mut ATRA +/- GO AMLSG 09-09 Molecular Diagnostics 48h* All others such as • CN-AML (triple neg) • various • MDS-related AML Courtesy of Lars Bullinger Azacitidine + intensive induction Allogeneic transplant-strategy Azacitidine maintenance AMLSG 12-09 Clofarabine + ARAC + Idarubicin AMLSG 17-10 Personalized Therapy: a new horizon to get the right target gene(s) for the right therapy, for right patient “at the right dosage” Modified from Modern Pathology (2013) 26, S97–S110, Iacobucci I et al. Curr Cancer Drug Targets. 2013 Association among SNPs and liver toxicity The genotyping profile of 63 patients without liver toxicity (70%) was compared to that of 28 patients (30%) with grade I/II liver toxicity. 10,463 T>C (rs2515641) -333 T>A (rs2070673) CYP2E1 2 1 3 4 5 6 7 8 9 10 11 10q24.3-qter Gene and variant Allele Freq. Allele Freq. No Toxicity Grade I/II Toxicity Allele Chr. Position CYP2E1 -333 T >A (rs2070673) A 10 135190557 0.23 CYP2E1 10463 T>C, F421F (rs2515641) T 10 135201352 0.17 Fisher p value OR 0.04 0.001 0.13 0.02 0.003 0.09 Suggestions for discussion • As EHA Association we strongly belive that hematological diseases are probably the best suitable model for diffuse patients oriented personalized therapy. • My short presentation of “state of the art” and NGS-PTL project and especially of the new frontiers in blood cancer research strongly suggests that EHA and European haematologists researcher are proud to have increased so much in the last years a “real” applied personalized therapy, to have improved the diagnostic tools for better stratification of leukemic groups, and to have extensively use of target therapy. • Haematology and their research are “fit” with the H2020 and with EAPM aims to improve patients survival with targeted and personalized (individualized) therapy but need for more research funding, more easier access to academic sponsored innovative clinical trials, more regulatory support for conducing “patients oriented” therapy. • We need research funding for blood cancers: it looks like Horizon 2020 gives better opportunities, but these must be translated into call texts. The personalized “avatar” “Avatar” Diagnosis: es. BCR-ABL1 like ALL for each haematological patient to get right target therapy, in a correct dosage, (possible at home) 1 week work Genome Analyzer II (Illumina/Solexa)/Roche 454 reads for each gene CURE diagnosis relapse RNA/DNA Simulation or Extra Rapid (mins not months) Computer assisted decision, Bioinformatics NGS analysis in vitro identification of new drugs, etc. ( e.g. KNOME analysis) Design and apply experimental “individual” done by a medical doctor and personalized “Back to bed, soon” clinical trial (need regulatory EMEA changes ) 1 day work Individual new therapy Old therapy combined with new (eg.TKI) therapy Old Classic therapy + ? (ex. Tki, Antibiotic, Vitamin,..) Individual New Target(s) Conclusions The identification of novel diagnostic and prognostic biomarkers, identified through the genomic and transcriptomic signatures, is expected to guide tailored approaches to hema/leukemia and to improve unified deep analysis of He,matological disease complexity as well as the anti-leukemia therapeutic success, guaranteeing the sustainability and efficiency of the healthcare system. unique footprints common path to cure