1 / 25

Ramon V. Tiu, MD | July 12, 2013

Molecular Mutations in Myeloid Malignancies: Practical Applications in Clinical Hematology and Oncology . Ramon V. Tiu, MD | July 12, 2013. Objectives. To provide an overview of new genetic discoveries in Myeloid neoplasms To discuss the frequency of these mutations based on disease type

donnel
Download Presentation

Ramon V. Tiu, MD | July 12, 2013

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Molecular Mutations in Myeloid Malignancies: • Practical Applications in Clinical Hematology and Oncology • Ramon V. Tiu, MD|July 12, 2013

  2. Objectives • To provide an overview of new genetic discoveries in Myeloid neoplasms • To discuss the frequency of these mutations based on disease type • To discuss the emerging role of molecular mutations in prognosis, therapy and diagnosis in myeloid malignancies • To discuss the limitation in the interpretation of results from current studies • To provide some practical uses for molecular markers

  3. Genotypic Diversity in MDS Histone Modification • EZH2 • ASXL1 Somatic Mutations DNA Methylation • TET2 • IDH1/2 • DNMT3A Transcription Factors • RUNX1 • TP53 Cytogenetic Defects Germline Defects Epigenetic Modifiers Signal Transduction • NRAS • JAK2 • CBL RNA Splicing • SF3b1 • SRSF2 • U2AF1 MDS Variability in Treatment Responses Morphologic Differences Heterogeneity in Clinical manifestations Different Natural Histories Illustrated by Ramon V. Tiu

  4. Introduction Immunohistochemistry Cytogenetics Flow cytometry Microscopy 1982 1989 1992 1993 Prognostic Markers LDH BM fibrosis Hypercellularity ALIP Cytopenias BM Blasts Age Dysmega Dysgranulo Gender MC 1982 2002 2008 FAB Old WHO New WHO Classification Systems 1985 1989 1990 1992 1993 1997 2012 2007 Prognostic Scoring Systems IPSS-R IPSS Bournemouth Spanish Goasguen Dusseldorf Lille WPSS Excludes Cytogenetics Includes Cytogenetics Prepared by Ramon V. Tiu

  5. Frequency of molecular mutations By disease type † - 58% in UPD 11q ‡ - mainly in complex karyotype Tiu R et al. CurrHematolMalig Rep. 2011 Jun;6(2):126-35; Visconte V et al. Leukemia. 2012 May 15; Marcucci G et al. J ClinOncol. 2011 Feb 10;29(5):475-86; Bejar R N Eng J Med. 2011 Jun 30;364(26):2496-506..

  6. Impact on Prognosis Tiu R et al. CurrHematolMalig Rep. 2011 Jun;6(2):126-35; Visconte V et al. Leukemia. 2012 May 15; Marcucci G et al. J ClinOncol. 2011 Feb 10;29(5):475-86; Bejar R N Eng J Med. 2011 Jun 30;364(26):2496-506. Patel J et al. N Engl J Med. 2012 Mar 22;366(12):1079-89. Qian J et al. PLoS One. 2012;7(9):e45760

  7. Impact on Prognosis (MDS) Mutations in Lower Risk MDS by IPSS Overview: N=288, median ff-up 4.5 years, 22 molecular mutations evaluated. Treatment received not taken into account Bejar R et al. J Clin Oncol. 2012 Sep 20;30(27):3376-82.

  8. Impact on Prognosis (MDS) Bejar R et al. J Clin Oncol. 2012 Sep 20;30(27):3376-82.

  9. Predicting Therapeutic Response (MDS) Mutations in Patients treated with DNMT inhibitors Overview: N=92, 9 molecular mutations evaluated. Treatment with 5-azacitidine and decitabine were taken into account Favorable (Risk score= 0-9) Intermediate (Risk score= 10-13) Unfavorable (Risk score= >13) 37 months % Survival 24 months 4 months Overall Survival (months) Traina F et al. 53rd ASH Meeting Abstract 461 (Tiu Lab) 2011. Manuscript submitted

  10. 100% TET2 DNMT3A IDH1/2 ASXL1 EZH2 UTX RUNX1 p53 CBL RAS SF3B1 U2AF1 SRSF2 80% 60% 40% 20% Methylation Histone Transcription Signaling Spliceosome 0% Predicting Therapeutic Response (MDS) Patients Treated with 5-azacytidine and/or Decitabine % Response No Response Responded Wild Type Mutant % Mutations Wild type % of Patients Mutant TET2 DNMT3A IDH1/2 ASXL1 EZH2 UTX RUNX1 p53 CBL RAS SF3B1 U2AF1 SRSF2 Traina F et al. 53rd ASH Meeting Abstract 461 (Tiu Lab) 2011. Manuscript submitted

  11. 100% 80% 60% 40% 20% 100% 80% 0% 60% 40% 20% 0% Predicting Therapeutic Response (MDS) Genes Involved in DNA Methylation Pathway 5-azacytidine 5-azacytidine and/or Decitabine % Response p= 0.004 p= 0.005 p= 0.02 p= 0.006 No Response 30% 30% 34% 35% Wild Type Responded Mutant 69% 73% 67% 67% % Mutations % of Patients Wild type Mutant TET2/ DNMT3A/ IDH1/2 TET2/ DNMT3A TET2/ DNMT3A/ IDH1/2 TET2/ DNMT3A Traina F et al. 53rd ASH Meeting Abstract 461 (Tiu Lab) 2011. Manuscript submitted

  12. Predicting Therapeutic Response (MDS) Patients Treated with erythropoietin stim agents with or without G-CSF SF3B1 Mutant SF3B1 Wild Type Patients Response to Erythropoietin +/- G-CSF 15/19 (79%) P=.008 0/4 (0%) Response to lenalidomide underway underway Response to Decitabine/ Vidaza (our data shows better response and better survival after treatment with these agents in mutant cases) In-vitro Response to Erythropoietin +/- G-CSF underway underway Response to lenalidomide underway underway Response to Decitabine/ Vidaza Better response to decitabine in vitro in SF3B1 mutant Visconte V et al 54th ASH Meeting. Abstract 922

  13. Predicting Therapeutic Response (AML) Patel J et al. N Engl J Med. 2012 Mar 22;366(12):1079-89.

  14. Improving Diagnosis 60 SF3B1 Mutant Wild type 40 20 AML MDS Others MDS/MPN 0 0 sAML pAML 31% 21% 2.5% 5% 60 60 60 40 40 40 SF3B1 status 20 20 20 0 0 MDS-U 5q- RARS RCMD RCUD RAEB 1/2 MF ET/PV MCD* PNH AA/LGL RARS-T MDS/MPN-U CMML1/2 Visconte V et al Blood. 2012

  15. Improving Diagnosis Chronic cytopenias Molecular mutations can serve as clonal markers for disease + Chronic cytopenias Minimal dysplasia + + Minimal dysplasia MDS (Yes or No ?) Ring sideroblasts + + SF3B1 analysis may differentiate clonal causes of RS and non clonal causes of RS Normal karyotype Normal karyotype + Chronic alcohol intake

  16. Therapeutic Target Cell Killing by synthetic lethal approach Spliceosome inhibitor (MMA, Sudemycin) mut mut mut mut mut Preferential killing of heterozygous mutants Visconte V et al. Leukemia. 2012

  17. Current Limitations • MDS and AML are heterogeneous diseases • The impact of current MDS or AML treatments on status of molecular mutations is incompletely understood • Acquisition of Mutations is a dynamic process and other disease related factors may affect it. • The interpretation of the diagnostic, prognostic and predictive impact of these molecular mutations may not be the same when one use different genomic detection techniques. • There can be more than one mutation in the same patient or several mutations involving the same gene in the same patient.

  18. Current Limitations • MDS is a very heterogeneous disease • U2AF1 mutants do not have worse survival in del20q patients. p = .63 Tabarroki A et al. 54th ASH Meeting 2012. Abstract 3804.

  19. Current Limitations • Will it more meaningful to analyze mutations by pathway and in the context of therapy? Hasrouni E et al (Tiu Lab) . 54th ASH Meeting 2012. Abstract 3791.

  20. Current Limitations ASXL1 confers good prognosis in patients with MDS and MDS/MPN with Trisomy 8 Months from Diagnosis Patient #1 ASXL1 Cytogenetics /FISH Hemoglobin g/dL Months from Diagnosis Liu Y et al (Tiu Lab) . 54th ASH Meeting 2012..

  21. Current Limitations Months from Diagnosis Patient #2 Patient #2 ASXL1 Cytogenetics /FISH Hemoglobin g/dL Months from Diagnosis Liu Y et al (Tiu Lab) . 54th ASH Meeting 2012..

  22. Current Limitations • Impact on other treatment approaches like HCT Hamilton B et al (Tiu Lab). 54th ASH Meeting 2012. Abstract 1973.

  23. Current Limitations • Molecular mutations in MDS and AML are allowing us to better understand some of the pathogenesis of MDS and AML • Molecular Markers may allow us to better prognosticate patients with MDS and AML • Molecular markers may be helpful in guiding us in therapeutic decision making • New molecular mutations are opening new therapeutic options for patients with MDS (e.g. spliceosome inhibitors) • However, despite recent advances, there are still important limitations in interpreting the impact of molecular mutations in MDS and AML. Larger studies that takes into account important disease modifiers will need to be taken into account.

  24. Acknowledgements Our Patients Our Research/ Clinical Team Brian Bolwell, MD - Cancer Center Director (Cleveland Clinic) Yogen Saunthararajah, MD Saunthararajah Lab Reda Mahfouz Pathology James McMahon , MD Ramon V. Tiu Laboratory 1) Fabiola Traina, MD, PhD (Post-doc) - Completed now assistant professor 2) Valeria Visconte, PhD (post-doc) 3) Manoj Bupathi, MD (visiting resident) 4) Ali Tabarroki, MD (Post-doc) 5) Betty Hamilton, MD (Clinical Fellow) 6) Craig Portell, MD (Clinical Fellow) 7) Yang Liu (Medical student) 8) Edy Hasrouni (technician) Jaroslaw P. Maciejewski, MD, PhD Maciejewski Lab 1) Manuel Afable 2) Michael Clemente, MS 3) Kathryn Guinta Hematology/ Oncology Mikkael A. Sekeres, MD, MS Matt Kalaycio, MD Edward Copelan, MD Anjali S. Advani, MD Alan Lichtin, MD Bernard Silver, MD Leonard Horwitz, MD Ronald Sobecks, MD Hien K. Duong, MD Hematopathology Heesun J Rogers, MD, PhD Cytogenetics Shashirekha Shetty, PhD • Research Nurses • 1) Ricki Englehaupt, RN • 2) Joyce Juersivich, RN • 3) Kathleen Cooper, RN • 4)Tracy Cinalli , RN • 5) Kristin Dodd, RN Quantitative Health Sciences Paul Elson, ScD John Barnard, PhD Li Zhang, PhD

  25. Acknoweldgements Our Research/ Clinical Team Research Managers/ Coordinators Becky Habecker Cassie Kendeigh Sean Hobson Diane Banks Leslie Farhat Laura Bailey Madeline Schaub Bethann O’Brien • Collaborators: • 1) Fred Hsieh, MD Dept of Pathobiology • 2) Arthur Heuer, PhD CWRU • Molecular Genetics • Richard Padgett • Jarnail Singh Other Support Staff 1) John Desamito 2) JoAnn Bandera 3) Basel Rouphail 4) Ziad Chartouni

More Related