Management of Myelodysplastic Syndromes Peter L. Greenberg, MD Stanford Cancer Institute
Myelodysplastic Syndromes: Clinical & Molecular Advances for Disease Classification and Prognostication
MDSs: A Spectrum of Diseases Clinical heterogeneity (0.8-8.0 yr median OS) Marrow morphology: % blasts, dysplasia, fibrosis, ring sideroblasts, cellularity Hematopoietic Progenitor Cells/Blast Immunophenotype/Flow cytometry Prognostic classifications IPSS, WPSS, IPSS-R Therapeutic options/responses Biologic heterogeneity marrow stems & stroma Cytogenetic, Molecular Immunologic, Phagocytic, Aberrant Cytokines
Primary MDS 30% 40% t-mds 9% 4% 12% 22% 8% 75% Normal karyotype Balanced abnormalities Other unbalanced abnormalities Abnormal chromosome 5 and/or 7 Olney & LeBeau, 2006
Bejar & Steensma, Blood 2014
MDS Morphologic Classifications Marrow Blasts WHO/NCCN 2015 <5% RARS RCUD, MDS U del(5q) RCMD 5 9% 10 19% RAEB 1 RAEB 2 20 30% AML MLD/RAEB T >30% AML/AML
IWG-PM/IPSS-R 11 Countries: 7012 patients Austria Brazil Czech Rep France Germany Italy Japan Netherlands Scotland Spain USA
IPSS-R: Predictive Features for Disease Status Advances Beyond the IPSS IWG-PM, Greenberg et al, Blood 9/12, n=7012 Bone marrow blasts: or >10% Cytogenetic groups: 5 groups/16 types Depth of abnormal blood counts hemoglobin, neutrophils, platelets Age Other predictors performance status, serum tests (ferritin, LDH)
IPSS-R Cytogenetic Prognostic Groups Blood 9/12, n=7012 Very Good: Y, 11q Good: Nl,20q,5q,12p Int: +8, +19, i(17q), 7q, 1 or 2 other clones Poor: 7,double w/ 7q, der(3), Complex (3abn) Very Poor: Complex >3
IPSS R Prognostic Risk Based Categories Survival Freedom from AML Evolution Years Years IWG-PM, Blood 9/2012; http://advanced.ipss-r.com
t-mds & IPSS-R: Clinical Outcomes Probability Alive Very low Low Intermediate High Very High Probability Not Dead from Disease Very low Low Intermediate High Very High Cumulative incidence to leukemic evolution Very low Low Intermediate High Very High Overall Survival (years) Disease Specific Survival (years) Time (year) Ok CY et al, Leukemia 28:185, 2014; n=411 (MDA & MGH)
IPSS-R: OS t-mds vs de novo MDS Ok CY et al, Leukemia 28:185, 2014; n=411 (MDA & MGH)
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NCCN: APPROACHES FOR MANAGEMENT OF MDS Clinically Relevant Cytopenia(s) Age: > 60 years old Performance Status: Excellent, Good, Poor Prognostic Risk Category (IPSS/WPSS/IPSS R): Lower risk (Very Low,Low,Intermediate): Hematologic improvement Higher risk (Intermediate,High,Very High): Alter disease natural history HSCT candidate: Prognostic Risk Category, Age, PS, Donor NCCN Guidelines, Version 1.2016, www.nccn.org
MDS: Biospecific & Risk-Stratified Rx
Molecular Mechanisms in MDS Pathogenesis Mutations/deletions/epigenetic modulation of critical genes Recurrent driver genes defined Defective DNA repair/genomic instability Altered telomere dynamics mirna dysregulation Altered ribosomal function Deregulated signaling pathways/rna expression Abnormal transcriptional mrna splicing
Gene Mutations: Clinical Implications Multiple recurrent gene mutations within various functional families Patterns of cooperation/mutual exclusivity Present on MANY chromosomal loci Present w/ or w/o cytogenetic abnormalities Specific clinical features Prognostic implications from ~25+ genes Sequential/number of events critical CMML: 93% w/ 1 of 9 mutations RARS/RARS T:>67% w/ SF3B1m
Mutational Landscape in MDS ~90% pts have 1 oncogenic mutation 4 6 consistent mutations in only ~10% pts ~50 100 genes less frequently mutated ~25 gene mutations prognostic 2 3 driver genes at presentation w/ clonal evolution 100s associated passengers Genotype/phenotype associations SF3B1:RARS; TET2/SRSF2:CMML
MDS: Incidence of Recurrent Mutations NCCN Practice Guidelines, Version 1.2016 >20%: TET2^, SF3B1, ASXL1^ 10 20%: DNMT3A, RUNX1, SRSF2^ 5 10%: TP53, EZH2^, NRAS^, U2AF1, ZRSR2 <5%: CBL^, SETBP1^, IDH1/2, ETV6, JAK2, ^: more frequent in CMML
Recurrent Mutations in MDS Exclusivity/Cooperative Patterns Walter M et al, Leukemia 2013
Recurrent Mutations in MDS and AML: Differing Incidence Walter M et al, Leukemia 2013
MDS: Recurrent Gene Mutations Associated with Poor Prognosis Signaling/different n Cell cycle regulators Apoptosis Translation Transcription Epigenetic regulators Cohesin complex RAS, RUNX1* ^, ETV6* ; FMS, FLT3, SETBP1^,CUX1 TP53*, NPM1 BCL2 RPS14,L23,S4X,S25,S19 mrna splicing: SF3B1nm, SRSF2nm^,U2AF1,ZRSR2 TET2nm ^, DNMT3A ASXL1*^, EZH2* ^,BCOR * Bejar et al, NEJM 2011, Haferlach et al, Leuk 2014 ^ also for CMML
Temporal Order of Gene Mutations with Pairwise Precedences Papaemannuil et al, Blood 122:3616, 2013; n= 313
LFS Relative to Number of Oncogenic Mutations Papaemannuil et al, Blood 2013; n= 595
TP53 Mutations in MDS Kulasekararaj et al, BJHaem 2013, n=318 (NGS) Percent of Patients
Clinical Impact of TP53 Mutations in MDS Kulasekararaj et al, BJHaem 2013 OS: All Patients PFS: All Patients OS: Poor Risk Cytogenetics OS: 5q- alone
AML: Distinct Patterns of Mutations I: Secondary AML type (post MDS/CMML) SRSF2, ST3B1, U2AF1, ZRSR2, ASXL1, EXHE, BCOR, STAG2 II: De novo AML type NPM1, MLL/11q23 & CBF rearrangements III: TP53 mutation type Complex karyotype, OS (Non specific Pan AML mutations: DNMT3A, TET2, IDH1/2, WT1, RUNX1, CEBPA, GATA2, RAS, FLT3)
EFS of Genetically Classified de novo AML Lindsely et al, Blood 2015
AML: Gene Ontogeny Classification Gene mutations identify subsets of de novo w/ poor prognosis 8 gene mutations specific for secondary AML Early drivers, dysplasia, persist in CR Elderly, poorer outcomes ~30% de novo AML progressed from MDS Later mutations w/ progression, absent in CR Some AML akin to MDS Risk stratify heterogeneous de novo AML
Secondary MDS Genes Associated with Poor Prognosis Signaling/different n Cell cycle regulators Apoptosis Translation Transcription Epigenetic regulators Cohesin Complex RAS, RUNX1, ETV6; FMS, FLT3, SETBP1,CUX1 TP53, NPM1 BCL2 RPS14;L23,S4X,S25,S19 mrna splicing: SF3B1nm, SRSF2nm,U2AF1,ZRSR2 TET2nm, DNMT3A ASXL1, EZH2, BCOR
Age Related Prevalence of Somatic Mutations: Clonal Hematopoiesis w/ Indeterminate Potential Jaiswal Ebert, New Eng J Med 12/14, n=17,182 Normals DNMT3A TET2 ASXL1
Spectrum of Clonal Hematopoiesis, ICUS & MDS ICUS CHIP CCUS Lower Risk MDS Higher risk MDS Clonality + + + + Dysplasia + + Cytopenias + + + + BM Blast % <5% <5% <5% <5% (<10%) <19% (<30%) Overall Risk Very Low Very Low Low (?) Low High Treatments Obs/BSC Observation Obs/BSC/GF Obs/BSC/GF HMA/HSCT /IMiD/IST
Heterogeneity of Cytogenetic Loci for Recurrent Mutations in MDS Xp: ZRSR2, BCOR Xq: STAG2 1p:NRAS,WT1;1q:SETB1 2p: DNMT3A 2q: SF3B1,IDH1 3q: GATA2,EVI1 4q: TET2 5q: RPS14, NPM1 7q: CUX1, EZH2 10q: SMC3 11q: CBL 12p:ETV6; 12q: PTPN11 15q: IDH2 17p: TP53 17q: SRSF2 19q: UAF2 20q: ASXL2 21q: RUNX1
MDS: Defective DNA Damage Repair Age related hemopoietic DNA damage repair Inherited mutations α premature aging & MDS [ATM, Fanconi, Li Fraumeni (TP53), XP, Werners] Expression & polymorphisms of DNA repair genes Murine models of MDS of Δ HSC function MDS related cytogenetic/molecular Δ Microsatellite instability ( mismatch repair) Marrow microenvironmental factors Inhibitory cytokines, toxic oxidants
Cellular Responses to DNA Damage in MDS Zhou et al, Int J Mol Sci 16:966, 2015
Nobel Prize in Chemistry 2015 DNA Damage Repair Tomas Lindahl, Crick Institute, UK Cellular repair of DNA damage Paul Modrich, Duke DNA repair mechanisms during cell replication Aziz Sancar, U North Carolina DNA damage repair after irradiation
Testing for Recurrently Mutated MDS Genes NCCN Guidelines, Version 1.2016, www.nccn.org Consider in the appropriate clinical context Can establish clonal hematopoiesis Somatic (vs germline variants) NOT DIAGNOSTIC of MDS w/o other Dx criteria No mutation specific for MDS/± Age related Not all MDS patients have mutations Specific mutations are PROGNOSTIC Need confirmation, extension (IWG PM Molecular Project)
Future MDS Molecular Classifications Diagnostic/Adjuncts to Clinical Features Specificity vs Non clonal cytopenias ( mimics ) Polymorphisms α disease susceptibility Prognostic/Adjuncts to Clinical Features Specific mutations & number of abnormalities Predictive of treatment response IWG PM/Molecular global project Pathogenetic Driver vs passenger mutations Gene expression, signaling pathways, epigenetic Δ Therapeutic Identify biospecific targets
MDS: Directions Clinical Re structure classification & treatment Use clinical + adjunctive molecular features Improve biospecific treatment approaches Comparative trials based on molecular findings Biologic Focus on molecular Δ/gene expression of stem & stromal targets Economic Broad based forums warranted to evaluate cost effectiveness & potentially decrease costs
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