MDS/AML and epigenetics

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1 MDS/AML and epigenetics Moderator Prof.dr. J.H.E. Kuball 1st author / speaker Dr. G. Huls

2 Belangenverklaring In overeenstemming met de regels van de Inspectie van de Gezondheidszorg (IGZ) Naam: Organisatie: Gerwin Huls Radboud UMC Ik heb geen 'potentiële' belangenverstrengeling Ik heb de volgende mogelijke belangenverstrengelingen: Type van verstrengeling / financieel belang Naam van commercieel bedrijf Ontvangst van subsidie(s)/research ondersteuning: Ontvangst van honoraria of adviseursfee: Lid van een commercieel gesponsord speakersbureau : Financiële belangen in een bedrijf (aandelen of opties): Andere ondersteuning (gelieve te specificeren): Wetenschappelijke adviesraad: Johnson & Johnson and Celgene

3 MDS-AML epigenetics Papendal 2014 Dr. G. Huls, internist-hematoloog

4 What is epigenetics? How important is epigenetics? Drugs affecting epigenetics Clinical data/experience Future: new concepts

5 What is epigenetics? Epigenetic changes: heritable changes in gene expression which are reversible

6 Euchromatin: active transcription Heterochromatin: no active transcription

7 What is epigenetics?

8 DNA methylation

9 Histon modifications Un-acetylated histons Acetylated histons

10 How important is epigenetics(in leukemogenesis)? Reversibility: nuclear transfer experiment Number of mutations in AML: whole genome sequencing Mutations in genes involved in epigenetics

11 => Apparently epigenetic changes are important and, more importantly, reversible Hochedlinger K. et.al. Genes Dev. 2004;18:

12 Total 10 mutations: after sequencing of 1 AML -2 known (Flt3-ITD, NPM1) -8 unknown, however, also not detectable in 140 other AML samples -later mutated DNMT3a was found in this patient A stemcell divides every 38 days (mice): extrapolation would suggest 500 x during a human life 1 mutation for every cell division => 500 mutations 1% coding sequence => 5 mutations =>So epigenetic changes might be very important in leukemogenesis

13 Roleof epigeneticsin AML: many mutated genes involved in epigenetics N = % at leastonesomaticalteration Patelet al. NEJM, march2012

14 Roleof epigeneticsin MDS: many mutated genes involved in epigenetics Papaemmanuilet al. Blood

15 Drugs affecting epigenetics Currently 4 FDA-approved drugs: DNA methyltransferase inhibitors: 5-azacitidine (Vidaza) 2-deoxy-5-azacitidine (Decitabine = Dacogen) HDAC inhibitors: SAHA (suberoylanilide hydroxamic acid) (Zolinza) Romidepsin(Istodax)

16 Hypomethylating therapy Unmethylated DNA: active transcription Methylated DNA: Deacetylated DNA: no transcription demethylases DNA methyltransferases HDAC complex Chromatine condensation

17 Efficacy of azacitidine and decitabine in MDS AZA-001 trial (Fenaux et al., 2009) Decitabine trial (3 days) (Lubbert et al., 2011)

18 Efficacy of azacitidine and decitabine in AML AZA-001 trial: % blasts (Fenaux et al., 2010) Decitabine trial (5 days) (Kantarjian et al., 2012)

19 Conventional chemo vs epigenetic therapy (n=26) AML-M3 (n=97) Vidaza Intensive chemotherapy BSC UMCG experience: n=227; consecutiveaml patients, 60 years Quintas-Cardama A, et al. Blood 2012; 120: van der Helm, et al. J HematolOncol2013:6:29

20 Efficacy of decitabine in AML: 10 days schedule Decitabine (10 days) (Blum et al., 2010)

21 Predictors of response Disease associated factors? Patient associated factors (performance)? Methylome? Mutations in genes involved in epigenetics?

22 Predictors of response / OS WHO performance score Score Circulating blasts no yes - RBC transfusion dependency no yes - Cytogenetic risk low int high Low (score = 0) Intermediate (score = 1-3) High (score = 4-5) Itzykson et al., 2011

23 DNA methylation and clinical response? No direct link! Currently no established DNA methylation biomarkers that accurately predict patient responses Fandy T E et al. Blood 2009;114:

24 Azacitidine: predictors of response Platelet doubling after the first cycle of Azacitidine. Van der Helm et al., 2011

25 Predictivevalueof a DNMT3a ortet2mutations in AML/MDS treated with Decitabine or azacitidine Cohort of 46 AML patients 8 (17%) DNMT3a mutations Response on decitabine Cohort of 86MDS + AML patients 13(15%) TET2 mutations Response on azacitidine CR NO CR DNMT3a 6 2 mutated [p=0.05] NPM1 6 3 mutated [p=0.13] DNMT3a and 5 0 NPM1 [p=0.008] mutated TET2 mutated 3 5 [p=1.0] Metzeler et al., Leukemia, 2012 CR NO CR TET2 5 8 mutated [p=0.17] Overall response (=CR, PR, mcr) NO CR TET2 9 4 mutated [p=0.01] Itzykson et al., Leukemia, 2011

26 Future studies with azacitidine and decitabine in AML / MDS EORTC: phase III: 3+7 vs 10-day Decitabine HOVON: unfitolderaml: octopus design: Options: 10-day Decitabine; Azacitidine sc; Azacitdine oral + lenalidomide

27 All randomized patients CYCLE 1 R All randomized patients CYCLE 1 Ara-C 200mg/m 2 : D1-7 Daunorubicin 60 mg/m 2 : D1-3 PD Treatment off protocol Decitabine 20 mg/m 2 : D1-10 BM blasts < 5 % AND Neutro > 1000; OR BM blasts 5% independent of Neutro CYCLE 2 Ara-C 200mg/m 2 : D1-7 Daunorubicin 45 mg/m 2 : D1-3 PD BM blasts < 5 % CYCLE 2 Decitabine 20 mg/m 2 : D1-5 BM blasts 5 % CYCLE 2 Decitabine 20 mg/m 2 : D1-10 BM blasts < 5 % AND Neutro > 1000 CYCLE 3 (mandatory), CYCLE 4 (optional) CR or PR BM blasts < 5 % CYCLE 3 BM blasts 5 % CYCLE 3 Ara-C 100mg/m 2 : D1-5 Idarubicine 8 mg/m 2 : D1,3,5 Etoposide 100mg/m 2 : D1-3 Allogeneic HCT Decitabine 20 mg/m 2 : D1-5 Decitabine 20 mg/m 2 : D1-10 No maintenance Decitabine continuation 20 mg/m 2, D1-5, q4w till progression

28 R Proposal Octopus All randomized patients CYCLE 1 Oral Aza 300 mg: D1-14 Lenalid. 10 mg: D1-21 All randomized patients CYCLE 1 Azacitidine 75 mg/m 2 : D1-7 All randomized patients CYCLE 1 Decitabine 20 mg/m 2 : D1-10 All randomized patients CYCLE 2 Oral Aza 300 mg: D1-14 Lenalid. 10 mg: D1-21 All randomized patients CYCLE 2 Azacitidine 75 mg/m 2 : D1-7 BM blasts < 5 % CYCLE 2 Decitabine 20 mg/m 2 : D1-5 BM blasts 5 % CYCLE 2 Decitabine 20 mg/m 2 : D1-10 All randomized patients CYCLE 3 Oral Aza 300 mg: D1-14 Lenalid. 10 mg: D1-21 All randomized patients CYCLE 3 Azacitidine 75 mg/m 2 : D1-7 BM blasts < 5 % CYCLE 3 Decitabine 20 mg/m 2 : D1-5 BM blasts 5 % CYCLE 3 Decitabine 20 mg/m 2 : D1-10 Oral Aza 300 mg: D1-14 Lenalid. 10 mg: D1-21 till progression Azacitidine continuation 75 mg/m 2, D1-7, q4 w till progression Decitabine continuation 20 mg/m 2, D1-5, q4 w till progression

29 Drugable targets in epigenetics

30 Targeting epigenetic writers: blocking writers: DOT1L inhibition Daigle SR et al. Cancer Cell 2011:20:53-65 BerntKM et al. CancerCell2011: 20:66-78 Onder TT et al. Nature 483:

31 Dawson M. et al. NEJM 2012:367:647 Epigeneticreaders

32 Targeting epigenetic readers: BET Bromodomain inhibition Ac K14 in H3 Delmore JE, et al. Cell 2011:146: Dawson MA, et al. Nature 2011:478: Zuber J, et al. Nature 2011:478: LockwoodWW, et al. PNAS 2012: epub

33 Bromodomain inhibitors in vivo

34 Conclusion Epigenetics important in oncogenesis Epigenetics: reversible control of transcription New promising drugs in MDS/AML affecting epigenetics Requires different clinical thinking New insightsin epigeneticregulation(writers/erasers/readers) offers opportunities for drug development Preventingtranscriptionof c-myc(and bcl2) byinterferingwithbrd4 binding to acetylated H3K14 is very promising in pre-clinical models