MDS/AML and epigenetics

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

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

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

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

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

Euchromatin: active transcription Heterochromatin: no active transcription

What is epigenetics?

DNA methylation

Histon modifications Un-acetylated histons Acetylated histons

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

=> Apparently epigenetic changes are important and, more importantly, reversible Hochedlinger K. et.al. Genes Dev. 2004;18:1875-1885

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

Roleof epigeneticsin AML: many mutated genes involved in epigenetics N = 398 97.3% at leastonesomaticalteration Patelet al. NEJM, march2012

Roleof epigeneticsin MDS: many mutated genes involved in epigenetics Papaemmanuilet al. Blood. 2013.

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)

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

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

Efficacy of azacitidine and decitabine in AML AZA-001 trial: 20-30 % blasts (Fenaux et al., 2010) Decitabine trial (5 days) (Kantarjian et al., 2012)

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; 120:4850-4855 van der Helm, et al. J HematolOncol2013:6:29

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

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

Predictors of response / OS WHO performance score Score 0 1 2 0-1 2 - 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

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;114:2764-2773

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

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

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

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

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

Drugable targets in epigenetics

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 483:598-602

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

Targeting epigenetic readers: BET Bromodomain inhibition Ac K14 in H3 Delmore JE, et al. Cell 2011:146:904-917 Dawson MA, et al. Nature 2011:478:529-533 Zuber J, et al. Nature 2011:478:524-528 LockwoodWW, et al. PNAS 2012: epub

Bromodomain inhibitors in vivo

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