AML- new studies. Moderator Prof. Edo Vellenga. 1st author / speaker Mojca Jongen-Lavrencic

Transcription

1 AML- new studies Moderator Prof. Edo Vellenga 1st author / speaker Mojca Jongen-Lavrencic

2 Belangenverklaring In overeenstemming met de regels van de Inspectie van de Gezondheidszorg (IGZ) Naam: Organisatie: M.Jongen-Lavrencic Erasmus MC Kanker Instituut, Rotterdam 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:

3 Intensive chemotherapy cornerstone of AML treatment AML survival %

4 Survival of patients with AML in the Netherlands (NCR-population-based registry ) 100% Relative survival rates 80% 60% 40% 20% 0% Years after diagnosis years ( ) years ( ) >70 years ( ) years ( ) years ( ) >70 years ( )

5 Intensive chemotherapy cornerstone of AML treatment AML survival % (7+3) +?

6 Better survival of AML patients in geographic regions with high % of intensive treatment (The Swedish AML registry) allo-tx years Intensive chemo years High allo-tx % High Low Juliusson et al Blood 2012 Gunnar et al Blood 2009

7 In the recent decade increased % of patients receiving allo-hsct (NCR-population-based registry )

8 AML treatment discovery Hovon Auto-Tx Allo-Tx Vellenga et al Blood 2011 Cornelissen et al Blood 2007

9 AML treatment discovery Hovon approach AML survival 100% Early development - Refractory/relapse - Fit elderly - Unfit elderly - Poor/very poor Innovative phase III Up-front young (adult 65 y)

10 AML treatment discovery Hovon approach AML survival 100% Early development - Refractory/relapse - Fit elderly - Unfit elderly - Poor/very poor Phase I/II (targeted) H103 (octopus) New H? (epigenetic) H116 (post-allo-tx epigenetic)

11 Early development refractory/relapse Phase I/II leukemogenesis in 11q23 AML depends on MLL-fusion genes Krivtsov A et al NATURE REVIEWS cancer 2007

12 DOT1L inhibitor blocks MLL-fusion mediated histone methylation and oncogenes activation Targeted therapy Epizyme: EPZ-5676 Phase 1 Study Krivtsov A et al NATURE REVIEWS cancer 2007

13 Early development Fit Elderly H-103 DNR/ARA-C R DNR/ARA-C + Bevacizumab DNR/ARA-C + Lenalidomide Randomized Phase II Phase III Winner X vs Y DNR/ARA-C + Tosedostat DNR/ARA-C + drug X NEW!!!

14 XPO1 has a function in nuclear transport of tumor suppressors

15 XPO1 inhibitor resulting in accumulation of tumor suppressors in the nucleus inducing cancer cell death

16 AML treatment discovery Hovon approach AML survival 100% Early development - Refractory/relapse - Fit elderly - Unfit elderly - very poor/poor Phase I/II ---> DOT1L inhibitor Fit elderly H > XPO1 inhibitor Unfit elderly H? Very poor/poor H116

17 Early development Unfit Elderly H-? R Epigenetic therapy better survival? azacitidine decitabine

18 Tsai et al Cell Research 2011

19 Effect of demethylating single agents in AML is limited Decitabine Azacitidine Kantarjian et al JCO 2012 Fenaux et al JCO 2010

20 R 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 All randomized patients CYCLE 2 BM blasts < 5 % CYCLE 2 BM blasts 5 % CYCLE 2 Decitabine Decitabine Oral Combination Aza 300 mg: D1-14 Azacitidine therapy 75 mg/m more 2 : effective 20 mg/m 2 : 20 mg/m 2 : Lenalid. 10 mg: D1-21 D1-7 D1-5 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

21 R 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

22 Cornelissen et al JCO 2012 Early development very poor/poor AML allo-hsct significantly reduces relapse rate

23 Immuno-therapeutic effect of allogeneic HSCT also present in AML with very poor prognosis Cornelissen et al JCO 2012

24 Early development very poor/poor AML new allo-hsct approach H116 new conditioning regimen- to reduce GVHD post-tx epigenetic/immuno therapy

25 AML treatment discovery Hovon approach AML survival 100% Early development - Refractory/relapse - Fit elderly - Unfit elderly - very poor/poor Phase I/II ---> DOT1L inhibitor Fit elderly H > XPO1 inhibitor Unfit elderly H? ---> 5-aza/decitabine Very poor/poor H > panobinostat/decitabine post allotx

26 AML treatment discovery Hovon approach AML survival 100% New prognostic markers New techology Innovative phase III H132 (adult 65 y)

27 Primary study objectives H-132 part A of the study: - the effect of Lenalidomide when combined with remission induction chemotherapy as regards clinical outcome ( event-free survival ) part B/C of the study: - the effect of Lenalidomide for prevention of relapse after postremission autohsct or chemotherapy

28 HOVON-132/ SAKK 30/13 phase III study in AML/RAEB R Ara-C 200mg/m2 d1-7c.i. Idarubicin 12 mg/m2 3-hr d1-3 Ara-C 200mg/m2 d1-7c.i. Idarubicin 12 mg/m2 3-hr d1-3 Lenalidomide days 1-21 Ara-C 1000mg/m2 3-hr bid d1-6 Daunorubicin 60 mg/m2 iv d1, 3, 5 Ara-C 1000mg/m2 3-hr bid d1-6 Daunorubicin 60 mg/m2 iv Lenalidomide days 1-21 d1, 3, 5 Cycle III, autohsct R + Lenalidomide - Lenalidomide allohsct R + Lenalidomide - Lenalidomide

29 Risk Classification HOVON-132 at diagnosis GOOD INTERMEDIATE Cytogenetic abnormalities POOR Molecular abnormalities WBC VERY POOR Early CR

30 Molecular diagnostics AML1-ETO RQ-PCR CBFB-MYH11 RQ-PCR EVI1 overexpression RQ-PCR FLT3 TKD mutations Centralized New markers New technology (next gen seq) CEBPA mutations NPM1 mutations ASXL1 mutations TP53 mutations RUNX1 mutations FLT3-ITD ratio Biobanking Next generation sequencing GS junior system IonTorrent PGM

31 New poor prognostic markers- ASXL1 mutations

32 ASXL1 mutations - associatiated with poor survival Schnittger S et al Leukemia 2013

33 New poor prognostic markers- high FLT3 ITD/wild type allelic ratio FLT3 wild type reads FLT3 ITD/ wild type reads < 0.6 FLT3 ITD/ wild type reads > 0.6 FLT3 ITD/FLT3 wild type reads >0.6 13% (FLT3 ITD positive AML) app. 3.5% (all AML) Courtesy to Valk P 2013

34 Risk Classification HOVON-132 during treatment GOOD INTERMEDIATE POOR MRD - immunophenotype - NPM1 VERY POOR

35 Increased relapse incidence in immuno-mrd+ AML 1st 2nd 3rd GOOD INTERMEDIATE POOR Terwijn M et al JCO 2013

36 Increased relapse incidence in NPM1- MRD+ AML Krönke C et al JCO 2011

37 Risk Classification HOVON-132 Intermediate risk MRD based decision making (auto vs allo-tx)

38 AML treatment discovery Hovon approach AML survival 100% New prognostic markers ---> at diagnosis and during treatment (MRD) New techology ---> next gen seq Innovative phase III H132 (adult 65 y)

39 AML treatment discovery Hovon approach AML survival 100% New compounds New allo-hsct concept New prognostic factors Early development - Refractory/relapse - Fit elderly - Unfit elderly - Poor/very poor Innovative phase III Up-front young (adult 65 y)

40 Acknowledgements Hovon Leukemia working group Bob Löwenberg Gert Ossenkoppele Peter Valk Gerwin Huls Jan Cornelissen