Concepts in AML Treatment. The AMLSG Genotype-adapted Approach

Transcription

1 Concepts in AML Treatment The AMLSG Genotype-adapted Approach Richard F. Schlenk, M.D. Co-Chair German-Austrian AMLSG Co-Chair German MPN-SG Head of Phase I/II Unit Head of Clinical Trials Office Head of Hematology Lab Department of Internal Medicine III University Hospital of Ulm

2 AMLSG Biomarker-Driven Treatment Trials Intensive Treatment APL [t(15;17)] ~10% CBF AML ~13% ATO+ATRA APL0406 GIMEMA / AMLSG / SAL Dasatinib AMLSG AML FLT3-ITD ~20 % Midostaurin AMLSG Molecular Screening hrs AML NPM1 mut ~17% ~35% Other subtypes (mainly high-risk) ATRA +/- GO AMLSG Azacitidine + induction, Allo HSCT (1 st priority), or HiDAC + AZA maintenance AMLSG C-IARA (Clofarabine), Allo HSCT (or HiDAC) AMLSG 13-09

3 AMLSG Biomarker-Driven Treatment Trials Non-Intensive Treatment A-EC A-EC A-EC A-EC A-EC A-EC NPM1 mut R AMLSG EC EC EC EC EC EC Molecular Screening hrs NPM1 wt AMLSG DECIDER R Decitabine Cycle 1-4 Decitabine Cycle VPA Decitabine Cycle ATRA Decitabine Cycle ATRA + VPA

4 AMLSG BiO Registry: Fast Biomarker Screening AMLSG Trial Centers AMLSG BiO registry 0 Informed Consent Courier Express BM&PB samples Reference Lab Molecular screening -PML-RARA -RUNX1-RUNX1T1 -CBFB-MYH11 -NPM1 -FLT3-ITD -FLT3-TKD -MLL-AF9 -CEBPA Web-based system Trial Center Clinical Trial Informed Consent Standard Care Hours Overnight hrs / 7d week

5 AMLSG BiO Registry: Fast Screening Within 48 hours 1.Flowcytometry 8-10 color analyses 2.Molecular screening PML-RARA RUNX1-RUNX1T1 CBFB-MYH11 NPM1 FLT3-ITD FLT3-TKD MLL-AF9 CEBPA Within 7 days 3.Cytogenetics All Reports are available directly in advance by Fax Final reports are send out by regular mail Bone marrow cytology will be integrated into the concept in mid 2013

6 Phase IB/II Study of Chemotherapy + Dasatinib in Patients with Newly Diagnosed Core-Binding Factor (CBF) AML - AMLSG Induction Consolidation x 4 Maintenance CBF Mutation Screening Within 48 Hours Daunorubicin Cytarabine + Dasatinib Phase IB n=89; Phase II n=132 High-Dose Cytarabine* + Dasatinib Dasatinib 1 year Companion studies, e.g.: Gene mutation analyses Minimal residual disease assessment (RQ-PCR) Pharmacodynamics studies (KIT plasma inhibitory activity) * Cytarabine: 18-60yrs: 3g/m 2, q12hr, d1-3; >60yrs: 1g/m 2, q12hr, d1-3 ClinicalTrials.gov Identifier: NCT (AMLSG), NCT (CALGB) PI: H. Döhner; supported by BMS

7 Phase II Study of Chemotherapy + Midostaurin Followed by Allogeneic HSCT and Midostaurin Maintenance in AML with FLT3-ITD (18-70 yrs) AMLSG Trial 1 st priority FLT3-ITD Mutation Screenin g Within 48 Hours n=142 Dauno Cytarabine midostaurin* High-Dose Cytarabine** Early Allogeneic HSCT 2 nd priority 3x High-Dose Cytarabine 1-yr maintenance Start: 30 d after allo 1-yr maintenance * Midostaurin: start on day 8, thereafter continuous dosing **Optional 1 st consolidation before allo HSCT ClinicalTrials.gov Identifier: NCT PI: R.F. Schlenk; supported by Novartis

8 AMLSG Trial: Pharmacodynamic Study of FLT3 Plasma Inhibitory Activity (PIA)* 1 st priority FLT3-ITD Mutation Screenin g Within 48 Hours Plasma sampling for PIA assay n=142 Dauno Cytarabine midostaurin* High-Dose Cytarabine** d0 d15 d28 d15 d28 Early Allogeneic HSCT 2 nd priority 3x High-Dose Cytarabine 1-yr maintenance Start: 30 d after allo 3-monthly 1-yr maintenance d15 d35 3-monthly * Levis M, et al. Blood. 2006;108:

9 Plasma Inhibitory Activity (PIA) Assay Incubation with MOLM 14 (FLT3-ITD positive AML cell line) Plasma collected during each cycle of TKI treatment Patient takes tyrosine kinase inhibitor (TKI) orally Western blot analysis and densitometry of immunoblots Advantages: in vitro target monitoring using surrogate biological material independent from myeloid blast cells read out for individual variable protein binding Levis M, et al. Blood. 2006;108:

10 Phase III Study of Chemotherapy in Combination with ATRA with or without Gemtuzumab Ozogamicin (Mylotarg) in Patients with NPM1 mut Acute Myeloid Leukemia AMLSG Induction x2 Consolidation 1 Consolidation 2+3 NPM1 Mutation Screening Within 48 Hours R ATRA-ICE n=276 (expected: 09/2013) ATRA-ICE +GO ATRA Cytarabine* ATRA Cytarabine* +GO ATRA Cytarabine* ATRA Cytarabine* All adult patients eligible for intensive therapy, no upper age limit * Cytarabine: 18-60yrs: 3g/m 2, q12hr, d1-3; >60yrs: 1g/m 2, q12hr, d1-3 PI: R.F. Schlenk; supported by Pfizer and Else Kröner-Fresenius-Foundation

11 AML with Mutated NPM1 in Older Patients >60 yrs Incidence 24% all, 43% CN-AML Schlenk RF, Döhner K, et al. Haematologica % probably CN-AML Büchner T, et al. J Clin Oncol % CN-AML Becker H, et al. J Clin Oncol Response to intensive induction OR, 3.17; 95%-CI, Schlenk RF, Döhner K, et al. Haematologica % CR rate Becker H, et al. J Clin Oncol. 2009

12 Treatment Schedules: AMLSG Arm A-EC*: Cytarabine 20 mg s.c. bid on days 1 to 7 Etoposide 50 mg/m² cont. i.v. on days 1 to 3 # ATRA 45 mg/m² p.o. on days 8 to 28 Arm EC*: Cytarabine 20 mg s.c. bid on days 1 to 7 Etoposide 50 mg/m² cont. i.v. on days 1 to 3 # * For a maximum of 6 cycles in the absence of progressive disease, repeated between day 29 and 43. # Starting with cycle 2 etoposide 100mg/die p.o. day 1-3

13 German-Austrian Acute Myeloid Leukemia Study Group Ubbo-Emmius-Klinik Aurich HELIOS Klinikum Bad Saarow Charité Berlin Vivantes Klinikum Neukölln, Berlin Klinikum Bochum Marienhospital Herne, Bochum-Herne University of Bonn Städtisches Klinikum Braunschweig Klinikum Bremen Klinikum Darmstadt University of Düsseldorf Klinikum Essen-Werden Klinikum Esslingen St. Franziskus-Hospital Flensburg Klinikum Frankfurt Höchst University of Freiburg Klinikum Fulda University of Gießen Wilhelm-Anton-Hospital Goch University of Göttingen University of Hamburg Krankenhaus Altona, Hamburg Klinikum Hamm Klinikum Hanau Klinikum Hannover Siloah Hannover Medical School SLK Kliniken Heilbronn University of Homburg University of Innsbruck Klinikum Karlsruhe University of Kiel Caritas Krankenhaus, Lebach Klinikum Lemgo Krankenhaus der Barmherzigen Schwestern Linz Krankenhaus der Elisabethinen Linz Klinikum Lüdenscheid University of Magdeburg University of Mainz Klinikum Minden Technical University of München Klinikum Schwäbisch-Gmünd Lukaskrankenhaus Neuss Klinikum Oldenburg Pius-Hospital Oldenburg Klinikum Passau Elisabeth Krankenhaus Recklinghausen Caritas-Klinik St. Theresia, Saarbrücken Salzburger Landeskliniken Klinikum Sindelfingen-Böblingen Klinikum Stuttgart Diakonie-Klinik, Stuttgart Klinikum Traunstein Krh. der Barmherzigen Brüder, Trier University of Tübingen University of Ulm Klinikum Villingen-Schwenningen Hanuschkrankenhaus, Wien HELIOS Klinikum Wuppertal Dr. Reichert, Dr. Janssen Dr. Reichardt PD Dr. Westermann, Prof. Dr. Dörken Prof. Dr. de Wit Dr. Teschendorf, Prof. Dr. Schmiegel Prof. Strumberg, Dr. Schultheis Prof. Dr. Brossart, PD Dr. v. Lilienfeld-Toal, Prof. Dr. Schmidt-Wolf Dr. Kersten, Prof. Dr. Krauter Prof. Dr. Hertenstein, Dr. Thomssen Prof. Dr. Bernhard, Dr. Kayser Prof. Dr. Germing, PD Dr. Kündgen, Prof. Dr. Haas PD Dr. Reimer, Dr. Wattad Dr. Schwänen, Prof. Dr. Geißler Prof. Dr. Basara Prof. Dr. Derigs, Dr. Östreicher Prof. Dr. Lübbert, Prof. Dr. Duyster Dr. Distelrath, Prof. Dr. Höffkes Dr. Tschischka, Dr. Burchardt, Prof. Dr. Rummel Prof. Dr. Runde, Dr. Westheider Prof. Dr. Trümper, Prof. Dr. Wulf, Prof. Dr. Haase Prof. Dr. Bokemeyer, Prof. Dr. Fiedler Dr. Salwender, Dr. Braumann Dr. Lange, Prof. Dr. Balleisen Dr. Sendler, PD Dr. Burk PD Dr. Kirchner, Dr. Maher Prof. Dr. Ganser, PD Dr. Heuser, Prof. Dr. Schlegelberger Prof. Dr. Martens, Dr. Huber Prof. Dr. Pfreundschuh, Prof. Dr. Held, Prof. Dr. Nachbaur, Prof. Dr. Gastl PD Dr. Ringhoffer, Prof. Dr. Bentz, Dr. Schützendübel Prof. Dr. Horst, Prof. Dr. Kneba, Dr. Harder Dr. Kremers, Dr. Täger Prof. Dr. Hartmann, Dr. Constantin Prof. Dr. Petzer, Dr. Aschauer Dr. Girschikofsky Prof. Dr. Heil, Dr. Schneider Prof. Dr. Fischer, Dr. Heinicke Prof. Dr. Herr, Prof. Dr. Theobald, PD Dr. Kindler Prof. Dr. Grießhammer, Dr. Tischler PD Dr. Götze, Prof. Dr. Peschel Prof. Dr. Hebart Dr. Hünerlitürkoglu, Dr. Tapprich Prof. Dr. Köhne, Dr. Schlön, Prof. Krämer Prof. Griesinger Prof. Dr. Südhoff, Dr. Nitsch Prof. Dr. Kloke, Dr. Corduan Prof. Dr. Matzdorff, Dr. Wehnes Prof. Dr. Greil, Dr. Russ PD Dr. Ritter Prof. Dr. Mergenthaler, Dr. Schleicher Prof. Dr. Heidemann, Dr. Mück Dr. Burkert, Dr. Kubin Dr. Kirchen, Prof. Dr. Kölbel Prof. Dr. Salih, Prof. Dr. Kanz Prof. Dr. Schlenk, Prof. Dr. K. Döhner, Prof. Dr. H. Döhner Prof. Dr. Brugger, Dr. Funke Dr. Koller, Dr. Pittermann-Höcker Prof. Dr. Raghavachar, Dr. Binder