Molecularly Targeted Therapies - Strategies of the AMLSG
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1 Molecularly Targeted Therapies - Strategies of the AMLSG Richard Schlenk Department of Internal Medicine III Ulm University, Germany
2 Genotype-adapted Leukemia Program NAPOLEON GIMEMA/AMLSG/SAL APL [t(15;17)] APOLLO +/- ATO-ATRA-Ida CBF-AML +/- Dasatinib AMLSG AML FLT3 mut Midostaurin AMLSG /- Crenolanib AMLSG AML NPM1 mut ATRA +/- GO AMLSG /- ATRA AMLSG Molecular Screening hrs AML MLL rearr EPZ 5676 (DOT1L) Other subtypes not genotype-specific, mainly high-risk CDK6-Palbociclib AMLSG /- agent X AMLSG /- Volasertib AMLSG /- Panobinostat AMLSG 22-14
3 Molecular Markers Guiding Therapy: CBF-AML Associated with KIT mutations (30-35%) exon 8 In vitro and in vivo evidence for mutant Kit as sufficient co-operative event Impact on prognosis: in general poor High KIT expression exon 17 Dasatinib Inhibition of wild-type and mutant KIT Schittenhelm et al. Cancer Res. 2006; Wang et al. PNAS Inhibition of human AML stem/progenitor cells Dos Santos et al. Blood in vitro differentiation of AML cells Fang et al. PLoS One in vivo differentiation of t(8;21)+ AML blasts Chevalier et al. Leukemia
4 Phase Ib Study of Chemotherapy + Dasatinib in Patients with Newly Diagnosed Core-Binding Factor (CBF) AML - AMLSG Induction Consolidation x 4 Maintenance Daunorubicin Cytarabine + Dasatinib High-Dose Cytarabine* + Dasatinib Dasatinib 1 year Phase Ib n=89 *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
5 AMLSG vs. Historical Control 100 Event-Free Survival Survival (%) AMLSG 11-08, n=89, CR: 93% median age: 49.5 yrs 40 Control, n=387, CR: 91% median age: 45 yrs 20 0 p= time (years) Preliminary data 05/2014; ClinicalTrials.gov Identifier: NCT Median follow-up: 26.2 months
6 Phase III Study of Chemotherapy with or without Dasatinib in Patients with Core-Binding Factor AML AMLSG Induction Consolidation x3 Maintenance CBF Mutation Screening Within 48 Hours R Daunorubicin Cytarabine n=277 Daunorubicin Cytarabine +Dasatinib High-Dose Cytarabine* MRD assessment by RQ-PCR High-Dose Cytarabine* +Dasatinib 1-yr Dasatinib Salvage / transplantation if MRD persists or recurs 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: H. Döhner; supported by Bristol-Myers Squibb
7 Molecular Markers Guiding Therapy: FLT3 PLX3397 ASP2215 Galanis A, et al. Cancer Res 2012;72:#3660. Midostaurin Chemo +/- midostaurin in younger pts. (n=719) with activating FLT3 mutations (RATIFY) Lestaurtinib Chemo +/- lestaurtinib in relapsed/refractory AML with FLT3 mutation (Levis M, et al. Blood 2011) Sorafenib Chemo +/- sorafenib in pts. with AML (Serve H, et al. JCO 2013, Röllig C, et al. ASH 2014) Quizartinib (AC220) Quizartinib monotherapy vs. salvage chemotherapy in relapsed / refractory AML with FLT3-ITD Crenolanib MC +/- crenolanib in relapsed / refractory AML with FLT3 mutations (AMLSG 19-13)
8 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 Screening Within 48 Hours n=284 Dauno Cytarabine midostaurin* High-Dose Cytarabine** Early Allogeneic HSCT 2 nd priority 3x High-Dose Cytarabine 1-yr maintenance Start: 30 d after allo midostaurin 1-yr maintenance midostaurin * 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
9 Standardized log-rank statistics Impact of FLT3-ITD Mutant/Wildtype Ratio on Induction Response and Survival Induction-Response FLT3-ITD Mutant/Wildtype Ratio 1 st interval 2 nd interval 3 rd interval 4 th interval n=81 n=80 n=81 n=81 CR 81% 80% 69% 57% RD 14% 15% 21% 38% ED 5% 5% 10% 5% Survival after Consolidation with Chemotherapy/Auto-HSCT Cut-point RFS OS Allelic Ratio Relapse-free survival (%) Allelic ratio 0.51, n=75 Allelic ratio 0.51, n=63 Time (years) p= Schlenk RF, Kayser S, et al. Blood 2014;124: Overall survival (%) Allelic ratio 0.51, n=75 Allelic ratio 0.51, n= Time (years) p=0.004
10 FLT3-ITD Mutant to Wild-type Ratio and its Impact on Allogeneic HSCT Simon-Makuch Plots allogeneic HSCT as time dependent covariable Mutant/Wildtype Ratio 0.51 Mutant/Wildtype Ratio < p= p=0.64 Overall survival (%) Allogeneic HSCT n=45 Overall survival (%) Allogeneic HSCT n= Time (years) Similar results: Time (years) Pratcorona M, et al. Blood. 2013;121: cut off value 0.50 Schlenk RF, Kayser S, et al. Blood 2014;124:
11 Patient Characteristics & Response AMLSG vs. Phase IB AMLSG 16-10* Historical Control No. of pts Age median range FLT3 mutation ITD (100%) ITD (100%) Response CR/CRi 113/151 (75%) 481/708 (68%) RD 26/151 (17%) 155/708 (22%) ED/HD 12/151 (8%) 72/708 (10%) * Preliminary data ; target accrual: n=284, expected 4/2016
12 Response Rates by FLT3 Mutant to Wild-type Allelic Ratio: Midostaurin vs. Historical Control AMLSG historical cohort (n=321) Ratio 1 st quartile 2 nd quartile 3 rd quartile 4 th quartile CR 81% (66/81) 80% (63/79) 69% (56/81) 57.5% (46/80) RD 14% (11/81) 15% (12/79) 21% (17/81) 37.5% (30/80) ED 5% (4/81) 5% (4/79) 10% (8/81) 5% (4/80) Midostaurin (n=150; AMLSG trial) Ratio 1 st quartile 2 nd quartile 3 rd quartile 4 th quartile CR 66% (25/38) 85% (28/33) 72% (28/39) 77% (31/39) RD 21% (8/38) 9% (3/33) 18% (7/39) 21% (8/39) ED 13% (5/38) 6% (2/33) 10% (4/39) 3% (1/39)
13 Phase III study of chemotherapy with or without crenolanib in relapsed / refractory AML with FLT3 mutations - AMLSG Induction Consolidation Maintenance Relapsed/ refractory AML with FLT3 mutations R MC + Placebo n=293, 1:1 MC + Crenolanib MC # + Placebo MC # + Crenolanib Allo HCT* HiDAC + Placebo Allo HCT* 3x HiDAC + Crenolanib 1-yr Placebo 1-yr Placebo 1-yr Crenolanib 1-yr Crenolanib # Optional second cycle of MC (mitoxantrone, intermediate-dose cytarabine) * First priority for consolidation is allogeneic HCT PIs: R.F. Schlenk, H. Döhner; supported by AROG Pharmaceuticals
14 Molecular Markers Guiding Therapy: NPM1 AML with NPM1 mut /FLT3-ITD neg : No allogeneic HSCT in CR1 Schlenk RF, Döhner K, et al. N Engl J Med Older patients with NPM1-mutated AML benefit from intensive chemotherapy Becker H, et al. J Clin Oncol 2009; Büchner T, et al. J Clin Oncol 2009; Schlenk RF, Döhner K, et al. Haematologica Falini B, Mecucci C, et al. N Engl J Med AMLSG trial - rationales: High CD33 expression -> anti-cd33 AB ATRA may improve survival Schlenk RF, Döhner K, et al. Haematologica 2009; Schlenk RF, et al. EHA. 2014, abstract #S646.
15 Phase III Study of Chemotherapy with or without ATRA in Younger Adult Patients with AML - AMLSG Trial All Patients ELN Favorable-Risk* 100 p= Favorable ATRA Overall survival (%) ATRA, n=511 no ATRA, n=508 Overall survival (%) Other no ATRA ATRA no ATRA p=0.02 p= Time (years) Schlenk RF, et al. EHA 2014, abstract #S Time (years) *inv(16), t(8;21), CEBPA dm, NPM1 mut /FLT3-ITD neg
16 Phase III Study of Chemotherapy in Combination with ATRA with or without Gemtuzumab Ozogamicin in Patients with NPM1 mut AML [AMLSG Trial] Induction x2 Consolidation 1 Consolidation 2+3 NPM1 Mutation Screening Within 48 Hours R n = 588 ATRA-ICE ATRA-ICE +Gemtuzumab Ozogamicin ATRA Cytarabine* ATRA Cytarabine* +GO ATRA Cytarabine* NPM1 MRD monitoring by RQ-PCR ATRA Cytarabine* *Salvage / transplantation if MRD persists or recurs 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 Else Kröner-Fresenius-Foundation & Pfizer
17 Phase III Study of Chemotherapy in Combination with ATRA with or without Gemtuzumab Ozogamicin in Patients with NPM1 mut AML [AMLSG Trial] AMLSG (n=293) Monat June 10 Aug 10 Oct 10 Dec 10 Feb 11 Apr 11 June 11 Aug 11 Oct 11 Dec 11 Feb 12 Apr 12 June 12 Aug 12 Oct 12 Dec 12 Feb 13 Apr 13 June 13 Aug 13 Oct 13 Dec 13 Feb 14 Apr historical control Age 61 years CR 83% (109/132) 66% (138/210) Age years CR 90% (148/165) 83% (689/823)
18 Survival in AML with NPM1 mut AMLSG Trial vs. Historical Control Age years Age 61 years AMLSG n= AMLSG n=158 Survival (%) 60 Survival (%) Historical control, n= Historical control, n= time (years) time (years)
19 AMLSG BiO Registry: Fast Biomarker Screening AMLSG Trial Center AMLSG BiO registry 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 0 Hours Overnight hrs / 7d week
20 AMLSG-BiO Project Generic Concept of Data Protection AMLSG Centers Personal Data AMLSG BiO-ID WEB-based Registration Personal Data AMLSG BiO-ID Samples AMLSG Reference Labs AMLSG BiO-ID AMLSG BioBank AMLSG BiO-ID AMLSG Clinical Trials Office AMLSG BiO-ID AMLSG Meta-database AMLSG BiO-ID Personal Data Trusted Third Party
21 Genotype-adapted Leukemia Program NAPOLEON GIMEMA/AMLSG/SAL APL [t(15;17)] APOLLO +/- ATO-ATRA-Ida CBF-AML +/- Dasatinib AMLSG AML FLT3 mut Midostaurin AMLSG /- Crenolanib AMLSG AML NPM1 mut ATRA +/- GO AMLSG /- ATRA AMLSG Molecular Screening hrs AML MLL rearr EPZ 5676 (DOT1L) Other subtypes not genotype-specific, mainly high-risk CDK6-Palbociclib AMLSG /- agent X AMLSG /- Volasertib AMLSG /- Panobinostat AMLSG 22-14
22 AMLSG Trial Sites Centers n=62 Germany n=57 Austria n=5 University Hospitals n=18
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