AML2012 Overview MEC R1 BM d22* R AD(x)E FLAD(x) HAM HA3E FLA BM** SCT for HR CR No CR Salvage therapy Inv(16) and SR

MEC MEC Cytarabine 200 mg/m2 12h ci iv Mitoxantrone 5 mg/m2 iv Mtx it* Cytarabine 200 mg/m2 12h ci iv Etoposide 150 mg/m2 iv Mitoxantrone 5 mg/m2 iv Day 6-12 Day 6-10 Inf 1 hour Day 1-5 Inf 2 hours Day 1 2 3 4 5 6 7 8 9 10 11 12 MEC Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg Children < 1y or < 10kg Cytarabine 6.7 mg/kg Etoposide 5 mg/kg Mitoxantrone 0.17 mg/kg

AD(x)E Cytarabine 100 mg/m2 ci Cytarabine 100 mg/m2 iv Mtx it Cytarabine 100 mg/m2 iv Etoposide 150 mg/m2 iv (liposomaal) Daunorubicine 60 mg/m2 iv Day 3-8, 30 min inf, every 12h Day 2,4,6 1 hour inf Day 6,7,8 2 hour Day 1 2 3 4 5 6 7 8 Cytarabine 100 mg/m2 ci Day 1,2 Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg Children < 1y or < 10kg Cytarabine 3.3 mg/kg Etoposide 5 mg/kg Daunoxome 2 mg/kg

FLAD(x) Fludarabine 30 mg/m2 iv (30min) Cytarabine 2000 mg/m2 inf (3h) (liposomaal)Daunorubicine 60 mg/m2 iv inf (1h) Day Day 1-5 Day 1-5 4h after fludarabine Day 2,4,6 immediately after fludarabine Mtx it 1 5 6 4 3 2 Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg Children < 1y or < 10kg Cytarabine 67 mg/kg Fludarabine 1 mg/kg Daunoxome 2 mg/kg

Overview of consolidation Inv(16) HA3E FLA Standard risk HAM HA3E FLA No donor High risk HAM SCT Note that SR patients with Inv(16) only receive two consolidation blocks

HAM Cytarabine 1000 mg/m2 inf (2h) Mitoxantrone 10 mg/m2 iv inf (1 hour) Day 1-3 every 12 hours Day 3,4,5 Mtx it Day 1 5 4 3 2 Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg Children < 1y or < 10 kg Cytarabine 33 mg/kg Mitoxantrone 0.33 mg/kg

HA3E Cytarabine 3000 mg/m2 inf (2h) Etoposide 100 mg/m2 inf (1h) Day 1-3 every 12 hours Day 1-5 MTX it Day 1 5 4 3 2 Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg Children < 1y or < 10 kg Cytarabine 67 mg/kg Fludarabine 1 mg/kg Daunoxome 2 mg/kg

FLA Fludarabine 30 mg/m2 iv (30min) Cytarabine 2000 mg/m2 inf (3h) Day Day 1-5 Day 1-5 4h after fludarabine Mtx it 1 5 4 3 2 Mtx it age-adjusted <1y 6 mg 1-<2y 8 mg 2-<3y 10 mg ≥ 3y 12 mg Children < 1y or < 10kg Cytarabine 67 mg/kg Fludarabine 1 mg/kg Daunoxome 2 mg/kg

Flowsheet induction BM + MRD Repeat BM + MRD weekly Start course 2 Day 22 after course 1 Repeat BM + MRD weekly until recovery of ANC and platelets Start course 2 immediately day after course 2 Salvage therapy If very aplastic BM consider repeat BM – see protocol text LC ≥ 5% LC < 5% on recovery after course 1 LC < 5% and recovery start HAM LC ≥ 0.1% assign HR BM +MRD + HAM* On recovery after course 2 LC before HAM ≥ 0.1% assign HR LC ≥ 15% Assign HR Assign RD

AML2012 Flow MRD sampling

Induction MRD Standard risk patients MRD before course 5* Diagnosis – MRD target search Day 22 – MRD all patients Good Response < 5% LC MRD repeated weekly Start course one Start course two Poor Response ≥ 5% LC Course 2 direct after regeneration MRD before consolidation MRD D22 Poor Response Off protocol Good Response Start consolidation High risk patients MRD before SCT

Consolidation MRD High risk patients MRD before SCT Standard risk patients MRD before course 5 The exact number of MRD samples cannot be determined but it is expected that 3-4 samples per patient will be taken during induction