Study: NCT04628026

Intervention type: DRUG
Group type: EXPERIMENTAL
Intervention: Venetoclax
Description: Venetoclax will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy

Intervention type: DRUG
Group type: PLACEBO_COMPARATOR
Intervention: Placebo
Description: Placebo will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy

Intervention type: COMBINATION_PRODUCT
Group type: EXPERIMENTAL
Intervention: Standard chemotherapy
Description: Induction cycle 1: Patients will receive cytarabine 200 mg/m2 continuous IV (days 1-7) and daunorubicin 60 mg/m2 IV (days 1-3). Induction cycle 2: Patients ≤ 60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-6, and daunorubicin 60 mg/m2 IV (days 1-3). Patients \>60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-6 without daunorubicin.~Consolidation chemotherapy option 1 consists of one cycle of mitoxantrone (10mg/m2 IV) and etoposide (100mg/m2 IV) (ME) days 1-5 (patients ≤60 yrs) or days 1-3 (patients \>60 yrs). Consolidation chemotherapy option 2 consists of intermediate doses of cytarabine. Patients ≤60 yrs will receive up to 3 cycles of IDAC (single dose 1500 mg/m2 every 12 hours, days 1-3). Patients who are \>60 yrs will receive up to 3 cycles of IDAC with single doses of 1000 mg/m2, every 12 hours, days 1-3. In patients \>60 yrs less than 3 cycles of IDAC or dose-reduced IDAC (500 mg/m2 per single dose) may be given based on an individual risk assessment.

Intervention type: COMBINATION_PRODUCT
Group type: PLACEBO_COMPARATOR
Intervention: Standard chemotherapy
Description: Induction cycle 1: Patients will receive cytarabine 200 mg/m2 continuous IV (days 1-7) and daunorubicin 60 mg/m2 IV (days 1-3). Induction cycle 2: Patients ≤ 60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-6, and daunorubicin 60 mg/m2 IV (days 1-3). Patients \>60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-6 without daunorubicin.~Consolidation chemotherapy option 1 consists of one cycle of mitoxantrone (10mg/m2 IV) and etoposide (100mg/m2 IV) (ME) days 1-5 (patients ≤60 yrs) or days 1-3 (patients \>60 yrs). Consolidation chemotherapy option 2 consists of intermediate doses of cytarabine. Patients ≤60 yrs will receive up to 3 cycles of IDAC (single dose 1500 mg/m2 every 12 hours, days 1-3). Patients who are \>60 yrs will receive up to 3 cycles of IDAC with single doses of 1000 mg/m2, every 12 hours, days 1-3. In patients \>60 yrs less than 3 cycles of IDAC or dose-reduced IDAC (500 mg/m2 per single dose) may be given based on an individual risk assessment.

Intervention type: OTHER
Group type: EXPERIMENTAL
Intervention: Autologous stem cell transplantation
Description: Busulfan/Cyclophosphamide will be administered as conditioning regime. Patients may proceed to autologous HCT when they have reached CR/CRi/MLFS after at least two cycles of chemotherapy and performance status permits continuation with high-dose chemotherapy. Venetoclax will not be added to or given after the conditioning regimen.

Intervention type: OTHER
Group type: PLACEBO_COMPARATOR
Intervention: Autologous stem cell transplantation
Description: Busulfan/Cyclophosphamide will be administered as conditioning regime. Patients may proceed to autologous HCT when they have reached CR/CRi/MLFS after at least two cycles of chemotherapy and performance status permits continuation with high-dose chemotherapy. Venetoclax will not be added to or given after the conditioning regimen.

Intervention type: OTHER
Group type: EXPERIMENTAL
Intervention: Allogeneic stem cell transplantation
Description: Generally, patients will proceed to allogeneic HCT upon completion of remission induction chemotherapy. It is however allowed, as per investigator's discretion, for a patient to receive 'bridging' consolidation chemotherapy in exceptional cases of delay towards transplantation. At baseline, HLA-compatible donor search must be initiated as soon as possible, first among siblings and second in the world donor bank for unrelated donors or cord blood. In order to avoid inappropriate delay in cases where no suitable sibling is present, high-resolution HLA typing should be performed immediately after registration, enabling a more rapid matched-unrelated donor search. In case no sibling or unrelated donor can be identified, haploidentical allogeneic HCT is allowed. Conditioning and GVHD prophylaxis will take place according to institutional guidelines. Patients who undergo allogeneic HCT will not receive venetoclax during conditioning, engraftment or after hematologic recovery.

Intervention type: OTHER
Group type: PLACEBO_COMPARATOR
Intervention: Allogeneic stem cell transplantation
Description: Generally, patients will proceed to allogeneic HCT upon completion of remission induction chemotherapy. It is however allowed, as per investigator's discretion, for a patient to receive 'bridging' consolidation chemotherapy in exceptional cases of delay towards transplantation. At baseline, HLA-compatible donor search must be initiated as soon as possible, first among siblings and second in the world donor bank for unrelated donors or cord blood. In order to avoid inappropriate delay in cases where no suitable sibling is present, high-resolution HLA typing should be performed immediately after registration, enabling a more rapid matched-unrelated donor search. In case no sibling or unrelated donor can be identified, haploidentical allogeneic HCT is allowed. Conditioning and GVHD prophylaxis will take place according to institutional guidelines. Patients who undergo allogeneic HCT will not receive venetoclax during conditioning, engraftment or after hematologic recovery.