| Eligibility |
Inclusion Criteria (at diagnosis) :
1. Age = 18 years and < 61 years
2. With a newly diagnosed de novo or secondary type AML (post myelodysplastic syndrome
MDS or therapy-related AML)
3. No prior treatment for neither AML (with the exception of hydroxyurea), nor MDS (with
the exception of EPO)
4. ECOG performance status = 3
5. Absence of severe uncontrolled infection
6. No cardiac contraindications for the use of anthracyclines : decompensated or
uncontrolled heart failure, recent myocardial infarction, current signs of cardiac
impairment, uncontrolled arrhythmias, LVEF (left ventricular ejection fraction) < 50%
7. Total bilirubin = 2 x upper limit of normal (UNL), ASAT(SGOT) and ALAT (SGPT) = 2.5 X
UNL, creatinine < 150 µmol/l, unless AML-related out of range values
8. Genetic mutation testing of the FLT3 (FLT3-ITD ou FLT3-TKD) gene, performed in local
or central laboratory
9. Use of appropriate methods of contraception:
- for patients treated with Midostaurin:
- women of childbearing potential should use appropriate methods of
contaception throughout treatment, and for 5 months post cessation of
treatment
- men will need to use condoms during intercourse throughout treatment, and
for 5 months post cessation of treatment with Midostaurin
10. Patients who are covered by or beneficiaries of a social security system (Social
Security or Universal Medical Coverage)
11. Patients who have read and understood the information sheet and signed the informed
consent form
Exclusion criteria (at diagnosis) :
1.Patients with acute promyelocytic leukemia (APL), as confirmed either by t(15;17) or by
the presence of PML-RARA fusion transcripts 2.Patients with core binding factor (CBF) AML,
as confirmed either by t(8;21), t(16,16) or inv(16), or by fusion transcripts resulting
from these cytogenetic abnormalities (RUNX1-RUNX1T1, CBFB-MYH11).
3.Patients with secondary AML arising from myeloproliferative disorders previously known
according to the 2008 WHO classification 4.Patients with Ph1+ AML or previous Ph1+ disorder
(chronic myelogenous leukemia) 5.Severe psychiatric or organic disorder, supposed to be
independent from AML, that would contraindicate treatment, including allogeneic HSCT 6.No
psychological, familial, social, or geographic reason that would compromise clinical follow
up 7.History of uncontrolled cancer for the last 2 years, with the exception of basal cell
carcinoma or carcinoma in situ of the cervix 8.Uncontrolled severe infection 9.Patients
with positive serology for HIV-1 and -2, or HTLV -1 and -2, or active hepatitis virus B or
C infection 10.Pregnant or lactating women 11.Legal incapacity (patients under tutorship,
curatorship or judicial protection)
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For randomization R4-VOS (post-induction/salvage) :
Inclusion criteria
1. Patients enrolled in the BIG-1 trial at diagnosis
2. Patient presenting with AML in first CR or CRp/CRi after induction or one cycle of
salvage therapy (confirmed in the 15 days preceding R4-VOS)
3. Favorable or intermediate risk AML patients, as stratified with BIG-1 prognostic
classification
4. Patients randomized to R2-IDAC arm (intermediate dose cytarabine)
5. ECOG performance status = 2
6. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition
(MUGA) scan or echocardiogram (ECHO)
7. Local clinical laboratory values as follows:
o Serum creatinine = 2.0 mg/dL
o Total bilirubin = 1.5 X the upper limit of normal (ULN)
- Aspartate aminotransferase (AST) = 2.5 X ULN
- Alanine aminotransferase (ALT) = 2.5 X ULN
8. Signed written informed consent for vosaroxin study (R4-VOS)
9. Women of childbearing potential must have a negative pregnancy test within 8 days
before randomization R4-VOS and commit to the use of effective contraception during
the period of treatment and up to 36 days after vosaroxin has been stopped. Men must
use effective contraception during the treatment period and up to 96 days after
vosaroxin has been stopped.
Exclusion criteria
1.Patients classified in the unfavorable risk group according to the BIG-1 protocol
classification 2.Complete remission is not attained (CR, CRp/CRi) after induction and/or
salvage therapy 3.Positive pregnancy test 4.Severe uncontrolled infection such as sepsis,
or multiple organ dysfunction syndrome, uncontrolled fever 5.Documented uncontrolled fungal
infection (positive blood test and cultures) 6.History of myocardial infarction, unstable
angina, cerebrovascular accident (CVA) or transient ischemic attack (TIA) in the 3 months
before randomization 7.Patient under hemodialysis (HD) or peritoneal dialysis (PD)
------------------------------------------
For randomization R4-DEX (post-induction/salvage) :
Inclusion criteria
1. Patients enrolled in the BIG-1 trial at diagnosis
2. Patient presenting with AML in first CR or CRp/CRi after induction or one cycle of
salvage therapy (confirmed in the 15 days preceding R4-DEX)
3. Favorable or intermediate risk AML patients, as stratified with BIG-1 prognostic
classification
4. ECOG performance status = 2
5. Local clinical laboratory values as follows:
- Serum creatinine = 150 µmol/L
- Total bilirubin = 1.5 X the upper limit of normal (ULN)
- Aspartate aminotransferase (AST) = 2.5 X ULN
- Alanine aminotransferase (ALT) = 2.5 X ULN
6. Signed written informed consent for dexamethasone study (R4-DEX)
Exclusion criteria
1.Severe uncontrolled infection such as sepsis, or multiple organ dysfunction syndrome,
uncontrolled fever 2.Documented uncontrolled fungal infection (positive blood test and
cultures 3.History of myocardial infarction, unstable angina, cerebrovascular accident
(CVA) or transient ischemic attack (TIA) in the 3 months before randomization 4.Patient
under hemodialysis (HD) or peritoneal dialysis (PD)
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For randomization R4-VEN (post-induction/salvage) :
Inclusion criteria
1. Age 18 - 60 years at inclusion in BIG-1 protocol
2. diagnosis of AML according to WHO classification de novo or secondary to
myelodysplastic syndrome (myelodysplastic syndrome must not have been treated except
by ESA, Lenalidomide or non-chemotherapy) or therapy-related AML
3. Patients included in the BIG-1 protocol
4. Patients in first CR or CRp/CRi following 1 or 2 courses of induction chemotherapy
according to BIG-1 protocol and who are planned to receive consolidation.
5. Patients stratified within the favorable and intermediate risk groups as defined by
BIG-1 protocol
6. ECOG performance status = 2
7. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition
(MUGA) scan or echocardiogram (ECHO)
8. Creatinine clearance = 30 ml/min (calculated by the usual method of each institution),
total bilirubin = 1.5 times the ULN; ASAT and ALAT = times the upper limit of normal
(ULN)
9. Absence of uncontrolled infection
10. Women of childbearing potential must agree to use effective contraception without
interruption throughout the study and for a further 3 months after the end of
treatment
11. Written signed informed consent
Exclusion criteria
1.AML stratified in the unfavorable BIG-1 risk-group. 2.Diagnosis of Acute Promyelocytic
Leukemia or CBF AML (ie. AML with t(8;21), t(16,16) or inv(16), or their molecular
equivalents RUNX1-RUNX1T1 and CBFB-MYH11) 3.AML secondary to prior myeloproliferative
disorder according to WHO classification (2008) and Philadelphia chromosome-positive AML
(Ph1+) 4.Absence of CR/CRp/CRi after a maximum of two chemotherapy cycles 5.Severe medical
or mental condition precluding the administration of protocol treatments 6.Prior history of
cancer unless controlled for at least 2 years and except for basocellular cutaneous cancers
and in situ cervix cancers 7.Positive pregnancy test 8.Breast feeding 9.Uncontrolled
infection such as sepsis, or multiple organ dysfunction syndrome, uncontrolled fever
10.Documented uncontrolled fungal infection (positive blood test and cultures) 11.Prior
venetoclax exposure 12.Known HBV with detectable viral load 13.Known HIV positive patients
14.Known hypersensitivity to any of the study medication 15.History of myocardial
infarction, unstable angina, cerebrovascular accident (CVA) or transient ischemic attack
(TIA) in the 3 months before randomization 16.Patient under hemodialysis (HD) or peritoneal
dialysis (PD) 17.Concomitant treatment with cytochrome CYP3A4 inhibitor which cannot be
stopped during venetoclax administration ONLY FOR PHASE 1 18.During the phase 2, for
patients randomized in the IDAC + Venetoclax arm, if concomitant treatment with cytochrome
CYP3A4 inhibitor cannot be stopped, a dose reduction of 70% of venetoclax must be apply
--------------------------------------
For randomization R3 (before AlloHSCT):
Inclusion criteria
1. Patients enrolled in the BIG-1 trial at diagnosis
2. Patient presenting with AML in first CR or CRp/CRi treated in the BIG-1 trial and
classified in the intermediate risk group, namely:
- either initially favorable but poor molecular responders for NPM1 MRD: NPM1
mutation, without FLT3-ITD mutation or with an FLT3-ITD ratio < 0.50 and MRD2
positive blood (decrease of less than 4 log from baseline at diagnosis)).
- Or initially favorable but requiring two cycles of chemotherapy (a salvage
therapy) to obtain the first CR/CRp/CRi
- Or other immediate intermediaries
3. No metastatic or progressive cancer, with the exception of basal cell skin carcinoma
and cervical carcinoma in situ
4. Patients with general condition preserved (ECOG = 3) and with no uncontrolled severe
infection
5. Women of childbearing age must make use of effective contraception
6. Patients who are covered by or beneficiaries of a social security system (Social
Security or Universal Medical Coverage).
7. Patients who have read and understood the information sheet and signed the informed
consent form
Exclusion criteria
1. Complete remission is not obtained (CR, CRp/CRi) after induction and/or salvage
therapy
2. Patient presenting with AML in first CR or CRp/CRi treated in the BIG-1 trial and
classified either in the favorable risk group or the unfavorable risk group
3. Patients with a severe organ or psychiatric pathology, presumed to be independent of
AML and contraindicating the allograft
4. Patients who, for family, social or geographic reasons, do not wish to be regularly
monitored via consultation
5. Uncontrolled severe infection at the time of inclusion
6. Serology positive for HIV 1 or 2 or HTLV 1 or 2, or active HBV or HCV viral infection
7. Pregnant women (beta-HCG positive) or currently breastfeeding
8. Adult patient who is incapacitated, under wardship, legal guardianship, or under the
protection of the courts
9. Patients under State Medical Assistance (AME)
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