Arm I (standard therapy):
o Induction 1: Patients receive cytarabine IT at the time of diagnosis or on day 1*. Patients
also receive cytarabine IV on days 1-10, daunorubicin hydrochloride IV over 6 hours on
days 1, 3, and 5, and etoposide IV over 4 hours on days 1-5. After 3 weeks of rest, all
patients (regardless of remission status) proceed to induction 2.
NOTE: *Patients with Central Nervous System (CNS) disease receive cytarabine IT twice
weekly until the cerebrospinal fluid is clear, followed by two additional IT treatments.
Patients with refractory CNS leukemia after 6 doses of IT treatment are removed from the
study.
Induction 2: Patients receive cytarabine IT on day 1, cytarabine IV on days 1-8,
daunorubicin hydrochloride IV over 6 hours on days 1, 3, and 5, and etoposide IV over 4
hours on days 1-5. After 3 weeks of rest, patients in complete remission (CR) proceed to
intensification 1. Patients with refractory disease are removed from protocol therapy.
Intensification 1: Patients receive cytarabine IT on day 1, high-dose cytarabine IV over 1
hour on days 1-5, and etoposide IV over 1 hour on days 1-5. After 3 weeks of rest, patients
in remission proceed to intensification 2, followed by intensification 3. Patients in remission
proceed to allogeneic SCT 2-8 weeks after blood counts recover. Patients with high-risk
disease with an alternative donor proceed to intensification 2 and 3, followed by allogeneic
SCT. Patients not in remission are removed from protocol therapy.
Intensification 2: Patients receive cytarabine IT on day 1, high-dose cytarabine IV over 2
hours on days 1-4, and mitoxantrone hydrochloride IV over 1 hour on days 3-6. After 3
weeks of rest, patients proceed to intensification 3.
Intensification 3: Patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and
9 and asparaginase intramuscularly on days 2 and 9.
o Arm II:
Induction 1: Patients receive treatment as in induction 1 of arm I. Patients also receive
gemtuzumab ozogamicin (GMTZ) IV over 2 hours on day 6.
Induction 2: Patients receive treatment as in induction 2 of arm I.
Intensification 1: Patients receive treatment as in intensification 1 of arm I.
Intensification 2: Patients receive treatment as in intensification 2 of arm I. Patients also
receive GMTZ IV over 2 hours on day 7.
Intensification 3: Patients receive treatment as in intensification 3 of arm I.
o Allogeneic SCT (for patients with intermediate- or high-risk disease):
MFD: Patients receive a conditioning regimen comprising busulfan IV over 2 hours every 6
hours on days -9 to -6 and cyclophosphamide IV over 1 hour on days -5 to -2. Patients
undergo allogeneic SCT on day 0. Patients receive cyclosporine IV or orally twice daily on
days -1 to 180 and methotrexate IV on days 1, 3, 6, and 11. Patients receive graft-vs-host
disease (GVHD) prophylaxis comprising cyclosporine IV over 1-4 hours or orally twice
daily on days -1 to 180 and methotrexate IV on days 1, 3, 6, and 11.
Matched alternative donor: Patients receive a conditioning regimen comprising busulfan
and cyclophosphamide as above. Patients also receive antithymocyte globulin IV over 6-8
hours on days -3 to -1. Patients then undergo allogeneic SCT and receive GVHD
prophylaxis as above.
After completion of study treatment, patients are followed periodically for 3 years and then
annually thereafter.
Summary
Active Comparator: Arm A: Standard Arm - No GMTZ, AML Pts w/out Down
Syndrome
Patients receive intrathecal (IT) cytarabine (ARA-C) at diagnosis or on day 1 of
treatment or twice a week for up to 6 doses. They also receive an infusion of ARA-
C on days 1-10; a 6-hour infusion of daunorubicin hydrochloride on days 1, 3, and
5; and a 4-hr infusion of etoposide on days 1-5.
After 3 weeks of rest, patients receive IT ARA-C on day 1. They also receive an
infusion of ARA-C on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5;
and a 4-hr infusion of etoposide on days 1-5.
After 3 weeks of rest, some patients receive IT ARA-C on day 1 and 1-hr infusions
of ARA-C and etoposide on days 1-5.
After 3 weeks of rest, some patients receive IT ARA-C on day 1; a 2-hr infusion of
ARA-C on days 1-4; and a 1-hour infusion of mitoxantrone on days 3-6. After 3
weeks of rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an
injection of asparaginase on days 2 and 9.
Interventions:
Drug: asparaginase
o
o Drug: cytarabine
o Drug: daunorubicin hydrochloride
o Drug: etoposide
o Drug: mitoxantrone hydrochloride
Experimental: Arm B: Experimental - with GMTZ, AML Pts w/out Down Syndrome
Pts receive IT ARA-C at diagnosis or on day 1 of treatment or twice a week for up
to six doses. They also receive an infusion of ARA-C on days 1-10; a 6-hr infusion
of daunorubicin on days 1, 3, & 5; a 4-hr infusion of etoposide on days 1-5; and a 2-
hr infusion of GMTZ - gemtuzumab ozogamicin (Mylotarg) on day 6. After 3 wks of
rest, patients receive IT ARA-C on day 1. They also receive an infusion of ARA-C
on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5; and a 4-hr infusion
of etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on
day 1 and 1-hr infusions of ARA-C and etoposide on days 1-5. After 3 wks of rest,
some patients receive IT ARA-C on day 1; a 2-hr infusion of ARA-C on days 1-4;
and a 1-hr infusion of mitoxantrone hydrochloride on days 3-6. They also receive a
2-hr infusion of gemtuzumab on day 7. After 3 weeks of rest, they receive a 3-hr
infusion of ARA-C on days 1, 2, 8, and 9 and an injection of asparaginase on days
2 and 9.
Interventions: Table 1. COG AAML0531 Therapeutic Regimen
Course and Agent Dose Days
o Drug: asparaginase IND1
Cytarabine 100 mg/m2/dose twice per day IV 1 to 10
o Drug: cytarabine
Daunomycin 50 mg/m2/dose IV 1, 3, 5
o Drug: daunorubicin hydrochloride Etoposide 100 mg/m2/dose IV 1 to 5
Gemtuzumab, arm B only 3 mg/m2/dose IV over 2 hours 6
o Drug: etoposide IND2
Cytarabine 100 mg/m2/dose twice per day IV 1 to 8
o Drug: gemtuzumab ozogamicin
Daunomycin 50 mg/m2/dose IV 1, 3, 5
o Drug: mitoxantrone hydrochloride Etoposide 100 mg/m2/dose IV 1 to 5
INT1
Active Comparator: Arm A: Standard Arm - No Cytarabine 1,000 mg/m2/dose twice per day IV 1 to 5
GMTZ, AML Patients with Down Syndrome Etoposide 150 mg/m2/dose IV 1 to 5
For patients not undergoing
stem-cell transplantation
Patients receive intrathecal (IT) cytarabine INT2
Mitoxantrone 12 mg/m2/dose IV 3 to 6
(ARA-C) at diagnosis or on day 1 of Cytarabine 1,000 mg/m2/dose twice per day IV 1 to 4
Gemtuzumab, arm B 3 mg/m2/dose IV over 2 hours 7
treatment or twice a week for up to 6 doses. only
They also receive an infusion of ARA-C on INT3
Cytarabine 3,000 mg/m2/dose twice per day IV 1, 2, 8, 9
days 1-10; a 6-hour infusion of daunorubicin Escherichia coli L- 6,000 mg/m2/dose IM 2, 9
asparaginase
hydrochloride on days 1, 3, and 5; and a 4-hr
infusion of etoposide on days 1-5.
For patients receiving
After 3 weeks of rest, patients receive IT matched family-donor
stem-cell
transplantation
ARA-C on day 1. They also receive an Busulfan, 16 total doses Age and weight based 9
infusion of ARA-C on days 1-8; a 6-hr < 10 kg or > 4 years 0.8 mg/kg/dose once every 6 hours old
IV
infusion of daunorubicin on days 1, 3, and 5; > 10 kg and < 4 years 1 mg/kg/dose every 6 hours IV old
All patients Adjusted AUC based on first dose —8 to —6
and a 4-hr infusion of etoposide on days 1-5. Cyclophosphamide 50 mg/kg/dose IV once per day —5 to —2
After 3 weeks of rest, some patients receive
IT ARA-C on day 1 and 1-hr infusions of
ARA-C and etoposide on days 1-5. Abbreviations: AUC, area under the concentration-time curve; COG, Chil- dren’s
Oncology Group; IM, intramuscular; IND1, induction course; INT, intensification
course; IV, intravenous.
After 3 weeks of rest, some patients receive
IT ARA-C on day 1; a 2-hr infusion of ARA-C
on days 1-4; and a 1-hour infusion of mitoxantrone on days 3-6. After 3 weeks of
rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an injection of
asparaginase on days 2 and 9.
Interventions:
o Drug: asparaginase
o Drug: cytarabine
o Drug: daunorubicin hydrochloride
o Drug: etoposide
o Drug: mitoxantrone hydrochloride
