Trial Information

A Collaborative Trial for the Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia

The study compares the effectiveness of two doses of cytarabine combined with set doses of
daunomycin and etoposide as an initial course of chemotherapy to eliminate minimal residual
disease. Subsequent therapy is tailored according to cytogenetic risk features, assessments
of minimal residual disease, and availability of a suitable donor for bone marrow
transplant. Patients with higher risk disease features are given more intense therapy. For
higher risk groups, transplant is given to patients with suitable donors.

Secondary objectives include:

- To assess the prognostic value of biological markers in childhood Acute Myeloid
leukemia (AML).

- To compare the amounts of leukemia cells in the blood and bone marrow to study minimal
residual disease(MRD).

- To relate non-invasive cardiac evaluation with health-related quality of life in AML
patients treated with cardiotoxic therapy during and following therapy.

Detailed Description of Treatment Plan Induction I Patients will be randomly assigned to
receive induction therapy that consists of daunomycin, etoposide, and high-dose or low-dose
cytarabine.

High-Dose Cytarabine (HDAC) arm:

Cytarabine 3 gm/m2 IV days 1, 3, 5 Daunomycin 50 mg/m2 IV days 2, 4, 6 Etoposide 100 mg/m2
IV days 2-6

Low-Dose Cytarabine(LDAC) arm:

Cytarabine 100 mg/m2 IV days 1-10 (20 doses) Daunomycin 50 mg/m2 IV days 2, 4, 6 Etoposide
100 mg/m2 IV days 2-6

Induction II

Patients who have < 1% MRD after Induction I will receive daunomycin, cytarabine, etoposide
(ADE):

Daunomycin 50 mg/m2 IV days 1, 3, 5 Cytarabine 100 mg/m2 IV 1-8 (16 doses) Etoposide 100
mg/m2 IV days 1-5

Patients who have ≥ 1% MRD after Induction I will receive daunomycin, cytarabine, etoposide
(ADE) + gemtuzumab ozogamicin:

Daunomycin 50 mg/m2 IV days 1, 3, 5 Cytarabine 100 mg/m2IV days 1-8 (16 doses) Etoposide:
100 mg/m2 IV on days 1-5 Gemtuzumab ozogamicin (GO) 3 mg/m2 IV on day 1.

Consolidation I (Chemotherapy course 3)

The chemotherapy administered in course 3 will be based on the participant's response and
cytogenetic/morphologic subgroup

MRD+ patients (except those who received ADE + GO) Gemtuzumab ozogamicin 6 mg/m2 IV on day 1

MRD+ patients who had No response(NR) to induction I

These patients should proceed to Stem Cell Transplant (SCT) as soon as possible. In cases
where SCT is delayed (e.g., during searches for unrelated donors), these patients should
receive chemotherapy according to their cytogenetic or morphologic subtype until the time of
SCT.

MRD- patients (i.e., patients who were MRD- after ADE or after GO) will receive risk-based
intensification (RBI)

t(9;11) and inv(16) Cytarabine 500 mg/m2/day by continuous infusion for 120 hours Cladribine
(2CDA) 9 mg/m2: IV over 30 minutes daily for 5 days

Amend 8 M4/M5 without t(9;11) or inv(16): CE Cytarabine 3 gm/m2 IV q12h x 6 doses (days
1-3) by continuous infusion for 3 hours. Etoposide 125 mg/m2 IV on days 2-5 by continuous
infusion for at least one hour

t(8;21) and others: HAM Cytarabine 3 g/m2 IV x 6 doses (days 1-3) Mitoxantrone 10 mg/m2 IV
days 3-4

Standard-risk patients with matched related donors and high-risk patients will proceed to
stem cell transplant per institutional practice

Consolidation II (Chemotherapy course 4):

Cytarabine 3 gm/m2 IV q12 hours on days 1, 2, 8, 9 (8 doses) L-Asparaginase 6000 Units/m2 IM
3 hours after 4th and 8th doses of cytarabine

Consolidation III (Chemotherapy course 5) Mitoxantrone 10 mg/m2 IV days 1-3 Cytarabine 1
gm/m2 IV over 2 hours q12 hours on days 1-3 (6 doses)

Patients who are in first remission are eligible to be enrolled on the St. Jude protocols
NKAML protocol and receive Natural Killer (NK) cell therapy instead of Consolidation III or
after Consolidation III. At the discretion of their primary physician, these patients will
be offered the option of enrolling on NKAML.

Some patients with biphenotypic leukemia respond poorly to AML-directed therapy, but respond
quite well to lymphoid-directed therapy. Patients with such markers who have no response to
induction I or who fail to achieve complete response (CR) after induction II will therefore
receive lymphoid directed induction therapy. Other biphenotypic patients will continue to
receive AML-directed therapy as described above

All patients will undergo lumbar puncture and receive an age-appropriate dose of intrathecal
(IT) cytarabine at the time of diagnosis.

Patients without Central Nervous System disease (CNS)(i.e., less than 5 leukocytes per
microliter of CSF (colony-stimulating factor) will receive one dose of intrathecal (IT)
methotrexate, hydrocortisone, and cytarabine (MHA) with each course of chemotherapy
beginning with induction II.

Patients with overt CNS leukemia (more or equal to 5 leukocytes per l microliter of CSF and
the presence of leukemic blast cells on CSF cytospin) will receive weekly IT MHA therapy
beginning 1 week after the initial dose of IT cytarabine and continuing until the CSF is
free of blast cells (minimum number of doses, 4). These patients will then receive 4
additional doses of intrathecal therapy with methotrexate, hydrocortisone, and cytarabine
(IT MHA) (minimum total number of doses, 8) at approximately 1-month intervals (generally
given with each subsequent course of chemotherapy).