Trial Information

A PHASE III STUDY IN CHILDREN WITH UNTREATED ACUTE MYELOGENOUS LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS)

OBJECTIVES:

Increase the remission induction rate to greater than 85% in children with untreated acute
myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) by replacing daunorubicin
(DNR) with idarubicin (IDA) in intensively timed DCTER chemotherapy (dexamethasone,
cytarabine (ARA-C), thioguanine, etoposide, and daunorubicin) in the first 4 days of each
course.

Increase the remission rate further by comparing the efficacy of consolidation chemotherapy
with intensively timed IDA DCTER/DCTER vs fludarabine (FAMP), ARA-C, and IDA in maintaining
remission and in achieving remission in patients with M2 disease (5%-29% blasts in marrow)
at the end of induction chemotherapy.

Compare overall survival, event-free survival, and disease-free survival in patients who
receive consolidation with IDA DCTER/DCTER vs FAMP, ARA-C, and IDA.

Compare overall survival, event-free survival, and disease-free survival in patients
receiving intensification with the Capizzi II regimen (high-dose ARA-C and asparaginase) vs
those receiving a matched-related allogeneic bone marrow transplantation.

Compare overall survival, event-free survival, and disease-free survival in patients treated
with interleukin-2 (IL-2) vs standard follow up care after Capizzi II intensification.

Determine whether multichannel flow cytometry detection of residual AML on a companion
biologic study protocol CCG-B942 predicts outcome, and determine whether any of these
treatment regimens eliminates minimal residual disease more effectively than another.

Register all patients with MDS treated or followed at CCG institutions and capture their
biologic, historical and outcome data.

Determine, on a companion biologic study protocol CCG-B972, whether levels of IL-2 soluble
receptor (sIL-2R) and absolute lymphocyte count (ALC) before, during, and after therapy
correlates with outcome.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
center, diagnosis (acute myelogenous leukemia vs other), and response to induction (partial
vs complete remission). After induction, patients with M1/M2 marrow are randomized to arm I
or II. Patients in complete remission after consolidation who have an HLA-identical or
1-antigen mismatched sibling or parent donor are randomly assigned to the allogeneic bone
marrow transplantation (AlBMT) regimen; all others in complete remission are nonrandomly
assigned to the Capizzi II regimen, then are randomly assigned to arms III or IV. Patients
with refractory anemia (RA) or RA with ringed sideroblasts with indolent disease may be
registered and followed. Other patients with myelodysplastic syndromes may receive 2961
chemotherapy or go directly to AlBMT. Patients with chloromas (granulocytic sarcomas)
receive optional radiotherapy on arm V.

Induction: Patients receive idarubicin IV over 30 minutes on days 0-3, cytarabine and
etoposide IV continuously on days 0-3, and oral thioguanine twice a day and oral
dexamethasone 3 times a day on days 0-3. Patients then begin course 2, which consists of
cytarabine, etoposide, thioguanine, and dexamethasone on days 10-13, daunorubicin IV
continuously on days 10-13, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 16
and continuing until blood counts recover. Patients also receive CNS prophylaxis/therapy
consisting of cytarabine intrathecally (IT) on days 0 and 14 (if no CNS disease at entry) or
on days 0, 5, and 7 (if CNS disease present at entry). Disease is reassessed on day 28-42.
Patients with M1 or M2 marrow proceed to consolidation while those with M3 marrow or
progressive disease go off study.

Consolidation:

Arm I: Patients receive treatment as in induction therapy, plus G-CSF SC beginning on day 16
and continuing until blood counts recover. If CSF is clear by day 10 of induction, patients
receive cytarabine IT on days 0, 10, and 35. If CSF is not clear, patients receive triple
intrathecal therapy (TIT; cytarabine, hydrocortisone, methotrexate) on days 0 and 10.

Arm II: Patients receive fludarabine IV over 24 hours on days 0 and 1, cytarabine IV over 72
hours on days 2-4, and idarubicin IV over 15 minutes on days 0-2. G-CSF begins on day 6 and
continues until blood counts recover. Patients also receive TIT on days -1 and 7, if CSF is
not clear on day 10 of induction. Patients on both arms are reassessed on day 35. Those
patients with M1 marrow proceed to intensification; all others are removed from the study.

Intensification:

Capizzi II regimen: Course 1: Patients receive cytarabine IV over 3 hours every 12 hours on
days 0, 1, 7, and 8 and asparaginase IM on days 1 and 8. Course 2: Patients also receive
cytarabine IT or TIT on days 0, 7, and 14.AlBMT regimen: Therapy begins within 2-8 weeks of
hematologic recovery. Patients may receive interim therapy consisting of oral thioguanine
for about 2 weeks. Patients then receive oral busulfan every 6 hours on days -9 to -6 and
cyclophosphamide IV over 1 hour on days -5 to -2. AlBMT is infused over 4 hours beginning
36-48 hours after the last dose of cyclophosphamide. Patients in complete remission after
completing the Capizzi II regimen proceed to maintenance therapy on arm III.

Arm III: Patients receive interleukin-2 IV continuously on days 1-4 and 9-18.

Arm IV: No further treatment.

Arm V: Patients undergo radiotherapy to the chloroma 5 days a week for 2 weeks.

Patients are followed monthly for 18 months, every 3 months for 1 year, and then every 6
months until 5 years from diagnosis.

PROJECTED ACCRUAL: Approximately 880 patients with de novo acute myelogenous leukemia will
be accrued for this study within 4 years. It is expected that 178 patients per year will be
randomly assigned for consolidation, that 39 patients per year will undergo allogeneic bone
marrow transplantation while 120 patients per year will receive chemotherapy as
intensification, and that 102 patients per year will be randomly assigned for
polychemotherapy immunomodulation. An additional 80 patients with myelodysplastic syndromes
will be accrued for this study.