Trial Information

A Phase III Randomized Trial of Gemtuzumab Ozogamicin (Mylotarg) Combined With Conventional Chemotherapy for De Novo Acute Myeloid Leukemia (AML) in Children, Adolescents, and Young Adults

OBJECTIVES:

Primary

- Compare the event-free survival (EFS) and overall survival (OS) of young patients with
newly diagnosed acute myeloid leukemia (AML) treated with conventional combination
chemotherapy with vs without gemtuzumab ozogamicin (GMTZ).

Secondary

- Compare the remission induction rates after two courses of therapy in these patients.

- Compare disease-free survival and OS in patients who are eligible for an HLA-matched
family donor (MFD) stem cell transplant (SCT) by virtue of their risk classification,
with patients assigned to MFD SCT if a MFD is available, or to chemotherapy if a MFD is
not available.

- Determine the outcome of patients with Down syndrome who are 4 years of age or older at
diagnosis and treated with conventional combination chemotherapy without GMTZ.

- Compare the EFS and OS of patients with de novo AML treated with conventional
combination chemotherapy with vs without GMTZ censoring MFD SCT recipients.

- Determine the prevalence and prognostic significance of molecular abnormalities of KIT,
CEBPα and MLL-PTD genes in these patients.

- Determine the leukemic involvement of hematopoietic early progenitor and its role in
defining response to therapy.

- Assess the ability of a second-generation flow cytometric assay to predict patients at
high risk for relapse during periods of clinical remission.

- Examine whether GMTZ significantly improves EFS and OS in patients with higher CD33
concentrations/intensity.

- Examine whether GMTZ significantly improves complete remission, EFS, and OS in each of
the cytogenetic risk groups (high-, intermediate-, and low-risk) identified in prior
Medical Research Council trials.

- Utilize fluorescence in situ hybridization (FISH) analysis to identify variant patterns
among subgroups of patients who demonstrate the same G-banded chromosomal abnormality
(e.g., inv[16]/t[16;16], t[8;21], 11q23 abnormality) and determine whether these
variant patterns account for the heterogeneity of responses to therapy.

- Examine the impact of complex karyotypes (≥ 3, ≥ 4, and ≥ 5 abnormalities) on OS and
EFS in intermediate-risk patients for whom no high-risk or low-risk cytogenetic
abnormalities exist.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
relapse risk (high vs intermediate vs low). Patients are randomized to 1 of 2 treatment
arms. Patients with Down syndrome are nonrandomly assigned to arm I (but do not undergo
allogeneic stem cell transplant [SCT]).

- Arm I (standard therapy):

- 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 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.

- 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.

- 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.

PROJECTED ACCRUAL: A total of 1,012 patients will be accrued for this study.