Decitabine as Maintenance Therapy After Standard Therapy in Treating Patients With Previously Untreated Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the efficacy, feasibility, and toxicities when one year of maintenance
therapy with decitabine is given to patients < 60 years with untreated acute myeloid leukemia
(AML) who achieve and maintain first complete remission (CR) following an established
induction and intensification regimen.

II. To determine the 1-year disease free survival rate for AML patients in first CR treated
with maintenance decitabine.

SECONDARY OBJECTIVES:

I. To measure biologic response to decitabine in evaluable patients with fusion genes to
determine eradication of minimal residual disease.

II. To measure surrogates for deoxyribonucleic acid (DNA) demethylation including
downregulation of DNA methyltransferase 1 (DNMT1) and induction of fetal hemoglobin.

III. To examine the significance of gene re expression following ex vivo decitabine exposure
in primary AML cells taken at the time of diagnosis on clinical outcome and on gene
expression at the time of relapse after in vivo decitabine exposure.

IV. To continue to evaluate the effectiveness of a cytogenetically risk-adapted approach for
consolidation therapy for patients with core binding factor (CBF) or non-CBF AML.

V. To continue the investigation begun in Cancer and Leukemia Group B (CALGB) 19808 aimed at
correlation of the rate of relapse and toxicity with intravenous (IV) busulfan
pharmacokinetics when busulfan and etoposide are used as the preparative regimen for
autologous stem cell transplantation for AML patients in first CR.

VI. To correlate outcome measures such as complete response (CR), disease-free survival
(DFS), event-free survival (EFS), and overall survival (OS), with pretreatment
characteristics such as age, sex, race, blood counts, morphology, immunophenotype,
cytogenetics, and molecular features of AML.

OUTLINE:

REMISSION INDUCTION THERAPY: Patients receive cytarabine IV over 168 hours on days 1-7 and
daunorubicin hydrochloride IV over 5-10 minutes and etoposide IV over 2 hours on days 1-3.
Patients undergo bone marrow biopsy on day 14. Patients with residual leukemia proceed to
second remission induction therapy. Patients achieving complete remission (CR) proceed to
intensification therapy.

SECOND REMISSION INDUCTION THERAPY: Patients receive cytarabine IV over 120 hours on days 1-5
and daunorubicin hydrochloride IV and etoposide IV over 2 hours on days 1 and 2. Patients
undergo bone marrow biopsy on day 42. Patients with residual leukemia are removed from the
study. Patients achieving CR proceed to intensification therapy.

INTENSIFICATION THERAPY: Patients are stratified and receive intensification therapy
according to cytogenetic findings (favorable cytogenetics [t(8;21)(q22q22), inv(16)(p13;q22),
or t(16;16)(p13;q22) by cytogenetic and/or molecular analysis] vs unfavorable cytogenetics
[all other cytogenetic findings, including normal cytogenetics]).

FAVORABLE CYTOGENETICS: Within 2-4 weeks after achieving CR, patients receive high-dose
cytarabine IV over 3 hours twice daily on days 1, 3, and 5.

Treatment repeats every 28 days for up to 3 courses.

UNFAVORABLE CYTOGENETICS: Peripheral blood stem cell (PBSC) mobilization: Within 2-4 weeks
after achieving CR, patients receive etoposide IV over 96 hours and high-dose cytarabine IV
over 2 hours twice daily on days 1-4 and filgrastim (G-CSF) subcutaneously (SC) once daily
beginning on day 14 and continuing until blood counts recover. Patients then proceed to
transplantation.

PBSC OR BONE MARROW TRANSPLANTATION: Patients receive busulfan IV over 2 hours 4 times daily
on days -7 to -4 and etoposide IV over 4 hours on day -3. Patients undergo autologous PBSC or
bone marrow transplantation on day 0 and receive G-CSF SC once daily beginning on day 0 and
continuing until blood counts recover.

UNFAVORABLE CYTOGENETICS AND UNABLE TO UNDERGO PBSC TRANSPLANTATION: Within 2-4 weeks after
achieving CR, patients receive etoposide, high-dose cytarabine, and G-CSF as in unfavorable
cytogenetics (PBSC mobilization) followed by 2 courses of high-dose cytarabine as in
favorable genetics.

MAINTENANCE THERAPY: Within 60-90 days after completion of intensification therapy, patients
receive decitabine IV over 1 hour on days 1-5. Treatment repeats every 6 weeks for up to 8
courses.

After completion of study treatment, patients are followed up every 2 months for 1 year,
every 6 months for 2 years, and then yearly for 2 years.

Inclusion Criteria:

- Unequivocal histologic diagnosis of AML (> 20% blasts in the bone marrow based on the
World Health Organization [WHO] and/or French American British [FAB] classifications),
excluding M3 (acute promyelocytic leukemia); patients with antecedent myelodysplasia
are eligible for treatment on this trial only if there were no bone marrow biopsy
showing myelodysplastic syndrome (MDS) > 3 months prior to enrollment; patients with
therapy-related AML are eligible if they have been free of their primary disease and
have not received any chemotherapy for at least 2 years

- No prior 5-azacitidine or decitabine therapy

- No prior treatment for leukemia or myelodysplastic syndrome with four permissible
exceptions:

- Emergency leukapheresis

- Emergency treatment for hyperleukocytosis with hydroxyurea

- Cranial radiation therapy (RT) for central nervous system (CNS) leukostasis (one
dose only)

- Growth factor/cytokine support