Azacitidine and Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To test whether outcomes of patients of age 60 or older with previously untreated non-M3
acute myeloid leukemia treated with azacitidine plus gemtuzumab ozogamicin are sufficient to
warrant phase III investigation.

II. To estimate the frequency and severity of toxicities of this regimen in the good- and
poor-risk groups of patients.

III. To investigate in a preliminary manner the disease-free survival of patients who achieve
complete remission and receive post-remission therapy on this study.

IV. To investigate in a preliminary manner the cytogenetic response rates of patients treated
with this regimen.

V. To investigate in a preliminary manner the effects of cytogenetic abnormalities, promoter
and global methylation changes, and multidrug resistance on overall survival and response to
azacitidine plus gemtuzumab ozogamicin therapy.

OUTLINE: Patients are stratified according to risk status (good [60-69 years of age OR Zubrod
performance status [PS] 0-1] vs poor [>= 70 years of age AND Zubrod PS 2-3]).

REMISSION INDUCTION THERAPY: Patients receive azacitidine intravenously (IV) over 10-40
minutes or subcutaneously (SC) once daily (QD) on days 1-7 and gemtuzumab ozogamicin IV over
2 hours on day 8. Patients with residual leukemia (blast count >= 5%) receive a second course
of induction therapy beginning between days 15-29. Patients achieving complete remission (CR)
or morphologic complete remission with incomplete blood count recovery (CRi) go on to receive
consolidation therapy.

CONSOLIDATION THERAPY: Patients receive one course of azacitidine and gemtuzumab ozogamicin
as in induction therapy (with azacitidine given SC only).

MAINTENANCE THERAPY: Patients receive azacitidine SC on days 1-7. Treatment repeats every 28
days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients
undergo bone marrow biopsies for cytogenetic studies at baseline, remission, and relapse or
progression (and at completion of treatment if it does not correspond to one of these time
points). Marrow and blood samples are submitted to correlatives studies and submitted to
Southwest Oncology Group (SWOG) acute lymphoblastic leukemia (ALL)/chronic lymphocytic
leukemia (CLL)/chronic myelogenous leukemia (CML) Repository in Seattle, WA.

After completion of study therapy, patients are followed every 2 months for 2 years, every 3
months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.

Inclusion Criteria:

- Morphologically confirmed diagnosis of acute myeloid leukemia (AML) with
classification other than WHO acute promyelocytic leukemia (FAB M3), based on bone
marrow examination performed within 14 days prior to registration; patients with World
Health Organization (WHO) acute promyelocytic leukemia (FAB M3) or blastic
transformation of chronic myelogenous leukemia are not eligible

- Zubrod performance status 0-3

- No known hypersensitivity to azacitidine, mannitol, hydroxyurea, orgemtuzumab
ozogamicin

- No prior systemic chemotherapy for acute leukemia with the exception of hydroxyurea;
administration of hydroxyurea to control high white blood cell (WBC) count prior to
registration is permitted

- Patients with a history of prior myelodysplastic syndrome (MDS) are eligible according
to the following criteria:

- No prior treatment of MDS with AML induction-type chemotherapy or high-dose
chemotherapy with hematopoietic stem cell support

- Prior cytarabine allowed if dose < 100 mg/m^2/day

- Prior hematopoietic growth factors, thalidomide, lenalidomide, arsenic trioxide,
and signal transduction inhibitors for treatment of MDS allowed

- No prior treatment with azacitidine, decitabine, or gemtuzumab ozogamicin

- At least 30 days since prior therapy for MDS and recovered

- Bilirubin =< 2.0 x institutional upper limit of normal (IULN) within 14 days to
registration, unless the elevation is believed to be due to hepatic infiltration by
AML

- Hyperbilirubinemia due primarily to elevated unconjugated hyperbilirubinemia
secondary to Gilbert syndrome or hemolysis is allowed

- Serum glutamic oxaloacetic transaminase (SGOT) aspartate aminotransferase (AST) =< 2 x
IULN, or serum glutamic pyruvate transaminase (SGPT) alanine aminotransferase (ALT) =<
2.0 x IULN , unless the elevation is believed to be due to hepatic infiltration by AML

- Serum creatinine =< 1.5 x IULN

- Left ventricle ejection fraction (LVEF) >= 40% by multi-gated acquisition scan (MUGA)
or echocardiogram (ECHO) AND no clinical evidence of congestive heart failure within
the past 56 days

- Pretreatment cytogenetics must be performed on all patients; collection of
pretreatment specimens must be completed within 14 days prior to registration to
S0703; specimens must be submitted to the site's preferred cytogenetics laboratory

- Patients must consent to submit specimens to the Southwest Oncology Group (SWOG) acute
lymphoblastic leukemia (ALL)/chronic lymphocytic leukemia (CLL)/chronic myelogenous
leukemia (CML) repository for cellular and molecular studies; collection of
pretreatment blood and/or marrow specimens must be completed within 14 days prior to
registration; if a marrow specimen is available, either from the diagnostic marrow or
a repeat pre-registration marrow, then it must be submitted along with a peripheral
blood specimen; otherwise peripheral blood alone must be submitted; residual specimens
will only be banked if the patient provides separate consent; sites are required to
offer patients the opportunity to participate in banking

- No central nervous system (CNS) involvement; if central nervous involvement is
clinically suspected, it must be ruled out by a lumbar puncture

- Women of reproductive potential must have a pregnancy test within 28 days prior to
registration; patients must not be pregnant or nursing because of the teratogenic
potential of the drugs used in this study; women/men of reproductive potential must
have agreed to use an effective contraceptive method

- Patients not known to be human immunodeficiency virus positive (HIV+) must be tested
for HIV infection within 14 days prior to registration

- HIV-positive patients must meet the following criteria:

- No history of acquired immunodeficiency syndrome (AIDS)-defining events

- CD4 cells >= 500/mm^3

- Viral load of < 50 copies HIV messenger ribonucleic acid (mRNA)/mm^3 if on cART
or < 25,000 copies HIV mRNA if not on cART

- No zidovudine or stavudine as part of cART Patients who are HIV+ and do not meet
all of these criteria will not be eligible for this study

- No other prior malignancy except for a) adequately treated basal cell or squamous cell
skin cancer or b) any diagnosis of malignancy made within the past 2 years earlier, of
which there is no clinically evident cancer, and for which the patient has completed
all chemotherapy and radiotherapy at least 6 months prior to study registration; prior
treatment with AML induction-type chemotherapy is not allowed; concurrent hormonal
therapy is allowed

- All patients must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and federal
guidelines

- At the time of patient registration, the treating institution's name and
identification (ID) number must be provided to the Data Operations Center in Seattle
in order to ensure that the current (within 365 days) date of institutional review
board approval for this study has been entered into the data base

- Patients must have complete remission (CR) or CRi, documented by blood and marrow
examinations performed within 42 days before this registration

- Following completion of induction therapy, the blood counts must recover to absolute
neutrophil count (ANC) >= 1,000/mcL and platelets >= 90,000/mcL (without transfusion),
and must be maintained at these levels during the 7 days prior to registration

- Patients must have serum creatinine =< 1.5 x IULN and SGOT or SGPT =< 1.5 x IULN
within 28 days before registration

- Patients must have recovered to =< Grade 2 from any induction cycle non-hematologic
toxicities