Alvocidib, Cytarabine, and Mitoxantrone Hydrochloride or Cytarabine and Daunorubicin Hydrochloride in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To compare the rate of complete remission (CR) after 1 course of induction therapy with
the timed-sequential combination of alvocidib (flavopiridol), cytarabine (cytosine
arabinoside [ara-C]), and mitoxantrone hydrochloride (FLAM) vs traditional "7+3" cytarabine
and daunorubicin hydrochloride (ara-C + Daunorubicin) for adults (age 18 to 70) with newly
diagnosed, previously untreated, intermediate-risk or poor-risk acute myelogenous leukemia
(AML).

SECONDARY OBJECTIVES:

I. To evaluate and compare the toxicities of FLAM vs 7+3. II. To compare the 2-year
disease-free survival (DFS) and overall survival (OS) in response to FLAM vs 7+3.

III. To detect and compare the presence of minimal-residual disease (MRD) remaining after
FLAM vs 7+3.

IV. To determine the expression of ABC transport proteins multidrug resistance 1 (MDR1,
ABCB1) and breast cancer resistance protein (BCRP, ABCG2) on AML blasts pretreatment and
correlate the expressions of one or both proteins with CR and DFS in response to FLAM vs
7+3.

OUTLINE: This is a multicenter study. Patients are stratified according to risk features:
age (< 50 vs >= 50), secondary AML (pre-existing myelodysplatic syndrome [MDS],
myeloproliferative diseases [MPD], treatment-related [t]-AML, or severe multi-lineage
dysplasia) and/or known adverse cytogenetics, and hyperleukocytosis (white blood cells [WBC]
>= 50,000/mm^3). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive alvocidib intravenously (IV) over 1 hour on days 1-3, cytarabine IV
over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.
Patients who achieve complete or partial response to the first course (completion of all
doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days
following blood count recovery, and/or undergo allogeneic bone marrow transplant.

ARM II: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin
hydrochloride IV on days 1-3. Patients who have residual disease on day 14 may receive
additional cytarabine for 5 days and daunorubicin hydrochloride for 2 days. Patients may
undergo blood and bone marrow collection for correlative studies.

After completion of study therapy, patients are followed up every 3 months for 2 years,
every 6 months for 5 years, and then annually thereafter.

Inclusion Criteria:

- All adults with established, pathologically confirmed diagnoses of newly diagnosed
AML and adults with newly diagnosed AML, excluding newly diagnosed core-binding
factor (CBF) AMLs and acute progranulocytic leukemia (APL, M3), will be considered
eligible for study

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-3

- Patients >= 65 years of age must have ECOG PS =< 2 prior to developing leukemic
symptoms

- Serum creatinine ≤ 2.0 mg/dL

- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 5 times upper
limit of normal (ULN) (unless leukemic infiltration)

- Total bilirubin =< 2.0 mg/dL (unless Gilbert disease, hemolysis, or leukemia)

- Left ventricular ejection fraction ≥ 45%

- Newly diagnosed AML, subtypes M0, 1, 2, 4-7 but excluding M3 (APL), including those
with the following poor risk features:

- Antecedent hematologic disorder including myelodysplasia (MDS)-related AML
(MDS/AML) and prior myeloproliferative disorder (MPD)

- Treatment-related myeloid neoplasms (t-AML/t-MDS)

- Myeloid sarcoma, myeloid proliferations related to Down Syndrome, and blastic
plasmacytoid dendritic cell neoplasm

- AML with multilineage dysplasia (AML-MLD)

- Adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 21q,
or 17p; t(6;9); t(9;22); trisomy 8; trisomy 13; trisomy 21; and complex
karyotypes (≥ 3 unrelated abnormalities)

- Patients who have received hydroxyurea alone or have received non-cytotoxic therapies
previously for myelodysplasia (MDS) or myeloproliferative disorder (MPD) (e.g.,
thalidomide or lenalidomide, interferon, cytokines, 5-azacytidine or decitabine,
histone deacetylase inhibitors, low-dose cyclophosphamide [cytoxan], tyrosine kinase
[TK] or dual TK/src inhibitors) will be eligible for this trial

- At least 24 hours since prior leukopheresis or hydroxyurea for cytoreduction

Exclusion Criteria:

- Any previous treatment with flavopiridol

- Concomitant chemotherapy, radiation therapy, or immunotherapy

- Hyperleukocytosis with >= 50,000 blasts/uL; leukopheresis or hydroxyurea may be used
immediately prior to study drug administration for cytoreduction; must be stopped 24
hours before first dose of study chemotherapy

- CBF AMLs associated with t(8;21) or M4eo subtype (inv[16] or t[16;16]), as diagnosed
by morphologic criteria, flow cytometric characteristics, and rapid cytogenetics or
FISH or molecular testing

- Acute Progranulocytic Leukemia (APL, M3)

- Active central nervous system (CNS) leukemia

- Active, uncontrolled infection; patients with infection under active treatment and
controlled with antibiotics are eligible

- Active, uncontrolled graft vs. host disease (GVHD) following allogeneic transplant
for non-AML condition (e.g. MDS, lymphoid malignancy, aplastic anemia); patients with
GVHD controlled on stable doses of immunosuppressants are eligible

- Presence of other life-threatening illness

- Patients with mental deficits and/or psychiatric history that preclude them form
giving informed consent or from following protocol

- Pregnant and nursing patients are excluded