Decitabine Followed by Idarubicin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes

PRIMARY OBJECTIVES:

I. To determine the morphologic complete remission (CR) rates using a decitabine
(DAC)-priming followed by idarubicin (IDA) and cytarabine (ARAC) in patients with relapsed
or refractory acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. To determine CR without minimal residual disease (CRMRD-), CR with incomplete blood count
recovery (CRi), CR with minimal residual disease (CRMRD+), and CR with incomplete blood
count recovery and with minimal residual disease (CRiMRD+) rates.

II. To estimate the frequency and severity of regimen-related toxicities.

III. To identify biomarkers (e.g., deoxyribonucleic acid [DNA] methylation and expression
changes including interferon regulatory factor [IRF]8) associated with clinical responses.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive decitabine intravenously (IV) over 1 hour on days -4 to 0,
cytarabine IV continuously over 24 hours on days 1-7, and idarubicin IV over 10-15 minutes
on days 1-3.

ARM II: Patients receive decitabine IV over 1 hour on days -9 to -5 and cytarabine and
idarubicin as in Arm I.

In both arms, treatment repeats every 28 days for up to 3 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 5 years.

Inclusion Criteria:

- Written informed consent

- All patients except those with acute promyelocytic leukemia (APL) who have
morphological diagnosis of myelodysplastic syndromes (MDS) refractory anemia with
excess blasts (RAEB)-II or AML by World Health Organization (WHO) diagnostic criteria
and have either refractory or early relapsed disease; NOTE:

- Diagnosis of refractory or relapsed disease must be based on evaluation of a
bone marrow (BM) aspirate or peripheral blood (PB) flow cytometry; other
standard MDS and AML prognostic studies such as cytogenetics, flow, and
molecular testing are highly recommended prior to initiating DAC

- A previous BM evaluation or PB flow cytometry from an outside facility are
acceptable if the results have been deemed to be adequate for confirming the
diagnosis and staging by University of Washington (UW)/Seattle Cancer Care
Alliance (SSCA)/Fred Hutchinson Cancer Research Center (FHCRC) review

- A BM biopsy is not routinely required but should be obtained if the previous
evaluation is not deemed to be adequate for confirming diagnosis and staging by
UW/SCCA/FHCRC review

- Must have received at least one previous cycle of treatment for myelodysplastic
syndrome (MDS) or AML and be either refractory as defined as not responded to this
therapy or in early relapse as defined as developing recurrence of the disease within
12 months of obtaining a CR

- May have previously received demethylating agents (e.g., DAC, 5-azacytidine [5AZA])
or histone deacetylases (e.g., suberoylanilide hydroxamic acid) for their MDS or AML
if these demethylating agents were not used in combination with systemic
anthracycline and ARAC chemotherapy

- May have received hematopoietic growth factors, thalidomide/lenalidomide, signal
transduction inhibitors, or low dose cytarabine (=< 20 mg/m2/day)

- May not have received any therapy for their MDS or AML other than hydroxyurea or
leukapheresis for at least 14 days prior to start of the first dose of DAC; all
non-hematologic toxicities must have resolved to < grade 2

- Must have a "simplified" treatment-related mortality (TRM) score =< 9.2

- Females of childbearing potential must have a negative pregnancy test prior to
initiation of the protocol therapy; females are considered not of child bearing
potential if they are surgically sterile (they have undergone a hysterectomy,
bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal

- Females of childbearing potential and males must be willing to use an effective
method of contraception (hormonal or barrier method of birth control; abstinence)
from the time consent is signed until 12 weeks after treatment discontinuation

- Patients with an active or history of other malignancies are eligible, if their
projected overall survival for that malignancy is at least 6 months

- Prior hormonal therapy such as aromatase inhibitors, selective estrogen receptor
modulators, estrogen receptor down-regulators, luteinizing hormone-releasing hormone
(LHRH) agonists and antagonists, and anti-androgens, must be completed at least 30
days prior to initiation of protocol therapy and must remain off hormonal therapy
until the patient has finished chemotherapy for their MDS-RAEBII or AML

- Direct bilirubin =< 2.5 mg/dL (assessed within 14 days prior to registration) unless
elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or
hemolysis

- No known hypersensitivity to decitabine (DAC), aracytidine triphosphate (ARAC), or
idarubicin hydrochloride (IDA)

- No clinical evidence of central nervous system (CNS) involvement with leukemia,
unless a lumbar puncture confirms the absence of leukemic blasts in the cerebrospinal
fluid (CSF)

- No prior positive test for the human immunodeficiency virus (HIV)

- No uncontrolled systemic infection

Exclusion Criteria:

- Previous therapy with demethylating agents (e.g., DAC, 5AZA, etc.) or histone
deacetylases (e.g., suberoylanilide hydroxamic acid, etc.) that was combined with
daunorubicin (DNR) or IDA and ARAC

- Patients with acute promyelocytic leukemia (APL)

- Known hypersensitivity to DAC, ARAC, or IDA

- Clinical evidence of CNS involvement with leukemia, unless a lumbar puncture confirms
the absence of leukemic blasts in the CSF

- Prior positive test for HIV

- Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment)

- A "simplified" TRM score > 9.2

- Bilirubin > 2.5 mg/dl (assessed within 14 days prior to registration), unless
elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or
hemolysis

- Patients who have a projected overall survival < 6 months due to malignancies other
than MDS or AML

- Documented symptomatic congestive heart failure or a documented left ventricular
ejection fraction < 40% assessed by multigated acquisition (MUGA), echocardiography,
or heart catheterization within 21 days prior to start of decitabine