Decitabine, Filgrastim, Cladribine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. Estimate the maximum tolerated dose (MTD) of decitabine when used concomitantly with
filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride (G-CLAM) in patients with
newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).

II. Compare, within the limits of a phase 1/2 study, the rate of complete remission without
measurable residual disease (minimal residual disease negative [MRDneg] complete remission
[CR]) with decitabine + G-CLAM at the MTD compared to similar patients treated previously
with G-CLAM alone.

SECONDARY OBJECTIVES:

I. Evaluate, within the limits of a phase 1/2 study, disease response (complete remission,
overall response rate) relapse-free survival (RFS), event-free survival (EFS), and overall
survival (OS) in patients with newly-diagnosed AML / high-risk MDS.

II. Describe, within the limits of a phase 1/2 study, the toxicity profile of the study
regimen.

OUTLINE: This is a dose de-escalation study of decitabine.

INDUCTION: Patients receive decitabine intravenously (IV) over 1 hour on days 1-10. Patients
also receive filgrastim subcutaneously (SC) on days 0-5, cladribine IV over 2 hours on days
1-5, cytarabine IV over 2-4 hours on days 1-5, and mitoxantrone hydrochloride IV over 60
minutes on days 1-3.

RE-INDUCTION: Patients who do not achieve MRDneg CR after first induction are eligible for
re-induction. Patients receive the same treatment as during induction except that decitabine
is omitted.

CONSOLIDATION THERAPY: Beginning 6 weeks after achieving MRDneg CR or CR/CR with incomplete
count recovery (CRi) after induction and/or re-induction, patients are eligible to receive
filgrastim, cladribine, and cytarabine as in Induction. Treatment may be repeated for up to 4
courses in the absence of disease progression or unacceptable toxicity. Subsequent
consolidation cycles would be given after recovery from the previous cycle (roughly 4-6
weeks).

After completion of study treatment, patients are followed up at for 1 month and every 3
months for up to 5 years.

Inclusion Criteria:

- For patients with newly diagnosed disease: diagnosis of "high-grade" MDS (>= 10%
blasts by morphology) or AML other than acute promyelocytic leukemia (APL) with
t(15;17)(q22;q12) or variants according to the 2016 World Health Organization (WHO)
classification; for patients with relapsed/refractory disease: prior diagnosis of
"high-risk" MDS or non-APL AML, with relapsed/refractory disease according to 2003
recommendations of the International Working Group, requiring first or subsequent
salvage therapy; patients with mixed phenotype acute leukemia (MPAL) are eligible

- Outside diagnostic material is acceptable as long as peripheral blood and/or bone
marrow slides are reviewed at the study institution; flow cytometric analysis of
peripheral blood and/or bone marrow should be performed according to institutional
practice guidelines

- Patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT)
are eligible if relapse occurs provided symptoms of graft-versus host disease are well
controlled with stable use of immunosuppressive agents

- Treatment-related mortality (TRM) score =< 9.2 as calculated with simplified model

- Should be off any active therapy for AML with the exception of hydroxyurea for at
least 14 days prior to study registration unless patient has rapidly progressive
disease, and all grade 2-4 non-hematologic toxicities should have resolved

- May have previously received monotherapy with demethylating agents for MDS or AML or
treatment with a mitoxantrone- or cladribine-based regimen for MDS or AML, including
G-CLAM, but not demethylating agent as priming for or in combination with chemotherapy

- Patients with symptoms/signs of hyperleukocytosis or white blood cells (WBC) >
100,000/uL can be treated with leukapheresis or may receive up to 2 doses of
cytarabine (up to 500 mg/m^2/dose) prior to enrollment

- Bilirubin =< 2.5 x institutional upper limit of normal (IULN) unless elevation is
thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis
(assessed within 14 days prior to registration)

- Serum creatinine =< 2.0 mg/dL (assessed within 14 days prior to registration)

- Left ventricular ejection fraction >= 45%, assessed within 3 months prior to
registration, e.g. by multigated acquisition scan (MUGA) scan or echocardiography, or
other appropriate diagnostic modality and no clinical evidence of congestive heart
failure; if the patient had anthracycline-based therapy since the most recent cardiac
assessment, cardiac evaluation should be repeated if there is clinical or radiographic
suspicion of cardiac dysfunction, or if the previous cardiac assessment was abnormal

- Women of childbearing potential and men must agree to use adequate contraception

- Ability to understand and willingness to sign a written consent

Exclusion Criteria:

- Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not
considered candidate for tyrosine kinase inhibitor treatment

- Concomitant illness associated with a likely survival of < 1 year

- Active systemic fungal, bacterial, viral, or other infection, unless disease is under
treatment with anti-microbials and/or controlled or stable (e.g. if specific,
effective therapy is not available/feasible or desired [e.g. chronic viral hepatitis,
human immunodeficiency virus (HIV)]); patient needs to be clinically stable as defined
as being afebrile and hemodynamically stable for 24-48 hours

- Known hypersensitivity to any study drug

- Pregnancy or lactation

- Patients may not be receiving any other investigational agents