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

PRIMARY OBJECTIVES:

I. Estimate the maximum tolerated dose (MTD) of dose-intensified mitoxantrone hydrochloride
(mitoxantrone) as part of the filgrastim (G-CSF), cladribine, cytarabine, mitoxantrone
hydrochloride (G-CLAM) regimen separately for adults with newly diagnosed acute myeloid
leukemia (AML) and those with relapsed/refractory AML receiving first or greater salvage
therapy.

SECONDARY OBJECTIVES:

I. To determine, within the limits of a phase 1/2 study, disease response and duration of
remission separately for patients with newly diagnosed and relapsed/refractory AML.

II. To describe, within the limits of a phase 1/2 study, the toxicity profile of the study
regimen separately for patients with newly diagnosed and relapsed/refractory AML.

OUTLINE: This is a phase I, dose-escalation study of mitoxantrone hydrochloride followed by
phase II study.

INDUCTION CHEMOTHERAPY (G-CLAM): Patients receive G-CLAM chemotherapy comprising filgrastim
subcutaneously (SC) daily on days 0-5, mitoxantrone hydrochloride intravenously (IV) over 60
minutes on days 1-3, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2
hours daily on days 1-5. Patients achieving complete remission with incomplete peripheral
blood count recovery (CRi), partial remission, or persistent disease may receive a second
course of induction chemotherapy. Patients achieving complete remission (CR) or CR with
incomplete platelet count recovery (CRp) may continue on to Consolidation Chemotherapy.

CONSOLIDATION CHEMOTHERAPY (G-CLA): Beginning within 6 weeks of achieving CR/CRp/CRi,
patients receive G-CLA comprising filgrastim SC on days 0-5, cladribine IV over 2 hours daily
on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Treatment continues for up to
4 courses in the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- For patients with newly diagnosed disease: diagnosis of "high-risk" myelodysplastic
syndrome (MDS) (>= 10% blasts) or AML other than acute promyelocytic leukemia (APL)
with t(15;17)(q22;q12) or variants according to the 2008 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
standard criteria requiring first or subsequent salvage therapy; patients with
biphenotypic AML 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

- For patients with relapsed/refractory disease: patients with prior autologous or
allogeneic hematopoietic cell transplantation (HCT) for MDS/AML 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 =< 6.9 as calculated with simplified model

- The use of hydroxyurea prior to study registration is allowed; patients with
symptoms/signs of hyperleukocytosis or white blood cell (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

- For patients with relapsed/refractory disease: patients may have previously received
chemotherapy with a mitoxantrone- or cladribine-based regimen for MDS or AML; if that
patient has received G-CLAM before and has been sensitive to this regimen, eligibility
will be determined on a case-by-case basis by the study principal investigator (PI)

- Should be off any active systemic 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

- 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 study day 0)

- Serum creatinine =< 2.0 mg/dL (assessed within 14 days prior to study day 0)

- Left ventricular ejection fraction >= 45%, assessed within 3 months prior to study day
0, e.g. by multi gated 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

- Provide written informed 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 hours; patients with fever thought
to be likely secondary to leukemia are eligible

- Known hypersensitivity to any study drug

- Pregnancy or lactation

- Treatment with any other investigational agent