Higher or Lower Dose Cladribine, Cytarabine, and Mitoxantrone in Treating Medically Less Fit Patients With Newly Diagnosed Acute Myeloid Leukemia or Myeloid Neoplasm

PRIMARY OBJECTIVES:

I. To evaluate the feasibility of randomizing medically less fit adults with newly diagnosed
acute myeloid leukemia (AML) or analogous myeloid neoplasms to either intensive or
non-intensive induction and post remission chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate the attitude of patients and physicians toward randomization and explore
reasons for treatment preference.

II. To evaluate whether the ability to assess fitness for intensive chemotherapy can be
improved by an augmented treatment-related mortality (TRM) score that includes additional
(co-morbidity) factors, and to compare the ability of physicians and the prediction
algorithm(s) to assess the likelihood of early death.

III. To compare, within the limits of a pilot study, response, duration of response, and
survival between patients receiving intensive and those receiving non-intensive chemotherapy.

IV. To describe the impact of treatment intensity on quality of life of patients undergoing
chemotherapy for newly diagnosed AML.

V. To describe the impact of treatment intensity on medical resource utilization and care
cost of patients undergoing chemotherapy for newly diagnosed AML.

OUTLINE: Patients agreeable to randomization are randomized to 1 of 2 treatment arms.
Patients not agreeable to randomization receive treatment based on their preference.

ARM I (HIGHER-DOSE):

INDUCTION: Patients receive granulocyte colony-stimulating factor (G-CSF) subcutaneously (SC)
on days 0-5, higher dose cladribine intravenously (IV) over 2 hours on days 1-5, higher dose
cytarabine IV over 2 hours on days 1-5, and higher dose mitoxantrone IV over 60 minutes on
days 1-3. Treatment repeats every 6 weeks for up to 4 courses in the absence of disease
progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve complete response (CR)/CR with incomplete count recovery
(CRi) with up to 2 courses of Induction receive G-CSF, cladribine, and cytarabine as in
Induction. Courses repeat every 6 weeks for up to 4 courses in the absence of disease
progression or unacceptable toxicity.

ARM II (LOWER-DOSE):

INDUCTION: Patients receive G-CSF SC on days 0-5, lower dose cladribine IV over 2 hours on
days 1-5, lower dose cytarabine IV over 1 hour on days 1-5, and lower dose mitoxantrone IV
over 60 minutes on days 1-3. Treatment repeats every 6 weeks for up to 12 courses in the
absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve complete response (CR)/CR with incomplete count recovery
(CRi) with up to 6 courses of Induction receive G-CSF, cladribine, and cytarabine as in
Induction. Courses repeat every 6 weeks for up to 12 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:

- Diagnosis of untreated ?high-grade? myeloid neoplasm (>= 10% myeloid blasts by
morphology in bone marrow and/or peripheral blood) 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; patients with acute leukemias of
ambiguous lineage are eligible; outside diagnostic material is acceptable as long as
peripheral blood and/or bone marrow slides are reviewed at the study institution and
cytogenetic/molecular information is available

- Treatment-related mortality (TRM) score >= 13.1 as calculated with simplified model

- The use of hydroxyurea before enrollment is permitted; hydroxyurea should be
discontinued prior to start of study treatment; patients with symptoms/signs of
hyperleukocytosis or white blood cell count (WBC) >100,000/uL can be treated with
leukapheresis or may receive up to 1 dose of cytarabine (up to 500 mg/m^2) anytime
prior to enrollment

- Patients may have received treatment (e.g. azacitidine/decitabine, lenalidomide,
growth factors) for antecedent low-grade myeloid neoplasm

- Left ventricular ejection fraction (LVEF) >= 45%, assessed within 3 months prior to
registration, e.g. by multigated acquisition (MUGA) scan or echocardiography, or other
appropriate diagnostic modality

- Women of childbearing potential and men must agree to use adequate contraception
beginning at the signing of the consent until at least 4 weeks after the last dose of
study drug

- Ability to understand and the willingness to sign a written informed consent document

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; patients with fever
thought to be likely secondary to leukemia are eligible; known hypersensitivity to any
study drug

- Known hypersensitivity to any study drug used in this trial

- Pregnancy or lactation

- Concurrent treatment with any other anti-leukemia agent