This phase II trial studies how well isavuconazole works in preventing invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndrome and neutropenia. Isavuconazole may help to prevent invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndrome and neutropenia.

PRIMARY OBJECTIVES:

I. To assess whether prophylaxis with isavuconazole effectively prevents the occurrence of proven or probable invasive fungal infections (IFIs) in patients with newly diagnosed acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) receiving successive cycles of intensive chemotherapy or other therapies for up to 100 days from prophylaxis initiation.

SECONDARY OBJECTIVES:

I. To evaluate the incidence of invasive aspergillosis (IA) within 100 days of beginning isavuconazole prophylaxis in newly diagnosed patients with AML/MDS receiving intensive chemotherapy or other therapies.

II. To evaluate the incidence of other IFIs within 100 days of beginning isavuconazole prophylaxis in newly diagnosed patients with AML/MDS receiving intensive chemotherapy or other therapies.

III. To evaluate the composite outcome of treatment success versus (vs.) failure in this patient population.

IV. To measure the overall survival (OS) of study participants. V. To measure the IFI-free survival of study participants. VI. To document the time to death from any cause in the study population. VII. To document the time to death related to IFI in the study population. VIII. To document the time to diagnosis of proven or probable IFI in the study population.

IX. To document the time to initiation of empiric anti-fungal therapy in the study population.

X. To characterize the safety, tolerability and adverse event (AE) profile of isavuconazole in the prophylactic setting.

EXPLORATORY OBJECTIVES:

I. To assess the potential role, if any, of therapeutic drug monitoring (TDM) of isavuconazole levels in the prophylactic setting in patients with newly diagnosed AML/MDS receiving cytotoxic chemotherapy or other therapies.

II. To determine the in vitro susceptibility of agents causing "breakthrough" IFIs to antifungal agents.

OUTLINE:

Patients receive isavuconazole orally (PO) every 8 hours for 6 doses and then once daily (QD) or intravenously (IV) over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

• Patients with either newly diagnosed AML or MDS who have either begun (within 4 days of starting study drug) or are planned to begin specific treatment for their AML/MDS; hydroxyurea and cytarabine used for cytoreduction while awaiting initiation of definitive therapy are not considered "specific" treatment; patients who are participating in other therapeutic clinical trials for their AML/MDS may participate in this trial
• Patients must have or be anticipated to have neutropenia (absolute neutrophil count [ANC] < 0.5 x 10^9/L) (75) for >= 7 days as a result of treatment of their AML/MDS
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Total bilirubin =< 3 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5 x ULN
• Patients must be able to take oral medications, although a brief period of IV therapy (< 4 days) is permitted at trial entry
• Patients must be willing and able to provide written informed consent for the trial
• Women of childbearing potential (WOCBP) must practice 2 effective methods of birth control during the course of the study; male patients who are partners of WOCBP should also practice an effective method of contraception; effective methods of birth control include diaphragm or condoms with spermicidal foam or jelly, birth control pills (BCPs), injections or patches, intra-uterine devices (IUDs) and surgical sterilization
• Postmenopausal women must be amenorrheic for >= 12 months to be considered of non-childbearing potential
• Women and men must continue birth control for the duration of the trial and >= 3 months after the last dose of study drug
• All WOCBP MUST have a negative pregnancy test prior to first receiving study medication

Exclusion Criteria:

• Proven, probable or possible IFI within the previous 30 days
• Use of any systemic antifungal therapy for > 72 hours during the week prior to study drug initiation
• History of hypersensitivity or idiosyncratic reactions to azoles
• Patients with familial short QT syndrome or with corrected QT (QTc) interval =< 300 ms
• Patients on strong CYP3A4 inducers or inhibitors that cannot be discontinued
• Women who are pregnant or nursing, or intend to be/do so during the course of the study
• Patients with severe hepatic impairment (Child-Pugh class C)
• Patients with known or suspected Gilbert's syndrome at the time of study enrollment
• Patients with known gastrointestinal conditions that could potentially interfere with absorption of orally administered medications
• Any condition that, in the opinion of the investigator, may interfere with the objectives of the study, e.g., any condition requiring the use of prohibited drugs or unstable medical conditions other than AML/MDS, such as a cardiac or neurologic disorder expected to be unstable or progressive during the course of the study (e.g., seizures or demyelinating syndromes, acute myocardial infarction within 3 months of study entry, myocardial ischemia or unstable congestive heart failure, unstable arrhythmias)