Caspofungin Versus Fluconazole in Preventing Invasive Fungal Infections (IFI) in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine if prophylaxis with caspofungin administered during periods of neutropenia
following chemotherapy for acute myeloid leukemia (AML) is associated with a lower incidence
of proven or probable invasive fungal infections (IFI) compared with fluconazole.

SECONDARY OBJECTIVES:

I. To determine if prophylaxis with caspofungin will result in a lower incidence of proven or
probable cases of invasive aspergillosis (IA) compared with fluconazole. (Clinical) II. To
determine if prophylaxis with caspofungin will result in improved survival compared to
fluconazole. (Clinical) III. To determine if prophylaxis with caspofungin will result in less
empiric antifungal therapy compared to fluconazole. (Clinical) IV. To determine the
sensitivity, specificity, and positive and negative predictive value of biweekly
galactomannan (GM) and beta-D glucan testing in diagnosing IFI. (Biological) V. To test the
association between single nucleotide polymorphisms (SNPs) in genes involved in innate
immunity and proven or probable IFI. (Biological) VI. To develop predictive models of IFI
using SNP in genes involved in immunity and clinical covariates. (Biological)

OUTLINE: Patients are randomized to one of two treatment arms during their first chemotherapy
course for AML.

ARM I: Patients receive caspofungin acetate intravenously (IV) over one hour once daily (QD)
beginning within 24-72 hours following the last dose of chemotherapy for each course. and
continuing until absolute neutrophil count (ANC) > 100-500/uL following the nadir or the next
chemotherapy course begins.

ARM II: Patients receive fluconazole IV over 1-2 hours or orally (PO) QD beginning within
24-72 hours following the last dose of chemotherapy for each course.

Protocol prophylaxis was continued in both arms, until ANC increased to > 100-500/uL
following the nadir or the next chemotherapy course began. Prophylaxis was given for all
courses of planned AML chemotherapy or until the patient met one of the following
off-protocol therapy criteria: development of proven or probable IFI according to
institutional diagnosis, initiation of conditioning for hematopoietic cell transplantation,
initiation of a new chemotherapy regimen for relapsed or refractory AML, refusal of further
protocol therapy by patient, parent or guardian, or physician determines it is in the best
interest of the patient.

Regardless of duration of prophylaxis, subjects in both arms are monitored for IFI until the
earliest of the following criteria is met: two weeks after recovery of neutropenia following
the last planned AML chemotherapy course, initiation of conditioning for hematopoietic cell
transplantation, initiation of a new chemotherapy regimen for relapsed or refractory AML,
withdrawal of consent for any further data submission, or death.

Patients were followed for overall survival up to two years from enrollment.

Inclusion Criteria:

- Patients must have one of the following diagnoses and/or treatment plans:

- Newly diagnosed de novo AML

- First or subsequent relapse of AML

- Secondary AML

- Treatment with institutional standard AML therapy in those without AML (for
example, myelodysplastic syndrome, bone marrow blasts > 5% or biphenotypia)

- Note: Patients with a history of prolonged antifungal therapy (example, relapsed
AML) are eligible

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

- =< 0.4 mg/dL (age 1 month to < 6 months)

- =< 0.5 mg/dL (age 6 months to < 1 year)

- =< 0.6 mg/dL (age 1 to < 2 years)

- =< 0.8 mg/dL (age 2 to < 6 years)

- =< 1 mg/dL (age 6 to < 10 years)

- =< 1.2 mg/dL (age 10 to < 13 years)

- =< 1.4 mg/dL (females age >= 13 years)

- =< 1.5 mg/dL (males age 13 to < 16 years)

- =< 1.7 mg/dL (males age >= 16 years)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age AND Serum glutamic
oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate
pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x ULN for age

- All patients and/or their parents or legal guardians must sign a written informed
consent

Exclusion Criteria:

- Patients with the following diagnoses are not eligible:

- Acute promyelocytic leukemia (APL)

- Down syndrome

- Juvenile myelomonocytic leukemia (JMML)

- Patients with a documented history of invasive fungal infection (IFI) within the
previous 30 days are not eligible

- Patients with a history of echinocandin or fluconazole hypersensitivity are not
eligible

- Patients receiving treatment for an IFI are not eligible

- Female patients of childbearing age must have a negative pregnancy test

- Patients must agree to use an effective birth control method

- Lactating patients must agree not to nurse a child while on this trial