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.

• Caspofungin Acetate (Drug), also known as Cancidas: Given IV
• Fluconazole (Drug), also known as Diflucan: Given IV or PO
• Laboratory Biomarker Analysis (Other): Correlative studies

Primary outcomes

• Percentage of Participants With Proven or Probable Invasive Fungal Infections (IFI) [Up to 5 months since enrollment]: Proven or probable IFI is defined according to criteria developed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG).

Secondary outcomes

• Percentage of Participants With Proven or Probable Invasive Aspergillosis (IA) [Up to 5 months since enrollment]: Proven or probable invasive aspergillosis (IA) is defined according to the criteria developed by the EORTC/MSG. Kaplan Meier approach will used to estimate the incidence.
• Overall Survival [Up to 2 years post enrollment]: Kaplan Meier method will be used to estimate overall survival. Time to event is from enrollment to date of death (by any cause). Participants are censored at last contact or 2 years anniversary of enrollment into this study, whichever occurred first.
• Percentage of Participants That Need Empiric Antifungal Therapy [Up to 5 months since enrollment]: The percentage of participants requiring empiric antifungal therapy will be determined based on the presence of prolonged fever and neutropenia during each neutropenia course.

Other outcomes

• Sensitivity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI [Up to 5 months since enrollment]: Sensitivity for the diagnosis of proven or probable IFI will be determined for the fungal biomarkers galactomannan and beta-D glucan assays. Sensitivity will be estimated for the combination of the two fungal biomarkers.
• Specificity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI [Up to 5 months since enrollment]: Specificity of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Specificity will be estimated for the two fungal biomarkers together.
• Positive Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI [Up to 5 months since enrollment]: Positive predictive value of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Positive predictive value will be estimated for the two fungal biomarkers together.
• Negative Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI [Up to 5 months since enrollment]: Negative predictive value of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Negative predictive value will be estimated for the two fungal biomarkers together.
• Genotyping Assays for Single Nucleotide Polymorphism Analysis [Up to 2 years post enrollment]: Descriptive statistics will be used to summarize the prevalence of single nucleotide polymorphisms.

Sex: All, ages: 3 Months to 30 Years

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

Participant flow

Outcome results

• Percentage of Participants With Proven or Probable Invasive Fungal Infections (IFI) (Primary), Number, Percentage of participants: Arm I (Caspofungin Acetate) 3.1 (1.3 to 7.0); Arm II (Fluconazole) 7.2 (4.4 to 11.8)
• Percentage of Participants With Proven or Probable Invasive Aspergillosis (IA) (Secondary), Number, Percentage of participants: Arm I (Caspofungin Acetate) 0.5 (0.1 to 3.5); Arm II (Fluconazole) 3.1 (1.4 to 6.9)
• Overall Survival (Secondary), Number, Percentage of participants: Arm I (Caspofungin Acetate) 68.8 (62.3 to 74.4); Arm II (Fluconazole) 70.8 (64.6 to 76.1)
• Percentage of Participants That Need Empiric Antifungal Therapy (Secondary), Number, Percentage of participants: Arm I (Caspofungin Acetate) 71.9 (65.1 to 78.4); Arm II (Fluconazole) 69.5 (63.1 to 75.7)
• Sensitivity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI (Other pre specified)
• Specificity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI (Other pre specified)
• Positive Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI (Other pre specified)
• Negative Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI (Other pre specified)
• Genotyping Assays for Single Nucleotide Polymorphism Analysis (Other pre specified)

Adverse events

Time frame: Up to 12 months of receiving protocol treatment

Serious adverse events by term

Other adverse events by term

5 more terms not shown.

79 more sites not listed.

• Results publication: Fisher BT, Zaoutis T, Dvorak CC, Nieder M, Zerr D, Wingard JR, Callahan C, Villaluna D, Chen L, Dang H, Esbenshade AJ, Alexander S, Wiley JM, Sung L. Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia: A Randomized Clinical Trial. JAMA. 2019 Nov 5;322(17):1673-1681. doi: 10.1001/jama.2019.15702. PMID 31688884

• Study Protocol and Statistical Analysis Plan (PDF, 2014-04-22)

• Theoklis E Zaoutis, Principal investigator, Children's Oncology Group

NIH grants: U10CA095861, UG1CA189955