Empirical Versus Preemptive Antifungal Therapy

European Organisation for Research and Treatment of Cancer (EORTC)

Status and phase

Completed

Phase 3

Conditions

Fungal Infection

Leukemia

Myelodysplastic Syndromes

Treatments

Drug: caspofungin acetate

Study type

Interventional

Funder types

NETWORK

Identifiers

NCT01288378

2010-020814-27 (EudraCT Number)

EORTC-65091-06093

MK-0991-070 (Other Identifier)

Details and patient eligibility

About

RATIONALE: Caspofungin acetate may be effective in treating fungal infections in patients with acute myeloid leukemia or myelodysplastic syndrome who are receiving treatment for their cancer. It is not yet known whether caspofungin acetate is more effective when treatment starts after development of a fever or after the infection is shown in laboratory test, chest x-ray, or CT scan.

PURPOSE: This randomized phase III trial is studying the best time to start caspofungin acetate therapy in treating patients with acute myeloid leukemia or myelodysplastic syndrome that is newly diagnosed or in first relapse.

Full description

OBJECTIVES:

Primary

To compare empirical approach (i.e., fever driven) versus preemptive approach (i.e., diagnostic driven), for starting antifungal therapy with caspofungin acetate, in patients with acute myeloid leukemia or myelodysplastic syndrome who are starting chemotherapy (for attaining remission induction) or myeloablation (to prepare for an allogeneic hematopoietic stem cell transplantation) for newly diagnosed disease or disease in first relapse.

Secondary

To evaluate clinical validity and utility of a standardized Aspergillus PCR assay.
To evaluate clinical validity and utility of beta-D-glucan.
To determine the occurrence of single nucleotide polymorphisms (SNPs) and the predictive value of SNPs for identifying patients at higher risk of developing invasive fungal infection.

OUTLINE: This is a multicenter study. Patients are stratified according to institution, prior allogeneic stem cell transplantation (yes vs no), and type of air flow (laminar air flow vs high-efficiency particulate air). Patients are randomized to 1 of 2 treatment arms.

Arm A (Empirical approach): Patients start caspofungin acetate treatment when one of the following criteria are met:
- Presence of unexplained persistent fever refractory to 4 full days of broad-spectrum antibacterial therapy with any of the following regimens either alone or in combination with an aminoglycoside or a glycopeptide:
  - Ceftazidime
  - Cefepime
  - Piperacillin/tazobactam
  - Imipenem-cilastatin
  - Meropenem
- New fever occurring > 2 days after resolution of a first fever while continuing broad-spectrum antibacterial therapy as defined above for which no obvious cause has been documented and fungal infection cannot be excluded Patients receive caspofungin acetate IV once daily. Treatment continues until neutrophil recovers.
Arm B (Preemptive approach): Patients start caspofungin acetate treatment when at least one of the following criteria* are met:
- Single plasma or serum galactomannan ELISA with index > 0.5
- New pulmonary infiltrate on chest x-ray and IFD cannot be readily excluded
- New dense well-circumscribed lesions with or without a halo sign, on a CT scan, consistent with IFD
- Aspergillus sp. recovered by culture from sputum Patients receive caspofungin acetate IV once daily. Treatment continues until neutrophil recovers.

NOTE: *These criteria are not sufficient to warrant preemptive caspofungin acetate therapy: skin lesions evocative of IFD, sinusitis or orbititis, hepatosplenic abscesses (hypodensities on CT scan), or unexplained persistent fever for more than 7 days or recurrent fever whatever its duration.

All patients undergo blood sample collection periodically for the detection of galactomannan and beta-D-glucan and for the detection of single nucleotide polymorphisms. Some patients undergo blood sample collection for the detection of Aspergillus via PCR. An economic evaluation is performed for cost-effectiveness analysis.

After completion of study treatment, patients are followed periodically.

Enrollment

556 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)
- Newly diagnosed disease or disease in first relapse after hematological remission lasting for a minimum of 6 months AND meets one of the following criteria:
  - Starting remission-induction chemotherapy within 3 days prior to study randomization
  - Starting myeloablative conditioning regimen to prepare for a first allogeneic hematopoietic stem cell transplantation within 3 days prior to study randomization
Planning a hospital admission for the duration of the neutropenic phase (ANC < 0.5 x 10^9 /L)
Planning to receive oral or intravenous fluconazole for Candida prophylaxis at a dose of 400 mg/day
- Fluconazole is discontinued during caspofungin acetate administration
No previous or current history of proven or probable invasive fungal disease (IFD)

PATIENT CHARACTERISTICS:

See Disease Characteristics
Not pregnant or nursing
Negative pregnancy test
Fertile patients muse use effective contraception during and for at least 3 months after completion of study therapy
No current clinical diagnosis of pneumonia
No serious, uncontrolled, concomitant disease or comorbidity that, in the opinion of the investigator, may compromise adherence to the study protocol
No history of allergy or any adverse reaction to echinocandin drugs (i.e., caspofungin acetate, micafungin, or anidulafungin)
No hypersensitivity to caspofungin active substance or to any of the excipients
No inadequately treated infection
No documented HIV infection
No psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
No history of liver cirrhosis or severe hepatic insufficiency (i.e., Child Pugh Class C, D, or E)

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
No concurrent participation on another clinical trial using an investigational drug for infectious diseases
No other concurrent systemic antifungal therapy (oral or intravenous)