Empirical Versus Pre-emptive (Diagnostic-driven) Antifungal Therapy of Patients Treated for Haematological Malignancies or Receiving an Allogeneic Stem Cell Transplant. A Therapeutic Open Label Phase III Strategy Study of the EORTC Infectious Diseases and Leukemia Groups
- 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.
- 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
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:
- 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.
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Supportive Care
Overall survival at 42 days after randomization
6 weeks after randomization
J. Peter Donnelly
Universitair Medisch Centrum St. Radboud - Nijmegen
Belgium: Federal Agency for Medicinal Products and Health Products