Empirical Versus Preemptive Antifungal Therapy

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

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia; Fungal Infection
• Intervention / Treatment: Drug: caspofungin acetate

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 556
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brugge, Belgium
    • A.Z. St. Jan
  • Brussels, Belgium
    • Hôpitaux Universitaires Bordet-Erasme - Institut Jules Bordet
  • Brussels, Belgium
    • Cliniques Universitaires Saint-Luc
  • Leuven, Belgium
    • U.Z. Gasthuisberg
  • Liège, Belgium
    • C.H.U. Sart-Tilman
• Czechia
  • Brno, Czechia
    • Masaryk University
• France
  • Caen, France
    • CHU de Caen - Hopital Cote de Nacre
  • Créteil, France
    • C.H.U. Henri Mondor AP-HP
  • Lille, France
    • CHRU de Lille - Hopital Hurie
  • Limoges, France
    • CHU de Limoges - Hôpital Dupuytren
  • Strasbourg, France
    • Hopital Universitaire Hautepierre
  • Villejuif, France
    • Institut Gustave Roussy
• Germany
  • Freiburg, Germany
    • Universitaetsklinikum Freiburg
  • Wuerzburg, Germany
    • Universitaetsklinikum Wuerzburg - Medizinische Klinik und Poliklinik II
• Netherlands
  • Nijmegen, Netherlands
    • Radboud University Nijmegen Medical Centre
• Slovakia
  • Bratislava, Slovakia
    • National Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Empirical; Empirical approach (fever driven) for starting antifungal therapy	Drug: caspofungin acetate; intravenous route, at a 70 mg loading dose on day 1 of antifungal therapy, followed by 50 mg once a day thereafter.
Experimental: Pre-emptive; Pre-emptive approach (diagnostic driven) for starting antifungal therapy	Drug: caspofungin acetate; intravenous route, at a 70 mg loading dose on day 1 of antifungal therapy, followed by 50 mg once a day thereafter.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival at 42 days after randomization	6 weeks after randomization

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival at 84 days after randomization	12 weeks after randomization
Development of proven or probable invasive fungal disease (IFD) during the 42 and 84 days following randomization	during 84 days after randomization
Proper management according to allocated treatment arm (i.e., appropriate administration of caspofungin acetate in compliance to protocol, and compliance to the treatment strategy) during the 42 and 84 days after randomization	during 84 days after randomization
Survival-free of fungal infection during the 42 and 84 days following randomization	during 84 days after randomization
Safety (adverse event [AE] and serious adverse event [SAE]) as assessed by CTCAE criteria v4.0	during 84 days after randomization
Number of days under caspofungin treatment or under another antifungal treatment administered after caspofungin (evaluation will be done at day 42 and day 84 after randomization)	at day 42 and day 84 after randomization
Costs related to the strategy for initiating and monitoring antifungal treatment during the 42 and 84 days following randomization	during 84 days after randomization

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Investigators: Study Chair: J. Peter Donnelly, Universitair Medisch Centrum St. Radboud - Nijmegen; Study Chair: Johan Maertens, MD, University Hospital, Gasthuisberg; Study Chair: Catherine Cordonnier, MD, PhD, Centre Hospitalier Universitaire Henri Mondor; Study Chair: Tom Lodewyck, AZ Sint-Jan

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): April 4, 2019
• Study Completion (Actual): April 4, 2019

Study Registration Dates

• First Submitted: February 1, 2011
• First Submitted That Met QC Criteria: February 1, 2011
• First Posted (Estimated): February 2, 2011

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 8, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); secondary acute myeloid leukemia; recurrent adult acute myeloid leukemia; untreated adult acute myeloid leukemia; fungal infection; adult acute myeloid leukemia with del(5q)
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Bacterial Infections and Mycoses; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia; Mycoses; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antifungal Agents; Caspofungin
• Other Study ID Numbers: EORTC-65091-06093; 2010-020814-27 (EudraCT Number); MK-0991-070 (Other Identifier: Merck (MSD))