Anidulafungin in Patients With Hematologic Malignancies - An Open-label, Prospective Study to Evaluate the Safety Profile at Prophylactic and Therapeutic Dosages
Treatment of patients with hematologic disorders is frequently complicated by invasive
fungal infections (IFI). The current spectrum of pathogens in this patient population is
characterised by an increasing rate of aspergillosis, atypical moulds and yeasts, which
might be explained by an extended application of myelosuppressive chemotherapy and
prophylactic use of antibiotic therapy, but also more sensitive diagnostic tools. Although
several new antifungal drugs have been approved recently for the treatment of invasive
fungal infections, the mortality rates remain unacceptably high. In patients with suspected
IFI invasive diagnostic procedures can often not be performed due to thrombocytopenia and
blood testing of fungal antigens with ELISA or PCR-methods are at most additive tools at
this time. Thus, antifungal drugs are frequently applied empirically when neutropenic fever
persists despite of antibiotic therapy or preemptive in case of radiological or laboratory
suspicion of IFI. The antifungal armamentarium consists mainly of azoles, polyenes, and
echinocandins. Therapy with azoles is frequently complicated by hepatological side effects
and drug interactions, whereas the application of polyenes is often associated with a
worsening of the renal function, severe hypopotassemia and shivering. Because of their
favourable efficacy and outstanding safety profile, nowadays echinocandins are increasingly
used in hematologic wards, especially in patients with renal or liver comorbidity.
Anidulafungin is a novel echinocandin with potent invitro fungicidal activity against
several pathogen yeasts and moulds like Candida- or Aspergillus spp. It has recently been
approved by the EMEA for treatment of invasive candidiasis in non-neutropenic patients. A
low cytochrome P450 interaction profile has been reported and dose adaption in case of
hepatical or renal impairment is not recommended. In the pivotal clinical trial
anidulafungin achieved a superior response rate for treatment of invasive candida infection
in comparison with fluconazole. In this trial, only a quarter of patients had cancer and
only 3% had neutrophil counts below 500/cm3 blood at randomisation. Although the clinical
experience of the efficacy and tolerability of anidulafungin in adult hematologic patients
is limited, the Infectious Diseases Society of America recently recommended anidulafungin
for use in neutropenic patients with candidiasis.
Safety: For all patients who will receive anidulafungin without regard to indication the
incidence of (serious) adverse events and changes of important laboratory parameters (in
particular liver and renal function parameters) with clinical impact will be reported.
For patients receiving anidulafungin as prophylaxis the number and rate of breakthrough
infections will be reported. If breakthrough infection occurs the type of salvage therapy
and the outcome will also be documented. For patients receiving anidulafungin as treatment
of a current episode of a fungal infection the primary efficacy outcome is defined as the
proportion of patients alive at week six after inclusion in the study or at the time that a
patient is censored. A second evaluation of survival will be done at week 12. Reason of
death will be analyzed according to toxicity of study drug and progression of IFI,
The efficacy outcome will be categorized into the following:
Complete response: Survival within the prespecified period of observation, resolution of all
attributable symptoms and signs of disease and radiological abnormalities, and mycological
evidence of eradication of disease.
Partial response: Survival within the prespecified period of observation, improvement in
attributable symptoms and signs of disease and radiological abnormalities, and evidence of
clearance of cultures or reduction of fungal burden, as assessed by a quantitative and
validated laboratory marker.
Failure: Stable response: Survival within the prespecified period of observation and minor
or no improvement in fungal disease, but no evidence of progression, as determined on the
basis of a composite of clinical, radiological, and mycological criteria.
Progression: Evidence of progressive fungal disease based on a composite of clinical,
radiological, and mycological criteria.
Death: Death during the prespecified period of evaluation, regardless of attribution.
Survival data (overall mortality and attributable mortality, if applicable) for all patients
and the time-to-negativity of a blood culture will be reported in this study.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
Safety: incidence of (serious)adverse events and changes of important laboratory parameters (in particular liver and renal function parameters) with clinical impact will be reported.
day 1-5, 10 , end of treatment and study.
Michael Girschikofsky, MD
Elisabethinen hospital Linz GmbH
Austria: Agency for Health and Food Safety
Anidulafungin - MG-ECALTA1