Prophylaxis of invasive fungal infections in high risk patients with hematologic malignancies

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Prophylaxis of invasive fungal infections in high
risk patients with hematologic malignancies
Antifungal Prophylaxis
Olaf Penack
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Background

• Incidence IFI in neutropenia 3 - 40
• High mortality rates
• Prophylaxis in allogeneic HSCT/BMT !
• Prophylaxis in chemotherapy and autologous
  HSCT/BMT ?

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Antifungal Prophylaxis in Non-Allo-BMT High Risk
Patients - Drugs

• Azoles Fluconazole (-), Itraconazole (-),
  Posaconazole (), Voriconazole (-)
• Polyenes Conventional Amphotericin B (-),
  Liposomal-Amphotericin B ()
• Echinocandins Caspofungin (-), Micafungin (-)

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Posaconazole

• 304 patients with AML/MDS
• 304 Posaconzole (600 mgs), vs 298 Fluconazole or
  Itraconazole
• Significant difference in incidence of fungal
  infections
• Survival difference

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Posaconazole
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Posaconazole Ben De Pauw (Editorial NEJM)

• Safety 4 of patients receiving posaconazole
  with cardiac adverse events (QT time, atrial
  fibrillation, hart failure, torsade de pointes)
• Pharmacological interactions of azoles?
• Costs? Number needed to treat depends on
  incidence in each center
• Drug is not available for intravenous
  application
• Do patients need fatty died for good drug
  absorption?

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Ambisome (L-AmB)

• Low dose liposomal amphotericin B as prophylaxis
  of invasive fungal infections in patients with
  prolonged neutropenia a randomized phase III
  trial

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Inclusion Criteria

• Hematologic malignancy and chemotherapy,
• neutropenia gt 10 d
• Autologous stem cell transplantation
• Age gt 17 years
• Written informed consent

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Exclusion Criteria

• Probable or proven invasive fungal infection
• Pneumonia
• Fever of unknown origin
• Hypersensitivity to polyene antifungals
• Renal insufficiency (GFR 70ml/min),
• Liver impairment (bilirubin gt 50µmol/l)

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Interventions
50 mg L-AmB i.v. every second day Start 1-3 d
prior neutropenia End Neutrophil count
gt500/mm³ Development IFI
Unacceptable drug toxicity Use of
systemic antifungals
Arm A
No systemic antifungal prophylaxis
Arm B
Prospective, randomized, non blinded
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Objectives and Outcomes

• Superiority of L-AmB vs. no systemic prophylaxis
  
• Primary endpoint -
  Prophylactic failure, proven or probable IFI
• Secondary endpoints - Pneumonia
• - Use of systemic antifungals - Superficial
  fungal infections - Overall mortality,
  Mortality related to IFI

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Patient Characteristics
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Efficacy Primary Endpoint
p 0.001
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Incidence of IFI According to the Duration
of Neutropenia
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Frequency of Probable/Proven Aspergillosis
p 0.005
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Frequency of Candidiasis
p 0.06
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Safety Analysis

• No grade 3 or 4 toxicities
• No difference in laboratory abnormalities
  (Hypokalemia, liver impairment, renal
  insufficiency)
• Adverse events possibly related to study drug in
  5 NE (Erythema 4, nausea 3, infusion
  related chills 1)
• Discontinuation of treatment in 3 of 110 NE
• (Erythema 2, infusion related chills 1)

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Efficacy Secondary Endpoints
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Antifungal Prophylaxis
Cost-Benefit Assessment of Antifungal Prophylaxis
with Liposomal Amphotericin B
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Cost-Benefit Assessment

• Additional costs for L-AmB prophylaxis 630 Euro
• Total medication costs 1220 Euro vs. 2815 Euro
  (plt0.001)
• Including medical procedures 1100 Euro net
  benefit
• Hospitalization 43 days vs. 52 days (p 0.09)

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Cost-Benefit Assessment
2.6
97.4
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Conclusions

• Antifungal prophylaxis should be considered in
  patients with acute leukemia
• Intermittent application of L-AmB safe and potent
  as antifungal prophylaxis
• Also cost savings realizable
• Our data support prophylactic use of low dose
  L-AmB
• in high risk patients with hematologic
  malignancies and neutropenia
• Use of posaconazole also good option, possibly
  higher cardiac toxicity, costs?

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Thanks !
All participating Nurses and Physicians Gilead
Sciences
Dr. Igor Wolfgang Blau Prof. Eckhard Thiel Anja
Ullrich Prof. Peter Martus
Contact olaf.penack_at_charite.de