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

Antifungal Prophylaxis. Prophylaxis of invasive fungal infections in high risk patients with hematologic malignancies. Olaf Penack . Background . Incidence IFI in neutropenia 3% - 40% High mortality rates Prophylaxis in allogeneic HSCT/BMT !

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

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

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

  3. 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 (-)

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

  5. Posaconazole

  6. 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?

  7. Ambisome (L-AmB) Low dose liposomal amphotericin B as prophylaxis of invasive fungal infections in patients with prolonged neutropenia: a randomized phase III trial

  8. Inclusion Criteria • Hematologic malignancy and chemotherapy, • neutropenia > 10 d • Autologous stem cell transplantation • Age > 17 years • Written informed consent

  9. 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 > 50µmol/l)

  10. Interventions Arm A 50 mg L-AmB i.v. every second day Start: 1-3 d prior neutropenia End: Neutrophil count >500/mm³ Development IFI Unacceptable drug toxicity Use of systemic antifungals Arm B No systemic antifungal prophylaxis Prospective, randomized, non blinded

  11. 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

  12. Patient Characteristics

  13. Efficacy – Primary Endpoint p = 0.001

  14. Incidence of IFI According to the Duration of Neutropenia

  15. Frequency of Probable/Proven Aspergillosis p = 0.005

  16. Frequency of Candidiasis p = 0.06

  17. 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)

  18. Efficacy – Secondary Endpoints

  19. Antifungal Prophylaxis Cost-Benefit Assessment of Antifungal Prophylaxis with Liposomal Amphotericin B

  20. Cost-Benefit Assessment • Additional costs for L-AmB prophylaxis 630 Euro • Total medication costs: 1220 Euro vs. 2815 Euro (p<0.001) • Including medical procedures 1100 Euro net benefit • Hospitalization: 43 days vs. 52 days (p = 0.09)

  21. Cost-Benefit Assessment 2.6 % 97.4 %

  22. 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?

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

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