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

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