Oliver A Cornely1, Thibaut Leguay2, Johan Maertens3, Maria J G T Vehreschild4, Achilles Anagnostopoulos5, Carlo Castagnola6, Luisa Verga7, Christina Rieger8, Mustafa Kondakci9, Georg Härter10, Rafael F Duarte11, Bernardino Allione12, Catherine Cordonnier13, Claus Peter Heussel14, C Orla Morrissey15, Samir G Agrawal16, J Peter Donnelly17, Mark Bresnik18, Michael J Hawkins18, Will Garner18, Nicola Gökbuget19. 1. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Department I of Internal Medicine, Clinical Trials Centre Cologne (ZKS), Center for Integrated Oncology (CIO KölnBonn), German Centre for Infection Research (DZIF), partner site Bonn-Cologne, University of Cologne, Cologne, Germany. 2. Service d'hématologie clinique et Thérapie cellulaire, Hôpital du Haut-Lévèque, CHU de Bordeaux, France. 3. KU Leuven-University of Leuven, Department of Microbiology and Immunology, University Hospitals Leuven, Department of Hematology, B-3000 Leuven, Belgium. 4. Department I of Internal Medicine, University of Cologne, Cologne, Germany. 5. Haematology Department - BMT Unit, George Papanicolaou Hospital, Thessaloniki 57010, Greece. 6. Department of Hematology Oncology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy. 7. Ospedale San Gerardo, Monza, Italy. 8. Medizinische Klinik und Poliklinik III, Klinikum der Universität München, Munich, Germany. 9. Klinik für Hämatologie, Onkologie und klin. Immunologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany. 10. Zentrum für Hormon- und Stoffwechselerkrankungen und Infektiologie, MVZ Endokrinologikum Ulm, and Department of Internal Medicine III, Ulm University Hospital Medical Center, Ulm, Germany. 11. Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid 28222, Spain. 12. Hematology, Ospedale S. Giovanni Battista Molinette, Torino, Italy. 13. AP-HP-Henri Mondor, Hematology Department and University Paris-Est Creteil, F-94010 Créteil, France. 14. Thoraxklinik, Universitätsklinikum Heidelberg, Heidelberg, Germany. 15. Department of Infectious Diseases, Alfred Health and Monash University, Melbourne, Australia. 16. Division of Haemato-Oncology, St Bartholomew's Hospital, Barts Cancer Institute, Queen Mary University, London, UK. 17. Department of Haematology, Radboud UMC, Nijmegen, the Netherlands. 18. Gilead Sciences, Foster City, CA, USA. 19. Department of Medicine II, University Hospital, Goethe University, Frankfurt, Germany.
Abstract
Objectives: To prevent invasive fungal disease (IFD) in adult patients undergoing remission-induction chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL). Patients and methods: In a double-blind multicentre Phase 3 study, patients received prophylactic liposomal amphotericin B (L-AMB) at 5 mg/kg intravenously or placebo twice weekly in a 2:1 random allocation during remission-induction treatment. The primary endpoint was the development of proven or probable IFD. Secondary endpoints included those focused on the safety and tolerability of prophylactic L-AMB. Results:Three hundred and fifty-five patients from 86 centres in Europe and South America received at least one dose ofL-AMB ( n = 237) or placebo ( n = 118). Rates of proven and probable IFD assessed independently were 7.9% (18/228) in the L-AMB group and 11.7% (13/111) in the placebo group ( P = 0.24). Rates of possible IFD were 4.8% (11/228) in the L-AMB and 5.4% (6/111) in the placebo group ( P = 0.82). The remission-induction phase was a median of 22 days for both groups. Overall mortality was similar between the groups: 7.2% (17/237) for L-AMB and 6.8% (8/118) for placebo ( P = 1.00). Hypokalaemia and creatinine increase were significantly more frequent with L-AMB. Conclusions: The IFD rate among adult patients undergoing remission-induction chemotherapy for newly diagnosed ALL was 11.7% in the placebo group, and was not significantly different in patients receiving L-AMB, suggesting that the L-AMB regimen studied is not effective as prophylaxis against IFD. The IFD rate appears higher than previously reported, warranting further investigation. Tolerability of L-AMB was what might be expected. Further studies are needed to determine the optimal antifungal strategy during remission-induction chemotherapy of ALL.
RCT Entities:
Objectives: To prevent invasive fungal disease (IFD) in adult patients undergoing remission-induction chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL). Patients and methods: In a double-blind multicentre Phase 3 study, patients received prophylactic liposomal amphotericin B (L-AMB) at 5 mg/kg intravenously or placebo twice weekly in a 2:1 random allocation during remission-induction treatment. The primary endpoint was the development of proven or probable IFD. Secondary endpoints included those focused on the safety and tolerability of prophylactic L-AMB. Results: Three hundred and fifty-five patients from 86 centres in Europe and South America received at least one dose of L-AMB ( n = 237) or placebo ( n = 118). Rates of proven and probable IFD assessed independently were 7.9% (18/228) in the L-AMB group and 11.7% (13/111) in the placebo group ( P = 0.24). Rates of possible IFD were 4.8% (11/228) in the L-AMB and 5.4% (6/111) in the placebo group ( P = 0.82). The remission-induction phase was a median of 22 days for both groups. Overall mortality was similar between the groups: 7.2% (17/237) for L-AMB and 6.8% (8/118) for placebo ( P = 1.00). Hypokalaemia and creatinine increase were significantly more frequent with L-AMB. Conclusions: The IFD rate among adult patients undergoing remission-induction chemotherapy for newly diagnosed ALL was 11.7% in the placebo group, and was not significantly different in patients receiving L-AMB, suggesting that the L-AMB regimen studied is not effective as prophylaxis against IFD. The IFD rate appears higher than previously reported, warranting further investigation. Tolerability of L-AMB was what might be expected. Further studies are needed to determine the optimal antifungal strategy during remission-induction chemotherapy of ALL.
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