Randomized comparison of liposomal amphotericin B versus placebo to prevent invasive mycoses in acute lymphoblastic leukaemia

Livio Pagano, Giuseppe Gentile, Oliver A. Cornely, Thibaut Leguay, Johan Maertens, Maria J.G.T. Vehreschild, Achilles Anagnostopoulos, Carlo Castagnola, Luisa Verga, Christina Rieger, Mustafa Kondakci, Georg Härter, Rafael F. Duarte, Bernardino Allione, Catherine Cordonnier, Claus Peter Heussel, C. Orla Morrissey, Samir G. Agrawal, J. Peter Donnelly, Mark BresnikMichael J. Hawkins, Will Garner, Nicola Gökbuget, G. Jarchum, M. Dictar, S. Ramirez Borga, A. Valledor, P. Knoebl, R. Greil, W. Linkesch, H. Sill, B. De Prijck, A. Sonet, K. Theunissen, D. Selleslag, A. Vargas Schwarzbold, M. L.M. Nucci, C. Lopes De Castro Lobo, L. Fogliatto, C. Bonmati, P. Turlure, R. Herbrecht, A. Thiebaut, M. Michallet, T. Leguay, G. Egerer, G. Silling, M. Pfreundschuh, J. Hasenkamp, D. M. Kraemer, M. Topp, W. Heinz, C. Junghanss, M. A. Schaich, S. Parmentier, C. Roellig, H. J. Beck, A. Hüttmann, S. Mousset, U. N. Duenzinger, S. Schwartz, G. Haerter, M. Kondakci, H. Ostermann, C. Rieger, O. A. Cornely, M. J.G.T. Vehreschild, P. Tsirigotis, P. Matsouka, M. K. Angelopoulou, M. Karakantza, A. Spyridonidis, A. Anagnostopoulos, A. Kolomansky, A. Moses, N. Horowitz, G. Rahav, F. Aversa, A. Velardi, G. Gentile, M. Gobbi, M. Luppi, A. M. Nosari, A. Rambaldi, A. Candoni, L. Marbello, G. Rossi, E. Pogliani, B. Allione, C. Castagnola, I. Moreira, A. Nunes, A. Botelho De Sousa, A. I. Rubio Tejero, C. Vallejo, L. Vazquez, J. Besalduch Vidal, V. Gomez-Garcia De Soria, M. Jurado Chacon, J. González Campos, E. Olavarria, P. Barba, J. De La Serna Torroba, R. Duarte, D. Heim, S. Zimmerli, B. Gerber, M. Akova, A. Z. Bolaman, F. Tabak, H. Akan, E. Senol

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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 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, andwas 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.
Original languageEnglish
Pages (from-to)2359-2367
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume72
DOIs
Publication statusPublished - 2017

Keywords

  • Administration, Intravenous
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amphotericin B
  • Antifungal Agents
  • Chemoprevention
  • Double-Blind Method
  • Europe
  • Female
  • Humans
  • Invasive Fungal Infections
  • Male
  • Middle Aged
  • Placebos
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • South America
  • Treatment Outcome
  • Young Adult

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