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Liposomal amphotericin B versus placebo to prevent invasive mycoses in acute lymphoblastic leukaemia

August 14 2017

In a multicenter, randomized, double-blind, placebo-controlled trial, Cornely et al. showed that liposomal amphotericin B (L-AMB) was not effective as prophylaxis against invasive fungal disease (IFD) in patients with newly diagnosed acute lymphoblastic leukaemia (ALL).

Individuals with ALL are at high risk of infectious complications due to functional neutropenia and further chemotherapy-induced myelosuppression. Triazole antifungals may increase the serum concentration of vinca alkaloids, a key component of ALL chemotherapy. Neurotoxicity, a major side effect of vincristine, can be potentiated by co-administration of azoles. L-AMB offers an alternative prophylactic option.

In the AmbiGuard study adults treated for ALL were randomized to receive L-AMB 5mg/kg or placebo twice weekly. The investigators selected 2:1 randomization due to ethical considerations. Sample size calculation was based on an expected 75% reduction in IFD incidence which may have been too optimistic. In the intention-to-treat analysis the rate of proven/probable IFD was 7.9% (18/228) for the treatment arm and 11.7% (13/111) for the placebo arm (p=0.24). Overall mortality was similar in both arms. No difference in IFD rates was identified among patients who had neutropenia (ANC <500 cells/μL) for ≥10 days, or among patients without major protocol deviations. Expectedly more patients were affected by hypokalaemia and elevated creatinine in the L-AMB group.

In this study, L-AMB was administered at 10 mg/kg per week which is almost half of the standard treatment dose (21 mg/kg per week). In a subset of patients, L-AMB trough concentrations were measured and found to be appropriate. Of note, L-AMB 3 mg/kg three times weekly has been found as effective as a combination of fluconazole plus itraconazole in preventing IFD in patients with acute myelogenous leukaemia [Mattiuzzi et al, Cancer 2003 Jan 15; 97(2): 450-6]. A better understanding of amphotericin B pharmacokinetics is needed to determine effective dosing schemes.

The study was conducted from April 2011 to November 2013. Interestingly, IFD rates were higher than previously reported in retrospective studies. This may reflect advances in diagnostics with the use of non-culture based assays.