When Azoles Cannot Be Used: The Clinical Effectiveness of Intermittent Liposomal Amphotericin Prophylaxis in Hematology Patients

Abstract

Background: Patients unable to take azoles are a neglected group lacking a standardized approach to antifungal prophylaxis. We evaluated the effectiveness and safety of intermittent liposomal amphotericin B (L-AMB) prophylaxis in a heterogenous group of hematology patients.

Methods: A retrospective cohort of all hematology patients who received a course of intravenous L-AMB, defined as 1 mg/kg thrice weekly from July 1, 2013 to June 30, 2018, were identified from pharmacy records. Outcomes included breakthrough-invasive fungal disease (BIFD), reasons for premature discontinuation, and acute kidney injury.

Results: There were 198 patients who received 273 courses of L-AMB prophylaxis. Using a conservative definition, the BIFD rate was 9.6% (n = 19 of 198) occurring either during L-AMB prophylaxis or up to 7 days from cessation in patients who received a course. Probable/proven BIFD occurred in 13 patients (6.6%, 13 of 198), including molds in 54% (n = 7) and non-albicans Candidemia in 46% (n = 6). Cumulative incidence of BIFD was highest in patients with acute myeloid leukemia (6.8%) followed by acute lymphoblastic leukemia (2.7%) and allogeneic stem cell transplantation (2.5%). The most common indication for L-AMB was chemotherapy, or anticancer drug-azole interactions (75% of courses) dominated by vincristine, or acute myeloid leukemia clinical trials, followed by gut absorption concerns (13%) and liver function abnormalities (8.8%). Acute kidney injury, using a modified international definition, complicated 27% of courses but was not clinically significant, accounting for only 3.3% (9 of 273) of discontinuations.

Conclusions: Our findings demonstrate a high rate of BIFD among patients receiving L-AMB prophylaxis. Pragmatic trials will help researchers find the optimal regimen of L-AMB prophylaxis for the many clinical scenarios in which azoles are unsuitable, especially as targeted anticancer drugs increase in use.

Keywords: antifungal prophylaxis; breakthrough fungal infection; invasive fungal disease; liposomal amphotericin B; malignant hematology.

Figure 1.

Swimmers plot demonstrating breakthrough invasive fungal disease (BIFD) relative to course of liposomal amphotericin B (L-AMB) prophylaxis shown by lanes, using 3 definitions (a, b, c). The BIFD definitions are adapted from [15] in (a, a conservative definition being up to 7 days from cessation of at least one course of L-AMB); [16] in (a+b, an intermediate definition being up to 15 days from cessation of at least one course of L-AMB), and a modified intention-to-treat analysis in (a+b+c, a broad definition being at any time point after at least one dose of L-AMB). ALL, acute lymphoblastic leukemia; allo-HSCT, allogeneic-hematopoietic stem cell transplant; AML, acute myeloid leukemia; BPDCN, blastic plasmacytoid dendritic cell neoplasm; CML, chronic myeloid leukemia; MM, multiple myeloma; Myelodys, myelodysplasia; NHL, Non-Hodgkin’s lymphoma.

Figure 2.

Cumulative incidence curves of time to breakthrough-invasive fungal disease (n = 26) stratified by acute leukemia and allogeneic hematopoietic stem cell transplant (Allo-HSCT ) status. This was taken from date of leukemia diagnosis and date of HSCT to 3-year interval. Cumulative incidence in percentages are as follows: overall, 13.8% (95% confidence interval [CI], 9.53 to 19.9); acute myeloid leukemia (AML), 6.75% (95% CI, 3.85 to 11.7); acute lymphoblastic leukemia (ALL), 2.69% (95% CI, 1.13 to 6.34); and Allo-HSCT, 2.48% (95% CI, 0.93 to 6.51).

Figure 3.

Kaplan-Meier curve showing survival from start of liposomal amphotericin B prophylaxis in patients with breakthrough-invasive fungal disease (BIFD) versus others with known outcome: overall, 84 deaths in 166 patients (17 with BIFD using intention-to-treat definition, 149 without BIFD).