Clinical Response in ABLC-Treated Mould Infections, the CLEAR II™ Registry.

Abstract Mould infections are an important complication in immunocompromised patients. Aspergillus spp. is the most common mould pathogen and invasive aspergillosis (IA) is associated with high morbidity and mortality, with limited clinical response rates to available antifungals. Amphotericin B has been proven to be effective on IA, although it's tolerability and toxicity often limit the ability to provide full courses of therapy. It is hypothesized that high doses and/or prolonged duration of therapy might contribute to improved outcomes in IA and other invasive mould infections, but previous data were lacking. With the availability of amphotericin B lipid complex (ABLC), toxicities related to Amphotericin B (the parent compound) are attenuated and therefore, increased dosing is better tolerated. The CLEAR II study, a clinical practice registry study of ABLC utilization, provided data to evaluate the possibility that higher dose and longer duration of therapy might affect outcome of invasive mould infections. Data are from CLEAR II™, a multi-center registry in which patients with fungal infections are prospectively enrolled and data about organism, site clinical presentation and course and therapy are retrospectively collected. Patients with proven or probable mould infections were identified according to MSG criteria and available 1-month-post-treatment-start clinical response data were included. Outcomes included clinical response according to treatment with or without ABLC, as well as outcomes in patients treated with high dose (HD; ≥ 5 mg/kg/d), long duration (LDUR; ≥ 15 days) ABLC vs. low dose (LD), short duration (SDUR) ABLC. Also, outcomes according to ABLC use as initial versus second-line therapy were evaluated. Of the 735 patients who have been enrolled to date, baseline data has been entered for 378. One-month post-treatment-start clinical response data are available for 59 mould (45 proven or probable) infections. Among the 45 proven or probable mould infections (patients' mean age 54.3 yrs., 53.3% female, 73.3% Caucasian), 17 infections included treatment with ABLC while 28 did not; the majority of patients in both groups received more than 1 antifungal. Aspergillus spp. was the most common pathogen (53% in ABLC-treated; 69% in non-ABLC) and the lung was the most common infection site. The most common underlying diseases were hematologic malignancy (35.6%), chronic lung disease (15.6%), liver disease (11.1%), solid organ transplant (11.1%), and autoimmune disease (8.9%). 28.9% were neutropenic and 22.2% had a prior HSCT. Complete or partial response was achieved in 47.7% of ABLC -treated infections (those who received any amount of ABLC) vs. 23.3% of non-ABLC-treated infections. Complete or partial response was achieved in: 44.4% of infections treated with ABLC as an initial therapy (n=9) vs. 37.5% of infections treated with ABLC as a 2nd-line therapy (n=8). Complete or partial response was achieved in 50.0% of patients (n=6) receiving HD/LDUR vs. 33.3% of LD/SDUR ABLC patients (n=3). ABLC-associated response rates appear to be double relative to rates in non-ABLC-treated mould infections. High-dose, long duration ABLC appears to be more effective than low dose, short duration, as does 1st vs. 2nd line. More data will be available in the next few months and allow for a larger sample size from which to base conclusions and recommendations. A complete description of antifungal agents used including length of therapy will also be available.