Efficacy outcomes in a randomised trial of liposomal amphotericin B based on revised EORTC/MSG 2008 definitions of invasive mould disease

Abstract

In 2008, the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) published revised definitions for diagnosing invasive fungal disease. A previous prospective trial of liposomal amphotericin B for invasive mould disease (AmBiLoad) used modified EORTC/MSG 2002 criteria. We wished to re-evaluate the response and survival based on the revised definitions to compare the outcomes of early vs. late treatment. Patients who had received an allogeneic haematopoietic stem cell transplant or who were neutropaenic (absolute neutrophil count <500 μl(-1) within 14 days of study entry) had been recruited on the basis of a halo or air crescent sign on chest computerised tomography. Originally classified as probable invasive mould disease, they were categorised as possible invasive mould disease using 2008 criteria. Patients had received liposomal amphotericin B at either 3 or 10 mg kg(-1) QD for 14 days, followed by 3 mg kg(-1) QD. Response at end of treatment and the 12-week survival were re-calculated according to 2008 definitions. Six-week survival was estimated by Kaplan-Meier analysis. Of 201 patients with invasive mould disease, 118 (59%) had a diagnosis based on halo signs (possible cases). Mycological evidence was present in 83 (41%) cases (probable/proven cases). Survival rates at 12 weeks for possible vs. probable/proven cases in the 3 mg kg(-1) QD group were 82% vs. 58% (P = 0.006), and 65% vs. 50% (P = 0.15) in the 10 mg kg(-1) QD group. At 6 weeks, rates were 87% vs. 69% in the 3 mg kg(-1) QD group (P = 0.009), and 75% vs. 61% in the 10 mg kg(-1) QD group (P = 0.01). Patients with possible invasive mould disease based on EORTC/MSG 2008 criteria had improved survival rates compared with those treated for probable/proven invasive mould disease. As possible invasive mould disease probably reflects an early-stage of disease, a better outcome might be expected when treatment with liposomal amphotericin B is started preemptively.

Performance of Galactomannan Antigen, Beta-d-Glucan, and Aspergillus-Lateral-Flow Device for the Diagnosis of Invasive Aspergillosis

“…Only three serum samples from patients without IA were false positive at a threshold of C0.7 with the modified procedure. Our findings confer the statement of possible IA as early aspergillosis resulted from the re-analysis of big drug trials according to revised EORTC/MSG criteria [12,13]. In patients with pulmonary IA the halo sign on a CT scan was reported to be the first reliable sign of IA, with a low sensitivity (33 %), but high specificity (93 %) [14].…”

Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis

“…The apparently better results from our trial may have been achieved by the higher dose and the less rigid enrolment criteria. In particular, waiving the necessity of microbiological evidence in our trial may have allowed earlier treatment of invasive aspergillosis, leading to better treatment results (6,10). However, our trial was not designed to determine the efficacy of caspofungin in the treatment of IA, and differences across trials must be rated with caution; the observed effect may as well be random.…”

“…Two recently published trials investigated the caspofungin standard maintenance doses of 50 mg once a day (QD) for first-line treatment of IA and yielded response rates of 33 and 42% (13,25). While these response rates were below the expected outcomes (7,12), they have been attributed to the severely ill patient groups enrolled in these trials and the rigorous enforcement of the EORTC/MSG consensus criteria (8), which may result in a delayed treatment trigger (6,10).…”

Diagnosis and Antimicrobial Therapy of Lung Infiltrates in Febrile Neutropenic Cancer Patients

“…In patients refractory to more than 48 h of broad-spectrum antibacterial therapy, CXR show LI in about 10%, whereas computed tomography (CT) at the same time point reveals pulmonary lesions in approximately 50% of patients [22]. Early detection of lesions indicating invasive fungal infection facilitates prompt institution of pre-emptive mold-active antifungal treatment [15,17,23] and may significantly reduce mortality due to invasive pulmonary aspergillosis (IPA) [15,16]. CT findings such as consolidation, "halo sign" and "aircrescent" may be important signs of filamentous fungal disease [24].…”

“…Therefore, early pre-emptive antifungal treatment is frequently started in febrile patients with severe neutropenia and LI presenting with radiological and laboratory findings not typical for a non-fungal origin [1, 14•]. Also, after successful management, IA may have an unfavorable impact on further treatment of the patients' underlying malignancy, while early initiation of moldactive antifungal treatment has been shown to improve overall survival of febrile neutropenic patients with IA [15][16][17]. Early intervention with mold-active antifungal treatment may be facilitated by serial Aspergillus galactomannan (GM) or beta-D-glucan testing in blood samples of high-risk patients [18].…”