Assessing the Impact of Prophylactic Anidulafungin during Remission Induction of Acute Myeloid Leukemia - a Propensity-Score Matching Analysis
Authors: Silva Wellington F , Mendes Fernanda Rodrigues , Melo Raphael Bandeira , Velloso Elvira , Rocha Vanderson , Rego Eduardo M 
Published: November 2021

Abstract
Introduction: Invasive fungal disease (IFD) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed during intensive chemotherapy, and posaconazole has recently emerged as a drug of choice for this purpose. In our setting, alternative strategies such as no upfront prophylaxis, fluconazole, or echinocandins have been used during the remission induction, as posaconazole is not available. While few reports have pointed to micafungin as an option for this aim, studies addressing the use of anidulafungin in AML are lacking. In this study, we aimed to examine the impact of prophylactic anidulafungin during intensive AML remission induction.
Methods: This retrospective cohort encompassing newly diagnosed AML adult patients (pts) treated at Instituto do Cancer do Estado de Sao Paulo, Brazil, between June 2011 and June 2020. We used a slight modification of European LeukemiaNet 2010 classification previously published by our group - Adapted Genetic Risk (AGR) (Silveira et al., 2020). Over these years, local policies regarding AP changed. All patients received the "7+3" regimen and were divided into three groups: pts who did not receive any AP and pts who received fluconazole (15-400 mg/day) or anidulafungin (100 mg/day) as AP. Local recommendations for IFD treatment were followed, and they also changed over time. The primary endpoint was IFD rate during the first 60 days from the beginning of chemotherapy, following the recommendation of EORTC/MSG. Multivariable analysis (MVA) was performed by logistic regression. Aiming to equalize subgroups for IFD risk factors, a propensity-score matching was performed using the nearest neighbor method.
Results: Overall, 204 pts were included, with a median age of 54 years (range,17-74). The main baseline features of this cohort are summarized in Table 1. Regarding AP, 108 pts received anidulafungin, 82 pts did not receive AP, and 14 pts received fluconazole. The incidence of IFI was 26.6% (95% CI 20.8-33.3), classified as possible, probable, and proven in 65.5%, 1.8%, and 32.7%, respectively. Regarding the fungus specimen, Aspergillus sp. responded for most cases (60%), followed by Fusarium sp. (23%), Candida sp. (11%), and Zygomycetes (4%). Complete response was documented at the end of induction in 49%, with the remaining patients being either refractory (27%) or not available (24%). The 60-day mortality was 25.8%. MVA showed that lower neutrophil counts at the AML diagnosis are associated with IFD during induction (OR=2.8, 95% CI 1.3-6.2), whereas age, genetic classification, and lymphocyte counts were not. Comparing the three abovementioned groups (AP: none, anidulafungin, or fluconazole), significant differences could be seen in AGR and anthracycline doses (Table 2). To analyze the impact of anidulafungin in comparison with 'no AP', a post-matched cohort with 164 subjects was created, matching for neutrophil and lymphocyte counts and AGR. The use of anidulafungin was not significantly related to less IFD during induction (OR=0.7, 95% CI 0.3-1.6), while neutrophil counts remained significant. Few subjects received fluconazole as AP, and it also was not related to less IFD (p=0.35). At the end of induction, complete response status did not relate to IFD during this period (p=1). Treatment for IFD with amphotericin B and voriconazole was given for 60.2% and 13.1% during induction, respectively. Patients under prophylactic anidulafungin received less amphotericin B (p&lt;0.001) but not voriconazole (p=0.49). Fusarium sp. cases that occurred during induction (n=12) received mostly prophylactic fluconazole (42%), which was statistically relevant in comparison to other AP (p&lt;0.001). Among these 12 cases, no favorable genetic risk was found. The occurrence of IFD during induction did not correlate with early mortality (HR=0.97, 95% CI 0.5-1.8) in our cohort.
Conclusion: To our knowledge, this is the first study addressing the role of anidulafungin during AML induction. Here, the use of AP did not decrease IFD incidence within this phase. Our results point to the fact that the fungistatic activity of echinocandins in molds might be suboptimal for immunocompromised pts. Furthermore, these results strengthen the role of posaconazole in this setting, especially for baseline neutropenic patients or higher risk subsets, such as primary refractory cases.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.