How to Improve the Design of Trials of Antifungal Prophylaxis among Neutropenic Adults with Acute Leukemia

Abstract

The risk for invasive fungal infections in patients with acute leukemia is generally low (4%-8%), and the routine use of fungal prophylaxis is not warranted except in specific high-risk groups that should be identified among this population. In a prophylactic study with a new agent, fluconazole or itraconazole oral solution represent good choices for the comparator because they are proven better than placebo or oral nonabsorbable antifungal agents in reducing the risk of invasive fungal infections in patients with acute leukemia. Because prophylaxis is most valuable when the risk of infection is high, patients with well-understood risk factors (severe mucosal disruption caused by chemotherapy, impaired cell-mediated immunity caused by steroids or fludarabine, use of a central venous catheter, and colonization by Candida species) should be selected. The end points for antifungal prophylactic trials should focus on proven and probable invasive fungal infections. Superficial and mucosal fungal infections do not represent a primary end point for these studies. Poor compliance should be considered as an interruption of treatment due to side effects and should be included in the criteria for failure. Fungus-related mortality should be evaluated as a failure of prophylaxis, whereas overall mortality may be influenced by many other cofactors. Differences in gastrointestinal toxicity of antifungal agents may limit the use of double-blind designs in some situations.The risk of invasive fungal infections in patients with acute leukemia ranges from 4% to 8% [1][2][3] and is lower than the rate of 16%-18% observed in patients who have undergone hematopoietic stem cell transplantation [4,5]. Thus, the relevance of fungal prophylaxis in patients with acute leukemia has been less apparent, and the routine use of prophylaxis has not been thought to be warranted. However, antifungal prophylaxis might be warranted for patients with acute leukemia who have well-understood risk factors (severe mucosal disruption caused by chemotherapy, impaired cell-mediated immunity caused by steroids or fludarabine, use of a central venous catheter, and colonization by Candida species), and we need carefully conducted studies involving such higher-risk patients, who may

Polymerase chain reaction screening for fungemia and/or invasive fungal infections in patients with hematologic malignancies

“…The criteria used in this study were based on the definitions proposed by the EORTC/MSG consensus [11], which may lead to an underestimate of the incidence of IFI infections. However, candidemia rates of 6.3% [22] and aspergillosis rates of 6% [23] were found in previous reports at our institution, and recently, similar rates have been published [24]. A substantial number of studies have been focusing on the rising of IFI incidence in the last decades [3,4,11,18]; there is, however, a considerable variation in the range of organisms isolated in different hospitals, and unfortunately, it is difficult to have precise numbers [3,5].…”

Primary antifungal prophylaxis during curative-intent therapy for acute myeloid leukemia

“…Therefore, RCT findings may not be generalizable to all patients with AML. 75 However, retrospective and prospective observational studies support the use of posaconazole rather than itraconazole or fluconazole in AML patients undergoing intensive chemotherapy 76,77 or allogeneic HCT 78 and complement the RCT data. Still, strategies for antifungal prophylaxis in a broader range of patients with AML are needed such as those with end-organ toxicity for whom individual assessments should be made.…”

Antifungal drug usage in haematologic patients during a 4‐year period in an Asian university teaching hospital

“…Both potential causes can be considered reasons for failure of prophylaxis. 12 For the three remaining cases, the IFD was due to organisms resistant to itraconazole, including Fusarium, Mucor and Rhizopus. In the two cases of mucormycosis, the diagnosis was only made postmortem.…”