Prophylactic Antifungal Agents in Acute Myeloid Leukemia

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Yoav Golan, MD, MS, FIDSA, attending physician and associate professor of medicine at Tufts University School of Medicine, Boston, MA, compares the spectrum of activity of various antifungal agents and their critical role in antifungal prophylaxis in acute myeloid leukemia (AML).

When it comes to antifungal prophylaxis, of course, the first most important step is what to choose, which antifungal we should use. We already discussed some of the characteristics that would make an antifungal attractive for prophylaxis availability as an oral agent, as well as activity against molds and not just against Candida.

One of the most important and informative studies is a study that compared the use of posaconazole as compared to other commonly used antifungal prophylaxis itraconazole in AML patients who undergo chemotherapy including fluconazole. This study included patients who had AML or myelodysplastic syndrome, and were 13 years of age and older. In this study, patients were randomized to receive either posaconazole or fluconazole and were treated multiple times around cycles of neutropenia. Important endpoints in this study was overall mortality by the end of induction therapy for AML and occurrence of invasive fungal infections, and particularly invasive mold infections. The study showed that the group treated with posaconazole had a lower risk of invasive fungal infection and particularly lower risk of invasive Aspergillosis. The study also showed that the all-cause mortality at the end of chemotherapy and after the end of antifungal prophylaxis was substantially lower for this group of patients treated with posaconazole.

Another antifungal that’s commonly used for prophylaxis in the AML population is voriconazole. Voriconazole has activity against Candida as well as molds. There haven’t been clinical trials that show superiority of voriconazole over fluconazole or itraconazole, which are considered, in some centers, as standard prophylaxis. However, voriconazole is being used in many centers for this indication.

Many of the centers around the country, as well as in many other countries, use posaconazole for their high-risk patients, meaning those with severe neutropenia that’s expected to last for more than seven days. Over the past year-and-a-half or so, we have seen the addition of new formulations of posaconazole to our armamentarium. In the past, we had posaconazole solution that would be taken three times a day, and one of the shortcomings was the reduced bioavailability of this agent. We now have a posaconazole pill that’s typically given as 300 mg once daily. This pill, and the way it’s produced, has increased the bioavailability of posaconazole, allowing its administration only once daily and resulting in blood levels of posaconazole that are much higher than the blood levels achieved with the prior formulation of solution. In addition to that, we also saw the addition of intravenous posaconazole that can be given to those patients who cannot ingest any pills because of severe mucositis or other reasons.

When deciding on an antifungal prophylactic agent, in addition to effectiveness, one has to consider the cost of an agent. Of course, this criterion should not stand by itself and has to be contrasted with the potential benefit from the agent, and a cost-effectiveness should be then calculated. The question is not just how much we have to spend to acquire a pill, but whether the insurance covers it—which is the case with most antifungals including posaconazole—but rather is it beneficial to the patient and affordable? Does it have reasonable cost? When looking at antifungal prophylaxis in general, one would strongly argue that allowing a fungal infection to happen and treating a fungal infection—which requires prolonged admissions and the use of very costly antifungals for a very long period of time—as well as the consequences of those infections, will clearly suggest from a cost-effectiveness perspective that prevention is the best way to go. And there are several studies that highlighted the attractive cost-effectiveness profile of antifungal strategies.

Of the available antifungal strategies, we have discussed, specifically, the fact that posaconazole showed superiority over other agents in a clinical trial of AML patients. But the question is can we afford posaconazole? When looking at the cost of posaconazole, including the cost of the newer formulations of posaconazole, again, as opposed to the cost of being in the hospital and the cost of a fungal infection, it becomes immediately clear that the daily cost that’s measured by hundreds of dollars is contrasted with thousands and tens of thousands of dollars that are invested in treating existing fungal infections. That leads to the conclusion that effective antifungal therapies and antifungal therapies that have better ability to prevent invasive antifungal infections have a potential of also being cost-effective because they reduce the cost of care overall.