Fungal Infections in Hematologic Patients -- Best Strategies for Prevention and Treatment

Roxanne Nelson

January 28, 2010

January 28, 2010 — The incidence of invasive fungal infections has dramatically increased over the past several decades, and the majority of these infections are in patients with hematologic malignancies. They remain a leading cause of morbidity and mortality in this population, especially among patients with acute myeloid leukemia (AML) and those who have undergone allogeneic hematopoietic stem cell transplantation.

However, since 2001, a number of new systemically administered antifungal agents have been approved for clinical use and, according to Italian researchers, they "offer an opportunity to revise traditional approaches to antifungal therapy and to perhaps improve outcomes."

Study authors Livio Pagano, MD, from the Istituto di Ematologia, Università Cattolica del Sacro Cuore in Rome, Italy, and colleagues write in their paper, published online January 5 in Blood Reviews, that these new therapies represent a major advance in antifungal therapy. A wide range of preventive and treatment approaches have been developed that are based on the patient's risk or likelihood of fungal infection or on clear evidence that an infection is present.


For patients at high risk for infection, a number of new and old antifungal agents can be safely administered prophylactically over prolonged periods, the researchers note. But it is not always easy to identify patients who might benefit from the therapy or to delineate the ''at-risk" period, and there are limitations to prophylactic therapy, including drug resistance, toxicity, drug interactions, and high costs.

Meta-analyses of clinical trials examining the use of primary antifungal prophylaxis in patients with hematologic malignancies found that they significantly reduced the incidence of mycoses, particularly superficial ones. There was also a decrease in mortality related to fungal infection. In addition, secondary prophylaxis was effective in the prevention of a fungal-infection reactivation, say the authors.

On the basis of published literature and professional guidelines, Dr. Pagano and colleagues offer the following practice points:

  • Antifungal prophylaxis is indicated in patients at high risk for invasive fungal infections.

  • The best prophylactic antifungal agent should confer protection against either molds or yeasts.

  • Currently, the best results have been provided by posaconazole prophylaxis.

Empirical and Preemptive Therapy

Empirical therapy is used as an early treatment for occult fungal infection. It can be started when clinical signs and symptoms first appear, but prior to identification of a pathogen or radiological signs. The authors write that the concept of empirical antifungal therapy emerged because of the difficulty in diagnosing fungal infections in neutropenic patients and the increase in mortality associated with delays in instituting targeted therapy.

Preemptive treatment is administered to neutropenic patients with persistent fever who also present with radiologic documented pneumonia, acute sinusitis, or a positive galactomannan test. This approach was suggested in response to concerns about the risk for overtreatment and high expenditures related to the empirical approach, say the authors.

A recent randomized trial that compared empirical and preemptive antifungal strategies found that survival was similar with both strategies (Clin Infect Dis. 2009;48:1042-1051). Probable or proven invasive fungal infections were more commonly observed in patients who received preemptive treatment, and the majority of infections occurred during induction therapy.

In a subgroup analysis, however, the length of neutropenia was a "crucial discriminating factor," and the results suggest that empirical antifungal treatment results in higher survival rates in AML patients receiving induction chemotherapy. Thus, the authors of the randomized trial concluded that preemptive therapy was a safe and cost-effective option only for neutropenic patients with an expected neutropenia of less than 15 days.

There is no standardization for preemptive antifungal treatment at this time, but several guidelines for empirical therapy are available. Guidelines from the Infectious Diseases Society of America, the Gruppo Italiano Trapianto di Midollo Osseo (GITMO), and the European Conference on Infections in Leukemia all recommend empirical antifungal therapy for "high-risk patients with prolonged neutropenia who remain persistently febrile despite broad-spectrum antibiotic therapy," but the grades of their recommendations vary.

The researchers point out that even though the majority of current guidelines recommend empirical antifungal therapy for persistent fever and neutropenia, there is still no solid evidence that it reduces mortality related to fungal infection. "More compelling studies are needed . . . before current clinical practice is changed from an empirical to a preemptive approach," they write, and offer the following practice points:

  • Empirical treatment should be considered a valid option in particular subsets of patients (i.e., AML patients in first induction of remission), even with the risk for overtreatment.

  • Preemptive treatment might reduce this limit, but its role remains to be established.

Targeted Therapy

This strategy is applicable to patients who present with clear evidence of a fungal infection. The advantage to targeted therapy is that it offers the opportunity of administering an antifungal agent that is really effective against the pathogen, note the researchers. It also reduces the use of antifungal drugs, compared with the empirical approach.

However, there are some disadvantages to targeted therapy, they point out. The diagnosis can be late, and there also can be "frequent inapplicability of histological exams" in patients with hematologic malignancies because of factors such as thrombocytopenia, hemodynamic instability, and performance status.

The authors offer the following practice points for targeted therapy:

  • Effective treatment options are available for the majority of mold and yeast infections.

  • Echinocandin drugs are more effective against Candida in nonneutropenic patients; in spite of little experience in hematologic malignancies, they can be considered a good choice for this population.

  • Currently, voriconazole has been recognized as the gold standard among anti-Aspergillus treatments.

  • Zygomycosis must be considered a rare, not emerging, fungal infection. Treatment with liposomal amphotericin B or posaconazole improves the prognosis.

Newer agents, better supportive care, and more effective diagnostic tools have significantly reduced the mortality rate associated with fungal complications, the authors conclude.

But invasive fungal infections remain a significant cause of morbidity and mortality, and "future efforts should focus on further improvements in diagnostic techniques, which would allow for the timely application of antifungal therapy and would reduce the use of treatments in inappropriate settings," they write.

The study was partly funded by a research grant from MURST (Ministero Università e Ricerca Scientifica e Tecnologica). Dr. Pagano reports receiving research grants and honoraria as a speaker and consultant from Mercks, Gilead, Pfizer, and Schering Plough. His coauthors have disclosed no relevant financial relationships.

Blood Rev. Published online January 5, 2010. Abstract


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