Nancy A. Melville

May 17, 2011

May 17, 2011 (Milan, Italy) — Antifungal combination therapy is safe and effective in the treatment of invasive fungal diseases in patients with leukemia and other hematologic diseases, according to research presented here at the 21st European Congress of Clinical Microbiology and Infectious Diseases.

The prospective clinical trial — said to be the first multicenter prospective observational study investigating combination therapy for hematologic patients with invasive fungal diseases — involved 84 patients at 20 hematologic centers in Italy.

Of the 84 patients, 68 (81%) had acute leukemia as the underlying disease. Their median age was 34 years (range, 1 to 73), and 37% were younger than 18 years.

The most common combinations were caspofungin plus voriconazole (in 35/84 patients [42%]), caspofungin plus liposomal amphotericin B (LAmB) (20/84 [24%]), and LAmB plus voriconazole (15/84 [18%]). The median duration of combination treatment was 19 days (range, 3 to 180).

Twenty-one patients (25%) had disease that was in the onset stage, 18 (21%) were in remission, and 45 (54%) were in the refractory stage or relapse.

The main site of the fungal infection was the lung, with or without the involvement of other sites. Etiologic agents identified were Aspergillus sp (n = 68 [81%]), Candida sp (n = 6 [8%]), zygomycetes (n = 4 [5%]), Fusarium sp (n = 4 [5%]), and other agents (n = 2).

No significant differences were seen between the combination regimens, and the overall response rate was 73% (61/84 responders). The factor that significantly influenced the response rate was polymorphonucleocyte antifungal activity during the antifungal therapy (< .0001).

There were no differences in response or adverse events between pediatric and adult patients, and only 1 patient discontinued therapy (because of voriconazole-related neurotoxicity).

Twenty-two percent of patients experienced other mild and reversible adverse events, including hypokalemia and increases in aspartate aminotransferase/alanine aminotransferase and creatinine.

The mortality rate attributable to invasive fungal infection in patients receiving the combination therapies was only 17%.

"The results of this study indicate that combination therapy was well tolerated in pediatric hematologic patients and in adults," said lead author Anna Candoni, MD, a hematologist from the division of hematology and bone marrow transplantation, Department of Medical and Morphological Research, University Hospital, Udine, Italy.

"The overall response rate was 73%, and the mortality from related invasive fungal diseases was only 17%. The most used combination therapy regimens were caspofungin plus voriconazole and caspofungin plus LAmB," she said.

"The study demonstrated in univariate and multivariate analyses that [polymorphonucleocyte] recovery during combination therapy predicts a better outcome."

Despite the findings, the benefits of antifungal monotherapy, compared with combination therapy, for hematologic patients remains the subject of debate, said Dimitrios P. Kontoyiannis, MD, professor of medicine and director of the mycology research program in the Department of Infectious Diseases, Infection Control, and Employee Health at the University of Texas M.D. Anderson Cancer Center in Houston.

"There is controversy over whether [combination] antifungal therapy adds anything more to single-drug therapy for fungal infections," Dr. Kontoyiannis said.

"In the past 5 or 6 years, studies have shown that, irrespective of the approach, outcomes for fungal infections have been improving. Maybe that's due to the better supportive care that these patients get, earlier prophylaxis, less immunosuppressant chemotherapy, or earlier diagnosis."

"It's very hard to say that combination therapy improves outcome, because this has been a trend for Aspergillus for the past 5 or 6 years in the United States and Europe," he said. "I don't think the study addresses issues such as the cost-effectiveness or overall clinical value of this in the average patient."

Dr. Kontoyiannis added that in many cases, he still supports monotherapy treatment.

"In my opinion, combination therapy does have merit in a very sick patient with a lot of burden of disease, but not everybody. For the majority of average-risk patients, monotherapy is as good as combination therapy. The issue of which patients can benefit from combination therapy remains unclear. We really need better-organized prospective studies to address this."

Dr. Candoni reports receiving research support and honoraria from Gilead and Merck. Dr. Kontoyiannis reports receiving research support from Merck, Pfizer, and Astellas.

21st European Congress of Clinical Microbiology and Infectious Diseases (ECCMID): Abstract 0154. Presented May 8, 2011.


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