Antifungals Go Head-to-Head in Pediatric Leukemia Trial

Upending an interim analysis that suggested futility, caspofungin (Cancidas) proved superior to fluconazole (Diflucan) as antifungal prophylaxis for children and young adults with leukemia, a randomized trial indicated.

Among over 500 acute myeloid leukemia (AML) patients undergoing intensive chemotherapy, the cumulative incidence of either probable or confirmed invasive fungal disease at 5 months was 3.1% among those on caspofungin compared with 7.2% for those on fluconazole (HR 0.37, 95% CI 0.15-0.94, P=0.03), reported Brian Fisher, DO, MSCE, of the Children's Hospital of Philadelphia, and colleagues.

As described in JAMA, the overall reduction appeared to be driven by lower incidence of invasive aspergillosis in the caspofungin group (0.5% vs 3.1%, P=0.046).

"Those are the types of infections that we would like to prevent because invasive aspergillosis is an invasive mold infection that has significant morbidity, mortality, and probably more morbidity and mortality than, say, yeast infections like invasive candidiasis," Fisher told MedPage Today, during an interview in which a media relations representative was present.

Young AML patients are subjected to prolonged and repeated periods of severe neutropenia while undergoing chemotherapy, putting them at significant risk for invasive fungal diseases. Infections are challenging to treat and can delay anti-leukemic therapy, said Fisher.

"The fact that we reduced all invasive fungal disease, and probably more specifically invasive aspergillosis, by giving caspofungin -- without an increase in toxicity -- is to me a positive sign that this is a very reasonable intervention to consider for this specific patient population that sustains long periods of vulnerability with neutropenia," he added.

In the trial of patients with mostly newly diagnosed disease, no significant differences were seen for rates of overall survival at 2 years, which reached 68.8% in the caspofungin group and 70.8% in the fluconazole group. Or for guideline-recommended use of empirical antifungal therapy (with voriconazole or amphotericin B lipid formulation) for those experiencing fever and neutropenia for 4 days or more -- 71.9% for the caspofungin group versus 69.5% with fluconazole.

Fisher said he plans to take the study findings to the drug usage evaluation committee for anti-infectives at his institution to determine whether to change practice there.

"Our center uses fluconazole prophylaxis, but I would be supportive of the transition to caspofungin or another agent in the class that caspofungin comes from called the echinocandins," said Fisher. "These agents are thought to have very similar activities."

Most prior studies using large enough cohorts to determine which prophylactic agent should be used have been performed in adults. Posaconazole (Noxafil), for instance, proved superior to fluconazole or itraconazole as antifungal prophylaxis in adults with AML or myelodysplastic syndrome, but came with added toxicity. Due to a lack of safety and efficacy data on posaconazole in children, or an appropriate dosing schedule, an antifungal prophylaxis guideline for pediatric cancer patients recommends fluconazole for those with AML.

Fluconazole has no activity against mold pathogens like Aspergillus, Fisher noted, while echinocandins are active against both Candida and Aspergillus species. Echinocandins are well tolerated, and caspofungin has been studied extensively in children and is approved for use in children as young as 3 months.

For the current study, the Children's Oncology Group ACCL0933 trial randomized 517 children, adolescents, and young adults with AML (median age 9 years) at 115 sites in the U.S. and Canada to caspofungin or fluconazole prophylaxis from 2011 to 2016. About 85% of participants in each group had newly diagnosed disease.

The trial had originally planned to enroll 550 patients, but an unplanned futility analysis from the data and safety monitoring board suggested futility during a June 2016 analysis of 394 patients. As the concern was not safety related, the trial continued to enroll another 123 patients before the determination was made to close the trial to enrollment. The final analysis are based on data from a June 2018 cutoff.

Fisher suggested that the intense review process to determine a probable or proven invasive fungal disease -- three oncologists or infectious disease doctors who were blinded to the treatment arm -- led to fewer events at the time of the interim analysis, as patients with suspected infections were still being reviewed.

"The central review committee could come to a conclusion quite quickly that the patient didn't have invasive fungal disease," he said. "It led to an opportunity for earlier patients who completed the review process to have fewer events."

Both antifungals were administered daily starting with the first cycle of chemotherapy. Caspofungin was given intravenously at 70 mg/m² on day 1 followed by 50 mg/m² per day thereafter. Fluconazole was administered either intravenously or orally at 12 mg/kg for children 3 months old to under 18 years, and 6 mg/kg for those ages 18 to 30 years.

In all, there were 23 cases of either probable or proven invasive fungal disease, six in the caspofungin group and 17 in the fluconazole group. These were comprised of 14 molds (four vs 10, respectively), seven yeasts (two vs five), and two fungi not otherwise specified (none vs two).