Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia: A Randomized Clinical Trial

Key PointsQuestionDoes prophylaxis with caspofungin compared with fluconazole reduce the risk of invasive fungal disease during periods of neutropenia after chemotherapy for children, adolescents, and young adults with acute myeloid leukemia? FindingsIn this randomized clinical trial, which was terminated early after enrolling 517 patients, the incidence of proven or probable invasive fungal disease was statistically significantly lower in the caspofungin group than in the fluconazole group (5-month cumulative incidence, 3.1% vs 7.2%). MeaningThe findings suggest that caspofungin may be considered for prophylactic therapy against invasive fungal disease in children, adolescents, and young adults with acute myeloid leukemia. ImportanceChildren, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. ObjectiveTo compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. Design, Setting, and ParticipantsThis multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). InterventionsParticipants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n=257) or fluconazole (n=260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. Main Outcomes and MeasuresThe primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. ResultsThe second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P=.03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P=.046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P=.78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P=.66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). Conclusions and RelevanceAmong children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility. Trial RegistrationClinicalTrials.gov Identifier: NCT01307579 This randomized trial compares the effect of prophylactic caspofungin vs fluconazole on invasive fungal disease among patients between the ages of 3 months to 30 years with acute myeloid leukemia.