Micafungin Versus Posaconazole Anti-Fungal Prophylaxis in Adult Patients with Acute Leukemia Undergoing Induction Chemotherapy

Posaconazole has been shown to be effective in reducing the incidence of invasive fungal infections (IFI) in high-risk, neutropenic leukemia patients following induction chemotherapy. Its clinical utilization, however, may be limited by decreased oral absorption secondary to mucositis and other adverse events that occur during therapy. Micafungin is a broad spectrum antifungal agent approved for prophylaxis in stem cell transplant recipients. Nonetheless, its safety and efficacy in neutropenic leukemia patients has not been established. We therefore designed a prospective randomized study comparing micafungin to posaconazole as anti-fungal prophylaxis in patients with acute leukemia undergoing induction chemotherapy. The aim of this interim analysis is to compare (1) the total time on study drug between the micafungin and posaconazole treatment groups and (2) the percentage of patients completing the planned treatment course between the two groups.

Patients > 18 years of age were eligible for study with newly diagnosed acute leukemia (either AML or ALL) or MDS who were to receive myeloablative therapy with an anticipated neutropenic period of at least 7 days following anthracycline-based chemotherapy. Patients with first relapse of AML and ALL were also eligible. Patients who were pregnant, unable to swallow, hypersensitive to azoles, taking medications known to interact with posaconazole, and those receiving dasatinib were excluded from the study. Patients with a history of invasive fungal infection requiring therapy within 30 days of randomization, prolonged QTc interval on EKG, and moderate or severe liver dysfunction were also excluded.

Participants were randomized to receive micafungin (100 mg IV daily) or posaconazole (400 mg orally twice daily). The absolute neutrophil count (ANC) was monitored daily. Neutrophil recovery was defined as ANC ≥500 cells/μl for two consecutive days. Prophylaxis completion was defined as continuation of treatment until neutrophil recovery or 28 days after treatment initiation, whichever was earlier. Prophylaxis failure was defined as discontinuation of study drug due to adverse event, persistent neutropenic fever requiring change to an alternative antifungal agent, or withdrawal from the study before 28 days. Fungal markers (Galactomannan, BD glucans) were followed weekly from randomization to neutrophil recovery. Continuous and categorical variables were tested with Wilcoxon rank-sum test and chi-square tests, respectively. Kaplan-Mayer method was used to measure the completion rates of anti-fungal prophylaxis, and the log-rank test was used to compare the completion between two groups.

From March 2011 to May 2012, 46 patients were randomized to prophylaxis with either micafungin (n=23) or posaconazole (n=23). The two groups did not differ in age, sex, race, neutropenic duration, or liver dysfunction (p=0.35, 0.56, 0.36, 0.07 and 0.4366, respectively). Nineteen patients (83%) completed micafungin therapy while only eight (35%) completed posaconazole (p=0.001). Median number of days on prophylaxis was 18.2 days for the micafungin group and 14.8 days for the posaconazole group (p=0.0584). Eight patients (34.8%) were removed from study in the posaconazole group after developing colitis or being made NPO by the treating physician. There were no positive fungal markers during the study period. Nine patients (20%) underwent bronchoscopy because of new chest CT abnormalities while on study drug. Bronchoalveolar lavage was sent for routine cultures, cytology, Galactomannan, and pan-fungal PCR (University of Washington). Two patients (one from each treatment group) had IFI identified by PCR (Rhodotorula nothofagi and Cryptococcus species).

For patients undergoing myeloablative therapy for the treatment of acute leukemia or MDS, micafungin prophylaxis is associated with a superior completion rate and longer time to failure of prophylaxis compared to posaconazole. In addition, there is no difference in breakthrough fungal infections between the two treatment groups. Micafungin as antifungal prophylaxis is well tolerated and appears as effective as posaconazole prophylaxis for leukemia patients with prolonged neutropenia from induction chemotherapy. Our ongoing clinical study will continue to assess the efficacy of micafungin in this patient population.

No relevant conflicts of interest to declare.