Efficacy and Safety of Micafungin, an Echinocandin Antifungal Agent on Systemic Fungal Infections in Patients with Hematological Disorders.

Background and Purpose: Severe infections in patients (pts) with hematological disorders (HD) are mostly the result of a compromised immune system by the underlying disease itself including neutropenia aggravated by chemotherapy and conditioning treatment for hematopoietic stem cell transplantation (HSCT). Systemic fungal infections (SFIs) particularly are often encountered in this field associated with morbidity and mortality. It is deemed crucial to initiate an early introduction of antifungal therapy by using criteria for an early diagnosis. Micafungin (MCFG) that was launched in Japan in 2002 and approved in another 3 countries is shown to be safe and efficacious for SFIs. Since there are few clinical reports on the effects of MCFG in a large number of patients, a multicenter study (87 institutions) was initiated to see its efficacy and safety.

Methods: The study was conducted from Apr. 03 to Mar. 05 on pts diagnosed with HD, who met any of the following criteria: pts

1. who are found to have a causative fungus identified by mycological or pathological testing (proven),

2. with a SFI defined by clinical symptoms/findings and serological testing or diagnostic imaging (probable/possible), or

3. with a suspected SFI identified by unexplained persistent fever (an axillary temperature higher than 37.5 °C) and clinical symptoms/findings (refractory to antibacterial treatment).

Efficacy was evaluated by the degree of improvement in clinical symptoms/findings, mycological findings, imaging study findings such as chest X-ray or CT, and fungal serological tests. The overall effects were rated as either “effective” or “ineffective”, based on an algorithm combining these indices.

Results: A total of 277 pts were registered to the central office and 276 were evaluable for safety assessment. Eighty-one pts were not evaluable for efficacy due to a violation of entry criteria, etc. Thus 196 pts were assessed for clinical efficacy by the steering committee (118 males and 78 females, the mean age: 56.8). There were 62 pts with HSCT and 134 with chemotherapy in whom 67 had acute leukemia. The mean dosage and duration of MCFG were 170.8mg per day and 21.8days, respectively. Overall clinical effects were achieved in 134 out of 196 pts (68.4%). Clinical response was seen in 72.6% (45/62) for those with HSCT and 66.4% (89/134) for those of chemotherapy and particularly 68.7% (46/67) of the pts with chemotherapy for acute leukemia, respectively. The success rates were 87.5% (7/8) for pts with proven SFIs like candidemia, 44.7% (17/38) for probable SFIs, 62.9% (39/62) for possible SFIs, and 80.7% (71/88) for those who failed to respond to antibacterial treatment. The success rate for 13 pts with persistent fever on antibacterials and neutrophil counts below 500/μL before and after MCFG treatment was 69.2%. The incidence of adverse events related to MCFG was 30.1% (83/276), and the most common one was elevation of liver transaminase levels.

Conclusions: MCFG demonstrated excellent clinical efficacy and safety when used to treat possible to proven SFIs in pts with HD, indicating its usefulness as a novel therapeutic drug for both empirical and targeted therapy for deep-seeded fungal infection.