Safety and Efficacy of Caspofungin as Preventive and Empirical Antifungal Treatment of Neutropenic Allografted Patients.

Antifungal therapy is appropriate in neutropenic patients who have unexplained persistent fever, despite receipt of few days of antibacterial therapy. Conventional or liposomal amphotericin B are the preferred agents in this situation for allografted patients but toxicity or interaction with other drugs could limit their prescription. Caspofungin, the first inhibitor of fungal cell wall glucan synthesis, is the only echinocandin approved by the FDA for treatment of candidiasis. In case of suspected or documented aspergillosis infection, caspofungin is generally reserved to patients who failed to respond to amphotericin B or voriconazole. Recently, Walsh et al (ICAAC 2003) demonstrated in a randomised trial that caspofungin was comparable to liposomal amphotericine B in overall success as empirical antifungal therapy of persistently febrile neutropenic patients and was better tolerated. Here, we report our experience of caspofungin as preventive and empirical anti-fungal treatment, between November 2002 and May 2003, in 19 allografted patients with neutropenia (< 500/mm³ neutrophils) ± persistent fever despite at least 4 days of appropriate antibacterial therapy (n=12). There were 15 adult and 4 children, 11 male and 8 female. Median age was 33 years (range: 3–57). There were 6 ALL, 5 AML, 1 Myelodysplasia, 1 CML, 1 Hodgkin disease, 1 NHL, 1 myeloma, 1 aplastic anemia, 1 carcinoma and 1 Ewing sarcoma. A myeloablative conditioning regimen was used in 14 patients consisting of total body irradiation (TBI) plus high-dose chemotherapy in 9 patients and busulfan plus cyclophosphamide in 5 patients. A non myeloablative conditioning regimen was used in 5 patients. For graft-versus-host disease prophylaxis, the regimen was cyclosporin plus methotrexate in 13 patients or ATG in 6 patients. Nine patients received a bone marrow graft, 9 received granulocyte-colony-stimulating factor (G-CSF) mobilized peripheral blood stem-cells and 1 received an unrelated cord blood transplant. Twelve/19 patients have received prophylaxis with fluconazole from day 0 of the graft. Patients received caspofungin at an initial dose of 70 mg then 50 mg per day. Caspofungin was initiated within a median of 10 days after allograft (range: 0–174) including 7 patients receiving preventive caspofungin treatment at the date of aplasia. The mean duration of caspofungin therapy was 16 days (range: 3–72).

Caspofungin was well tolerated and not stopped because of toxicity: WHO grade 1 and 2 hepatotoxicity occurred in 5 patients including 3 with previous hepatic abnormalities, WHO grade 1 and 2 nephrotoxicity occurred in 6 patients. No infusion reaction was observed.

Only one patient developed a probable invasive bronchopulmonary aspergillosis on day 30 while receiving caspofungin. Seventeen/19 (89%) patients remain alive at least 7 days after the end of caspofungin administration without documented or suspected fungal, bacterial, or viral infection. Resolution of fever occurred in 11/12 febrile neutropenic patients in a median of 2 days (range:2–13) after starting caspofungin.

We conclude that caspofungin is safe and effective as preventive and empirical antifungal treatment of neutropenic allografted patients.