Clinical efficacy of caspofungin in the treatment of invasive aspergillosis

Medical Mycology September 2006, 44, S363
S366 Clinical efficacy of caspofungin in the treatment of invasive aspergillosis M. AOUN Institut Jules Bordet, Infectious Diseases Department, Brussels, Belgium Keywords caspofungin, salvage therapy, empiric therapy, safety profile Introduction Modern-day medicine has advanced the therapy for many life-threatening underlying diseases with more frequent use of peripheral stem cell and organ transplantation, more intense chemotherapy for cancer patients, and more successful supportive care in intensive and neonatal units. Consequently, an increasing number of immunocompromised patients has emerged [1], paralleled by a rising incidence of opportunistic infections, mainly invasive aspergillosis [2]. Aspergillus species are ubiquitous in nature and are frequently isolated from the environment, soil, food and even from water [3], making community and nosocomial acquisitions both important sources of infection. Two major risk factors have been identified: granulocytopenia lasting more than ten days and corticosteroid therapy [4]. However, the incidence is variable between institutions due to infection control Correspondence: M. Aoun, Institut Jules Bordet, Infectious Diseases Department, rue Héger-Bordet 1, 1000 Brussels, Belgium. Tel: /32 2 541 37 06; fax: /32 2 541 32 95. E-mail: nathalie.cardinal@ bordet.be – 2006 ISHAM measures, environmental conditions and the underlying disease. Two categories of risk for invasive aspergillosis can be distinguished. The category at high-risk with an incidence of 10
25% includes cardio-pulmonary transplantation, chronic granulomatous disease, acute leukaemia and allogeneic stem cell transplantation. Another category at lower risk with an incidence of 1
10% includes autologous stem cell transplantation, liver and kidney transplantation, autoimmune or systemic diseases and AIDS [5]. The mortality associated with invasive aspergillosis derived from the most recent trials [6,7], varies between 30 and 42% globally, but can be as high as 55
92% in the transplant population. The clinical experience The eukaryotic nature of fungi has been a major hindrance for the development of active antifungal agents with low toxicity for the host cells. However, during recent years, a better understanding of the fungal cell wall structure allowed the targeting of components not present in mammalian cells. Caspofungin, the main representative of the echinocandin DOI: 10.1080/13693780600860961 Caspofungin, the main representative of the echinocandin family has undergone a clinical experience that covers gradually the whole spectrum of the standard care of invasive aspergillosis (IA). Caspofungin salvage therapy in cases of previous therapy refractoriness or intolerance resulted in a 45% response rate. Empiric therapy with caspofungin compared with L-AMB in neutropenic patients with persisting fever showed an overall response rate of approximately 34%, with less toxicity for caspofungin. Combination therapy of caspofungin with other antifungal drugs has been studied mainly retrospectively in open non randomized trials and in one prospective non comparative small study showing an encouraging response rate of 55% as salvage combined treatment. The clinical experience with caspofungin as first-line therapy in IA is limited to 32 patients with an overall response rate of 56%. Caspofungin is well tolerated with very few histamine-release reactions and a good toxicity profile. S364 Aoun Salvage therapy Chronologically, the first issue to be explored was salvage therapy in a multicenter, open, non comparative trial, in patients with proven or probable invasive aspergillosis, and who were refractory to or intolerant of previous standard therapies. Eighty-three evaluable patients were analysed, among which 72% had haematological malignancy, 11% were organ transplant patients, 13% received corticosteroids, 4% had solid tumours and 23% were neutropenic. The majority (86%) were refractory to standard therapy and 77% had pulmonary invasive aspergillosis. A favourable response rate at the end of therapy occurred in 37 patients (45%). In the neutropenic subgroup, the favourable response rate was 26% as compared with 50% in non neutropenics [8]. Another salvage study, in a very similar population, enrolled 48 patients, mainly for refractoriness to previous antifungal therapy (88%) and showed a similar favourable response rate of 44% [9]. The reported favourable response rates for the different antifungal drugs given as salvage therapy, including the lipid formulations of amphotericin B, voriconazole, itraconazole and posaconazole, vary between 38 and 48% [10
14]. However, what differentiates caspofungin from the other salvage studies is the high rate of refractoriness (
/80%) among patients enrolled as well as the high percentage of proven cases of invasive aspergillosis (
/40%), which confers more consistency to the response rate obtained with caspofungin over the other antifungals used for salvage therapy. Empiric therapy Caspofungin was also evaluated as empiric antifungal therapy in neutropenic patients with persisting fever despite broad-spectrum antibiotics [15]. In this setting, caspofungin was compared with a formulation of amphotericin B (L-AMB), in a randomized doubleblind trial including 1111 treated patients, 901 being evaluable (81.1%). A composite end-point containing 5 parameters measuring both efficacy and toxicity served as the basis of assessment. Caspofungin was as effective as L-AMB with an overall response rate of approximately 34% for both drugs. However, caspofungin was superior to L-AMB for the successful treatment of baseline infections (51.9% versus 25.9%; P/0.043) and no premature discontinuation (89.7% versus 85.5%; P /0.034). Caspofungin influenced beneficially the survival with a higher rate after 7 days post therapy (92.6% versus 89.2%; P /0.051), and better survival from baseline infection (88.9% versus 55.6%; P B/0.01). This was the first empiric trial that actually showed a statistical survival advantage. Breakthrough infections which represented approximately 5%, were caused mainly by Aspergillus and Candida species, similarly in both arms. Very few emerging fungal agents such as zygomycetes, Fusarium or Trichosporon species were reported: 4 cases in caspofungin as compared with 1 case in LAMB arm. Caspofungin was better tolerated with significantly lower rates of nephrotoxicity, infusionrelated events, and premature discontinuation due to adverse events. Primary therapy The experience with caspofungin as first line therapy in invasive aspergillosis, is still very limited. The first assessment in this indication could be drawn from the previously mentioned empiric trial where 12 cases of proven (7 cases) or probable (5 cases) invasive aspergillosis received caspofungin as first-line therapy, with a response rate of 41.7%. Candoni et al . [16] reported their experience (...truncated)