A Multicenter Phase II Study to Evaluate the Safety, Tolerability and Efficacy of Caspofungin as Prophylactic Treatment of Invasive Fungal Infections in Patients With Acute Leukemia Undergoing Induction Chemotherapy

Invasive aspergillosis (IA), and particularly invasive pulmonary aspergillosis (IPA), is an important cause of morbidity and mortality in patients who are receiving chemotherapy for acute leukemia (AL), being the the most common invasive mycosis which develops in these patients. Proven invasive aspergillosis has been reported in 6,5% of patients with acute leukemia in a retrospective multicenter study (Pagano, Haematologica 2001) but that frequency may be underestimated, since definite diagnosis is difficult to obtain, particularly in leukemic patients.

When the recently developed, internationally recognized IFIGC/MSG/EORTC diagnostic criteria were retrospectively applied to a consecutive series of acute leukemia patients, the overall frequency of IPA was 25,3% (proven/probable 8,5%; possible 16,9%). Criteria for a diagnosis of IPA were fulfilled in 62,8% of pulmonary infiltrates developing in AL patients (proven/probable 17,1%; possible 45,7%). IPA developed both in AML and in ALL patients. Proven/probable IPA developed in 83% of cases during the first induction cycle (Borlenghi, EHA 2003). It may be estimated that such figures would be higher when patients would be followed prospectively and strictly monitored, particularly with GM antigenemia.

The mechanisms by which common colonizing agents like Aspergillus spp. can become invasive pathogens and cause severe tissue damage are only partially known. Recent experimental data in animal models raised the hypothesis that the long pentraxin Ptx3 may play an important role in resistance to selected microbial agents, in particular to Aspergillus fumigatus (Garlanda, Nature 2002).

Caspofungin is an echinocandin with potent antifungal activity against Aspergillus species. Its mechanism of action differs from that of the antifungal agents used so far, like amphotericin and azoles. It has proven effective and well tolerated and its use is therefore currently approved as salvage treatment in patients with invasive aspergillosis refractory to amphotericin, as well as for the empiric treatment of febrile neutropenia. Indeed it has been recently evaluated as empirical treatment in neutropenic patients with persistent fever of unknown origin and proved equally effective and better tolerated than liposomal amphotericin.

There are as yet no data on the use of caspofungin as primary prophylaxis in patients with acute leukaemia, a setting in which the lack of effective preventive treatments together with the generally favourable safety profile and efficacy of caspofungin makes it particularly attractive for investigation.