Efficacy of Caspofungin as Secondary Prophylaxis in Patients Undergoing Stem Cell Transplantation with Prior Pulmonary and/or Systemic Fungal Infection.

Fungal infections (FI) are a major cause of TRM after stem cell transplantation (SCT). Within a prospective phase II study of secondary prophylaxis, Caspofungin 70 mg followed by 50 mg daily, was given iv from the start of conditioning regimen until either day +30 or stable engraftment of PMN>1x10⁹/l. Oral Itraconazol was given after suspension of Caspofungin. 27 patients with history of possible (n=14) probable (n=8) or proven (n=5) FI in the past were included in this study. 21 patients were affected by AL, 3 by NHL and 1 by HD, LMC and MDS, respectively. Prior FI was diagnosed at a median of 4.11 months (0.56–25.10) before SCT. Site of FI was pulmonary in 26 patients, associated in 3 cases with liver, skin or liver + spleen, respectively. In 1 patient, FI consisted of multiple liver, spleen and kidney localizations following candidemia. In the 5 proven infections, the fungal agent was aspergillus fumigatus in 2 cases, aspergillus flavus in 1, aspergillus terreus and niger in 1 and candida albicans in 1. SCT were HLA-matched related (n=14), unrelated (n=8) or autologous (n=5). Standard regimen was given to 19 and reduced intensity to 8 cases. Patients were followed for 6 months after SCT and evaluated at days 30 and 180. In 12 patients, pharmacodynamic and kinetic properties of Caspofungin were determined by HPLC with fluorescence detection at the end of 1h infusion the first day and then weekly within 28 days of treatment (peak and trough levels). Caspofungin was well tolerated with no evidence of side effects in all cases. 3 patients died before day 30 for TRM (n=2) or leukemia relapse (n=1). In the first 2 cases no sign of FI was evident, while in the last patient a concomitant progression of the previous probable FI was present. 1 patient had treatment discontinued before day +30 for VOD, but was evaluated for response of FI. Of the 24 surviving patients at day +30, 8 improved and 16 had stable FI. 3 patients died between day 30 and 180 for TRM (n=2) or leukemia progression (n=1) and 6 were too early for day 180 evaluation, although in no case progression of the previous FI was documented. Of the 15 patients evaluated at day 180, 8 showed a further improvement of fungal lesions, while 7 maintained stable FI. When only probable and proven infections were considered, 3/10 surviving patients at day 30 improved and 7 had stable infection, while in the 6 patients evaluated at day 180, the previous FI was improved in 3 and stable in 3. Mean plasma drug concentrations were maintained above the target of 1 mg/L in all measurements, therefore exceeding MIC₉₀ of the most clinically relevant species of Candida and Aspergillus sp, while the AUC/MIC ratio was ≥100 for isolates with MIC ≤1 mg/L. In conclusion, we confirmed that Caspofungin is a safe antifungal agent in patients undergoing SCT and the maintenance of effective plasma levels during the period of administration allows an optimal prophylaxis in patients at high risk of invasive FI.