Objective: In a Phase I study, mild transient ALT elevations were seen in 5 of 12 healthy subjects after one day of caspofungin + CsA. As a result, use of CsA with caspofungin has not been recommended unless the benefit to the patient outweighs the potential risk. Limited data on caspofungin + CsA in clinical studies showed no elevations in LFTs after dosing up to 56 days. To obtain additional data and to determine whether transient ALT elevations were associated with more significant hepatic effects, a retrospective cohort study was conducted. Methods: Patients treated with caspofungin and concomitant CsA were identified in US clinical sites with the highest use of marketed caspofungin. All patients who received concomitant therapy ( 1 day of caspofungin + CsA) for any reason, from 26JAN01 (initial US approval of caspofungin) through 01SEP02 were included. Comprehensive clinical data and all lab values for liver enzymes (ALT, AST, alkaline phosphatase, bilirubin) for the study period (day -30 to 14 days post-therapy) were abstracted from the medical record. The principal investigator (PI) at each site evaluated the abstracted data and assessed: (1) whether the patient had hepatotoxicity (elevations in liver enzymes 3 X baseline or 5 X ULN, or clinical evidence of hepatic dysfunction) on 1 day; (2) the reason for discontinuation of concomitant therapy; and (3) causality of any toxicity. Results: 40 patients at 4 sites were included. Preliminary data are available for all patients. Mean age was 46 years (range 9 - 67). Most (83%) had an allogeneic Hematopoietic Stem Cell Transplantation; 10% had a solid organ transplant. All patients received multiple concomitant therapies and had other significant medical conditions; 25 (63%) had active Graft versus Host Disease (GVHD). Patients received concomitant therapy for 1 to 290 days (mean: 33 days). 48% of patients were treated with caspofungin for documented invasive fungal infections (IFI); the rest were treated empirically for presumed IFI or as prophylaxis. As expected in this population, LFT abnormalities were common and were often considered due to GVHD, sepsis, other medical conditions, or other medications. Protocol defined elevations in ALT and/or AST occurred in 14 (35%) patients. 5 (13%) patients had an elevation in AST, and none had an elevation in ALT, considered at least possibly related to caspofungin/CsA. 4 patients discontinued therapy due to laboratory hepatotoxicity; 2 due to GVHD and 2 considered related to multiple causes, including caspofungin/CsA. Conclusions: In seriously ill, complex patients treated with caspofungin/CsA for long durations, significant elevations in transaminases were infrequent. Most LFT elevations had other causes and discontinuations due to clinical evidence or laboratory evidence of hepatotoxicity were uncommon. There were no significant hepatic adverse events in this cohort of patients receiving caspofungin concomitantly with CsA.
Full conference title:
American Society of Hematology 45th Annual Meeting
- ASH 45th (2003)