Abstract

Background: IFI remain an important cause of morbidity and mortality in pts with acute myelogenous leukemia or high risk myelodysplastic syndrome (AML/HR-MDS). We have previously shown that voriconazole (VORI) or LIPO AB 3 mg/kg/day TIW were effective prophylactic regimens in AML/HR-MDS. LIPO AB given once every week achieves tissue levels expected to prevent IFI, decreases the risk for infusion-related adverse events (IRE) and would simplify prophylaxis.

Materials and Methods: We conducted a 3-arm randomized trial comparing LIPO AB, 3 mg/kg/d TIW (LIPO AB 3); versus LIPO AB 9 mg/kg/d, 1/week (LIPO AB 9); versus VORI 200 mg PO 2/day among pts with AML/MDS undergoing induction or salvage chemotherapy (CHEMO). Pts were stratified by age and disease status and randomized to receive any of the 3 regimens 24 hours after completion of CHEMO. Serum Galactomannan Index (GMI) was obtained 2/week while CT scan of chest (CT) was performed for persistent fever after 3 days of broad spectrum antibiotics. Proven and probable IFI were defined according to EORTC/MSG criteria. The results of the first 59 pts (of 150 planned) enrolled between Dec 06 -July 07 are presented.

Results: Pts characteristics and response are shown in Table 1. All pts had Zubrod performance status ≤ 2 and most underwent remission induction chemo (90% in each group). No significant differences were observed on key baseline characteristics. Three of the 59 pts did not receive study drug (AMBI 9=2; VORI=1) and were excluded from efficacy and safety analysis. There were no proven IFI; 3 pts developed probable pulmonary Aspergillosis [GMI(+); CT (+), cultures (−) ], while 10 pts received additional empirical antifungal therapy (AFT) because of FUO [ 7 pts; GMI (−), CT (−), cultures (−)] or pneumonia [ 3 pts; GMI (−), cultures (−)]. None of these 10 pts developed proven/probable IFI. Two pts in each study arm developed reversible side effects that lead to drug discontinuation [AMBI 3: Grade 2 hyperbilirubinemia (1); Grade 3 infusion related events (1); AMBI 9: Grade 3 infusion related event (2); VORI: Grade 2 hyperbilirubinemia (1), visual hallucinations (1)]. Overall mortality was 5% (1 pt/arm). There were no IFI-related deaths.

Conclusion: Intermittent LIPO AB (3 mg/kg/d TIW or 9 mg/kg/d, 1/week) and VORI 200 mg PO 2/day prophylaxis appear to be effective and well-tolerated regimens. Enrollment of additional pts is ongoing.

Table 1
LIPO AB 3 (n=20)LIPO AB 9 (n=20)VORI (n=19)
*p=ns; **p=0.061 
Median age* (range) 60 (40–79) 60 (23–69) 58 (31–77) 
Pts in protected environment* (%) 80 65 79 
Diabetes mellitus**, n(%) 1 (5) 1 (5) 5 (26) 
Median days on prophylaxis* (range) 17 (1–34) 14 (1–37) 17 (1–37) 
Efficacy and adverse events    
 LIPO AB 3 (n=20) LIPO AB 9 (n=18) VORI (n=18) 
No IFI*, n(%) 14 (70) 14 (78) 15 (83) 
Proven/Probable IFI*, n(%) 2 (10) 1 (5) 
Empiric AFT*, n(%) 4 (10) 3 (17) 3 (17) 
Adverse events*, n 
All drug-related*, n(%) 2 (10) 2 (11) 2 (11) 
LIPO AB 3 (n=20)LIPO AB 9 (n=20)VORI (n=19)
*p=ns; **p=0.061 
Median age* (range) 60 (40–79) 60 (23–69) 58 (31–77) 
Pts in protected environment* (%) 80 65 79 
Diabetes mellitus**, n(%) 1 (5) 1 (5) 5 (26) 
Median days on prophylaxis* (range) 17 (1–34) 14 (1–37) 17 (1–37) 
Efficacy and adverse events    
 LIPO AB 3 (n=20) LIPO AB 9 (n=18) VORI (n=18) 
No IFI*, n(%) 14 (70) 14 (78) 15 (83) 
Proven/Probable IFI*, n(%) 2 (10) 1 (5) 
Empiric AFT*, n(%) 4 (10) 3 (17) 3 (17) 
Adverse events*, n 
All drug-related*, n(%) 2 (10) 2 (11) 2 (11) 

Author notes

Disclosure:Consultancy: MGI, Pfizer, Merck. Research Funding: Astellas, MGI, Novartis.