2nd ECMM/CEMM Workshop Milano, September 25, 2010 What have we learned about systemic antifungals currently available on the market? Prof. Dr. Georg Maschmeyer Dept. of Hematology, Oncology & Palliative Care Klinikum Ernst von Bergmann Potsdam, Germany gmaschmeyer@klinikumevb.de www.dghoinfektionen.de
Transparency Declaration Speaker fees: MSD, Pfizer, Gilead, Cephalon; Consultant: MSD, Pfizer, Gilead; Travel grants: Pfizer, MSD
Newer and Classical Antifungal Agents Amphotericin B Deoxycholate IV Liposomal Amphotericin B (AmBisome) IV AmB Lipid Complex (Abelcet) IV AmB Colloidal Dispersion (Amphocil/Amphotec) IV Fluconazole (Diflucan) IV/PO Voriconazole (Vfend) IV/PO Itraconazole (Sporanox/Sempera) IV/PO Posaconazole (Noxafil) PO Caspofungin (Cancidas) IV Micafungin (Mycamine) IV Isavuconazole/BAL4815/8557 IV/PO Anidulafungin (Ecalta/Eraxis) IV Ravuconazole 5-Flucytosine (Ancotil) IV/PO Albaconazole Terbinafine (Lamisil) PO Aminocandin IV Enfumafungin PO Anti-hsp90/Mycograb/Efungumab IV
Fluconazole Prophylaxis Prevents Candidiasis and Improves Survival After HSCT 1.00 Related and Unrelated Donor Transplant Survival Probability 0.75 0.50 0.25 Fluconazole Placebo p = 0.002 0.00 0 1 2 3 4 5 6 7 8 9 Years After Transplant Slavin MA et al, J Infect Dis 1995;171:1545-52 Marr KA et al, Blood 2000;96:2055-61
Fungal Infections at Autopsy Post AlloBMT n = 355 autopsies at FHCRC Invasive Fungus Aspergillus/Mucor Candida - Hepatosplenic Fluconazole 37% 29% 8% 3% No Fluconazole 43% 18% 27% 16% 1987 incidence of IA 6% 1993 11% Van Burik JA et al (Seattle), Medicine 1998;77:246-54
Fluconazole vs Itraconazole post-allosct n = 304 Discontinuation of itraconazole: 36% Itraconazole appears to prevent IMI in the subset of patients who tolerate the drug Marr KA et al (FHCRC Seattle), Blood 2004;103:1527-33
Flu- vs Itraconazole in Neutropenic Patients Glasmacher A et al, J Antimicrob Chemother 2006;57:317-25
Posaconazole vs Flu- or Itraconazole in Patients with AML or MDS NNT = 16 Cornely OA et al, N Engl J Med 2007;356:348-59
Micafungin vs Fluconazole post SCT: Treatment Success 1 0,9 p = 0.025 Proportion of Patients with Treatment Success 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 Problems: 46% autologous SCT Too short Empir AF = failure Micafungin (N=425) Fluconazole (N=457) 0 0 10 20 30 40 50 60 70 Days to Treatment Failure Van Burik JA et al, Clin Infect Dis 2004;39:1407-16
Posaconazole Prophylaxis in AlloSCT Recipients With GvHD Incidence of Proven or Probable IFI 30 Posaconazole Fluconazole p =.074 Number of IFIs 25 20 15 10 p =.004 22 p =.001 17 16 27 p =.006 21 5 7 7 0 3 All IFIs Invasive Aspergillosis All IFIs Invasive Aspergillosis While on treatment Primary time period 112 days after randomization Ullmann AJ et al, N Engl J Med 2007;356:335-47
Posa vs Flu / Vori vs Flu Prophylaxis in AlloSCT Patients Posaconazole trial* Characteristics Study Period (120 days) Total Aspergillus spp. POS n (%) 16 (5) 7 (2) FLU n (%) 27 (9) 21 (7) Proven/Prob. IFIs OR (95% CI) 0.56 (.30 1.07) 0.31 (0.13 0.75) N = 600 total patients (301 POS group, 299 FLU group). *N Eng J Med 2007;356:335-47 BMT CTN trial** Characteristics VORI n (%) FLU n (%) Proven/Prob. IFIs OR (95% CI) Study Period (180 days) Total Aspergillus spp. 13 (4.2) 7 (2.2) 23 (7.8) 16 (5.4) N = 600 total patients (305 VORI group, 295 FLU group). ** Wingard J et al, Blood 2010 P Value 0.07 0.006 P Value 0.11 0.05
New mechanism of resistance: Cyp51A amino acid substitution at codon 98 (L98H) together with a tandem repeat in the gene promoter Genotyping: no evidence for clonal spread of a single A. fumigatus genotype Verweij PE et al, N Engl J Med 2007;356:1481-3
Time to First Negative Blood Culture Percent of Patients 100 90 80 70 60 50 40 30 20 10 0 Caspofungin (n=92) Amphotericin B (n=94) Caspofungin Amphotericin B Day 4 19.6% 19.1% Day 7 12.0% 9.0% Day 9 6.5% 6.4% 0 1 2 3 4 5 6 7 8 9 1011 12131415161718192021222324 Study Day Mora-Duarte J et al, N Engl J Med 2002;347:2020 9
Micafungin vs Liposomal Amphotericin B for Invasive Candidiasis Phase III, double-blind; 100 mg/d vs 3 mg/kg/d Success at end of therapy in the per-protocol treated patients Micafungin n = 202 AmBisome n = 190 Success 181 (89.6%) 170 (89.5%) C.albicans C.tropicalis C.glabrata 88.4% 92.3% 82.6% 89.3% 95.3% 80.0% MITT response rates: 74.1 vs 69.6% Significantly less infusion-related AE and nephrotox in mica arm Kuse ER et al, Lancet 2007;369:1519-27
Anidulafungin vs Fluconazole for Invasive Candidiasis and Candidemia Double-blind, phase III: 200/100 mg A vs 800/400 mg F (n = 256) C.krusei excluded Transition to oral fluconazole allowed (26 vs 29%) Success at end of IV therapy: 76 vs 60% (p = 0.01) In C.albicans: 81.1 vs 62.3% C.glabrata (16/22 pts.): 56.3 vs 50.0% C.parapsilosis (11/12): 63.6 vs 83.3% Reboli A et al, N Engl J Med 2007;356:2472-82
Micafungin vs Caspofungin for Invasive Candidiasis Response Rate Micafungin 100 mg Micafungin 150 mg Caspofungin 70/50 n = 200 n = 202 n = 193 Total 73.9% 70.3% 71.4% In subgroups Candida albicans 76.3% 69.6% 73.8% Candida non-albicans 75.2% 70.9% 71.1% Pappas PG et al, Clin Infect Dis 2007;45:883-93
Voriconazole vs AmB => Fluconazole in Non-Neutropenic Patients with Candidemia n = 248 vs 122 Response EoT: 65 vs 71% Median time to neg. BC: 2 days in both groups Survival day 98: 63 vs 58% More nephrotoxicity in AmB/FLU recipients Kullberg BJ et al, Lancet 2005;366:1435-42
ECIL Guidelines 2007 First-Line Antifungal Therapy in Candidemia Before Species Identification Herbrecht R et al, Eur J Cancer Suppl 2007;5:49-59
ECIL Guidelines 2009 First-Line Antifungal Therapy of IPA www.ichs.org; www.eortc.be; www.ebmt.org
Randomized Comparison of Voriconazole vs AmB for Primary Therapy of Invasive Aspergillosis Herbrecht R et al (EORTC IFICG), N Engl J Med 2002;347:408-15
Improved Response with Pre-Emptive Treatment Based on Halo Sign (p < 0.01) 3 mo survival = 71% vs 53% (p < 0.01) Greene RE et al, Clin Infect Dis 2007; 44:373-9
L-AmB (3 vs 10 mg/kg/d) in Immunocompromised Patients with Invasive Filamentous FI Response at EoT [MITT] N (%) Favorable Overall Response at EoT CR PR L-AmB 3mg n=107 53 (50) 1 (1) 52 (49) L-AmB 10mg n=94 43 (46) p = 0.65 2 (2) 41 (44) Cornely OA et al (AmBiLoad Study), Clin Infect Dis 2007;44:1289-97
L-AmB (3 mg/kg/d) in Immunocompromised Patients with Invasive Filamentous FI: Survival in Patients with Possible vs Proven/Probable IPA Cornely OA et al (AmBiLoad Study), Mycoses 2010 (in press)
Voriconazole in 86 Patients with Cerebral Aspergillosis: Retrospective Analysis Age 9 mo - 81 y., proven or probable CNS aspergillosis Biopsy-proven: A.fumigatus 34 pts. A.nidulans 5 pts. Aspergillus spp 24 pts. Underlying condition BMT Hematological malignancy Organ TxP n 32 13 11 Median Rx days (range) 20 (3 390) 96 (5 522) 39 (7 825) Efficacy % 16 54 36 Chronic imm. suppression 11 122 (9 1128) 45 Other 14 82 (1 946) 50 Total 81 51 (1 1128) 35 Schwartz S et al, Blood 2005;106:2641-5
Caspofungin Salvage for IA: Expert Panel Assessment of Outcome Favorable Response Efficacy Analysis n/n (%) Primary: All patients with diagnosis who receive at least 1 dose of caspofungin 37/83 (44.6) Secondary: Patients who received >7 days of caspofungin 37/66 (56.1) Maertens J et al, Clin Infect Dis 2004;39:1563-71
Posaconazole in Patients with IA Refractory to or Intolerant of Conventional AF Therapy n = 107, vs historical control (n = 86) from same institutions (Lor D-AmB, itra, investigational AF) 74% hematological malignancy, 51% SCT Success at End of Treatment: 42 vs 26% (p = 0.006) CR 7 vs 9%, PR 36 vs 16% Walsh TJ et al, Clin Infect Dis 2007;44:2-12
Treatment of Mucormycoses Pulmonary Liposomal AmB (A-II); dosage 5mg/kg (B-III) ABLC (A-III) Posaconazole (A-III) Posaconazole as maintenance therapy in patients with a partial response (C-III) CNS or sinus involvement plus surgical intervention, if feasible (B-III) Böhme A et al (AGIHO), Ann Hematol 2009;88:97-110
Greenberg RN et al, Antimicrob Agents Chemother 2006;50:126-33
Posaconazole for Salvage Treatment in 91 Patients with Mucormycoses 60% CR/PR, 21% SD CR/PR in Leukemia/Lymphoma (48) 58.3% Steroid treatment (31) 51.6% Diabetes mellitus (30) 60.0% GvHD (30) 60.0% Neutropenia < 500 (29) 62.1% SCT (27) 51.9% Serum albumin < 3 (22) 45.5% SOTxP (10) 60.0% Van Burik JA et al, Clin Infect Dis 2006;42:e61-5
Synopsis: Use of Newer Antifungals Caspofungin First-line therapy of invasive candidiasis Second-line therapy of invasive aspergillosis Micafungin First-line therapy of invasive candidiasis Anidulafungin First-line therapy of invasive candidiasis Voriconazole First-line therapy of invasive aspergillosis Second-line therapy of invasive aspergillosis after L-AmB First- or second-line therapy of invasive candidiasis in selected patients (simultaneous Aspergillus coverage; oral maintenance in fluconazole-resistant cases) Posaconazole Second-line therapy of invasive aspergillosis Oral treatment of mucormycoses