What have we learned about systemic antifungals currently available on the market?

Transcription

1 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

2 Transparency Declaration Speaker fees: MSD, Pfizer, Gilead, Cephalon; Consultant: MSD, Pfizer, Gilead; Travel grants: Pfizer, MSD

3 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

4 Fluconazole Prophylaxis Prevents Candidiasis and Improves Survival After HSCT 1.00 Related and Unrelated Donor Transplant Survival Probability Fluconazole Placebo p = Years After Transplant Slavin MA et al, J Infect Dis 1995;171: Marr KA et al, Blood 2000;96:

5 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% % Van Burik JA et al (Seattle), Medicine 1998;77:246-54

6 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:

7 Flu- vs Itraconazole in Neutropenic Patients Glasmacher A et al, J Antimicrob Chemother 2006;57:317-25

8 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

9 Micafungin vs Fluconazole post SCT: Treatment Success 1 0,9 p = 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) Days to Treatment Failure Van Burik JA et al, Clin Infect Dis 2004;39:

10 Posaconazole Prophylaxis in AlloSCT Recipients With GvHD Incidence of Proven or Probable IFI 30 Posaconazole Fluconazole p =.074 Number of IFIs p = p = p = 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

11 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 ( ) 0.31 ( ) N = 600 total patients (301 POS group, 299 FLU group). *N Eng J Med 2007;356: 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 P Value

12 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

13 Time to First Negative Blood Culture Percent of Patients Caspofungin (n=92) Amphotericin B (n=94) Caspofungin Amphotericin B Day % 19.1% Day % 9.0% Day 9 6.5% 6.4% Study Day Mora-Duarte J et al, N Engl J Med 2002;347:2020 9

14 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:

15 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:

16 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

17 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:

18 ECIL Guidelines 2007 First-Line Antifungal Therapy in Candidemia Before Species Identification Herbrecht R et al, Eur J Cancer Suppl 2007;5:49-59

19 ECIL Guidelines 2009 First-Line Antifungal Therapy of IPA

20 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

21 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

22 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= (50) 1 (1) 52 (49) L-AmB 10mg n=94 43 (46) p = (2) 41 (44) Cornely OA et al (AmBiLoad Study), Clin Infect Dis 2007;44:

23 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)

24 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 Median Rx days (range) 20 (3 390) 96 (5 522) 39 (7 825) Efficacy % Chronic imm. suppression (9 1128) 45 Other (1 946) 50 Total (1 1128) 35 Schwartz S et al, Blood 2005;106:2641-5

25 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:

26 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

27 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

28 Greenberg RN et al, Antimicrob Agents Chemother 2006;50:126-33

29 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

30 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