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1 Treatment of Fungal infections in Hematologic Malignancies George Samonis M.D. PhD Professor of Medicine The University of Crete.

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Presentation on theme: "1 Treatment of Fungal infections in Hematologic Malignancies George Samonis M.D. PhD Professor of Medicine The University of Crete."— Presentation transcript:

1 1 Treatment of Fungal infections in Hematologic Malignancies George Samonis M.D. PhD Professor of Medicine The University of Crete

2 22 Challenges of Diagnosing Opportunistic Infections at the Bedside

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4 4 Usual fungal infections in immunocompromised patients Candidiasis Aspergillosis Mucormycosis Fusariosis Cryptococcosis Candidiasis Aspergillosis Mucormycosis Fusariosis Cryptococcosis

5 5 Risk factors for development of IFIs Neutropenia Lymphopenia Corticosteroids Immunosuppressives Chemotherapy Bone Marrow Transplantation Broad-spectrum antibiotics Mucositis Parenteral alimentation Central venous catheters (CVCs) Hospital construction Neutropenia Lymphopenia Corticosteroids Immunosuppressives Chemotherapy Bone Marrow Transplantation Broad-spectrum antibiotics Mucositis Parenteral alimentation Central venous catheters (CVCs) Hospital construction

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32 32 Wingard 1987 O’Donnell 1994 Morrison 1994 Baddley 2001 Baddley 2001 Martino 2002 Martino 2002 Increased Incidence of Mould Infection Martino R, Subira M. Ann Hematol. 2002;81: Aspergillus spp % 6.0% 11.4% 13.0% 11.0%

33 33 Distribution of IA in the Post-Engraftment Phase of HSCT Marr KA et al. Blood. 2002;100: % (n=99) >180 (n=31) Number of Days Post HSCT Incidence of IA in HSCT 53% 17% <40 (n=57)

34 34 Incidence of Aspergillosis in HSCT Recipients Is Growing 1-Year Cumulative Incidence of Aspergillosis at FHCRC* (%) Allograft recipients Autograft recipients Data from 1990 through 1992 were obtained from another study. *FHCRC, Fred Hutchinson Cancer Research Center Adapted from Marr KA et al. Clin Infect Dis. 2002;34: Data from 1990 through 1992 were obtained from another study. *FHCRC, Fred Hutchinson Cancer Research Center Adapted from Marr KA et al. Clin Infect Dis. 2002;34: Incidence (%) Year

35 35 IA Risk Neutropenia Invasive Aspergillosis Risk Increases During the Post-Engraftment Period 1.Marr KA. Oncology. 2001;15: Hagen EA et al. Clin Infect Dis. 2003;36:9-15. Pre-engraftment Immunosuppression: GVHD Corticosteroids Diminished T-cell function Immunosuppression: GVHD Corticosteroids Diminished T-cell function Post-engraftment IA Risk

36 36 Aspergillus-Related Mortality in Allogeneic HSCT Remains Relatively High 31.6%* Lin Cornet Thursky Cordonnier Upton % 71.0% 68.0% 56.0% 1. Lin SJ et al. Clin Infect Dis. 2001;32: Cornet M et al. J Hosp Infect. 2002;51: Thursky K et al. Bone Marrow Transplant. 2004;34: Cordonnier C et al. Clin Infect Dis. 2006;42: Upton A et al. Clin Infect Dis. 2007;44: Studies used crude mortality rate or attributable mortality rates. * Crude mortality rate at 4 months post IA diagnosis.

37 37 Pre-mortem Chamilos The Majority of IFIs Are Identified Post-mortem *Incidence of moulds and yeasts in AML patients (7.9% due to moulds). †Prevalence of invasive moulds and Candida (22% due to moulds). 1. Pagano L et al. Haematologica. 2006;91: Chamilos G et al. Haematologica. 2006;91: *Incidence of moulds and yeasts in AML patients (7.9% due to moulds). †Prevalence of invasive moulds and Candida (22% due to moulds). 1. Pagano L et al. Haematologica. 2006;91: Chamilos G et al. Haematologica. 2006;91: Post-mortem 33% † 12.3%* Pagano Only 1/4 Diagnosed Pre-mortem How Can We Better Identify Patients With IFI During Life?

38 38 Invasive Aspergillosis Role of Early Diagnosis & Therapy Have We Made Progress??

39 39 Non-Culture Based Diagnosis of Invasive Aspergillosis Galactomannan – Sandwich ELISA (Platelia) PCR – 18s ribosomal DNA – Multi-copy or single target genes  -D-glucan – Amebocyte Limulus lysate – Chromogenic (Glucatell, FungiTec G) – Kinetic (Wako) Galactomannan – Sandwich ELISA (Platelia) PCR – 18s ribosomal DNA – Multi-copy or single target genes  -D-glucan – Amebocyte Limulus lysate – Chromogenic (Glucatell, FungiTec G) – Kinetic (Wako)

40 40 Early diagnosis and treatment of invasive aspergillosis Impact of early diagnosis of IA in patients with acute leukemia: Impact of early diagnosis of IA in patients with acute leukemia: – 90% mortality when treatment instigated ≥ 10 days after first clinical or radiological sign of disease – 40% mortality when treatment is instigated early Serial HR CT scanning: Serial HR CT scanning: – early and systematic high resolution CT scan in high-risk patients improves outcome (von Eiff M, et al. Ann Hematol. 1995) (Reprinted with permission from Caillot D, et al. J Clin Oncol. 1997) Days After IPA Survival (%) IA: CT Scanning Systematic CT Non-Systematic CT P = (Logrank Test)

41 41 Relationship between hospital mortality and the timing of antifungal treatment Hospital mortality (%) < 12 Delay in start of antifungal treatment (hours) 12–2424–48> 48 Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5

42 42 Patients with Satisfactory Treatment Response categorized by Baseline CT Findings 42% 52% 41% 29% 16% 62% *Note: Required positive mycology Greene R et al. ECCMID 2003

43 43 Utility of Galactomannan Detection in BAL Samples # pt 160 Sens (%) Spec (%) PPV (%) NPV (%) Serum BAL GM detection in CT-based BAL fluid has a high PPV for diagnosing IPA early in untreated patients Becker et al. Br J Haematol 2003; 121: 448

44 44 Treatment definitions Prophylactic therapy: Use of antifungals from chemotherapy until prolonged febrile neutropenia Chance of infection: remote Empirical therapy: Use of antifungals from febrile neutropenia to culture and/or tissue evidence of fungal infection Chance of infection: possible Preemptive therapy: Use of antifungals based on early clinical and/or laboratory markers of invasive disease Chance of infection: probable Prophylactic therapy: Use of antifungals from chemotherapy until prolonged febrile neutropenia Chance of infection: remote Empirical therapy: Use of antifungals from febrile neutropenia to culture and/or tissue evidence of fungal infection Chance of infection: possible Preemptive therapy: Use of antifungals based on early clinical and/or laboratory markers of invasive disease Chance of infection: probable

45 45 Lack of Consensus on the Use of Empirical Antifungal Therapy Pros Development of resistance Toxicity Cost Development of resistance Toxicity Cost Cons Reduces mortality Addresses diagnostic concerns Reduces mortality Addresses diagnostic concerns Broad-Spectrum antibiotics >96 h Persistent or recurring fever of unknown origin >38  C Persistent neutropenia Absolute neutrophil count <500 cells/mm 3 Wingard JR. N Engl J Med. 2002;346:

46 46 Antifungal treatment evolution AMB deoxycholate 5-fluocytosine 1 st generation azoles (ketoconazole, miconazole) 2 nd generation triazoles (fluconazole, itraconazole) Lipid and liposomal formulations of AMB Extended spectrum triazoles (voriconazole, posaconazole) Echinocandins (caspofungin, micafungin, anidulafungin) AMB deoxycholate 5-fluocytosine 1 st generation azoles (ketoconazole, miconazole) 2 nd generation triazoles (fluconazole, itraconazole) Lipid and liposomal formulations of AMB Extended spectrum triazoles (voriconazole, posaconazole) Echinocandins (caspofungin, micafungin, anidulafungin)

47 47 Cellular Targets of Antifungal Therapy Polyenes: Target membrane function Echinocandins: Target cell wall synthesis Azoles: Target ergosterol synthesis

48 48 Pts on azole prophylaxis Pts with sinusitis or pneumonia Pts with prolonged neutropenia (e.g. leukemia) Pts with history of invasive aspergillosis (IA) or positive surveillance cultures for Aspergillus spp. Pts at institutions undergoing construction Fluconazole: Not a good choice for empirical therapy in certain patients

49 49 L-AMB vs. AMB for empirical therapy of febrile neutropenia Ambisome  AMB Ambisome  AMB Patients Acute Leukemia Success5049 BFI (%) * Infusion Fever (%) † 1744 Nephrotoxicity (%) 1934 * p=0.009 † p<0.001 Walsh NEJM 1999; 340:764

50 50 Polyene Therapy for Invasive Aspergillosis Hiemenz JW et al. Blood 1995;86(suppl 1):849a; Leenders ACAP et al. Br J Haem 1998;103:205; Bowden RA et al. Clin Infect Dis 2002;35: Response % Historical Control 23% DAMB 29% DAMB 23% ABCD 18% L-AMB 52% ABLC 42% Note: ABLC=amphotericin B lipid complex; L-AmB=liposomal amphotericin B; ABCD=amphotericin B colloidal dispersion; D-AMB=amphotericin B deoxycholate

51 51 Comparative Aspergillosis Study: Better Outcomes & Survival of Voriconazole Number of days of Therapy Probability of Survival Amphotericin B arm Voriconazole arm Hazard ratio = % CI (0.40, 0.89) Outcomes at wk 12 Vori AmB ■Survival 70.8% 57.9% ■Response 56.8% 31.6% Poor efficacy of AmB prior “gold standard” Vori recommended for primary therapy Questions? ■Role of Other Licensed Antifungal therapy ■Lipid for primary therapy ■Efficacy in high risk ■Combinations Herbrecht R et al NEJM 2002;347:408-15

52 52 Voriconazole vs. Ambisome  in febrile neutropenia Vorico(N=415) LAMB (N=422) P Composite success 26% 31% NS Breakthrough fungal infections1.9%5%0.002 Survival rate 87%90%NS Toxicity-related withdrawal 13%10%NS Nephrotoxicity (SCr>1.5) 11%19%<0.001 Visual changes 4.3%0.5%<0.001 Walsh et al. N Engl J Med. 2002; 346:

53 53 Voriconazole: need for monitoring

54 54 Voriconazole Treatment

55 55 Subtherapeutic Voriconazole - Omeprazole

56 56 Posaconazole Posaconazole: broad spectrum of activity only oral formulation variable absorption variable bioavailability Established for prophylaxis in acute leukemia and HSCT Posaconazole: broad spectrum of activity only oral formulation variable absorption variable bioavailability Established for prophylaxis in acute leukemia and HSCT

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58 58 Posaconazole

59 59 Echinocandins  Latest class of antifungal drugs  First discovered in 1970s in screening programs for new antibiotics  Cell-wall active agents: nhibition of (1, 3)-β-D glucan synthetase  cell wall glucan depletion  osmotic instability  cell lysis  Latest class of antifungal drugs  First discovered in 1970s in screening programs for new antibiotics  Cell-wall active agents: nhibition of (1, 3)-β-D glucan synthetase  cell wall glucan depletion  osmotic instability  cell lysis

60 60 Echinocandins  Formerly known as Pneumocandins due to activity against Pneumocystis carinii  Rapidly fungicidal against most Candidae including azole-resistant strains  Fungistatic against most Aspergillus spp  Limited or no activity against Fusarium spp and Zygomycetes.  No activity against Cryptococcus neoformans  Formerly known as Pneumocandins due to activity against Pneumocystis carinii  Rapidly fungicidal against most Candidae including azole-resistant strains  Fungistatic against most Aspergillus spp  Limited or no activity against Fusarium spp and Zygomycetes.  No activity against Cryptococcus neoformans

61 61 Mechanism of action ECALTA ® SPC. 2- Odds F.C., Brown A.J.P., Gow N.A.R. Antifungal agents: mechanism of action. Trends Microbiol. 2003;11: Debono M., Turner W.W., LaGrandeur L. et al. Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem. 1995;38(17): Raasch R.H. Anidulafungin: review of a new echinocandin antifungal agent. Expert Rev Anti Infect Ther. 2004;2: Mechanism of action involves a target specific for fungus 4 inhibitor of 1,3-  -D-glucan synthase 1 Enzyme is present in fungal, but not mammalian, cells 1 Glucan is essential to fungal cell wall integrity 2-4 Without it, fungal cells are osmotically fragile and easily lysed 4

62 62 Echinocandins  IV administration  Long half life  CNS penetration: poor  Dose: once daily  Little infusion related toxicity  Little or no renal and hepatic toxicity  Drug-drug interaction limited (cyclosporin)  Potential combination with other antifungals (AMB or azoles)  Animal data suggest synergistic effect  Echinocandins: Caspofungin Anidulafungin Micafungin  IV administration  Long half life  CNS penetration: poor  Dose: once daily  Little infusion related toxicity  Little or no renal and hepatic toxicity  Drug-drug interaction limited (cyclosporin)  Potential combination with other antifungals (AMB or azoles)  Animal data suggest synergistic effect  Echinocandins: Caspofungin Anidulafungin Micafungin

63 63 Echinocandins : In vitro activity 1 1- Cappelletty D. et al. Reviews of therapeutics : the echinocandins Pharmacotherapy 2007, 27(3): AnidulafunginMicafungin*Caspofungin Candida species MIC 50 (µg/ml) MIC 90 (µg/ml) MIC 50 (µg/ml) MIC 90 (µg/ml) MIC 50 (µg/ml) MIC 90 (µg/ml) albicans glabrata tropicalis dubliniensis krusei lusitaniae parapsilosis guilliermondiiND > 8 Minimum inhibitory concentrations of the echinocandins against Candida species MIC 50 or MIC 90 = minimum inhibitory concentration for 50% or 90%, respectively, of tested strains; ND = not done.

64 64 Caspofungin in Invasive Aspergillosis Well-documented disease Efficacy – High risk pts – Progressive infection – Multiple prior antifungals Excellent tolerability Clinical utility – No data for primary therapy – Combination therapy – Optimal dose not known Well-documented disease Efficacy – High risk pts – Progressive infection – Multiple prior antifungals Excellent tolerability Clinical utility – No data for primary therapy – Combination therapy – Optimal dose not known Maertens J, et al. Clin Infect Dis 2004;39: % %

65 65 Caspo (556) L-AmB (539) Composite Success 33.9%33.7% Success Baseline Infections 14/27 (52%)7/27 (26%) Breakthrough Infections 29 (5.2%)24 (4.5%) Etiological Agents* Aspergillus 10 9 Candida Fusarium 1 0 Zygomycetes 2 0 Other 1 1 Caspo (556) L-AmB (539) Composite Success 33.9%33.7% Success Baseline Infections 14/27 (52%)7/27 (26%) Breakthrough Infections 29 (5.2%)24 (4.5%) Etiological Agents* Aspergillus 10 9 Candida Fusarium 1 0 Zygomycetes 2 0 Other 1 1 Efficacy of Caspofungin vs Empirical L-AmB in Neutropenic Patients * Walsh TJ et al, New Eng J Med, 2004;351: *Patients may have had more than one organism

66 66 Anidulafungin Clinical data Anidulafungin vs Fluconazole Reboli A.C. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:

67 67 Global success at the end of IV therapy ECALTA ® demonstrated superiority vs fluconazole: Significantly greater response rate in the anidulafungin group Difference: 15.4% (95% CI: 3.9% to 27.0%) Mean (median) duration of IV therapy: fluconazole: 12.1 (11) days anidulafungin: 13.5 (14) days Primary endpoint 1 1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:

68 68 *2.0 mg/kg/day in patients weighing ≤ 40 kg † Treatment continued until at least one week after resolution of clinical signs and symptoms and obtaining of two sequential negative blood cultures ‡ Maximum 8 weeks in chronic disseminated candidiasis, Candida osteomyelitis or Candida endocarditis Micafungin 100 mg/day*L-AmB 3 mg/kg/day Treatment period † 2–4 weeks ‡ Randomisation (1:1) 12 weeks Post-treatment period Phase III study micafungin vs. L-AmB Study design Kuse ER, et al. Lancet 2007; 369:1519–27

69 69 Phase III study micafungin vs. L-AmB Overall treatment success Kuse ER, et al. Lancet 2007; 369:1519–27 mITT = modified intent-to-treat; PP = per-protocol set Treatment success rate (%) mITTPP MicafunginL-AmB n =

70 70 *70 mg loading dose on Day 1 † 8 weeks in chronic disseminated candidiasis or Candida endophthalmitis; switch to oral fluconazole permitted after 10 days in patients meeting protocol-specified criteria ‡ Time from last dose day of protocol-defined antifungal therapy to final evaluation Micafungin 100 mg/day CAS 50 mg/day* Treatment period † Max 4 weeks † Randomisation (1:1:1) 6 weeks ‡ Post-treatment period Phase III study micafungin vs. caspofungin Study design Micafungin 150 mg/day Pappas PG, et al. Clin Infect Dis 2007; 45:883–93 CAS = caspofungin Patients were stratified by region and APACHE II score (≤ 20 or > 20)

71 71 Phase III study micafungin vs. caspofungin Treatment success Pappas PG, et al. Clin Infect Dis 2007; 45:883–93 n = 191n = 188n = 199 Caspofungin 50 mg/day* Treatment success rate (%) n = Micafungin 100 mg/day Micafungin 150 mg/day *Loading dose 70 mg; mITT population

72 72 Micafungin vs Caspofungin in febrile neutropenia

73 73 Conclusions Micafungin as effective and safe as caspofungin in empirical treatment of fungal infections in patients with febrile neutropenia Conclusions Micafungin as effective and safe as caspofungin in empirical treatment of fungal infections in patients with febrile neutropenia Micafungin vs Caspofungin in febrile neutropenia

74 74 Empirical micafungin treatment of IFIs in hematologic malignancies

75 75 Empirical micafungin treatment of IFIs in hematologic malignancies

76 76 Micafungin vs fluconazole for prophylaxis of invasive fungal infections during neutropenia in hematopoietic stem cell transplantation patients Study endpoints Primary endpoint: treatment success (absence of proven, probable, or suspected systemic fungal infection until the end of prophylaxis therapy and the absence of a proven or probable systemic fungal infection until the end of the 42-day post-treatment period) Secondary endpoints included: use of systemic antifungal agents for treatment of suspected fungal infections; frequency of proven or probable fungal infections throughout the post-treatment period; pathogen-based frequency of proven infections Primary endpoint: treatment success (absence of proven, probable, or suspected systemic fungal infection until the end of prophylaxis therapy and the absence of a proven or probable systemic fungal infection until the end of the 42-day post-treatment period) Secondary endpoints included: use of systemic antifungal agents for treatment of suspected fungal infections; frequency of proven or probable fungal infections throughout the post-treatment period; pathogen-based frequency of proven infections van Burik JA, et al. Clin Infect Dis 2004; 39:1407–16

77 77 Phase III study micafungin vs. fluconazole Overall treatment success Treatment success (%) van Burik JA, et al. Clin Infect Dis 2004; 39:1407–16 p = 0.03 MicafunginFluconazole MicafunginFluconazole n =

78 78 Is combination of antifungals indicated?

79 79 Randomized blinded trial of high-dose fluconazole plus placebo vs fluconazole plus AMB as therapy for candidemia in non-neutropenic patients. The combination of fluconazole and AMB was evaluated versus monotherapy with high-dose fluconazole in 219 non-neutropenic patients No difference in survival between the two groups; however, candidemia cleared more rapidly with combination therapy, suggesting potential use in persistent Candida infections Rex JH, et al. Clin Infect Dis 2003; 36: The combination of fluconazole and AMB was evaluated versus monotherapy with high-dose fluconazole in 219 non-neutropenic patients No difference in survival between the two groups; however, candidemia cleared more rapidly with combination therapy, suggesting potential use in persistent Candida infections Rex JH, et al. Clin Infect Dis 2003; 36:1221-8

80 80. Efficacy and Toxicity of Caspofungin in Combination with L-AMB as Primary or Salvage treatment of Invasive Aspergillosis in Patients with Hematologic Malignancies. Kontoyiannis DP, et al Cancer 2003; 98: patients with documented or possible IA The majority (65%) received CAS/L-AMB as salvage therapy for progressive IA despite  7 days of previous L-AMB monotherapy Overall response rate 42% No significant toxicity Factors associated with failure: documented IA, significant steroid use, duration of combination therapy < 14 days Response rate in patients with progressive documented IA 18% Conclusions: The CAS/L-AMB combination is a promising preemptive therapy 48 patients with documented or possible IA The majority (65%) received CAS/L-AMB as salvage therapy for progressive IA despite  7 days of previous L-AMB monotherapy Overall response rate 42% No significant toxicity Factors associated with failure: documented IA, significant steroid use, duration of combination therapy < 14 days Response rate in patients with progressive documented IA 18% Conclusions: The CAS/L-AMB combination is a promising preemptive therapy

81 81 Combination antifungal therapy for invasive aspergillosis. Marr KA, et al. Clin Infect Dis. 2004; 39: Salvage therapy with the combination of voriconazole and caspofungin was associated with reduced mortality, compared with voriconazole monotherapy Salvage therapy with the combination of voriconazole and caspofungin was associated with reduced mortality, compared with voriconazole monotherapy

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84 84 Br J Haematol. 2004; 126:

85 85 Conclusions  Patients at high risk may benefit from empirical therapy  Patients under close surveillance may receive preemptive treatment after early prodromal clues of infection No clear drug of choice, decisions should be individualized  No clear drug of choice, decisions should be individualized Lipid AMB, voriconazole and echinocangins: high risk pts  Lipid AMB, voriconazole and echinocangins: high risk pts Fluconazole, itraconazole: lower risk pts  Fluconazole, itraconazole: lower risk pts Limited data point out to combination treatments for selected high risk pts  Limited data point out to combination treatments for selected high risk pts  Patients at high risk may benefit from empirical therapy  Patients under close surveillance may receive preemptive treatment after early prodromal clues of infection No clear drug of choice, decisions should be individualized  No clear drug of choice, decisions should be individualized Lipid AMB, voriconazole and echinocangins: high risk pts  Lipid AMB, voriconazole and echinocangins: high risk pts Fluconazole, itraconazole: lower risk pts  Fluconazole, itraconazole: lower risk pts Limited data point out to combination treatments for selected high risk pts  Limited data point out to combination treatments for selected high risk pts

86 86 Future issues Should we move from empirical to preemptive therapy based on surrogate markers of early diagnosis of IFIs? Is sequence of antifungals important? Which combinations are more effective?

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