Jean KLASTERSKY, M.D., Ph. D. Institut Jules Bordet, Brussels, Belgium ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENIC PATIENTS REVIEW OF TREATMENT CHOICES AND STRATEGIES Jean KLASTERSKY, M.D., Ph. D. Institut Jules Bordet, Brussels, Belgium

G.S. MARTIN et al., NEJM 2003

Mc Neil M, CID 2001;13:;641-647

Frequency of non-Aspergillus mould infections at Fred-Hutchinson Cancer Research Center (Seattle). The number of patients who developed proven or probable infection with Fusarium species, Zygomycetes and Scedosporium species from 1985 through 1999 are shown

fluconazole for prophylaxis (1984-1997). Pathogenic Candida species in BMT recipients : Candida species that caused candidemia are compared over 2 decades at the Fred Hutchinson Cancer Research Center. The incidence of candidemia decreased from 11.4 % in 1980-1986 (72) compared to 4.6 % after adoption of fluconazole for prophylaxis (1984-1997). Marr K & Bowden R, Transplant Infectious Diseases 1999;1:237-246.

Antifungal prophylaxis in leukemia patients : ECIL recommendations

Comparative trials of antifungal agents in candidemia and invasive candidasis Response rate Overall mortality Fluconazole vs amphotericin B 70 % vs 79 % 33 % vs 40 % Itraconazole vs amphotericin B 35 % vs 41 % 40 % ABLC vs amphotericin B 63 % vs 68 % 41 % vs 39 % Caspofungin vs amphotericin B 73 % vs 62 % 30 % vs 34 % Voriconazole vs amphotericin B 41 % vs 41 % 36 % vs 42 % Micafungin vs Ambisome 89 % vs 89 % Anidulafungin vs fluconazole 75 % vs 60 % 26 % vs 31 %

Why does the frequency of fungal infection increase ? I.V. devices Immunosuppression Neutropenia Broad spectrum antibiotics Diabetes

Rational for Empirical Antifungal Therapy in Neutropenic Patients with Persistent Fever Delayed treatment increases mortality Success of antibacterial empirical therapy Early diagnosis of many fungal infections is difficult

Follow Daily And Reassess After 72 Hours An Algorithm for Therapy of Febrile Neutropenia after Initial Empirical Therapy with Broad Spectrum Antibiotics Follow Daily And Reassess After 72 Hours Clinical response Yes No Continue for 7 days Pathogen isolated Yes No Adjust to sensitivity Look for localized infection Use G/GM-CSF? Repeat cultures and serology Perform chest CT and BAL Add amphotericin, and possibly metronidazole, antivirals and/or G/GM-CSF as indicated Look for non infectious causes of fever 10

Possible Causes of Persistent Fever Approximate frequency in high risk patients (%) Fungal infections susceptible to empirical therapy 40 Fungal infections resistant to empirical antifungal therapy 5 Bacterial infections (with cryptic foci and resistant organisms) 10 Toxoplasma gondii, mycobacteria, or fastidious pathogens (legionella, mycoplasma, chlamydia, bartonella) Viral infections (cytomegalovirus, Epstein-Barr virus, human herpes virus 6, varicella-zoster virus, herpes simplex virus) and respiratory pathogens such as parainfluenza virus, respiratory syncytial virus, influenza viruses Graft-versus-host-disease after hematopoietic stem-cell transplantation Undefined (e.g. drug fever, toxic effects of chemotherapy, antitumor responses, undefined pathogens) 25 L. COREY and M. BOECKH, NEJM 2002

Infectious Complications in Each of the Groups Following Randomization Randomization group N° Clinically documented Bacterial Fungal Viral Protozoal Shock Discontinue KGC 16 2 3 1 6 Continue KGC alone 5 KGC + Ampho B 18 KGC : cephalotin (Keflin), gentamicin, carbenicillin P.A. PIZZO et al, Am J Med 1982 14

Clinical Response in Persistently (4 days) Febrile Neutropenic Patients Ampho B No Ampho B p Value Overall All patients 55/80 (68) 39/77 (50) 0.10 Prior antifungal prophylaxis No 21/27 (78) 9/20 (45) 0.04 Yes 19/31 (61) 24/39 (61) NS Infection documentation Clinical 22/29 (75) 14/31 (41) 0.03 Possible 25/39 (64) 20/33 (60) Granulocyte count at Day 4 < 100/µL 31/45 (69) 20/43 (46) 0.06 100-500/µL 16/23 (70) 14/21 (67) EORTC-IATCG, Am J Med 1989

Causes of Death with or without Empirical Ampho B in Persistently (4 Days) Febrile Neutropenic Patients Ampho B No Ampho B Overall mortality (at day 30) * 11 14 Fungal infection** 4 Bacterial infection 1 2 Pulmonary infection (no bacterial or fungal pathogen identified at autopsy) Other 9 8 (*) p = NS between the two groups (**) p = 0.05 between the two groups EORTC-IATCG, Am J Med 1989

Randomized Studies Comparing Empirical Treatment with Antifungal Agents for Persisting Fever during Neutropenia YEAR STUDY ANTIFUNGAL AGENTS COMPARED 1982 1989 1996 1998 1999 2000 2001 2002 2004 Pizzo et al EORTC Viscoli et al. Malik et al. White et al.. Walsh et al. Winston et al. Wingard et al. Boogaerts et al. Conventional ampho B vs no antifungal therapy Conventional ampho B vs fluconazole Conventional ampho B vs ampho B colloidal dispersion Conventional ampho B vs liposomal ampho B Liposomal ampho B vs ampho B lipid complex Conventional ampho B vs itraconazole Liposomal ampho B vs voriconazole Liposomal ampho B vs caspofungin

Measures of the Success (%) of Empirical Antifungal Therapy with Conventional or Liposomal Amphotericin B, Voriconazole or Caspofungin Ampho B Liposomal Ampho B Voriconazole Caspofungin (Ampho B) (Vori) (Caspo) N° of patients 344 343 422 539 415 556 Overall success 49.4 50.1 30.6 33.7 26.0 33.9 Resolution of fever 58.1 58.0 36.5 41.4 32.5 41.2 No breakthrough fungal infection 89.2 90.1 95.0 95.5 98.1 94.8 Resolution of baseline infection 72.7 81.8 66.7 25.9 46.2 51.9 Survival for 7 day 89.5 92.7 94.1 89.2 92.0 92.6 No discontinuation for toxic effects 81.4 85.7 93.4 85.5 90.1 89.7 or lack of efficacy J. KLASTERSKY, NEJM 2004

Comments on the Walsh’s studies Large prospective controlled trials Composite score : « common language » BUT Survival and fever can be influenced by many other factors than just the nature of the empirical regimen What is the difference between « baseline » FI (<72h) and « breakthrough » FI (>72h) ? Discontinuation for toxicity or lack of efficacy : « mixing apples and pears » ?

Toxicity of Empirical Antifungal Therapy % Conventional amphotericin Liposomal amphotericin Voriconazole Caspofungin Total n° patients 344 1312 415 564 Chills Nephrotoxicity* 54 34 24 13 7 14 3 Discontinuation for toxicity 18 9 5** 5 * Creatinine increase 2 x base line ** Visual hallucinations more frequent with voriconazole (4.3 % vs 0.5 %)

Measures of the Success (%) of Empirical Antifungal Therapy with Conventional or Liposomal Amphotericin B, Voriconazole or Caspofungin Ampho B Liposomal Ampho B Voriconazole Caspofungin (Ampho B) (Vorico) (Caspo) N° of patients 344 343 422 539 415 556 Overall success 49.4 50.1 30.6 33.7 26.0 33.9 Resolution of fever 58.1 58.0 36.5 41.4 32.5 41.2 No breakthrough fungal infection 89.2 90.1 95.0 95.5 98.1 94.8 Resolution of baseline infection 72.7 81.8 66.7 25.9 46.2 51.9 Survival for 7 day 89.5 92.7 94.1 89.2 92.0 92.6 No discontinuation for toxic effects 81.4 85.7 93.4 85.5 90.1 89.7 or lack of efficacy J. KLASTERSKY, NEJM 2004

Cure of Base Line Fungal Infection Conventional ampho B Liposomal ampho B Voriconazole Caspofungin Total n° of patients 344 961* 415 556 Response/n° (%) 8/11 (72.7) 20/44 (45.4)** 6/13 (46.2) 14/27 (51.9) * 2 studies **Outcome in the study comparing conventional ampho B to liposomal ampho B was 9/11 (81.8)

Choice of a suitable denominator for the evaluation of empirical therapy based on microbiological results (T. Walsh) (J. Klastersky) Success of therapy Failure of therapy No breakthrough FI Total n° patients - Cure of baseline FI N° of baseline FI Breakthrough FI Total of n° of patients No cure of baseline FI

Outcome of Empirical Antifungal Therapy in Microbiologically Demonstrated Fungal Infections (FI) Ampho B Liposomal ampho B Voriconazole Caspofungin (344) (961) (415) (556) Breakthrough FI 37 (10.8) 45 (4.6) 8 (1.9) 29 (5.2) No cure of base line FI 3 (0.8) 22 (2.2) 7 (1.6) 13 (2.3) Total failures* 40 (11.6) 67 (6.9 %) 15 (3.6 %) 42 (7.7 %) *p = 0.03

% of invasive fungal infections Summary of trials of empirical antifungal therapy that evaluated alternatives to amphotericin B Study drugs % of invasive fungal infections n Arm 1 Arm 2 687 AmB L-Amb 8.7 5.0 384 Itraconazole 2.7 837 L-AmB Voriconazole 1.9* 1095 Caspofungin 4.3 5.2 * p< 0.5 J.R. Wingard, CID, 2004

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Aspergillus fumigatus

Galatomannan detection for the diagnosis of invasive aspergillosis Approved by FDA; standard : optical density index > 0.5 in 2 consecutive samples ? Positivity can preceed radiological findings In probable or proven cases levels are often higher and increase within days 81 % sensitivity; 89 % specificity; NPV:98 %; PPV:7-94 % False negatives : prophylactic use of mold-active azoles, early antifungal therapy and others ? False positives : use of piperacillin-tazobactam and others ?

Aspergillus Infections (AI) in Empirical Therapy Liposomal ampho B Voriconazole Caspofungin (961) (415) (556) Breakthrough AI 21 4 10 No cure of base line AI° 13* 4** 7 Total failures 24 (2.4 %) 8 (1.9 %) 17 (3.0 %) ° Assuming that 1/2 infections in the liposomal ampho B arm (*) and 4/7 infections in the voriconazole arm (**) were caused by Aspergillus

R. Herbrecht et al, N Engl J Med, 2002

T.J. Walsh et al, N Engl J Med 2002 1.9 % 4.9 % (p = 0.02) T.J. Walsh et al, N Engl J Med 2002

T.J. Walsh et al, N Engl J Med 2004

T.J.Walsh et al, N Engl J Med 2004

12 CR 6 PR voriconazole 2 SD rescue 12 No response (7 died < IFI) 8/12 : CR

K.A. MARR et al, CID 2004

N. Singh, Transplantation, 2006

The prevalence of fungal infections in patients receiving empirical therapy is 4-8 %

Prevalence of fungal infections in persistently neutropenic patients not receiving empirical therapy Pizzo et al. (1982) 18 EORTC (1989) 28 * Guiot et al. (1993) 26* Corey and Boeckh (2002) 45 Maertens et al. (2005) 21 * Autopsy-based data

CID, 2005

The preemptive approach (adapted from Maertens et al The preemptive approach (adapted from Maertens et al.) « Possible IFI » Diagnostic evaluation for IFI Reasons Procedures . FN refractory for 5 days . FUO relapsing after 48 h with N . Signs or/and symptoms suggestive of IFI . Isolation of molds/hypae in URT . Galactomannan assays positive (> 0.5) . HRCT of the chest (+ sinuses) . Bronchoscopy +BAL - Smears + cultures for bacteria, fungi, mycobacteria, Legionella - PCR for CMV, HSV, VZV, Toxoplasma, Pneumocystis, Mycoplasma, Chlamydia

The preemptive approach (adapted from Maertens et al The preemptive approach (adapted from Maertens et al.) « Possible IFI » Liposomal amphotericin B (5 mg/kg) IF > 2 consecutives EIA for galactomannan assays > 0.5) OR CT suggestive of IFI supported by microbiology

The preemptive approach of persistent febrile neutropenia in 88 patients (adapted from Maertens et al.) Persistent fever 35/117 (29 %) episodes Prevalence of IFI : 22 % (mortality 36 %) No aspergillar infection was missed Early therapy could be initiated in clinically not suspected cases Significant (78 %) reduction in use of antifungals

CID, 2005

Empirical versus preemptive therapy (liposomal amphotericin B) in patients with persisting fever and neutropenia Adapted from Maertens’ study 35 patients with persistent fever EMPIRICAL APPROACH * PREEMPTIVE APPROACH 1 episode of IA (2.4 %) 10 episodes of IA (28 %) ? Death 2 deaths (20 %) need of a controlled study * Estimation from J. Klastersky, NEJM 2004

Blood, 2006

293 patients c hematological malignancies Empirical (E ) vs pre-emptive approach (PE) Design 293 patients c hematological malignancies R Antifungal therapy E PE . Persistent or recurrent fever . Persistent or recurrent fever + . pneumonia . mucositis . septic shock . sinusitis . skin lesions . aspergillus colonisation . + gamacto-mannan

Empirical (E ) vs pre-emptive approach (PE) Results E 150 patients PE 143 patients Diagnosed IFI 4 (2.6 %) 13 (9.0) p < 0.02 Overall survival 147 (98 %) 136 (95 %) NS IFI related mortality 0 (0 %) 3 (2.1 %) p = 0.12 Mean cost (euros) 3595 3595 NS

Estimated prevalence of invasive fungal infection (IFI) in neutropenic patients according to the management strategy in exemplative studies N° patients N° IFI Prevalence % Controls ¹ 341 14 26.0 Prophylaxis ² (posaconazole) 291 7 2.4 Empirical therapy ³ (voriconazole) 415 15 3.6 Pre-emptive therapy (polyenes) 4 143 13 9.0 1 Guiot, CID, 1994 2 Ullmann, NEJM, 2007 3 Walsh, NEJM, 2002 4 Cordonnier, Blood, 2006

(amphotericin B < lipid preparations < voriconazole = caspo) Which Antifungal Drug is Best for the Empirical Treatment of Patients with Febrile Neutropenia? Few adverse effects (amphotericin B < lipid preparations < voriconazole = caspo) Superiority of action : conventional amphotericin looks to be the least effective voriconazole might be superior in reducing microbiologically proven failures Cost Resistance

Average Daily Cost of Antifungal Therapy (Jules Bordet Bruxelles) Dose Euros Conventional Amphotericin B 1 mg/kg 8 Liposomal amphotericin B 3 mg/kg 629 Voriconazole 400 mg IV 407 400 mg PO 84 Caspofungin 70 mg IV 644

Sensitivity of common pathogenic fungi Amphotericin B Voriconazole Caspofungin Candida sp. S C. lusitaniae R C. krusei S** C. glabrata Trichosporon sp. Aspergillus sp.* Fusarium sp. Mucorales C. neoformans *Except terreus **MIC are higher than for C. albicans but still < 3 ng/ml

Antifungal therapy in persistently febrile neutropenic patients Conclusions Voriconazole is presently the optimal choice for therapy and empirical therapy of suspected aspergillar infections Early therapy (empirical) is needed since mortality remains high (30-50 %) Empirical therapy reduces the incidence of IFI from + 25 % to + 3.5 %; the corresponding figures for liposomal ampho B and caspofungin being + 7 % Experience with the preemptive approach is still limited; it is demanding in terms of diagnostic procedures but it reduces the rate of overtreatment. There is evidence so far that pre-emptive therapy is inferior in efficacy and not more cost effective than the empirical approach

Needs for Improvement of Neutropenic Febrile Patients with Persistent Fever to Avoid Overtreatment Better diagnostic tools for EARLIER microbiological and clinical diagnosis : galactomannan, PCR, those caused by Aspergillus sp. More accurate IDENTIFICATION OF PATIENTS at high risk of fungal infections (cf MASCC score)

Thank you for your kind attention and « Au revoir »