Advances in Empirical Antifungal Therapy in Patients with Febrile Neutropenia. Marc A. Boogaerts

1. Advances in Empirical Antifungal Therapy in Patients with Febrile Neutropenia. Marc A. Boogaerts

2. Fungi 2003 : the problem • The incidence of fungal infections is increasing • The spectrum of fungal disease is changing • Selection of fungi is a reality • Resistance of fungi is on the rise • Cross resistance is increasingly recognized • Unit epidemiology is underscored

3. INCREASE IN FUNGAL INFECTIONS • Better diagnosis • More broadspectrum antibiotics • Higher age of patient population • More complex interventions (e.g.transplants) • More intensive cytotoxic therapy • More immunosuppressive therapy • Less mortality from other causes • More high risk patients

4. SYSTEMIC FUNGAL INFECTIONS AND GROUPS AT RISK • Prolonged deep neutropenia (>7 days;<500/mm3) • Stem Cell Transplants (allo>>>auto) • Solid Organ Transplants • AIDS patients • High Risk Environment • Prolonged antibiotic and/or corticosteroid use

5. ANTIFUNGAL STRATEGIES • Prophylaxis • Empirical use • Preemptive use • Treatment

6. WHAT DOES EMPIRICAL or PRE-EMPTIVE MEAN? Empirical : • based on observation or experiment , not on theory • regarding sense-data as valid information e.g. “an empiric = a quack doctor" Pre-emptive : • to make a bid in an auction high enough to prevent further bidding • to obtain by acting in advance of others • to occupy public land in order to lay claim to it • to purchase goods before they are formally put on sale • to go on the offensive in order to avert an enemy attack Oxford Dictionary

7. Concepts of antifungal strategies Likelihood of Fungal DiseaseTreatment • Remote 0-4% Prophylaxis • Possible 5-15% Empirical • Probable 15-35% Probable • Proven 100% Specific - + Days FUO

8. ‘CLINICIAN’S’ REASONS FOR EMPIRICAL/PRE- EMPTIVE ANTIFUNGALS • History of invasive fungal disease • ‘Atypical’ Pulmonary Infiltrate • Dry Cough and/or pleural rubbing/pain • Persisting fever in patients, known to be colonised • Second fever spike • Acute fever with muscular tenderness,rash, cutaneous lesions • Fever with unexplained further increase in CRP or alkaline phosphatase

9. ARGUMENTS AGAINST LIBERALEMPIRICAL USE OF ANTIFUNGALS * Introduces false confidence by reducing • the urge to establish a correct diagnosis • * Never shown to be unquestionably effective * Possible additional toxicity in high risk patients * Possible interactions of antifungal with other drugs * Because of toxicity and borderline indication lower dosages of antifungals might be used * Brings in emotions, not science

10. Emotional activity of physician Think about antifungal Add empirical antifungal Add CSF Add empirical antibiotic Start empirical antibiotic Duration of neutropenic fever 24 hr 72 hr 96 hr Realize cost of strategy

11. Prophylaxis Empirical Pre-emptive Specific PCR + Galactomannan Culture Tissue + + + Remote Possible Probable disease Proven Will laboratory tests guide treatment? Treatment 41 40 39 38 CT Temperature (°C) 37 36 10 0 Disease likelihood 1 Granulocytes (log10x109/L) 0.1 -14 -7 0 7 14 21 28 35 42 49 56 63 Days after transplant

12. Galactomann antigen titer Detection level ASPERGILLUS ANTIGEN FOR EARLIERDETECTION OF INVASIVE INFECTION Antifungal Indication for CT-scan Neutropenic fever 1.0 0.5? 0 3 6 9 12 15 20 days

13. ANTIFUNGAL STRATEGIES • Prophylaxis • Empirical use • Preemptive use • Treatment

14. FDA-approved drugs for empirical therapy

15. IN GOD WE TRUST FROM ALL OTHERS WE NEED HARD DATA

16. Itraconazole-Empirical Therapy An open randomized trial comparing the efficacy and safety of intravenous followed by oral itraconazole with intravenous amphotericin B for empiric therapy in neutropenic patients with hematologic malignancy Boogaerts et al, Annals of Internal Medicine, 2001

17. Itraconazole-Empirical Therapy Empirical therapy : • IV itra (7 to 14 days)  Itra oral solution (14 days) • IV ampho B (28 days) Patients with haematologic malignancies : • neutropenic (<0.5 x 109 ANC/l) • fever of unknown origin (>38° C) • 3 - 7 days broadspectrum antibiotics Objectives : • Compare efficacy (defervescence) • Compare efficacy (composite) • Safety • Blood levels of itraconazole

18. Number of subjects left 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Itra 173 172 165 151 128 112 96 80 73 64 57 47 45 42 39 33 25 23 21 17 14 14 11 10 8 6 6 6 Ampho B 171 167 152 134 121 109 96 81 66 57 51 40 34 33 29 26 24 22 19 19 15 14 13 11 11 7 7 6 Itraconazole-Empirical Therapy Time till end of neutropenia % subjects 100 80 60 Randomized group Itra 40 Ampho B p = 0.590 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 days in phase

19. Itraconazole-Empirical Therapy Global evaluation: defervescence ITR AMPHO B 60 184 186 40 Response 20 0 Unevaluable 20 Failure 40 60

20. Composite Endpoint: Overall Response Success, requires all of the following: • Survival for at least 7 days after D/C of study medication • No breakthrough fungal infection during neutropenia and for at least 7 days after D/C of study medication • Defervescence during neutropenia • Not D/C from study medication due to toxicity or lack of efficacy prior to recovery from neutropenia • Baseline infections: global response assessed as complete or partial at end of therapy

21. Empirical Itraconazole versus AmphoB Efficacy analysis p=0.156 p<0.001 p=0.055 2-sided 1-sided superiority equivalence test

22. Itraconazole versus amphotericin B as empirical therapy for persistent fever in neutropenic patients M. Boogaerts et al, 2001

23. Safety results Incidence of gastrointestinal side effects: • similar between treatment groups • similar for itraconazole recipients during IV and oral phases

24. Safety results • Incidence of chills and rigors: • significantly lower in itraconazole group: 10% vs 40% (p<0.0001) • rigors in itra group not related to infusion of study drug • Most common reasons for withdrawal: • nephrotoxicity and rigors in amphotericin group • nausea and rash in itraconazole group

25. 250 mg/ml 200 ITR 150 100 AMPHO B 50 0 SEL D3 D8 D11 D15 D18 D22 D24 D28 END Number of subjects ITR 191 165 123 73 50 24 19 13 9 186 AMPHO B 188 168 106 65 40 26 15 9 3 172 Itraconazole-Empirical Therapy Creatinine clearance

26. 687 patients, blinded, randomised Conventional ampho B 0.8mg/kg (c-Amb.) Randomised Liposomal ampho B 3 mg/kg (I-Amb) FUO: fever not responding to 4 days broad-spectrum antibiotics Neutropenia : neutrophils < 0.5 x 109 /l Large studies on empirical antifungal therapy T. Walsh et al.,1999

27. Tom Walsh et al.,1999 Composite endpoint Liposomal ampho B Conventional ampho B Success 171/343 (50%) 169/344 (49%) Proven deep fungal infections, breakthrough Liposomal ampho B Conventional ampho B 41 (3.2%) 27 (7.8%) P=0.009 Large studies on empirical antifungal therapy Toxicity Liposomal <<< Conventional

28. Empirical Voriconazole Study • Stratified - High vs Low Risk Neutropenic Fever • allogeneic transplant or relapsed leukemia vs autologous transplant or other neoplasm • Stratified –Systemic antifungal prophylaxis • Blinded DRC for review of fungal infections • Seeking to show voriconazole is at least as effective as L-AMB in terms of overall response Walsh et al, New Eng J Med 2002

29. Empirical voriconazole study: Primary composite endpoint Voriconazole failed to meet its primary endpoint Walsh et al, 2002

30. Empirical voriconazole study: Secondary endpoints Walsh et al, 2002

31. Breakthrough Infections According to Risk and Prophylaxis (MITT) *p = 0.003 Mortality : no difference

32. DRC Assessment of Global Response of Baseline Infection at End of Therapy (EOT)

33. Voriconazole vs Liposomal Amphotericin B as antifungal therapy for neutropenia and fever

34. A Randomized, Double-Blind, Multicenter Trial of Caspofungin vs. Liposomal Amphotericin B for Empirical Antifungal Therapy of Persistently Febrile Neutropenic Patients

35. Study Design(1) • Blinded, randomized, multicenter study in patients with persistent febrile neutropenia • Caspofungin 50mg daily (after 70 mg d1) vs liposomal amphotericin B (L-AMB) 3 mg/kg daily (up dosing permitted for lack of efficacy) • DSMB – first study of caspofungin in neutropenia • Blinded Adjudication Committee (BAC) to assess evidence of invasive fungal infection according to EORTC/MSG criteria

36. Study Overview •1123 patients enrolled over 31 months • 116 sites; 27 countries • N = 1111 treated ‣ 1095 MITT (98.6%) ‣ 901 Evaluable (81.1%) • N = 358 adjudicated by independent blinded committee

37. Primary Analysis – MITT

38. Primary Analysis – MITT

39. Breakthrough Infections (BTI) - MITT

40. Discontinuation due to Drug-Related Toxicity or Lack of Efficacy (by investigator) *P= 0.034

41. Drug Related Adverse Events

42. Ampho B Lipo Ampho B Fluco Itra Vori caspo Randomized controlled trials on empirical antifungal therapy in febrile neutropenia – composite endpoints

43. Safety profile: Current Agents * Cyclodextrin solubilizing excipient used in IV formulation accumulates in renal failure. AmB-d = amphotericin B deoxycholate; L-AmB = Liposomal amphotericin B ABLC = amphotericin B lipid complex; ABCD = amphotericin B colloidal dispersion

44. Safety profile: Current Agents (cont’d) CsA = cyclosporine; LFT = liver function test

45. Drug interactions and PK:Current Agents

46. THE IDEAL EMPIRICAL STRATEGY • USE ONLY • safe and effective antifungal drugs with spectrum adapted to local ecology and optimally adjusted dosage; booster host defense (CSF) first • INCLUDE ONLY, BUT QUICKLY • patients with high probability of fungal disease , belonging to a well defined high risk category • EXCLUDE CERTAINLY • patients with low risk profile or unlikely to have fungal disease • RELY EXCLUSIVELY ON • optimal batteries of clinical, radiologic and laboratory tests • AVOID ALWAYS • indiscriminate primary prophylaxis • ADOPT • pre-emptive strategy

47. The essence of wisdom is the ability to make the right decision on the basis of inadequate evidence Old saying in Finland….