Is pre-emptive therapy a realistic approach?

Transcription

1 Is pre-emptive therapy a realistic approach? J Peter Donnelly PhD, FRCPath Department of Haematology Radboud University Nijmegen Medical Centre Nijmegen, The Netherlands

2 Is pre-emptive therapy a realistic approach? YES NO

3 Contents Evolution of pulmonary IFD Treatment strategies Evidence for preemptive approach Future initiatives

4 Evolution of invasive mould disease

5 What if invasive mould disease at risk

6 begins with colonisation at risk

7 then progresses to infection at risk infection Nucleic acid galactomannan Prevalence beta-d-glucan >10%

8 and finally to disease. at risk infection disease Nucleic acid galactomannan Prevalence >10% beta-d-glucan

9 Deciding when to intervene at risk infection disease Nucleic acid galactomannan Prevalence >10% beta-d-glucan Targeted

10 Deciding when to intervene at risk infection disease Nucleic acid galactomannan Prevalence >10% beta-d-glucan Prophylaxis

11 Deciding when to intervene at risk infection disease Nucleic acid galactomannan Prevalence >10% beta-d-glucan Pre-emptive

12 Deciding when to intervene at risk infection disease Nucleic acid galactomannan Prevalence >10% beta-d-glucan Diagnostic driven

13 Are you happy with this model? YES NO

14 Treatment strategies

15 Defining invasive mould disease A B C D E Radiological signs & clinical symptoms Mycology results Clinical evidence of IFD Mycological evidence of IFI Final diagnosis

16 Defining invasive mould disease A B C D E - Radiological signs & clinical symptoms No Mycology results Negative Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No

17 Defining invasive mould disease A B C D E - - Radiological signs & clinical symptoms No Persistent Febrile neutropenia Mycology results Negative Negative Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No

18 Defining invasive mould disease A B C D E - - I Radiological signs & clinical symptoms No Persistent Febrile neutropenia No Mycology results Negative Negative Positive biomarker or microscopy or culture Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No No Yes

19 Defining invasive mould disease A B C D E - - I II Radiological signs & clinical symptoms No Persistent Febrile neutropenia No Clinical (any new infiltrate not fulfilling the EORTC/MSG criteria) Mycology results Negative Negative Positive biomarker or microscopy or culture Negative Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No No No Yes No

20 Defining invasive mould disease A B C D E - - I II III Radiological signs & clinical symptoms No Persistent Febrile neutropenia No Clinical (any new infiltrate not fulfilling the EORTC/MSG criteria) Mycology results Negative Negative Positive biomarker or microscopy or culture Negative Positive biomarker or microscopy or culture Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No No No No Yes No Yes

21 Defining invasive mould disease A B C D E - - I II III IV Radiological signs & clinical symptoms Mycology results No Persistent Febrile neutropenia No Negative Negative Positive biomarker or microscopy or culture Clinical (any new infiltrate not fulfilling the EORTC/MSG criteria) Negative Positive biomarker or microscopy or culture Radiological signs on CT (Dense, wellcircumscribed lesions(s) with or without a halo sign, air-crescent sign, or cavity) Negative Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No No Yes No No Yes No Yes No Possible IMD

22 Defining invasive mould disease A B C D E - - I II III IV - Radiological signs & clinical symptoms Mycology results No Persistent Febrile neutropenia No Negative Negative Positive biomarker or microscopy or culture Clinical (any new infiltrate not fulfilling the EORTC/MSG criteria) Negative Positive biomarker or microscopy or culture Radiological signs on CT (Dense, wellcircumscribed lesions(s) with or without a halo sign, air-crescent sign, or cavity) Negative Positive biomarker or microscopy or culture Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No No Yes Yes No No Yes No Yes No Yes Possible IMD Probable IMD

23 Defining invasive mould disease A B C D E - - I II III IV - Radiological signs & clinical symptoms Mycology results No Persistent Febrile neutropenia No Negative Negative Positive biomarker or microscopy or culture Clinical (any new infiltrate not fulfilling the EORTC/MSG criteria) Negative Positive biomarker or microscopy or culture Radiological signs on CT (Dense, wellcircumscribed lesions(s) with or without a halo sign, air-crescent sign, or cavity) Negative Positive biomarker or microscopy or culture Not considered necessary Tissue positive Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No No Yes Yes Yes No No Yes No Yes No Yes Yes Possible IMD Probable IMD Proven IMD

24 Are you happy with the EORTC/MSG definitions YES NO

25 Treating invasive mould disease Radiological signs & clinical symptoms Mycology results A B C D E - - I II III IV - No Persistent Febrile neutropenia No Negative Negative Positive biomarker or microscopy or culture Clinical (any new infiltrate not fulfilling the EORTC/MSG criteria) Negative Positive biomarker or microscopy or culture Radiological signs on CT (Dense, wellcircumscribed lesions(s) with or without a halo sign, air-crescent sign, or cavity) Negative Directed Positive biomarker or microscopy or culture Not considered necessary Tissue positive Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No No Yes Yes Yes No No Yes No Yes No Yes Yes Possible IMD Probable IMD Proven IMD

26 Treating invasive mould disease Radiological signs & clinical symptoms Mycology results A B C D E Prophylaxis - - I II III IV - No Persistent Febrile neutropenia No Negative Negative Positive biomarker or microscopy or culture Clinical (any new infiltrate not fulfilling the EORTC/MSG criteria) Negative Positive biomarker or microscopy or culture Radiological signs on CT (Dense, wellcircumscribed lesions(s) with or without a halo sign, air-crescent sign, or cavity) Negative Positive biomarker or microscopy or culture Not considered necessary Tissue positive Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No No Yes Yes Yes No No Yes No Yes No Yes Yes no IMD Possible IMD Probable IMD Proven IMD

27 Treating invasive mould disease Radiological signs & clinical symptoms Mycology results A B C D E - - I II III IV - No Empirical Persistent Febrile neutropenia No Negative Negative Positive biomarker or microscopy or culture Clinical (any new infiltrate not fulfilling the EORTC/MSG criteria) Negative Positive biomarker or microscopy or culture Radiological signs on CT (Dense, wellcircumscribed lesions(s) with or without a halo sign, air-crescent sign, or cavity) Negative Positive biomarker or microscopy or culture Not considered necessary Tissue positive Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No No Yes Yes Yes No No Yes No Yes No Yes Yes no IMD Adapted by Maertens & Donnelly from Herbrecht & Berceanu Clin Infect Dis. 2008;46: Possible IMD Probable IMD Proven IMD

28 Choices choices choices Febrile despite antibiotics Empirical therapy

29 Choices choices choices Still febrile despite antifungals Empirical therapy Diagnosis Change drugs

30 Choices choices choices Still febrile despite antifungals Empirical therapy Diagnosis Change drugs

31 Empirical integrated care pathway Fever Treatment Diagnosis Outcome Agrawal S et al. J. Antimicrob. Chemother. 2011;66:i45-i53

32 Empirical integrated care pathway Fever Treatment Diagnosis Outcome Agrawal S et al. J. Antimicrob. Chemother. 2011;66:i45-i53

33 Do you use empirical therapy? YES NO

34 Pre-emptive therapy

35 Diagnostic-driven strategy (Pre-emptive therapy)

36 Treating invasive mould disease Radiological signs & clinical symptoms Mycology results A B C D E - - I II III IV - No Persistent Febrile neutropenia No Negative Negative Positive biomarker or microscopy or culture Diagnostic driven Clinical (any new infiltrate not fulfilling the EORTC/MSG criteria) Negative Positive biomarker or microscopy or culture Radiological signs on CT (Dense, wellcircumscribed lesions(s) with or without a halo sign, air-crescent sign, or cavity) Negative Positive biomarker or microscopy or culture Not considered necessary Tissue positive Clinical evidence of IFD Mycological evidence of IFI Final diagnosis No No No No No Yes Yes Yes No No Yes No Yes No Yes Yes IMD or IFI Possible IMD Probable IMD Proven IMD

37 A diagnostic versus and empirical approach High risk hematology patients GM monitoring and clinical evaluation Positive GM (>0.5) >5 days of unexplained neutropenic fever refractory to antibiotics or relapsing fever New infiltrate on chest radiograph or signs/symptoms of invasive mycosis Positive respiratory culture or microscopy (moulds) High-resolution pulmonary CT scan (± CT sinus) Characteristic of invasive mycosis: Halo-sign Nonspecific Normal Bronchoscopy with BAL positive negative Broad-spectrum antifungal therapy Continued monitoring No antifungal therapy Maertens et al. Clin Infect Dis 2005; 41: 1242

38 A diagnostic versus and empirical approach High risk hematology patients GM monitoring and clinical evaluation Positive GM (>0.5) >5 days of unexplained neutropenic fever refractory to antibiotics or relapsing fever New infiltrate on chest radiograph or signs/symptoms of invasive mycosis Positive respiratory culture or microscopy (moulds) 6 ml blood collected daily serum screened 3 x weekly High-resolution pulmonary CT scan (± CT sinus) Autopsy for all fatalities Characteristic of invasive mycosis: Halo-sign Nonspecific Normal Bronchoscopy with BAL positive negative Broad-spectrum antifungal therapy Continued monitoring No antifungal therapy Maertens et al. Clin Infect Dis 2005; 41: 1242

39 Leuven s approach High-risk episodes N=136 (88 pts) neutropenic fever N=117 (86%) Persistent fever N=41 (30%) Antifungal therapy N=9 (7%) Maertens et al. Clin Infect Dis 2005; 41: 1242

40 Leuven s approach High-risk episodes N=136 (88 pts) neutropenic fever N=117 (86%) Persistent fever N=41 (30%) Antifungal therapy N=9 (7%) Maertens et al. Clin Infect Dis 2005; 41: 1242

41 The PREVERT study Randomization at start of chemotherapy Instituted from day 4 14 of fever Pre-emptive Pneumonia, severe mucositis,,septic shock, positive galactomannan antigen test, skin lesion, sinusitis or periorbital inflammation, neurological symptoms, diarrhea empirical Fever driven In both groups: Ampho B (1mg/kg/d) or liposomal Ampho B (3mg/kg/d) according to the daily assessment of the creatinine clearance Cordonnier et al Clin Infect Dis 48:

42 The PREVERT study - GM & CT 239 Pre-emptive empirical 143 neutropenia % IFD 3% % Antifungal therapy 66% % survival 97% 147 Cordonnier et al Clin Infect Dis 48:

43 The PREVERT study 239 Pre-emptive empirical 143 neutropenia 150 9% 13 IFD 3% % Antifungal therapy 66% % survival 97% 147 Cordonnier et al Clin Infect Dis 48:

44 The PREVERT study 239 Pre-emptive empirical 143 neutropenia % IFD 3% 4 46% 66 Antifungal therapy 66% % survival 97% 147 Cordonnier et al Clin Infect Dis 48:

45 The PREVERT study 239 Pre-emptive empirical 143 neutropenia % IFD 3% % Antifungal therapy 66% 99 95% 136 survival 97% 147 Cordonnier et al Clin Infect Dis 48:

46 The PREVERT study 239 Pre-emptive empirical 143 neutropenia % IFD 3% % Antifungal therapy 66% % survival 97% 147 Cordonnier et al Clin Infect Dis 48:

47 Diagnostic-driven integrated care pathway. Triggers Diagnosis Treatment Outcome Agrawal S et al. J. Antimicrob. Chemother. 2011;66:i45-i53

48 Diagnostic-driven integrated care pathway. Triggers Diagnosis Treatment Outcome Agrawal S et al. J. Antimicrob. Chemother. 2011;66:i45-i53

49 Empirical versus diagnostic-driven approach History Empirical Diagnostic driven Strategy developed to reduce Strategy developed to direct risk of fatal IFD in an era of few therapy more effectively once diagnostic tests and limited CT scan and tests such as GM drugs became widely available. Standard of care Most centres Principle Neutropenia and persistent or relapsing fever despite broadspectrum antibiotics for 3-7 days: no alternative microbiological etiology found AND IFD cannot be ruled out ECIL BII - Feasible Yes Unknown Few centres include all patients likely to have IFD and treat them with the safest and most effective drug: exclude all patients unikely to have IFD and adopt a Wait-and-see approach

50 Pre-requisites for a empirical approach? Yep. I m in charge

51 Pre-requisites for a diagnosis driven approach? Am I still in charge?

52 Pre-requisites for a diagnosis driven approach?

53 Is pre-emptive therapy a realistic approach? YES NO

54 Future initiatives

55 EORTC Empirical versus pre-emptive antifungal therapy of patients with haematological malignancies and recipients of an allogeneic HSCT following myeloablative therapy. A therapeutic phase III strategy study

56 EORTC Empirical versus pre-emptive antifungal therapy of patients with haematological malignancies and recipients of an allogeneic HSCT following myeloablative therapy. A therapeutic phase III strategy study Joint IDG- AL study Randomized phase III (new standard of care) Translational - utility of Aspergillus PCR and BDG and evaluation of potential genetic SNPs signatures 556 patients,10 countries, 22 centres

57 EORTC remission induction chemotherapy for acute myeloid leukaemia or myelodysplastic syndrome that is newly diagnosed or in first relapse OR a myeloablative conditioning regimen to prepare for an allogeneic HSCT Randomise on admission Oral or iv fluconazole for Candida prophylaxis; no other antifungal prophylaxis allowed Primary endpoint: survival at 42 days after radmonization

58 EORTC Expected to start Q

59 Thank you!