Optimal Management of Invasive Aspergillosis in the Context of New Guidelines in High Risk Haematological Patients

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1 Optimal Management of Invasive Aspergillosis in the Context of New Guidelines in High Risk Haematological Patients Shariq Haider Professor Medicine McMaster University

2 Conflict of Interest Disclosure Slide Disclosure of Relationship I am a member of an Advisory Board or equivalent with a commercial organization. I am a member of a Speaker Bureau. I have received payment from a commercial organization (including gifts or other consideration or in kind compensation). I have received a grant(s) or an honorarium from a commercial organization. I hold a patent for a product referred to in the CME/CPD program or that is marketing by a commercial organization I hold investments in a pharmaceutical organization, medical devices company or communications firms. I am currently participating in or have participated in a clinical trial within the past two years.). Company/Organization Merck, ViiV, Gilead, Avir Pharmaceuticals Merck, Gilead, Cidara

3 OBJECTIVES 1. Impact of Directed Antifungal Therapy on Survival in IA in High Risk Haematological Patients in the past 3 decades Evolution of Guideline Recommendations 2.Strategies in management of IA in High Risk Haematological Patients Guideline Recommendations. 3. Optimization of IA management in High Risk Haematological Patients using TDM Guideline Recommendations.

4 Clinical Success in the Primary Treatment of Invasive Aspergillosis Response rates (%) week survival 70% AmB LAmB ABCD Itra Vori (1. Bowden. CID 2002:35;359) (2. Lenders. Br J Haematol 1998:103;205) (3. Bowden. CID 2002:35;359) (4. Caillot. CID 2001:33;e83) (5. Herbrecht. NEJM 2002:347;408)

5 THE PROSPECTIVE ANTIFUNGAL THERAPY ALLIANCE REGISTRY: A TWO CENTER CANADIAN EXPERIENCE. Haider S, Rotstein C, Horn D, Laverdiere M, Azie N. CJIDMM 2014; 25(1)

6 Voriconazole+placebo vs. voriconazole+anidulafungin for primary treatment of IA Primary objective: Overall survival at 6 weeks POST HOC ANALYSIS KA Marr et al. Ann Intern Med 2015

7 Isavuconazole vs. Voriconazole in 1 st line Invasive aspergillosis SECURE Kaplan Meier analysis of allcause mortality Survival probability ITT Isavuconazole N = 258 Voriconazole N = Study day Maertens et al. The Lancet 2016

8 Invasive aspergillosis: Firstline Update ECIL6 (2015) Agent Grade Comments Voriconazole A I 2x6 mg/kg D1 then 2x4 mg/kg (initiation with oral: CIII) Isavuconazole A I LAmB B I dose 3 mg/kg ABLC B II dose 5 mg/kg Caspofungin C II Itraconazole C III ABCD Combination voriconazole + anidulafungin Other combinations Amphotericin B deoxycholate C I C I C III A Iagainst In the absence of data in 1 st line, posaconazole has not been graded

9 SHIFTING STRATEGIES

10 From treatment back to prophylaxis: A large overlap between the different strategies Prophylaxis Empirical Diagnosticdriven/preemptive Diagnosticdriven/preemptive Directed or targeted No symptoms/at risk No symptoms positive biomarker Persistent febrile neutropenia Clinical and/or radiological signs Clinical or radiological signs with positive biomarker or positive microbiology/histology Herbrecht R, Berceanu A. CID 2008;46: Drgona L et al. Eur J Clin Microbiol Infect Dis 2014; 33: 721

11 Preemptive or diagnosticdriven antifungal therapy Definition? Antifungal therapy given to neutropenic patients, with or without fever, and clinical and/or microbiological findings suspected to be related to an invasive fungal disease but insufficient to satisfy the criteria of proven or probable invasive fungal disease Can be surveillance (biomarker)driven or clinically (radiologically)driven Girmenia C et al. Hematol Oncol 2013; 31: Objectives: Target highrisk patients, less patients, shorter duration of treatment, lower toxicity, lower cost vs. empirical strategy

12 Summary of the main studies on the preemptive approach in neutropenic patients Reference Type Underlying condition Fungal marker Maertens 2005 feasibility Chemo or allosct 2 consecutive + GM (0.5) Oshima 2007 feasibility AlloSCT 2 consecutive + GM (0.6) or βdglucan Barnes 2009 feasibility Chemo or allosct 2 (or 1 > 0.7) consecutive + GM (0.5) or PCR Dignan 2009 feasibility AlloSCT No fungal marker Girmenia 2009 feasibility Chemo or autosct 2 consecutive + GM (0.5) AguilarGuisado 2009 feasibility Chemo or allosct GM (0.5) Cordonnier 2009 RCT Chemo or autosct 1 + GM (1.5) Hebart 2009 RCT AlloSCT 1 + PCR Blennow 2010 RCT AlloSCT 1 + PCR Tan 2011 RCT Chemo or allosct 2 consecutive +GM (0.5) or 1 + GM plus CT Morrissey 2013 RCT Chemo or allosct 1 + PCR or GM (0.5) EORTCIDG Results expected RCT Chemo or allosct 1 + GM (0.5) Modified from Girmenia C et al. Hematol Oncol 2013; 31:

13 Empirical versus preemptive antifungal strategy the Prevert study Chemotherapy expected to cause neutropenia for at least 10 days and autologous HSCT Enrolled at initiation of chemotherapy Stratified by risk and antifungal prophylaxis Antifungal strategy started on day 4 of persistent fever Treatment of fever > 14 days: upon the investigator Empirical Persistent or recurrent fever Preemptive Clinically and imagingdocumented pneumonia or acute sinusitis, septic shock, unexplained CNS symptoms, periorbital inflammation, skin lesions suggestive of IFI, HS abscesses, grade 3 mucositis, Aspergillus colonization, or one GMELISA ( 1.5) 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 C et al. Clin Infect Dis 2009; 48:

14 Empirical vs. Preemptive antifungal therapy in high risk neutropenic patients (n = 293) Overall survival Primary endpoint Proven and probable IFI 100% 97.0% 95.0% 20% 80% 15% % of patients 60% 40% % of patients 10% 9.0% 20% 5% *2.7% 0% Empirical, n=150 Preemptive, n=143 0% Empirical, n=150 Preemptive, n=143 p=ns *p<0.02 Cordonnier et al. CID 2009

15 Overview of Systematic Reviews of Antifungal Prophylaxis Review Gotzsche & Johansen 1997, 2002 Kanda et al Bow et al Glasmacher et al. 2003, 2005 No. of Trials No. of Pts Patient Selection Criteria Cancer patients w/ neutropenia Patients w/ neutropenia Haematological malignancies & neutropenia Haematological malignancies & neutropenia Treatment: Intervention Groups Ketoconazole Miconazole Amphotericin B Fluconazole Itraconazole Fluconazole Ketoconazole Miconazole Amphotericin B Fluconazole Itraconazole Itraconazole Treatment: Control Groups Placebo or no treatment Placebo, no treatment or oral polyenes Placebo, no treatment or oral polyenes Placebo, oral polyenes, or fluconazole Outcome Reduction in IFI Reduction in IFI & fungal related mortality No reduction in overall mortality Reduction in IFI & fungal related mortality No reduction in overall mortality Reduction in IFIs including Aspergillus spp. & fungal related mortality

16 Proven/Probable IFIs Number of IFIs % Posaconazole (n = 304) Standard azoles (n = 298) P <.001 All IFIs 25 8% P < % 2 1% Aspergillosis 14 P =.003 5% All IFIs 33 11% P < % 26 9% Aspergillosis While on Prophylaxis (On Therapy Plus 7 Days) Fixed Time Period (Through 100 Days). Cornely OA, et al. N Engl J Med. 2007;356:

17 Prospective, controlled studies on primary antifungal prophylaxis in allogeneic HSCT over the last 15 years Itraconazole versus fluconazole Marr KA et al. Blood 2004 Until 180 days after allo SCT, or until 4 weeks after discontinuation of GvHD therapy Micafungin versus fluconazole Van Burik et al. Clin Infect Dis 2004 Allogeneic and autologous HSCT only preengraftment Posaconazole versus fluconazole Ullmann A et al. NEJM 2007 Allogeneic HSCT only during GvHD Voriconazole versus fluconazole Wingard JR et al. Blood 2010 Allogeneic HSCT until 100 days or until 180 days if GvHD Voriconazole versus itraconazole Marks D et al. Br J Haematol 2011 Allogeneic HSCT until 100 days or until 180 days if GvHD

18 Voriconazole for prophylaxis of IFD after allogeneic HSCT Vs. Fluconazole Wingard et al. Blood 2010 FungalFree survival Vs. Itraconazole Marks et al. BJH 2011 Overall survival IFI at 12 m: 12.7% vs 13.7% Success (Treatment for 100 days+ fungalfree survival at d180): Voriconazole 48.7% vs. Itraconazole 33.2% (p = ) Mean duration of prophylaxis: Voriconazole 96d vs. Itraconazole 68d AML patients: less IFD in the Voriconazole group (8.5% vs. 21%; p=.04) and better fungalfree survival (78% vs. 61%; p=.04), but no in overall survival(81% vs. 72%; p=.32). Survival at d180: Voriconazole 81.9% vs. Itraconazole 80.9% Proven/probable IFD: Voriconazole 1.3% vs. Itraconazole 2.1% (p = 0.54)

19 Proven/Probable IFIs 15 Number of IFIs % Posaconazole n = 301 P = NS All IFIs 27 9% Fluconazole n = 299 P = % 7 2% 2% Aspergillosis Posaconazole n = 291 P =.004 All IFIs 22 7% 3 1% Fluconazole n = 288 P = % Aspergillosis Fixed Time Period (Through 16 Weeks) While on Prophylaxis (On Therapy Plus 7 Days) IFI : Invasive Fungal Infection 15.Ullmann AJ, et al. N Engl J Med. 2007;356:

20 Guidelines from the IDSA for prophylaxis of aspergillosis in neutropenic patients and HSCT recipients Evolution from 2008 to 2016 Walsh et al. CID 2008 (A,B,C/I, II, II) Highrisk neutropenia and GVHD Posaconazole Itraconazole AI BI Patterson et al. CID 2016 (GRADE) Highrisk neutropenia Posaconazole Voriconazole Micafungin Caspofungin Strong R, High QE Strong R, Moderate QE Weak R, Low QE Weak R, Low QE Voriconazole no data GVHD Posaconazole Voriconazole Strong R, High QE Strong R, Moderate QE R: Recommendation QE: Quality of evidence [Itraconazole (Strong R, Moderate QE) but therapy may be limited by absorption & tolerability]

21 ECIL recommendations for allogeneic HSCT recipients (2013) Update: ECIL 5, 2013 Antifungal prophylaxis Preengraftment Low risk for moulds Preengraftment High risk for moulds GvHD Fluconazole AI AIII against AIII against Itraconazole BI BI BI Voriconazole BI BI BI Posaconazole OS/Tablet BII BII AI Micafungin BI CI CII Caspofungin /anidulafungin No data No data No data Liposomal Amphotericin B CII CII CII Aerosolized amphotericin B plus fluconazole CIII BII No data

22 Current International Guidelines Antifungal Prophylaxis FLUCO VORI ITRA POSA CASPO LAmB MICA ECIL 5: CT allo HSCT(GVHD) Preengraftment CI AI BI B1 CI BI B1 AI AI B11 CI CI CII B1/C1 DGHO: neutropenic allo HSCT CI AI CII CII CI CI AI AI CI CII CI IDSA (against Candida) AL AlloHSCT IDSA (against Aspergillus) AMLMDS AI AI British guidelines AI AI AI AI AI A1 AI AI AI NCCN: AMLMDS allo HSCT 2B 2B 1 1 2B 2B 2B 1 ESCMID: AMLMDS allo HSCT CI AI ND AI CII BI CII AII NC CII ND BII/CIII ND AI/CIII

23 Prophylaxis vs. empirical or preemptive therapy: No prospective comparison Strategy Mean duration of neutropenia < 500/mm3 Incidence of proven+probable IFI Cornely et al 2007 (n=304 in the posa group) Posaconazole Prophylaxis (+ 27% of pts with empirical treatment ) 27 d ± 17 2% in the posa group Cordonnier et al 2009 (n=293) Empirical vs. Preemptive (+ 17% of pts with fluco or itra prophylaxis) 20 d (669) 2.7% in the empirical group 9% in the preemptive group

24 Neutropenic patients Which strategy for which patient? ü Define a risk according to the expected duration of neutropenia and the incidence of IFD in the center ü Choose a strategy and design an algorithm neutropenia < 10 days: IFD<1% neutropenia > 10 days: IFD 27%: preemptive or empirical IFD > 8%: prophylaxis ± PET

25 ECIL6 guidelines ( Retal.pdf) 1st line IA treatment 1st line IFI prophylaxis 1. PK variability? 2. Narrow therapeutic window? 3. Clear relation between exposure and efficacy/safety?

26 RealLife Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses. Tverdek FA et al. AAC August (8) Break thru IFI Proven/Probable8 patients( 2%) Patient No Identified fungal organism PCZ serum level (ng/ml) 1 Yeast, not otherwise specified Rhodotorula spp Not measured 3 Penicillium spp Aspergillus flavus Not measured 5 Fusarium spp Positive for galactomannan only Positive for galactomannan only Positive for galactomannan only Ø Among patients with data on serum levels: all IFI occurred in patients with serum level > 700 ng/ml

27 Choice of Directed Therapy In Patients Failing Posaconazole Tablet Prophylaxis Centers that employ this strategy would need to establish their local epidemiology of break through IFI. Recommendation Start with Liposomal Amphotericin with Caspofungin combination therapy. The key point is an aggressive diagnostic strategy BAL/ lung biopsy for histology, fungal culture, galactomannan and fungal PCR.