Disclosure of Potential Conflicts of Interest: How do anti-infectiveguidelines. patients with GvHD? Fungal infections

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1 Disclosure of Potential Conflicts of Interest: Der Qualitätsmanager How do anti-infectives apply to patients with GvHD? infections Andrew J. Ullmann, MD, FIDSA Julius-Maximilians-Universität Department of Internal Medicine II Division of Infectious Diseases Würzburg, Germany 1. Employment or Leadership Position 2. Advisory Role Basilea, Pfizer, MSD, Astellas, Gilead, Aicuris 3. Stock Ownership 4. Honoraria Astellas, Gilead, MSD, Astellas, and Pfizer 5. Financing of Scientific Research Astellas, Gilead, MSD, Astellas, Pfizer, and BioCryst 6. Expert Testimony 7. Other Financial Relationships none Topics Basics: GVHD Immunology Guidelines Selected topics: Primary Prophylaxis in GVHD Aspergillus: Time to Diagnosis of Aspergillosis after HSCT GvHD! Slow T-cell recovery! Other Issues in GVHD Rare fungal infections Neutropenia! Wald et al. JID 1997 Invasive Infections in allogeneic HSCT Risk Factors in Relation to Incidence Longitudinal analysis of Aspergillus-specific T-cell responses in patients with invasive aspergillosis after allogeneic SCT Overall incidence rate of IFI in 395 allogeneic HSCT: 14%! Risk Factors: Steroid prophylaxis Moderate- to- severe GVHD Martino et al. Brit J Haema 2002" Hebert et al. Blood 2002 Long-term control of invasive aspergillosis was associated with a lymphoproliferative response to EC SAB and a dominant release of IFN-Υ (patient no. 1), whereas a low SI (patient no. 2) n IFN-Υ; and IL-10 1

2 After one year: Frequency of CD4+ T-cells responding to A. fumigatus antigens with intracellular production of IFN-γ and TNF-α Which Guidelines? CD3/CD4 cells Beck O et al, Journal of Immunological Methods 335 (2008) Challenges Unmet need for s? Some national s Including diagnostic procedures How flexible is the? Can it be adapted for local use? If the current is making recommendations that differ significantly from those of previous s on the same subject, the differences should be reconciled Guidelines should suggest areas for further study Funding Dominance of North-American Guidelines Missing help for diagnostic procedures Not all patients are alike Not all areas in the world are alike Different epidemiology? Strength of Recommendation/QoE Strength of the EFISG Recommendation by Quality of Evidence Two Parts: Ø Strength of recommendation Ø Quality of Evidence Strength of recommendation Ullmann et al. CMI 2012 Pappas et al CID 2009 Grade A Grade B Grade C Grade D ESCMID (fungal infection study group) strongly supports a recommendation for use ESCMID (fungal infection study group) moderately supports a recommendation for use ESCMID (fungal infection study group) marginally supports a recommendation for use ESCMID (fungal infection study group) supports a recommendation against use 2

3 Strength of the EFISG Recommendation by Quality of Evidence Quality of evidence Level I Evidence from at least 1 properly designed randomized, controlled trial Level II* Evidence from at least 1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from >1 centre); from multiple time series; or from dramatic results of uncontrolled experiments Level III Evidence from opinions of respected authorities, based on clinical experience, descriptive case studies, or reports of expert committees Selected Topics Ullmann et al. CMI 2012 *: added index: r : meta-analysis (or systematic review of RCT); t : transferred evidence i.e. results from different patients cohorts, or similar immune-status situation; h : comparator group: historical control; u : uncontrolled trials a: for published abstract (presented at an international symposium or meeting) Case 1 Ø Sepsis and renal insufficiency Ø Despite different chemotherapy blasts persist Ø 2 months after primary diagnosis new chemotherapy with Gemtuzumab ozogamicin Ø 5 months after primary diagnosis MUD HCT (CMV donor negative; recipient positive) Ø GvHD-prophylaxis: CsA later tacrolimus Ø Prophylaxis? UPDATE ECIL : Summary slide Primary antifungal prophylaxis in leukemia patients Allogeneic hematopoietic stem cell transplantation: neutropenic phase Fluconazole 400 mg qd iv/oral: AI 2,5 Itraconazole 200 mg IV followed by oral solution 200 mg bid: BI 1,2,3 Posaconazole 200 mg tid oral: no data Micafungin 50 mg qd iv: CI Polyene 4 iv: CI Voriconazole 200 mg bid oral: provisional AI Aerosolized liposomal amphotericin B plus fluconazole: BII Allogeneic hematopoietic stem cell transplantation: GvHD phase Fluconazole 400 mg qd iv/oral: CI 2 Itraconazole 200 mg IV followed by oral solution 200 mg bid: BI 1,2,3 Posaconazole 200 mg tid oral: AI 2,3 Candins iv: insufficient data Polyene iv: CI Voriconazole 200 mg bid oral: provisional AI Aerosolized liposomal amphotericin B plus fluconazole: insufficient data Courtesy of W. J. Heinz, Würzburg, Germany Prophylaxis IDSA ECIL ESCMID Canada AGIHO AML:, fluconazole not recommended for Candida Only peds Prophylaxis in allogeneic HCT Intention: morbidity reduction (Candida) HSCT: itraconazole, micafungin GVHD, (voriconazole) (voriconazole) No Aspergillus Candida prophylaxis No Aspergillus Recommended, GVHD: Situa>on Recommenda>on References During early neutropenic phase During later phase within first 100 days During GVHD (moderate to severe) Fluconazole (AI); Itraconazole (BI); Posaconazole (AII t ), Voriconazole (AI); Micafungin (AI), Caspofungin (CII u ), Anidulafungin (ND), Liposomal AmB (BII) Fluconazole (AI); Itraconazole (BI); Posaconazole (CIII), Voriconazole (AI); Micafungin (CIII), Caspofungin (CII u ), Anidulafungin (ND), Liposomal AmB (CIII) Fluconazole (AI); Itraconazole (CI); Posaconazole (AI), Voriconazole (BI), others (ND) Goodmann JL NEJM 1992; Morgenstern G Brit J Haema 1999; Marr KA Blood 2004 (180 days); Cornely OA NEJM 2007; Wingard JR ( days) Blood 2010; van Burik CID 2004; Chou LS Pharmacotherapy 2007; Kelsey SM BMT 1999; Penack O Ann Onco 2006 Slavin M JID 1995, Winston DJ Ann Intern Med 2003 (180 days); Marr KA Blood 2004 (180 days); Cornely OA NEJM 2007; Wingard JR Blood 2010; van Burik CID 2004; Chou LS (up to 100 days) Pharmacotherapy 2007 Ullmann NEJM 2007; Wingard JR Blood 2010; Chou LS Pharmacotherapy 2007 Explanation/Reason/Issues/s: Due to safety issues with itraconazole and amphotericin B, those drug received a weaker strength of recommendation (Marr Blood 2004; Chou LS Pharmacotherapy 2007; Ullmann CID 2006) EFISG. in print CMI

4 Case 2 52 y/o female diagnosed with AML FAB M4 in early 2012 h/o Crohn s disease First induction: no blasts Allogeneic HSCT (MUD) in the second half of 2012 which was complicated by: Severe mucositis grade IV Severe sepsis ARF GI-tract bleeding Ileus // GVHD? SOB Lab: Recovery WBC GMI negative Case 2 Course of antifungal therapy: Voriconazole as therapy for suspected IFD (started prior to HSCT) Escalated to voriconazole and anidulafungin (sepsis and ARF) Skin lesions Culture positive for Fusarium species => skin and urine Which therapy? - Continue combination - Amphotericin B deoxycolate - Liposomal amphotericin B - Posaconazole - Itraconazole - Caspofungin Example Musa et al. British Journal of Haematology, 2000 High MICs for all azoles Acceptable MIC for AmB Problem Advice of Different Guidelines: Treatment of Fusarium species Despite driven prophylaxis: voriconazole Proven fungal disease? Fusarium: high MICs for numerous antifungal agents IDSA ECIL ESCMID Canada AGIHO n/a n/a CMI 2013 n/a n/a Did not really help the more complex problems in HSCT Microbiology Suscepbbility Tesbng/Fusarium species Popula>on Inten>on Interven>on QoE Reference MIC: EUCAST ref. method MIC: CLSI ref. method B* III EUCAST website Validated only for Candida and Aspergillus B* II M38- A2 Fusarium can be tested. MIC: Etest B* III Debourgog ne EJCMID 2012 MIC: Sensibtre B* III Linares JCM 2005 Clinical breakpoint determinabon AmB and VCZ vs. CLSI: Agreement 73% AmB and 92% VCZ % agreement with CLSI (few isolates). B* III M38- A2 Yet to be idenbfied or approved by CLSI or any regulatory agency. Popula>on Inten>on Interven>on QoE Reference Immunocom- promised pts (Hematol. & HSCT) with disseminated infecbon First line treatment Treatment/Fusarium species Voriconazole ADULTS Loading dose 6 mg/kg q12h IV (first 24 h) then 4 mg/kg q12h (3 days), then possible oral therapy (200 mg q12) CHILDREN <13 yrs 7 mg/kg q12h >12yrs 200mg q12h A II Perfect CID 2003 Lortholary AAC 2010 Campo J Infect 2010 Rojas MJHID 2012 Peman Ther Clin Risk Manag 2006 Inibal or salvage treatment: 47% complete/parbal response. Breakthrough infecbon reported in pts receiving prophylaxis. Therapeubc drug monitoring required * MIC gives an overview of in vitro resistance and therefore may support choice of anbfungals. CLSI method for guidance on treatment; other tests for epidemiology only Arendrup M et al. 2013, CMI 4

5 Treatment/Fusarium species Popula>on Inten>on Interven>on QoE Reference Granulocyte Transfusions/Cytokine Treatment/Fusarium species Liposomal Immunocom First line promised pts treatment AMB B II Nucci Cancer 2003 Isolates ooen AMB resistant Jensen CMI 2004 Reported superior to AMB Musa Br J Consider higher doses Haematol 2000 Immunocom First line AMB lipid promised pts treatment complex C III Paperson Clin Pediatr 1996 Isolates ooen AMB resistant Limited case reports Immunocom First line Convenbonal promised pts treatment AMB D II Nucci Cancer 2003 Jensen CMI 2004 Musa Br J Haematol 2000 Isolates ooen AMB resistant Breakthrough infecbons during empirical treatment Prognosis dismal unless PMN count recovers Immunocom First line Candins promised pts treatment D III Nucci CID 2004 Intrinsically resistant Rojas MJHID 2012 Immunocom First or promised pts second line treatment C III Rojas MJHID 2012 Campo J Infect 2010 Lortholary AAC 2010 Combinabon Therapy: LAMB + CAS LAMB + VOR VORI + CAS LAMB + candin or triazole: unclear if combinabon is more effecbve than drug alone Combinabon no beper than VORI alone Intention QoE Reference Hematological To improve Cytokine- sbmulated Cancer response to granulocyte infecbon transfusion + anbfungals B IIt Boutab EI Blood 1997 Resolubon only in pts who recovered of myelosuppression Neutropenic pabents B IIIt Dignani Leukemia pts included Granulocyto- To improve Granulocyte penic pabents response to transfusion + other infecbon intervenbons B IIIt Spielberger 1 pabent only Clin Infect Dis 1993 Leukemia B IIIt Helm Am Acad Dermatol 1990 To improve Granulocyte response to transfusion infecbon To improve Granulocyte response to transfusion infecbon 1 pabent only Surgical Debridement/Fusarium species Granulocyte Transfusions/Cytokine Treatment/Fusarium species Intention QoE Granulocytope To improve GM- CSF nic pabents response to (combined with infecbon anbfungals) B IIIt Spielberger 1 pabent Clin Infect Dis 1993 Leukemia B IIIt Helm J Am Acad Dermatol 1990 To improve GM- CSF response to (combined with infecbon anbfungals) Reference 1 pabent Summary High incidence of fungal diseases in GVHD, i.e. Aspergillosis Numerous s Primary prophylaxis against Aspergillosis Primary prophylaxis against fungal diseases (incl. Candida) Inten>on Leukaemia/ BMTX To cure infecbon Surgery A IIIt Lupinet, Ann Thorac Surg 1990 Lupinet, J Thorac Card Surg 1992 Successful outcome in pulmonary infecbons To cure solitary lung nodules Surgery A IIr Nucci CMR 2007 Independent protecbve factor To cure osteomyelibs surgical debridement A III Many case reports Aggressive surgical debridement of necrobc bssue needed Poor outcome To cure catheter- related infecbon Catheter removal + DAMB or LAMB A II Velasco Eur. J. 4/4 survival Clin. Micro. Infect. Dis QoE Reference Danke! DANKE Some haem/onc driven others ID/micro Posaconazole Posaconazole Voriconazole Fluconazole Rare fungal diseases e.g. fusariosis Unclear whether combination is better or not MIC important => for treatment orientation Multiple approaches, i.e. immunological and surgical if appropriate Old Stone Main Bridge Würzburg Guidelines are not the Holy Grail of medicine 5