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Fungal infections in hematology patients: advances in prophylaxis and treatment Vincent CC Cheng MBBS (HK), MD (HK), PDipID (HK), MCRP (UK), FRCPath (UK),

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Presentation on theme: "Fungal infections in hematology patients: advances in prophylaxis and treatment Vincent CC Cheng MBBS (HK), MD (HK), PDipID (HK), MCRP (UK), FRCPath (UK),"— Presentation transcript:

1 Fungal infections in hematology patients: advances in prophylaxis and treatment Vincent CC Cheng MBBS (HK), MD (HK), PDipID (HK), MCRP (UK), FRCPath (UK), FHKCPath, FHKAM (Path) Department of Microbiology Queen Mary Hospital ASIA-PACIFIC HEMATOLOGY CONSORTIUM

2 Mortality from invasive fungal infection in patients with acute leukemia and HSCT (40-50%) (>70%)

3 Biol Blood Marrow Transplant Oct;15(10): Phases of opportunistic infections among allogeneic HCT recipients

4 Antimicrob Agents Chemother Mar;33(3): Concentrations of Amphotericin B deoxycholate in tissues of 13 cancer patients Lung Kidney Spleen Liver Standard dose 1 mg / kg / day (BW 50 kg) 50 mg per day 10 days 20 days MIC level

5 Nystatin Amphotericin B Griseofulvin 5-FC Miconazole Ketoconazole Fluconazole Itraconazole L-AmB ABCD ABLC Terbinafine Time line of development of antifungal agents Caspofungin Micafungin Anidulafungin Voriconazole Posaconazole

6 Persistent neutropenic feverProphylaxisKnown pathogen therapy Liposomal Ampho B vs Ampho B deoxycholate Caspofungin vs Liposomal Ampho B Posaconazole vs Fluconazole (GVHD) Posaconazole vs Fluconazole or itraconzole (AML / MDS) Voriconazole vs Ampho B deoxycholate (Aspergillus) Caspo vs Ampho B (Candida) Anidula vs Flucon (Candida) ( ) Voriconazole vs Liposomal Ampho B

7 Risk group stratification for development of invasive fungal infections in patients with hematologic malignancies +/- hematopoietic cell transplant Transpl Infect Dis Dec;11(6):480-90; Br J Haematol Aug;110(2): Degree of neutropenia, diagnosis, type of transplant, exposure to corticosteroids, type of chemotherapy, and prior fungal colonization were the major criteria used for stratification High risk Prolong neutropenia (<0.1x10 9 /L for 3 wk and / or <0.5x10 9 /L for 5 wk) Allogeneic unrelated or mismatched BMT GVHD High dose Arabinose-C Corticosteroids > 1/mg/kg with neutropenia <0.1x10 9 /L over 1 wk Corticosteroids > 2 mg/kg over 2 wk Intermediate risk (high intermediate) Fungal colonization at 1 site with neutropenia x10 9 /L for 3-5 wk Fungal colonization at > 1 site AML Total body irradiation Allogeneic matched sibling donor BMT Intermediate risk (low intermediate) Neutropenia x10 9 /L < 3 wk Antibiotics + lymphopenia <0.5x10 9 /L Older age Presence of a central venous catheter Low risk Autologous BMT Lymphoma Childhood AML

8 Risk groupProphylaxisPre-emptiveEmpiricalTargeted HighYes Intermediate (high) Yes Intermediate (low) Yes? LowYes? Risk Based approach in antifungal treatment Degree of neutropenia, diagnosis, type of transplant, exposure to corticosteroids, type of chemotherapy, and prior fungal colonization were the major criteria used for stratification Br J Haematol Aug;110(2):

9 Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies and Hematopoietic cell transplant StudyPatientsDesignRegimenOutcome Fluconazole Goodman et al (1992) 356 (allo/ auto BMT) RCT (double blinded) FLU 400 mg qd po vs placebo IFI: FLU ↓ Mortality: FLU ↓ Winston et al (1993) 257 acute leukemia patients on chemo RCT (double blinded) FLU 400 mg qd po or 200 mg bd iv vs placebo IFI: No diff (3 cases of Aspergillus in both arms) Mortality: no diff Slavin et al (1995) 300 (allo/ auto BMT) RCT (double blinded) FLU 400mg qd po vs placebo IFI: FLU ↓ Mortality: FLU ↓ Rotstein et al (1999) 304 (44% auto BMT) RCT (double blinded) FLU 400mg qd po vs placebo IFI: FLU ↓ Mortality: FLU ↓ Goodman JL, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326 (13): Winston DJ, et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia: results of a randomized placebo-controlled, double-blind, multicenter trial. Ann Intern Med 1993; 7 (118): Slavin MA, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation : a prospective, randomized, double-blind study. J Infect Dis 1995; 171 (6): Rotstein C, et al. Randomized placebo controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. Clin Infect Dis 1999; 28 (2):

10 Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies and Hematopoietic cell transplant StudyPatientsDesignRegimenOutcome Itraconazole Morgenstern et al (1999) 445 (includes autologous and BMT) & HM patients Open- label ITR 2.5 mg/kg cyclodextrin solution bd po vs FLU 100 mg suspension qd po IFI: No diff Mortality: ITR ↓ Huijgen et al (1999) 213 patients (57% auto BMT; 31% HM on chemo RCT (double blinded) ITR 100 mg bd po vs FLU 50 mg bd po IFI: No diff Mortality: no diff Harousseau et al (2000) 557 HM patients (5% BMT) RCT (double blinded) ITR 2.5 mg/kg solution bd po vs AMB 500 mg capsule qid po IFI: No diff Mortality: No diff Marr et al (2004) 304 (allo BMT)Open- label ITR 2.5 mg/kg solution td po or 200 mg iv qd vs FLU 400 mg po or iv qd IFI: ITR ↓ Mortality: No diff Morgenstern GR, et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological alignancies. Br J Haematol 1999; 105 (4): Huijgens PC, et al. Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology. J Clin Pathol 1999; 52 (5): Harousseau JL, et al. Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B. Antimicrob Agents Chemother 2000; 44 (7): Marr KA, et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004; 103 (4):

11 Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies and Hematopoietic cell transplant StudyPatientsDesignRegimenOutcome Posaconazole Ullmann et al (2007) 600 (allo BMT)RCT (double blinded) POS 200 mg suspension td po vs FLU 400 mg qd po IFI: POSA ↓ Mortality: POS ↓ Cornely at al (2007) 602 AML or MDS patients on chemotherapy RCT (evaluator blinded) POS 200 mg suspension td po vs FLU 400 mg suspension qd po or ITR 200 mg solution bd po IFI: POSA ↓ Mortality: POS ↓ Micafungin van Burik et al (2004) 889 (46% auto BMT, 54% Allo BMT) RCT (double blinded) MICA 50 mg iv qd vs FLU 400 mg iv qd IFI: MICA↓ Mortality: No diff Ullmann AJ, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356 (4): Cornely OA, et al. Posaconazole vs fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356 (4): van Burik JA, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004; 39 (10):

12 A randomized, double-blind trial comparing voriconazole (200 mg twice daily) vs fluconazole (400 mg daily) in allograft recipients >2 years of age considered to be at standard risk of IFI Prophylaxis: at least 100 days extended to 180 days if receiving prednisone (>1 mg/kg daily) and/or CD4 cells <200/µL Serum galactomannan levels & intensive diagnostic process Fungal-free survival: 78% with voriconazole (6 mo) 75% with fluconazole (6 mo) 64% with voriconazole (12 mo) 65% with fluconazole (12 mo) Wingard JR, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood 2010; 116: 5111–5118.

13 Marks DI, et al. Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic stem cell transplanation. Br J Haematol 2011; 155: 318–327. A prospective, phase III, randomized, open label, multi-centre clinical trial Eligible patients: >12 years of age allogeneic HCT for acute leukaemia, transformed CML, or failure of lymphoma therapy Prophylaxis : at least 100 days antifungal continued until 80 days if IFI risk factors persisted Primary endpoint: Success of antifungal prophylaxis at day 180 (defined as fungal-free survival to day 180 without having discontinued study treatment for >14 days in total before day 100) Survival outcome at Day 100, 180, and 1 year (no difference)

14 Maertens J, et al. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3 – 2009 update. Bone Marrow Transplant 2011; 46: 709–718. Patient risk stratification and treatment recommendations for primary antifungal prophylaxis in haematology patients as per the ECIL-3 (3 rd European Conference on Infections in Leukemia) guidelines Serum drug concentrations of posaconazole and itraconazole be monitored to ensure therapeutic levels of these agents

15 Empirical antifungal therapy: fever-driven approach Empirical antifungal therapy: Targets haematology patients that have prolonged neutropenia Persistent or relapsing fever despite 4–7 days of adequate broad spectrum antibiotics Absence of other clinical symptoms/signs, conventional radiological and laboratory findings specific investigations aimed at documenting invasive fungal disease (e.g. CT scan, detection of circulating fungal markers) Based on moderate evidence from clinical trials with small sample size and debatable methodology/design May results in significant overtreatment, toxicity and expenditure Klastersky J. Antifungal therapy in patientswith fever and neutropenia—more rational and less empirical? N Engl J Med 2004; 351: 1445–7.

16 N Engl J Med Sep 30;351(14): Measures of the Success of Empirical Antifungal Therapy with Conventional or Liposomal Amphotericin B, Voriconazole, or Caspofungin Walsh TJ, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340: Walsh TJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346: Walsh TJ, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004;351: Liposomal Ampho B vs Ampho B deoxycholate Liposomal Ampho B vs Voriconazole Caspofungin vs Liposomal Ampho B

17 Bone Marrow Transplant 2011; 46: 709–718. ECIL 3 guidelines on empirical antifungal treatment in neutropenic patients with persistent or relapsing fever

18 Pre-emptive antifungal therapy: diagnostics-driven approach The time period between fungal replication, invasion and appearance of signs and symptoms represents a window of opportunity for earlier treatment. However, there is as yet no consensus definition of preemptive antifungal therapy. Such therapy should not be triggered by fever as a sole criterion, but should rest on: (i)a clear identification of those patients who are at risk of fungal disease (ii)utilization of sensitive techniques that facilitate rapid and early diagnosis of invasive mould infections, e.g. galactomannan, b-D-glucan or PCR testing as well as computerized radiological imaging techniques

19 Diagnostic toolsAdvantagesDisadvantages Galactomannan assay Noninvasive serum assay Biweekly testing may allow earlier detection of IA With the cutoff OD index reduced to 0.5 (from 1.5), greater overall sensitivity improved from 76% to 97% High percentage of false positives; sensitivity 100%-33% Exposure to mold-active antifungals considerably reduces sensitivity Some serum reactivity in patients on beta-lactam antibiotics (1, 3)-beta-Dglucan antigen test Noninvasive serum assay Detects Candida and Aspergillus species and other opportunistic fungal pathogens False-positive and false- negative Sensitivity lower in patients with localized Aspergillus infection Does not usually detect Cryptococcus species or Zygomycetes PCR assays Highly specific and sensitive Negative result can rule out IA and potentially limits empiric therapy need No pan-fungal assay available to date Lack of a standardized method Eur J Haematol Oct;87(4): Advantages and disadvantages of major non-culture-based laboratory diagnostic methods for IFI

20 Clin Infect Dis Nov 1;41(9): liposomal amphotericin B Fever-driven approach: Antifungal Rx: 41 of 136 episodes Pre-emptive approach: Antifungal Rx <25% episodes (but identified 10 episodes of fungal infection without fever or with the presence of confounding febrile conditions) No patient received mould-active prophylaxis (? improving the sensitivity of the assay and favoring the pre-emptive approach)

21 Clin Infect Dis Apr 15;48(8): patients with haematological malignancies (duration of neutropenia ≥ 10 days) 17 patients developed an IFI: 4 (2.7%) in empirical group 13 (9%) in pre-emptive group (P<0.02) Overall survival rates: 2 weeks after neutrophil recovery (95% vs 97%, P=0.12) Duration of neutropenia < 15 days: no difference Prolonged neutropenia: ↑risk of fungal infection in the pre-emptive therapy arm Pre-emptive approach significantly reduced the use of antifungal agents (39.2% vs 61.3%, P<0.001) Antifungal prophylaxis was given according to each center’s protocol Amphotericin B deoxycholate (1 mg/kg/day) Liposomal amphotericin (3 mg/kg/day)

22 Known pathogen therapy (Targeted therapy) of mould infections Voriconazole: first-line therapy of invasive aspergillosis based on the results of a prospective, randomized clinical trial with amphotericin B deoxycholate as comparative initial therapy in possible, probable or proven disease 149 (54%) of 277 patients were culture +ve for Aspergillosis Herbrecht R, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–15. Potential concern of using voriconazole: prior exposure to mould-active azoles, the concomitant use of contraindicated medication (e.g. sirolimus), the risk of severe drug interactions, moderate to severe hepatic or renal impairment

23 Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008; 46: 327–60. Treatment of aspergillosis: clinical practice guidelines of IDSA ConditionPrimary RxAlternative Rx Invasive pulmonary aspergillosis Invasive sinus aspergillosis Tracheobronchial aspergillosis Chronic necrotizing pulmonary aspergillosis (subacute invasive pulmonary aspergillosis) Aspergillosis of the CNS Voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 4 mg/kg IV every 12 h; oral dosage is 200 mg every 12 h) L-AMB (3–5 mg/kg/day IV), ABLC (5 mg/kg/day IV), Caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter), Micafungin (IV 100–150 mg/day; dose not established), Posaconazole (200 mg QID initially, then 400 mg BID PO after stabilization of diseased), Itraconazole (dosage depends upon formulation) Surgical debridement may be indicated

24 Known pathogen therapy (Targeted therapy) of mould infections Echinocandins in the primary therapy of invasive aspergillosis: limited data non-comparative Phase II study in two different cohorts: Viscoli C, et al. An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients. J Antimicrob Chemother 2009; 64: 1274–81. Herbrecht R, et al. Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients: an European Organisation for Research and Treatment of Cancer study. Bone Marrow Transplant 2010; 45: 1227–33. N=61 Favorable response: 33% N=24 Favorable response: 42%

25 Trends Microbiol 2003;11:272–279. Amphotericin B Caspofungin Micafungin Anidulafungin Fluconazole Itraconazole Voriconazole Posaconazole Choice of antifungal combination therapy

26 Cancer Feb 15;97(4): Cancer Jul 15;98(2):292-9.

27 Clin Infect Dis Sep 15;39(6): Choice of antifungal combination therapy Patients (HSCT or hemic malignancies) Pulmonary aspergillosis (proven or probable) Failure with amphotericin B P=0.048 Observational study of salvage therapy * historical control VoriconazoleCaspofungin

28 Antifungal treatment of other invasive mould infections Fusarium and Scedosporium spp: Voriconazole and lipid formulations of amphotericin B +/-surgical debridement of necrotic tissue Posaconazole can be used as salvage therapy for these infections Invasive mucormycosis: Lipid-based formulation of amphotericin B as first-line therapy Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin Microbiol Rev 2007; 20: 695–704. Troke P, et al. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother 2008; 52: 1743–50. Spellberg B, et al. Clinical practice: recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009; 48: 1743–51.

29 J Clin Microbiol Sep;47(9):

30 Roll-plating of allopurinol

31 Estimated number of preventable cases in HK (1 year period) *Attack rate = (mucosal + invasive) / total = 6 / 18 = 33.3% **Lives saved = 16 (only 1 / 8 = 12.5% symptomatic patients survived)


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