ASIA-PACIFIC HEMATOLOGY CONSORTIUM 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
Mortality from invasive fungal infection in patients with acute leukemia and HSCT (>70%) (40-50%)
Phases of opportunistic infections among allogeneic HCT recipients Biol Blood Marrow Transplant. 2009 Oct;15(10):1143-238.
Concentrations of Amphotericin B deoxycholate in tissues of 13 cancer patients Standard dose 1 mg / kg / day (BW 50 kg) 50 mg per day Liver Spleen Kidney Lung 20 days MIC level 10 days Antimicrob Agents Chemother. 1989 Mar;33(3):362-8.
Time line of development of antifungal agents Caspofungin Micafungin Anidulafungin Voriconazole Posaconazole L-AmB ABCD ABLC Terbinafine Itraconazole Griseofulvin Amphotericin B Fluconazole Ketoconazole Miconazole Nystatin 5-FC
(1999 - 2007) Persistent neutropenic fever Prophylaxis Known pathogen therapy Liposomal Ampho B vs Ampho B deoxycholate Posaconazole vs Fluconazole (GVHD) Voriconazole vs Ampho B deoxycholate (Aspergillus) Caspofungin vs Liposomal Ampho B Posaconazole vs Fluconazole or itraconzole (AML / MDS) Caspo vs Ampho B (Candida) Anidula vs Flucon (Candida) Voriconazole vs Liposomal Ampho B
Risk group stratification for development of invasive fungal infections in patients with hematologic malignancies +/- hematopoietic cell transplant High risk Prolong neutropenia (<0.1x109/L for 3 wk and / or <0.5x109/L for 5 wk) Allogeneic unrelated or mismatched BMT GVHD High dose Arabinose-C Corticosteroids > 1/mg/kg with neutropenia <0.1x109/L over 1 wk Corticosteroids > 2 mg/kg over 2 wk Intermediate risk (high intermediate) Fungal colonization at 1 site with neutropenia 0.1-0.5x109/L for 3-5 wk Fungal colonization at > 1 site AML Total body irradiation Allogeneic matched sibling donor BMT Intermediate risk (low intermediate) Neutropenia 0.1-0.5x109/L < 3 wk Antibiotics + lymphopenia <0.5x109/L Older age Presence of a central venous catheter Degree of neutropenia, diagnosis, type of transplant, exposure to corticosteroids, type of chemotherapy, and prior fungal colonization were the major criteria used for stratification Low risk Autologous BMT Lymphoma Childhood AML Transpl Infect Dis. 2009 Dec;11(6):480-90; Br J Haematol. 2000 Aug;110(2):273-84.
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. 2000 Aug;110(2):273-84.
Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies and Hematopoietic cell transplant 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): 845-851. 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): 495-503. 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): 1545-1552. Rotstein C, et al. Randomized placebo controlled trial of fluconazole prophylaxis for neutropeniccancer patients: benefit based on purpose and intensity of cytotoxic therapy. ClinInfect Dis 1999; 28 (2): 331-340.
Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies and Hematopoietic cell transplant Morgenstern GR, et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematologicalalignancies. Br J Haematol1999; 105 (4): 901-911. Huijgens PC, et al. Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology. J ClinPathol 1999; 52 (5): 376-380. Harousseau JL, et al. Itraconazoleoral 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. AntimicrobAgents Chemother2000; 44 (7): 1887-1893. Marr KA, et al. Itraconazoleversus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004; 103 (4): 1527-1533.
Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies and Hematopoietic cell transplant Ullmann AJ, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356 (4): 335-347. Cornely OA, et al. Posaconazolevs fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356 (4): 348-359. 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): 1407-1416.
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.
Patient risk stratification and treatment recommendations for primary antifungal prophylaxis in haematology patients as per the ECIL-3 (3rd European Conference on Infections in Leukemia) guidelines Serum drug concentrations of posaconazole and itraconazole be monitored to ensure therapeutic levels of these agents 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.
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.
Measures of the Success of Empirical Antifungal Therapy with Conventional or Liposomal Amphotericin B, Voriconazole, or Caspofungin Liposomal AmphoB vsAmphoB deoxycholateLiposomal AmphoB vsVoriconazoleCaspofunginvs Liposomal AmphoB Walsh TJ, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340:764-71. Walsh TJ, et al. Voriconazolecompared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346:225-34. 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;351:1391-402. N Engl J Med. 2004 Sep 30;351(14):1445-7.
ECIL 3 guidelines on empirical antifungal treatment in neutropenicpatients with persistent or relapsing fever Bone Marrow Transplant 2011; 46: 709–718.
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: • a clear identification of those patients who are at risk of fungal disease • utilization of sensitive techniques that facilitate rapid and early diagnosis of invasive mouldinfections, e.g. galactomannan, b-D-glucan or PCR testing as well as computerized radiological imaging techniques
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) liposomal amphotericin B Clin Infect Dis. 2005 Nov 1;41(9):1242-50.
293 patients with haematologicalmalignancies (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% vs97%, P=0.12) Duration of neutropenia < 15 days: no difference Prolonged neutropenia: ↑risk of fungal infection in the pre-emptive therapy arm Antifungal prophylaxis was given according to each center’s protocol Amphotericin B deoxycholate (1 mg/kg/day) Liposomal amphotericin (3 mg/kg/day) Pre-emptive approach significantly reduced the use of antifungal agents (39.2% vs 61.3%, P<0.001) Clin Infect Dis. 2009 Apr 15;48(8):1042-51.
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 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 Herbrecht R, et al. Voriconazoleversus amphotericin B for primary therapy of invasive aspergillosis. N EnglJ Med 2002; 347: 408–15.
Treatment of aspergillosis: clinical practice guidelines of IDSA Surgical debridement may be indicated 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.
Known pathogen therapy (Targeted therapy) of mould infections Echinocandinsin the primary therapy of invasive aspergillosis: limited data non-comparative Phase II study in two different cohorts: N=61 Favorable response: 33% N=24 Favorable response: 42% Viscoli C, et al. An EORTC Phase II study of caspofunginas first-line therapy of invasive aspergillosisin haematologicalpatients. J AntimicrobChemother 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.
Choice of antifungal combination therapy Caspofungin Micafungin Anidulafungin Amphotericin B Fluconazole Itraconazole Voriconazole Posaconazole Trends Microbiol 2003;11:272–279.
Choice of antifungal combination therapy Cancer. 2003 Feb 15;97(4):1025-32. Cancer. 2003 Jul 15;98(2):292-9.
Choice of antifungal combination therapy Patients (HSCT or hemic malignancies) Pulmonary aspergillosis (proven or probable) Failure with amphotericin B Voriconazole Caspofungin P=0.048 * historical control Observational study of salvage therapy Clin Infect Dis. 2004 Sep 15;39(6):797-802.
Antifungal treatment of other invasive mould infections Fusarium and Scedosporiumspp: Voriconazoleand lipid formulations of amphotericin B +/-surgical debridement of necrotic tissue Posaconazolecan 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 immunocompromisedpatients. Clin MicrobiolRev 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.
Estimated number of preventable cases in HK (1 year period) 54 36 18 12 18 6 *Attack rate = (mucosal + invasive) / total = 6 / 18 = 33.3% **Lives saved = 16 (only 1 / 8 = 12.5% symptomatic patients survived)