Fungal infections in hematology patients: advances in prophylaxis and treatment
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Fungal infections in hematology patients: advances in prophylaxis and treatment

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  • Good afternoon, lady and gentleman, it is my pleasure to attend this conference, and share with you the advances in prophylaxis and treatment of fungal infections in hematology patients
  • As you know, the mortality from invasive fungal infections in patients with hematological malignancy and transplantation is high.It ranges from 40-50% in patients with invasive candidasis, and over 70% in patients with invasive aspergillosis.
  • Among the blood and marrow transplant recipient, the spectrum of invasive fungal infection depends on the day after transplantation.
  • However, as time goes by, there are more and more antifungal agents in the market, especially the presence of echinocandin, and new azole group.
  • With the availability of news drugs, it is useful to stratify patients into different groups for the development of invasive fungal infections.
  • Basically, the risk stratification is depends on the degree of neutropenia, diagnosis, type of transplant, exposure to steroid, type of chemotherapy, and the presence of fungal colonization. Therefore, antifungal prophylaxis and empirical therapy is recommended in high and intermediate high risk group, while pre-emptive treatment is given in low or intermediate low risk group. Known pathogen therapy is always considered in all patient groups.We will discuss the treatment regimen one by one.
  • Antifungal prophylaxis. It has been well documented in the BMT setting. This is the first study to demonstrate the usefullness of fluconzolevs placebo in reducing the number of invasive fungal infection, mainly candidasis, and resulting in lower mortality. The findings can be reproduced in the subsequent studies a few years later. But the result is not that promising in patient with acute leukemia on induction chemotherapy.
  • Later on, itraconazole is used as antifungal prophylactic agent. It is supposed to have anti-aspergillus activity. But the results are not impressive.
  • However, a breakthrough in antifungal prophylaxis occurs when a new azole, posaconazole is introduced to market. It is a broad spectrum agent with anti-mold activity. In these two sutdies published togehter in NEJM, it was clearly shown that the use of posaconazole in both BMT patients and patients with AML or MDS on chemotherapy, reduced the number of invasive fungal infection and mortality.Micafungin was tested with Fluconzaole in a randomized double blind control trail. The use of mucafungin reduced the number of invasive fungal infection but not the mortality.
  • Recently,vorioconzole was tested in a randomized double blind trail. The drugs were given for at least 100 days in allograft recipients over 2 years of age and who were considered to be at standard risk of invasive fungal infection. Duration of prophylaxis would be extended to 180 days if they received steroid and with low CD4 count. Non-invasvie diagnostic test such as serum galactomannan antigen was measured, and followed by imaging studies. You can see that the fungal free survival was comparable between voriconzole and fluconazole in 6 and 12 mo times.
  • In addition, voriconazole was tested against itraconazole in multi-center clinical trail. The study design is similar to the previous study. Although the survival outcome had no difference, the composite end point suggests voriconzaole was superior to itraconazole.
  • Based on the previously mentioned clinical studies, the 3rd European Conference on infections in Leukemia comes up with a guideline on the use of antifungal prophylaxis. It is recommended that fluconazole is still first line agent for BMT patients with initial neutropenia, while posaconazole is to be used in patients with GVHD and during induction chemotherapy. However, since there is no iv formulation of posaconazole and the oral absorption of posaconazole may be erratic. Serum concentration of psoaconazole should be monitored to ensure the therapeutic drug level.
  • So much so for prophylaxis.Empirical antifungal therapy or fever driven approach has been an established clinical practice. When patient has persistent neutropenic fever not responding to broad spectrum antibiotic for 4 days (some studies suggest 3 days), without definitive infective diagnosis, empirical antifungal treatment would be given.However, this approach was only based on moderate evidence from clinical trails with small sample size.This approach may also result in over treatment, toxicity and expenditure.
  • In fact, overall rate of fever resolution are ranged from 40-60% according to three clinical trails (Lip Amp B vs conventional Amp B / Lip Ampho B vsVoriconzole / Caspofunginvs Lip Amp B) on the empirical antifungal therapy.
  • And based on these three clinical trails published in NEJM, the European guideline recommends the use of Lip Amp B or Caspofungin as empirical antifungal therapy in patients with persistent or relapsing neutropenic fever.
  • With the advance in laboratorydiagnostic and imaging studies, a pre-emptive or diagnostic driven approach was evolved. It is believed that the time period between ………..And such therapy should not be triggered by neutropenic fever alone. In fact, if the diagnostic test such as galactomannan antigen and CT scan showed the evidence of aspergillosis, antifungal treatment would be started even in patient without fever.However, there is no consensus definition of preemptive antifungal therapy at this stage.
  • This was the first prospective study to look at the feasibility of preemptive antifungal thearpy.Antifungal agents (lip Amp B) was given according to the protocol using galactomann antigen test and CT scan. Based on this preemptive approach, you can see that less than 25% of patients received antifungal therapy, even for those who did not have fever.One of the key point that we have to address is that no patient received mould active prophylaxis such as posaconazole during the study period, which may improve the sensitivity of galactomanna assay.
  • Recently, a randomized control trail was published in CID to look at the performance of two approaches in almost 300 patients with hematological malignancies. These patients were allowed to use antifungal prophylaxis according to the their protocols. Amph B were used if clinically indicated. It is expected that pre-emptive approach significantly reduced the use of antifungal agents.As for the clinical outcome, you can see that although the overall patient survival among two groups were similar, more patients in pre-emptive group developed invasive fungal infection, especially for those patient with prolonged neutropenia.
  • Finally, known pathogen therapy. Voriconazole is now recommended as the first line therapy for invasive aspergillosis according the results of a prospective randomized trail with Amp B. The response rate at 12 weeks was significantly better in voriconazole group. Among 277 patients recruited, about 54% if them had culture documentation of aspergillus.However, the use of voriconazole may be affected by drug interaction, impariment of liver and renal function, as well as preexisting exposure to mould active azole.
  • Anyway, based on this publication in NEJM, voriconzaole is recommended as primary treatment for almost all forms of invasive aspergillosis in IDSA guideline. Whereas the other antifungal agents are categorized as alternative treatment.
  • Echinocandin has been tested in limited number of patients with invasiveaspergillosis. The clinical response is ranged between 30-40%.
  • As you can see, the data on known pathogen therapy is rather limited, especially on antifungal therapy at this stage. As for the other invasive mould infections, the recommendation is mostly based on case reports.
  • If we can stop this outbreak by controlling food and allopurinol, we can save at least 16 lives every year. Total cases from Nov to Feb = 18 cases / 4 monthsNo. of symptomatic cases (mucosal + invasive) = 6 / 18 (5 invasive & 1 mucosal) = 1/3Total no. cases in 1 year = 18 x 3 = 54 per yearNo. of symptomatic cases = 54 x 1/3 = 18 per year

Fungal infections in hematology patients: advances in prophylaxis and treatment Fungal infections in hematology patients: advances in prophylaxis and treatment Presentation Transcript

  • 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
  • Mortality from invasive fungal infection in patients with acute leukemia and HSCT (40-50%) (>70%)
  • Biol Blood Marrow Transplant. 2009 Oct;15(10):1143-238. Phases of opportunistic infections among allogeneic HCT recipients
  • Antimicrob Agents Chemother. 1989 Mar;33(3):362-8. 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 daysMIC level
  • 5-FC Miconazole Ketoconazole Fluconazole Itraconazole L-AmB ABCD ABLC Terbinafine Time line of development of antifungal agents 0 2 4 6 8 10 12 14 1950 1960 1970 1980 1990 2000 Caspofungin Micafungin Anidulafungin Voriconazole Posaconazole
  • Persistent neutropenic fever Prophylaxis Known 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) (1999 - 2007) Voriconazole vs Liposomal Ampho B
  • Risk group stratification for development of invasive fungal infections in patients with hematologic malignancies +/- hematopoietic cell transplant Transpl Infect Dis. 2009 Dec;11(6):480-90; Br J Haematol. 2000 Aug;110(2):273-84. Degreeofneutropenia,diagnosis,typeoftransplant,exposureto corticosteroids,typeofchemotherapy,andpriorfungalcolonization werethemajorcriteriausedforstratification 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 Low risk Autologous BMT Lymphoma Childhood AML
  • Risk group Prophylaxis Pre-emptive Empirical Targeted High Yes Yes Yes Intermediate (high) Yes Yes Yes Intermediate (low) Yes ? Yes Low Yes ? Yes 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 Study Patients Design Regimen Outcome 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): 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 neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. Clin Infect Dis 1999; 28 (2): 331-340.
  • Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies and Hematopoietic cell transplant Study Patients Design Regimen Outcome 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): 901-911. Huijgens PC, et al. Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology. J Clin Pathol 1999; 52 (5): 376-380. 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): 1887-1893. Marr KA, et al. Itraconazole versus 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 Study Patients Design Regimen Outcome 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): 335-347. Cornely OA, et al. Posaconazole vs 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.
  • 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 (3rd European Conference on Infections in Leukemia) guidelines Serum drug concentrations of posaconazole and itraconazole be monitored to ensure therapeutic levels of these agents
  • 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.
  • N Engl J Med. 2004 Sep 30;351(14):1445-7. 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;340:764-71. 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; 346:225-34. 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. Liposomal Ampho B vs Ampho B deoxycholate Liposomal Ampho B vs Voriconazole Caspofungin vs Liposomal Ampho B
  • Bone Marrow Transplant 2011; 46: 709–718. ECIL 3 guidelines on empirical antifungal treatment in neutropenic patients with persistent or relapsing fever
  • 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
  • Clin Infect Dis. 2005 Nov 1;41(9):1242-50. 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)
  • Clin Infect Dis. 2009 Apr 15;48(8):1042-51. 293 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)
  • 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
  • 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 Condition Primary Rx Alternative 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
  • 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%
  • Trends Microbiol 2003;11:272–279. Amphotericin B Caspofungin Micafungin Anidulafungin Fluconazole Itraconazole Voriconazole Posaconazole Choice of antifungal combination therapy
  • Choice of antifungal combination therapy Cancer. 2003 Feb 15;97(4):1025-32. Cancer. 2003 Jul 15;98(2):292-9.
  • Clin Infect Dis. 2004 Sep 15;39(6):797-802. 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 Voriconazole Caspofungin
  • 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.
  • J Clin Microbiol. 2009 Sep;47(9):2834-43.
  • Roll-plating of allopurinol
  • Estimated number of preventable cases in HK (1 year period) Symptomaticcases Asymptomatic cases Total cases 0 10 20 30 40 50 60 Nov08 to Feb 09 1 year Symptomaticcases Asymptomaticcases Totalcases 18 12 6 54 36 18 *Attack rate = (mucosal + invasive) / total = 6 / 18 = 33.3% **Lives saved = 16 (only 1 / 8 = 12.5% symptomatic patients survived)